copyright by kenneth aaron miller 2007

Copyright

by

Kenneth Aaron Miller

2007

The Dissertation Committee for Kenneth Aaron Miller Certifies that this is the

approved version of the following dissertation

[Rh(CO)2Cl]2-Catalyzed Allylic Substitution Reactions and Domino

Sequences and Application of the Pauson-Khand Reaction to the

Synthesis of Azabicyclic Structures Total Synthesis of (-)-Alstonerine

Committee

Stephen F Martin Supervisor

Eric V Anslyn

Michael J Krische

John T McDevitt

Sean M Kerwin




by

Kenneth Aaron Miller BS

Dissertation

Presented to the Faculty of the Graduate School of

The University of Texas at Austin

in Partial Fulfillment

of the Requirements

for the Degree of

Doctor of Philosophy


May 2007

Dedication

To Stephanie Hall

v

Acknowledgements

Professor Stephen F Martin has played the most important role in shaping the

scientist that I am today For his guidance and support I will be eternally grateful

I would also like to thank Dr Vincent Lynch for his assistance with X-ray

crystallography and Dr Ben Shoulders and Stephen Sorey for their help with multiple

NMR experiments I owe an enormous debt to all members of the Martin group with

whom I have had countless helpful interactions In particular I am grateful to Dr Nathan

Fuller Dr William McElroy Jim Sunderhaus and Charlie Shanahan for proofreading

this dissertation Also Dr Hui Li and Jason Deck are thanked for numerous helpful

conversations I especially would like to thank Dr Brandon Ashfeld and Dr Chris Neipp

for their hard work and for laying the groundwork on which much of my subsequent

work was based

vi




Publication No_____________

Kenneth Aaron Miller Ph D

The University of Texas at Austin 2007

Supervisor Stephen F Martin

Examination of the scope of the [Rh(CO)2Cl]2-catalyzed allylic substitution

reaction as well as the development of a domino [Rh(CO)2Cl]2-catalyzed allylic

alkylationPauson Khand reaction is described A number of experiments were carried

out in order to explore the novel regioselectivity in the [Rh(CO)2Cl]2-catalyzed allylic

substitution reaction and the [Rh(CO)2Cl]2-catalyzed allylic substitution reaction was

found to give products resulting from attack of the nucleophile on the carbon bearing the

leaving group in a highly regioselective fashion in most cases Examination of allylic

carbonate substrates containing similar substitution at each allylic site was carried out

and conditions that minimize equilibration of active intermediates were determined

Intramolecular [Rh(CO)2Cl]2-catalyzed allylic alkylation was accomplished to synthesize

challenging eight-membered lactone ring systems Nucleophile scope was explored with

regards to the [Rh(CO)2Cl]2-catalyzed allylic substitution reaction and malonates

vii

substituted malonates aliphatic amines and ortho-substituted phenols were all

determined to be effective in the reaction A domino [Rh(CO)2Cl]2-catalyzed allylic

alkylationPauson-Khand reaction was developed which allows the rapid synthesis of

bicyclopentenone products from simple readily available starting materials

The first application of the Pauson-Khand reaction to the synthesis of azabridged

bicyclic structures is also described Various cis-26-disubstituted piperidines were

cyclized to the corresponding azabridged bicyclopentenones is high yields often in high

diastereoselectivities The effect of ring size nitrogen substituent and remote

functionality on the Pauson-Khand substrates was studied The methodology developed

was applied to the concise enantioselective total synthesis of the antimalarial and

anticancer indole alkaloid (-)-alstonerine Pauson-Khand reaction of a readily available

enyne synthesized in four steps from L-tryptophan provided a cyclopentenone in high

yield as one diastereomer Elaboration of the Pauson-Khand product required the

development of a one pot conversion of a five-membered cyclic silyl enol ether to a six-

membered lactone and the mild acylation of a glycal

viii

Table of Contents

List of Tables xii

List of Figures xiii

List of Schemes xiv

Chapter 1 Transition Metal-Catalyzed Reactions 1

11 Transition Metal Catalysis 1

12 Transition Metal Catalyzed Allylic Alkylations 2

121 Introduction2

122 Chemoselectivity in Transition Metal-Catalyzed Allylic Alkylations4

123 Regioselectivity in Transition Metal-Catalyzed Allylic Alkylations4

124 Regioselectivity in Intramolecular Transition Metal-Catalyzed Allylic Alkylations9

125 Nucleophile Scope in Transition Metal-Catalyzed Allylic Alkylations12

126 Olefin Geometry in Transition Metal-Catalyzed Allylic Alkylations14

13 Rhodium-Catalyzed Allylic Alkylations18

131 Tsujirsquos Early Contributions18

132 Evansrsquos Rhodium-Catalyzed Allylic Alkylation 20

133 Nucleophile Scope in Evansrsquos Rhodium-Catalyzed Allylic Alkylation 24

134 [Rh(CO)2Cl]2ndashCatalyzed Allylic Alkylation Reactions Developed in the Martin Group25

14 The Pauson-Khand Reaction33

141 Introduction33

142 Mechanism of the PKR34

143 Scope and Limitations of the PKR35

144 The Catalytic Pauson-Khand Reaction 37

ix

1441 Cobalt-Catalyzed PKR37

1442 Titanium-Catalyzed PKR38

1443 Ruthenium- and Rhodium-Catalyzed PKR38

145 Application of the Pauson-Khand Reaction in Synthesis 39

146 Synthesis of Bridged Structures via Pauson-Khand Reaction 42

15 Tandem Transition Metal-Catalyzed Reactions45

151 Introduction Catalysis of Multiple Mechanistically Different Transformations 45

152 Tandem Reactions Involving Alkene Metathesis 45

153 Tandem Reactions Which Include a PKR 46

1531 Chungrsquos PKR[2+2+2] and Reductive PKR 46

1532 Tandem Allylic AlkylationPauson-Khand Reaction 48

1533 Tandem Rh(I)-Catalyzed Allylic Alkylation-Carbocyclizations49

16 Conclusions51

Chapter 2 Regioselective Rhodium-Catalyzed Allylic Substitutions of Unsymmetrical Carbonates and Related Cascade Reactions53

21 [Rh(CO)2Cl]2 Catalyzed Transformations-Introduction53

22 [Rh(CO)2Cl]2ndashCatalyzed Allylic Substitution Reactions Scope and Limitations 56

221 Allylic Alkylations of Substrates With Sterically Similar Allylic Termini56

222 Regioselective Allylic Aminations 61

223 Phenol Pronucleophiles68

224 Intramolecular Allylic Alkylations to Synthesize Medium-Sized Lactones 72

225 Intramolecular Allylic Alkylations to Synthesize Medium-Sized Carbacycles 76

23 Cascade Reactions Initiated with [Rh(CO)2Cl]2ndashCatalyzed Allylic Alkylation Reactions78

231 Tandem Allylic Alkylation-Ortho-Alkylation 78

232 Tandem Allylic Alkylation-Metallo-ene Reaction 82

233 Tandem Allylic Alkylation-Pauson Khand Reaction 85

x

24 Conclusions95

Chapter 3 The Macroline Alkaloids97

31 Introduction97

311 Alstonerine98

32 MacrolineSarpagine Biogenesis 98

33 Cookrsquos Stratagies to Synthesize MacrolineSarpagine Alkaloids102

331 Cookrsquos Tetracycylic Ketone 323 103

332 Cookrsquos Streamlined Synthesis of 323 106

333 Cookrsquos Synthesis of the N1-Desmethyl Tetracyclic Ketone 107

334 Synthesis of Talpinine and Talcarpine109

335 Synthesis of Norsuaveoline115

336 Cookrsquos Synthesis of Vellosimine117

34 Other Approaches to the Tetracyclic Core of Macroline Alkaloids 118

341 Martinrsquos Biomimetic Synthesis of N-methyl-vellosimine 119

342 Martinrsquos Ring-Closing Metathesis Approach 122

343 Kuethersquos Aza-Diels-AlderHeck Approach 123

344 Baileyrsquos Strategy and Synthesis of (-)-Raumacline and (-)-Suaveoline124

345 Ohbarsquos Synthesis of (-)-Suaveoline 127

346 Rassatrsquos Fischer Indole Synthesis129

35 Previous Syntheses of Alstonerine131

351 Cookrsquos First Synthesis of Alstonerine 132

352 Cookrsquos Second Generation Synthesis of Alstonerine 136

353 Kwonrsquos Formal Synthesis of Alstonerine 138

354 Craigrsquos Synthesis of the Core of Alstonerine 140

36 Conclusions141

Chapter 4 Synthesis of Azabridged Bicyclic Structures via the Pauson-Khand Reaction Concise Enantioselective Total Synthesis of (-)-Alstonerine144

41 Introduction144

42 Hederacine A and 25-cis-Disubstituted Pyrrolidines148

421 Introduction148

xi

422 Preparation of the PKR Substrate 149

423 Protecting Group Removal 154

43 cis-26-Disubstituted Piperidines 158

431 Initial Studies 159

432 Synthesis and PKR of Various cis-26-Disubstituted Piperidine Enynes165

433 Sulfonamide and Amide Substrates 171

434 Modification of the C-4 Carbonyl Group 175

44 Total Synthesis of (-)-Alstonerine 181

441 Retrosynthesis 181

442 Pauson-Khand Reaction182

443 Baeyer-Villiger Approach187

444 HydrosilylationOxidative Cleavage Approach190

445 Acylation Strategies 200

446 Completion of the Total Synthesis205

45 Conclusions209

Chapter 5 Experimental Procedures 211

51 General 211

52 Compounds 212

References328

Vitahellip342

xii

List of Tables

Table 11 Evansrsquos Rh(I)-Catalyzed Allylic Alkylation 21 Table 12 [Rh(CO)2Cl]2-Catalyzed Allylic Alkylations-Initial Studies 27 Table 13 Reactions of Substituted Malonates 29 Table 14 Heteroatom Nucleophiles 32 Table 21 Optimization of the Alkylation of 218 59 Table 22 Rh(I)-Catalyzed Allylic Aminations 66 Table 23 Rh(I)-Catalyzed Allylic Etherifications 71 Table 24 Intramolecular Allylic Alkylation 76 Table 25 Optimization of the Tandem Allylic Alkylation-Metallo-Ene Reaction 84 Table 41 Reductive Silyl Enol Ether Formation 192 Table 42 OsO4 Oxidation of 4137 198

xiii

List of Figures

Figure 31 Macroline and Sarpagine 97 Figure 32 Alstonerine 98 Figure 33 Stratagies for the Synthesis of the ABCD-Core of the Macroline Alkaloids143 Figure 41 ORTEP of 424 153 Figure 42 X-Ray Crystal Structure of 451 163 Figure 43 X-Ray Crystal Structure of 4117 186

xiv

List of Schemes

Scheme 11 3 Scheme 12 4 Scheme 13 5 Scheme 14 6 Scheme 15 7 Scheme 16 8 Scheme 17 9 Scheme 18 10 Scheme 19 14 Scheme 110 15 Scheme 111 17 Scheme 112 22 Scheme 113 24 Scheme 114 25 Scheme 115 33 Scheme 116 35 Scheme 117 39 Scheme 118 40 Scheme 119 41 Scheme 120 41 Scheme 121 42 Scheme 122 43 Scheme 123 44 Scheme 124 49 Scheme 125 50 Scheme 126 51 Scheme 21 55 Scheme 22 57 Scheme 23 58 Scheme 24 58 Scheme 25 61 Scheme 26 65 Scheme 27 68 Scheme 28 69 Scheme 29 73 Scheme 210 73 Scheme 211 74 Scheme 212 75 Scheme 213 77 Scheme 214 79

xv

Scheme 215 81 Scheme 216 83 Scheme 217 86 Scheme 218 87 Scheme 219 90 Scheme 220 91 Scheme 221 92 Scheme 222 94 Scheme 223 95 Scheme 31 99 Scheme 32 100 Scheme 33 101 Scheme 34 102 Scheme 35 103 Scheme 36 105 Scheme 37 106 Scheme 38 107 Scheme 39 108 Scheme 310 109 Scheme 311 110 Scheme 312 111 Scheme 313 111 Scheme 314 112 Scheme 315 113 Scheme 316 114 Scheme 317 115 Scheme 318 116 Scheme 319 118 Scheme 320 119 Scheme 321 120 Scheme 322 121 Scheme 323 122 Scheme 324 123 Scheme 325 124 Scheme 326 126 Scheme 327 127 Scheme 328 129 Scheme 329 131 Scheme 330 132 Scheme 331 133 Scheme 332 134 Scheme 333 135 Scheme 334 136 Scheme 335 137 Scheme 336 138

xvi


xvii

Scheme 444 195 Scheme 445 196 Scheme 446 199 Scheme 447 200 Scheme 448 201 Scheme 449 202 Scheme 450 204 Scheme 451 203 Scheme 452 205 Scheme 453 206 Scheme 454 208

1

Chapter 1 Transition Metal-Catalyzed Reactions

11 Transition Metal Catalysis

The modern synthetic organic chemist is faced with a number of challenges in

terms of developing new reactions and optimizing previously developed reactions Such

goals include increasing reaction efficiency developing increasingly selective reaction

conditions eliminating toxic byproducts and minimizing the depletion of raw materials1

While the goals of high efficiency and selectivity have always been important modern

society has placed more of an emphasis on the impact of chemistry on the environment

An ideal reaction within this context would selectively combine two or more reactants

would generate no by products and would require only catalytic amounts of other

reagents Synthetic organic chemists have increasingly turned to transition metals to

develop organic transformations that meet these stringent criteria and transition metals

are ideal for such applications because the nature of the transition metal catalyst can be

tuned both sterically and electronically As a result research aimed at transition metal

catalysis has grown exponentially in the last 30 years and continues to be an extremely

fertile research area

Some commercial applications of transition metal catalysis to successfully

address the above goals include hydroformylation2 Ziegler-Natta polymerization3 and

hydrocyanation4 In the realm of the synthesis of complex organic molecules reactions

that form C-C bonds and that meet all of these criteria are still rare However a few

2

reactions are emerging as indispensable for their ability to form C-C bonds while

requiring low catalyst loadings and often achieving high levels of chemo- regio- stereo-

and enantioselectivity The following chapter is not intended as an exhaustive review of

these transition metal-catalyzed reactions Instead this discussion will be restricted to a

few transition metal-catalyzed carbon-carbon bond forming reactions that are beginning

to address many of the goals stated above namely allylic alkylations and the Pauson-

Khand reaction A discussion of the recent development of tandem reactions wherein the

same transition metal catalyst is utilized to effect multiple distinct transformations in one

reaction vessel will also be presented

12 Transition Metal Catalyzed Allylic Alkylations

121 Introduction

In the field of transition-metal catalyzed transformations few have received more

study than the allylic alkylation5 Early studies by Tsuji revealed that treatment of

stoichiometrically generated π-allylpalladium chloride with malonate and acetoacetate

derived nucleophiles gave alkylation products and firmly established that π-

allylpalladium complexes were in fact electrophilic6 Later methods for the catalytic

generation of π-allylpalladium intermediates allowed the use of substoichiometric

amounts of expensive palladium complexes Intensive study of the transition metal-

catalyzed allylic alkylation has since revealed conditions for exquisite control of chemo-

regio- diastereo- and enantioselectivity7

While there are a few exceptions most transition metal allylic alkylation reactions

proceed through nucleophilic attack on a metal stabilized allylic cation (Scheme 11)7

Despite the fact that the nature of the allyl-metal species can vary based on the choice of

3

transition metal and ligand in the majority of cases a π-allyl intermediate is invoked

Starting with an allylic substrate 11 coordination of the metal catalyst with the double

bond generates 12 and oxidative ionization of the leaving group X- generates a π-allyl

intermediate 13 In such a fashion relatively poor leaving groups can undergo facile

ionization under transition metal catalysis and appropriate leaving groups include esters

carbonates phosphates epoxides alcohols sulphones amines and ammonium salts5c

Once formed the π-allyl intermediate 13 can be intercepted by various nucleophiles to

give the metal-complexed substitution product 14 and decomplexation of the product

15 from the metal regenerates the catalyst

Scheme 11

M

X-Nuc-

11

X

12

X

M

13

M

14

Nuc

M

15

Nuc

4

122 Chemoselectivity in Transition Metal-Catalyzed Allylic Alkylations

While allylation of nucleophiles can certainly proceed in the absence of a

transition metal catalyst transition metal-catalyzed allylic alkylations offer high levels of

chemo- regio- diastereo- and enantioselectivity that are simply unattainable in the

absence of a metal catalyst An example that highlights the chemoselectivity available

for palladium-catalyzed allylic alkylations is the reaction of bromoester 16 with the

sodium salt of the phenylsulfonyl ester 17 in the presence or absence of a palladium

catalyst (Scheme 12)8 An SN2 displacement of the bromide to give 18 is exclusively

observed when the reaction is conducted in the polar solvent DMF However when the

reaction is conducted in THF wherein SN2 displacements are slower the addition of a

Pd(0) catalyst completely reverses the chemoselectivity and the product of allylic

alkylation 19 is observed

Scheme 12

Br

OAcPd(PPh3)4

THF

DMF

OAc

MeO2C

SO2Ph

Br

+CO2Me

SO2Ph

SO2Ph

CO2Me16 17

18

19

123 Regioselectivity in Transition Metal-Catalyzed Allylic Alkylations

Issues of regioselectivity arise when one utilizes an allylic substrate that can react

with a transition metal catalyst to give an unsymmetrical π-allyl intermediate (Scheme

13) Reaction of the allylic substrate 110 leads to an unsymmetrical π-allyl intermediate

5

111 and steric as well as electronic factors will dictate whether nucleophilic attack

occurs preferentially via path a or path b to give either 112 or 113 respectively

Scheme 13

R1 R2

X M

R1 R2

M

110 111

Nuc-Nuc-

a b

R1 R2

Nuc

112

R1 R2

113

Nuc

path a

path b

-X-

In general under palladium catalysis steric factors dominate and nucleophilic

attack occurs at the least sterically hindered carbon of the π-allyl intermediate (Scheme

14)9 As a result treatment of either allylic substrate 114 or 116 with a typical

palladium catalyst and a nucleophile gives the linear alkylation product 115 as the major

product Other transition metal catalysts Ru10 Mo11 W12 Ir13 and Rh14 typically favor

electronic control yielding the product of nucleophilic attack on the carbon that can best

stabilize developing positive charge Hence the branched product 117 is typically the

major product under Ru Mo W Ir or Rh catalysis regardless of whether 114 or 116 is

used as a substrate

6

Scheme 14

LG Nuc

LG Nuc

Pd

Pd

Ru Mo Rh Ir W

Ru Mo Rh Ir W

+ Nuc

115114

116 117

The differences in regioselectivities among transition metal catalysts is

highlighted by the reaction of the allylic acetate 118 with the sodium salt of dimethyl

malonate under either palladium or molybdenum catalysis (Scheme 15)15 The reaction

of 118 with dimethyl malonate in the presence of catalytic Pd(PPh3)4 gave a mixture of

119 and 120 in an 8614 ratio strongly favoring attack at the less substituted allylic

position However the same reaction utilizing W(CO)3(MeCN)3 as the catalyst gave

120 and 119 in a 946 ratio Thus tungsten catalysis seems to favor attack at the more

sterically hindered allylic terminus Similar regiochemistries were observed when

substituted malonates were utilized as nucleophiles

7

Scheme 15

NaHCH2(CO2Me)

OAc

118NaH

CH2(CO2Me)

Pd(PPh3)4

W(CO)3(MeCN)383

or

119 E = CO2Me

E

E

E E

120 E = CO2Me

+

119 E = CO2Me

E

E

E E

120 E = CO2Me

+

119120 = 8614

119120 = 496

In contrast the regioselectivity of molybdenum-catalyzed allylic alkylations is

subject to subtle changes in the steric environment of the nucleophile (Scheme 16)16

Treatment of either 121 or 122 with Mo(CO6) generates the same π-allyl intermediate

and the sodium salt of dimethyl malonate attacks the π-allyl intermediate at the more

hindered carbon to give exclusively 123 However the same reaction using the

substituted methyl dimethyl malonate as a nucleophile gave the product of exclusive

attack on the primary carbon 124 Thus choice of the nucleophile can have a great

impact on the product regiochemistry in molybdenum-catalyzed allylic alkylations

8

Scheme 16

OAc

OAc

NaHCH2(CO2Me)

Mo(CO)6

NaHHCMe(CO2Me)

orE

E

E

EMe

121 122

123 E = CO2Me

124 E = CO2Me

89

84

Work by Takeuchi on iridium-catalyzed allylic alkylations has revealed that

catalytic systems derived from this transition metal can offer vastly different

regioselectivities17 When the allylic acetate 125 was treated with the sodium salt of

dimethyl malonate and a catalytic amount of [Ir(COD)Cl]2 the product of nucleophilic

attack on the primary carbon 126 was obtained as the major regioisomer (Scheme 17)

However in order for the reaction to proceed to completion elevated temperatures and

long reaction times were required In contrast reaction of the same allylic acetate 125

under identical conditions but absent the P(OPh)3 gave the opposite regioisomer 127 in

excellent regioselectivity and the reaction only required one hour at room temperature

Takeuchi presented a number of additional examples of iridium-catalyzed allylic

alkylations with the addition of P(OPh)3 that give the product of nucleophilic attack on

the more substituted carbon but the notable regioselectivity in the absence of the

phosphite ligand was not explored further Takeuchi has noted that utilization of bulky

phosphine ligands can favor nucleophilic attack on the less substituted carbon of the

9

allylic terminus and these experiments will be discussed in more detail in subsequent

sections

Scheme 17

nPr OAc

THF reflux 19 h66

THF rt 1 h94

NaCH(CO2Me)2[Ir(COD)Cl]2 (2)

NaCH(CO2Me)2P(OPh)3 (4)

[Ir(COD)Cl]2 (2)

nPr

nPr

CO2Me

CO2Me

MeO2C CO2Me

126

125

127

126127 = 8812

+

nPr

nPr

CO2Me

CO2Me

MeO2C CO2Me

126 127

126127 = 397

+

The results above can be summarized in a general sense by stating that in

palladium-catalyzed allylic alkylations steric factors are dominant whereas in other

transition metal-catalyzed allylic alkylations of more electropositive transition metals

(Ru Mo W Ir or Rh) electronic factors tend to bias nucleophilic attack toward the more

hindered allylic terminus which can better stabilize positive charge However in all

cases several factors affecting the regiochemical outcome of the reaction are operating

simultaneously and as a result a number of notable exceptions to this trend have been

documented1316

124 Regioselectivity in Intramolecular Transition Metal-Catalyzed Allylic

Alkylations

When a nucleophile is tethered to an allylically disposed leaving group as in 127

two possible ring sizes can result from an intramolecular allylic alkylation (Scheme

10

18)18 The π-allyl metal intermediate 128 is generated from 127 and the

regioselectivity of the cyclization depends on which allylic site is attacked by the tethered

nucleophile The steric bulk of the nucleophile the substitution at each allylic site the

tether length and conformational preferences in cyclic tethers all have important effects

on the regioselectivity of these intramolecular reactions Thus the interplay of subtle

steric factors can play a large role in determining the regioselectivities of intramolecular

transition metal-catalyzed allylic alkylations especially in medium sized (8-11

membered) rings

Scheme 18

LG

Nuc Nuc

M

M

127 128

Formation of a π-allyl palladium intermediate from the allylic acetate 129

followed by nucleophilic attack by the tethered nucleophile can generate either a seven-

or nine-membered ring depending on which allylic site undergoes attack1819 Analysis of

the general regiochemical trend for intermolecular allylic alkylations would predict nine-

membered ring formation via attack on the less substituted allylic terminus However

competition between seven- and nine-membered ring formation under solely steric

control would be expected to favor seven-membered ring formation due to the

minimization of adverse transannular interactions in the seven-membered ring In

practice small steric changes can have a large impact on the regioselectivity Palladium-

catalyzed cyclization of 129 leads to the seven-membered product 130 (Eq 11)

11

However when the steric bulk of the tethered nucleophile is increased by switching a

methyl ester to a phenyl sulphone in 131 then the nine-membered ring 132 is strongly

favored (Eq 12)

O

O

OAcH

H

CO2Me

SO2Ph

NaH THF

Pd(PPh3)4 dppe60

O

O

SO2PhCO2Me

H

H

129 130

SO2Ph

OAc

SO2Ph

131

SO2Ph

SO2PhBSA THF

Pd(dppe)244

132

(11)

(12)

Competing steric effects can also strongly affect competitive six- versus eight-

membered ring formation The tethered β-keto sulphone nucleophile in 133 attacks the

less substituted allylic terminus to deliver the eight-membered ring product 134 with a

good level of regioselectivity (Eq 13)20 However when the nucleophile is changed to a

β-keto ester the substrate 136 forms the sterically less strained six-membered product

137 exclusively (Eq 14)21

12

O

SO2Ph

OO

SO2Ph

O134 135

O

SO2Ph

O

133

OAc

+

NaH Pd(PPh3)4Diphos

THF reflux73

134135 = 928

OPh

CO2Me

O

Pd(OAc)2 PPh3

62

CO2Me

O

136 137

(13)

(14)

125 Nucleophile Scope in Transition Metal-Catalyzed Allylic Alkylations

Nucleophiles utilized in transition metal-catalyzed allylic alkylations can be

divided into the two broad categories of soft nucleophiles (pKa lt 25) and hard

nucleophiles (pKa gt 25) The hardness or softness of the nucleophile determines which

mechanistic pathway the allylic alkylation reaction follows as shown below Soft

nucleophiles are most often stabilized carbanions of the generic formula RCXY in which

R is either alkyl or H and X and Y are electron withdrawing groups such as esters

ketones nitriles nitro groups sulphones and sulphoxides Other soft nucleophiles

include the cyclopentadienyl anion22 nitroalkanes23 phenols24 alcohols25 carboxylates26

amines27 sulphonamides28 and azides29 Hard nucleophiles have not been explored in as

much depth as soft nucleophiles but enolates30 silyl enol ethers31 and silyl ketene

acetals32 have all been used successfully Organometallic compounds of main group

metals (Mg Zn B and Sn)33 have also been utilized as nucleophiles

13

When soft nucleophiles are used the bond-breaking and bond-forming events

occur outside the coordination sphere of the metal (Scheme 19)5 The nucleophile

attacks the π-allyl intermediate 139 on the face opposite the metal to give 140

Decomplexation of the metal regenerates the active catalyst and gives the allylated

product 141 However when hard nucleophiles are employed attack occurs on the

metal itself to give 142 Reductive elimination gives 143 which upon decomplexation

of the metal catalyst gives the product 144 Notably the mechanistic dichotomy

associated with the two nucleophile classes leads to important issues of

diastereoselectivity Soft nucleophiles result in nucleophilic displacement of the leaving

group with net retention through a double inversion mechanism While all transition

metal catalysts give net retention with soft nucleophiles molybdenum-catalysis has been

shown to proceed via a double retention mechanism34 Use of hard nucleophiles proceeds

first by attack of the metal on 138 to displace the leaving group with inversion to form

the π-allyl intermediate 139 followed by direct nucleophilic attack on the metal in 139 to

give 142 and reductive elimination to give the product of net inversion 144

14

Scheme 19

soft Nuc-

hard Nuc-

H

Nuc

M

140

M

NucM

142

oxidativeaddition

H

Nuc

141

Nuc

H

M

143

reductiveelimination

Nuc

H

144

M

139

H

LG

138

M

M

126 Olefin Geometry in Transition Metal-Catalyzed Allylic Alkylations

Erosion of (Z)-alkene geometry in the course of palladium-catalyzed allylic

alkylations is common and the cause of this erosion has been the subject of significant

study Oxidative ionization of the (E)-allylic acetate 145 generates a syn π-allyl

intermediate 147 whereas the anti π-allyl intermediate 148 is obtained from the

corresponding (Z)-allylic acetate 146 (Scheme 110)7 The relative rate of nucleophilic

attack on the π-allyl intermediate compared with the rate of isomerization of the initially

generated syn and anti π-allyl intermediates determines the extent of erosion of alkene

geometry The choice of transition metal and ligand can play a large role in influencing

the rate of syn and anti isomerization In most cases palladium catalysis results in rapid

equilibration of the two π-allyl isomers strongly favoring the syn isomer in order to

minimize A13-strain

15

Scheme 110

R OAc OAc

R

145 146

R OAc OAc

R

147 148

MLnMLnπminusσminusπ

MLn MLn

syn anti

R Nuc Nuc

R

149 150

Nuc- Nuc-

The complete loss of (Z)-alkene geometry is observed in the reaction of 151 with

dimethyl malonate under palladium catalysis35 While two regioisomers 152 and 153

were isolated both contain only (E)-double bonds (Eq 15) Virtually identical results

are obtained when the (E)-allylic acetate 154 is used as a substrate (Eq 16) strongly

suggesting that both reactions proceed through the same anti π-allyl palladium

intermediate and that the rate of isomerization from syn to anti is much faster than the

rate of nucleophlic attack

16

Me

PhOAc

NaCH(CO2Me)2dppe Pd(PPh3)4

151

Me Ph

CO2MeMeO2C

152THF rt

99

Me

OAc


154

THF rt96

Ph

Me Ph

153

CO2MeMeO2C

Me Ph

CO2MeMeO2C

152

Me Ph

153

CO2MeMeO2C

+

+

152153 = 9010

152153 = 928

(15)

(16)

Notably when particularly reactive nucleophiles are used then preservation of

(Z)-alkene geometry can be obtained Kazmaier reported that when zinc-chelated ester

enolates such as 156 are employed as nucleophiles in the palladium-catalyzed allylic

substitution of 155 then only the (Z)-substituted product 157 was obtained (Eq 17)36

The authors note that the high reactivity of these chelated ester enolates allow the

reaction to be conducted at low temperature and consequently the rate of isomerization

between the anti and syn complexes is slow compared to the rate of nucleophilic attack

Unfortunately this work highlights that only when unusually strong nucleophiles are

employed can (Z)-olefin geometry be preserved from substrate to product under

palladium catalysis

Me

PhOAc

155

TfaN

Zn OOtBu

PPh3 [Pd(allyl)Cl]2

THF -78 degC - rt69

Ph157

tBuO2C

NHTfa

156

(17)

17

The rate of isomerization of π-allyl metal intermediates is greatly affected by the

nature of the transition metal utilized While palladium catalysts have already been noted

to produce π-allyl intermediates that readily isomerize to the more stable syn isomer to

eventually give (E)-alkene products iridium catalysts are notable in that (Z)-alkene

geometry is preserved to a significant extent Takeuchi has shown that when the (Z)-

allylic acetate 158 undergoes allylic substitution with [Ir(COD)Cl]2 and the bulky

phosphine ligand P(O-2-tBu-4-MeC6H3)3 the (Z)-substituted product 159 is the major

product with only small amounts of 160 and 161 present (Scheme 111)13 Utilization of

the bulky phosphine ligand was crucial for obtaining high regioselectivity presumably

because the bulky phosphine ligand directs reaction to the less substituted allylic

terminus One can conclude that the syn-anti isomerization of a π-allyl iridium complex

is slow compared to analogous π-allyl palladium complexes and consequently iridium

catalysis offers a convenient choice when the regiochemistry of palladium catalysis is

desired but preservation of (E)-alkene geometry is also critical

Scheme 111

nPr OAcTHF reflux

85

NaCH(CO2Et)2

P(O-2-tBu-4-MeC6H3)3 (4)[Ir(COD)Cl]2 (2)

158

nPr

159

CO2Et

CO2EtnPr

nPr

CO2Me

CO2Me

MeO2C CO2Me

160

161

+

+

159160161 = 9073

18

13 Rhodium-Catalyzed Allylic Alkylations

131 Tsujirsquos Early Contributions

Rhodium-catalyzed allylic alkylations were first reported by Tsuji and coworkers

in 1984 and these initial experiments provided hints as to the unique regioselectivity

displayed by rhodium catalysts14a Tsuji screened various well known Rh(I) complexes

and ligands to determine efficient reaction conditions for the allylation of the substituted

malonate 163 with allyl carbonate 162 (Eq 18) While Wilkinsonrsquos catalyst

RhCl(PPh3)3 was almost completely inactive as a catalyst addition of phosphines such

as PBu3 or phosphites such as P(OEt)3 gave excellent yields of the allylic alkylation

product 164 in 95 and 90 respectively when the reactions were conducted at

elevated temperatures (65 ˚C) However high yields and short reaction times could be

achieved under mild reaction temperatures if RhH(PPh3)4 was used as a catalyst and

PBu3 was employed as the ligand Under these optimized conditions 164 was obtained

in 93 yield in 1 h at room temperature

OCO2Me

OMe

O O

RhH(PPh3)4 (5)PBu3 (10)

CO2Me

O162

163

164

THF rt93

(18)

An interesting regioselectivity trend was discovered when unsymmetrical allylic

carbonates 165 and 168 were utilized as substrates14a When the primary allylic

carbonate 165 was explored using 163 as a nucleophile a mixture of regioisomers 166

19

and 167 were obtained in an excellent yield in a 7228 ratio favoring alkylation at the

primary carbon (Eq 19) However when the isomeric secondary carbonate 168 was

employed as a substrate under identical reaction conditions a mixture of the same

alkylation products 166 and 167 were isolated in a 1486 ratio in this case favoring

alkylation at the secondary carbon (Eq 110) Taken together these two experiments

indicated that the rhodium-catalyzed allylic alkylation did not proceed through the same

π-allylrhodium intermediate If these reactions were proceeding via a π-allylrhodium

complex then one would expect an identical regioselectivity to be obtained regardless of

whether one employed 165 or 168 as a substrate since each would generate the same π-

allylrhodium complex

OCO2Me

OMe

O O

RhH(PPh3)4 (5)PBu3 (10) CO2Me

O

CO2Me

O

+

165

163

166 167

168

OCO2Me

dioxane 100 degC97

OMe

O O

RhH(PPh3)4 (5)PBu3 (10)

163

dioxane 100 degC81

CO2Me

O

CO2Me

O

+

166 167

166167 = 7228

166167 = 1486

(19)

(110)

20

132 Evansrsquos Rhodium-Catalyzed Allylic Alkylation

Evans later revisited the rhodium-catalyzed allylic alkylations discovered by Tsuji

and further elaborated the novel regioselectivities displayed by this class of catalysts

Evans found that by modifying RhCl(PPh3)3 with either P(OMe)3 or P(OPh)3 a

catalytically active species is generated that delivers allylic alkylation products in high

yields and excellent regioselectivities from the corresponding allylic carbonates and

various nucleophiles14b

When Evans treated secondary and tertiary carbonates 169 with RhCl(PPh3)3

modified with either P(OMe)3 or P(OPh)3 and the sodium salt of dimethyl malonate

(Table 11) alkylation occurred preferentially at the more substituted carbon to give the

branched product 170 as the major product in excellent regioselectivity Secondary

carbonate substrates gave better yields and regioselectivities when treated with

Wilkinsonrsquos catalyst modified with P(OMe)3 (entries 1-3) However when tertiary

carbonate substrates were employed superior yields and regioselectivities were obtained

using a P(OPh)3 modified catalyst (entries 4-6) While the regioselectivities remained

high reduced yields were obtained when tertiary carbonates were utilized as substrates

The exact nature of the active catalyst is still uncertain but Evans proposes that the

phosphite additives exchange with the phosphine ligands present in Wilkinsonrsquos catalyst

to generate a new catalytically active species Evans invokes the increased π-accepting

ability of the phosphite ligands when bound to the rhodium center to explain the

increased turnover rates and high regioselectivities Alkylation at the more substituted

allylic terminus is commonly observed in Ru Mo Ir and W catalyzed allylic alkylations

21

(vide supra) and Evansrsquos results below are analagous to the regioselectivity trend

exhibited by these other transition metal catalysts

Table 11 Evansrsquos Rh(I)-Catalyzed Allylic Alkylation

991 91

982 89

OCO2Me

169

R1 R2

170

R1 R2CO2Me

CO2MeR1

171

R2

MeO2C

CO2Me

NaCH(CO2Me)2RhCl(PPh3)3 (5)

P(OMe)3 (20) orP(OPh)3

+

entry R1 R2 ratio 170171 yield

1

2

3

4

5

6

phosphite

H

H

H

Me

Me

Me

Me

nPr

Ph

Me

nPr

Ph

P(OMe)3

P(OMe)3

P(OMe)3

P(OPh)3

P(OPh)3

P(OPh)3

982

gt991

964

gt991

95

89

73

32

However Evans later determined that a number of factors can significantly alter

the regioselectivity of the Rh(I)-catalyzed allylic alkylation and these factors contributed

to Evans crafting a new mechanistic proposal37 Treatment of the secondary carbonate

168 with the sodium salt of dimethyl malonate in the presence of Wilkinsonrsquos catalyst

modified with P(OMe)3 gave a mixture of alkylation products 172 and 173 significantly

favoring 172 (Scheme 112) However when the isomeric primary allylic carbonate

165 was utilized as the substrate under identical conditions the same mixture of

alkylation products 172 and 173 was obtained only slightly favoring 172 These results

22

suggested that the two reactions were not proceeding through the same π-allylrhodium

intermediate or that the rate of σ-π-σ isomerization was slow compared to the rate of

nucleophilic attack

Scheme 112

OCO2Me

165

168

OCO2Me


P(OMe)3 (20) THF

173172

+

From 168 172173 = 421 99From 165 172173 = 21 83

or

MeO2C CO2Me

CO2Me

CO2Me

To determine whether the rate of σ-π-σ isomerization was indeed slow the

secondary deuterium labeled substrated 174 was allowed to react with the P(OPh)3

modified Wilkinsonrsquos catalyst using dimethyl malonate as a nucleophile and the

alkylation product 175 was obtained in excellent regioselectivity (Eq 111)37 The result

strongly suggested that the rate of σ-π-σ isomerization was indeed slow compared to

nucleophilic attack by the malonate and that the allyl-metal intermediate has substantial

σ-character The rate of isomerization of the allyl-rhodium intermediate is also not

effected by the steric environment imposed by adjacent substituents as shown in the

alkylations of 177 and 178 Starting with the secondary allylic carbonate 177 a 973

ratio of 179 and 180 respectively was obtained (Eq 112) However when the

isomeric secondary carbonate 178 was utilized the same alkylation products 179 and

180 were isolated with 180 dominating Thus the steric environment adjacent to each

allylic site plays little or no role in isomerization of the allyl-rhodium intermediate

23

whereas the extent of substitution at each allylic site significantly influences the rate of

isomerization as in the reaction of 165 and 168 as shown above (Scheme 112)

Me

OCO2Me

MeD

Me MeD

CO2MeMeO2C

Me Me

D

CO2MeMeO2C

+

P(OPh)3 (20) THF92


174 175 176

175176 = gt191

R1

OCO2Me

R2 Me iPr

CO2MeMeO2C

+

P(OPh)3 (20) THF92


179 180

From 177 179180 = 973From 178 179180 = 397

iPrMe

MeO2C CO2Me

177 R1=Me R2=iPr178 R1=iPr R2=Me

(111)

(112)

The combined results led Evans to invoke a rhodium enyl intermediate37 which

by definition incorporates discreet σ- and π-metal carbon interactions within a single

ligand38 Evans proposes that treatment of 181 (Scheme 113) with the in situ generated

rhodium catalyst generates an enyl intermediate 182 by SN2prime type oxidative addition

(path A) This intermediate undergoes SN2prime nucleophilic displacement at a much faster

rate than isomerization to 183 (k2gtk-1) However oxidative addition into the primary

carbonate 184 generates the isomeric enyl intermediate 185 which isomerizes in

competition with alkylation due to the differences in substitution at the allylic termini

(k1gtk3) providing a mixture of the isomers 183 and 186

24

Scheme 113

R

Rh(I)

R

Rh(III)

Nuc

R

LG

R

Rh(III)

NucRh(I)

Path A

Path B

R

LG

R

R

R

k1k-1

k2

k3

R

Nuc

R

RNuc

R

181 182 183

184185

186

133 Nucleophile Scope in Evansrsquos Rhodium-Catalyzed Allylic Alkylation

Evans also explored the nucleophile scope in the allylic substitution reaction

catalyzed by trimethylphosphite-modified Wilkinsonrsquos catalyst Starting with secondary

allylic carbonates 187 a variety of heteroatom nucleophiles could be employed to

deliver diverse products (Scheme 114) Utilization of copper (I) alkoxides as

nucleophiles delivered allyl ether products 188 and the copper anion was determined to

be crucial for high turnover and high regioselectivities25 Sodium phenoxides were also

productive as nucleophiles to give allyl aryl ethers 18924 A significant counteranion

effect was observed with sodium phenoxides providing the best results Allylic amine

products 190 could also be accessed if the lithium salt of N-toluenesulphonyl

benzylamine was used as a nucleophile28 In each case choice of counterion was

imperative for optimal regioselectivites and yields Also each reaction gave high levels

of enantiospecificity and when enantioenriched allylic carbonates 187 were used as

substrates virtually complete preservation of eersquos were observed with all three classes of

heteroatom nucleophiles

25

Scheme 114

R

OCO2Me NucRhCl(PPh3)3

P(OMe)3 THF R

OR

Nuc = ROCu ArONa BnTsNLi

R

OAr

R

TsNBnor or

187 188 189 190

Evansrsquos phosphite modified Wilkinsonrsquos catalyst allows the preparation of allyl

ethers and amines when heteroatom nucleophiles are employed as substrates The ease

with which enantiomerically enriched allylic carbonates can be prepared and the

enantiospecific nature of these reactions enables rapid access to enantiomerically

enriched allyl ethers and allyl amines

134 [Rh(CO)2Cl]2ndashCatalyzed Allylic Alkylation Reactions Developed in the Martin

Group

Rh(I)-catalyzed allylic alkylations complementary to the work of Tsuji and Evans

were recently discovered in the Martin group Dr Brandon Ashfeld found that not only

was [Rh(CO)2Cl]2 capable of catalyzing allylic alkylations of unsymmetrical allylic

carbonates using the sodium salt of dimethyl malonate as a nucleophile but the alkylation

products were obtained in high regiochemical ratios39 More importantly the

regioselectivity did not follow the general trends observed in rhodium-catalyzed allylic

alkylations (vide supra) in that the major product obtained in each case was the product

derived from nucleophilic attack on the carbon previously bonded to the carbonate

leaving group Specifically when primary carbonate 194 was treated with the sodium

salt of dimethyl malonate in the presence of [Rh(CO)2Cl]2 195 was obtained as the

major product in high regioselectivity (Table 12) In contrast tertiary carbonate 196

26

yielded allylic alkylation product 197 under identical conditions These two experiments

were striking in that the alkylation of carbonate 194 seemed to follow the general

regiochemical trend displayed by palladium catalysis whereas the alkylation of 196 was

consistent with other Rh(I)-catalyzed allylic alkylations Another notable example is the

alkylation of the cis-allylic carbonate 198 in which the cis-product 199 was obtained

with minimal loss of alkene geometry often seen in transition metal catalyzed allylic

alkylations Entries 4 and 5 further illustrate that [Rh(CO)2Cl]2 catalysis delivered the

product of nucleophilic attack on the carbon previously bearing the leaving group

Collectively the above results revealed a unique regiochemical trend displayed by

[Rh(CO)2Cl]2 that deserved further exploration

27

Table 12 [Rh(CO)2Cl]2-Catalyzed Allylic Alkylations-Initial Studies

OCO2MeR1

R2R3 R4 [Rh(CO)2Cl]2

NaCH(CO2Me)2 R1

R2R3 R4

CO2Me

CO2Me

+ MeO2CR4

R3R1 R2

CO2Me191 192

193

THF rt

Entry Carbonate Major Product Yield ()Ratio

majorminor

1

2

3

OCO2Me CO2Me

CO2Me

OCO2MeCO2Me

CO2Me

OCO2Me

CO2Me

CO2Me

75

80

86

928

946

991(973 ZE)

OCO2MeCO2Me

CO2Me

4 84 973

Ph OCO2Me PhCO2Me

CO2Me

593 9010

194

196

198

1100

1102

195

197

199

1101

1103

The use of substituted malonates as nucleophiles in the [Rh(CO)2Cl]2-catalyzed

allylic alkylation was also explored by Dr Ashfeld These more sterically demanding

nucleophiles often lead to eroded regioselectivities in transition metal-catalyzed allylic

alkylation reactions16 but high regioselectivities were once again observed using

[Rh(CO)2Cl]2 as a catalyst (Table 13) Dr Ashfeld was particularly interested in the use

28

of homopropargyl malonates such as 1104 as nucleophiles because the 16-enynes that

would be formed as products were known to be substrates for a variety of transition

metal-catalyzed reactions including Pauson-Khand annulations40 cycloisomerizations41

[5+2]-cycloadditions42 and ring closing metatheses43 Reaction of the primary carbonate

194 with the substituted malonate nucleophile 1104 gave the enyne 1107 in good yield

and excellent regioselectivity (entry 1) Employing the tertiary carbonate 196 allowed

the generation of two adjacent quaternary carbon centers in the product 1108 (entry 2)

Entry 3 highlights the conservation of Z-alkene geometry and entry 4 illustrates the ease

with which one can synthesize 16-enyne products containing vinyl cyclopropanes such

as 1111 that can serve as [5+2]-cycloaddition substrates

29

Table 13 Reactions of Substituted Malonates

OCO2MeR1

R2R3 R4

R1

R2R3 R4

CO2Me

CO2Me

+ MeO2CR4

R3R1 R2

MeO2C

191

11051106

THF


majorminor

1

2

3

OCO2Me

OCO2Me

OCO2Me

85

98

98

991

8812

1000(8812 ZE)

OCO2Me4 98 gt955

194

196

198

1110

CO2MeMeO2C

Me

+

NaH[Rh(CO)2Cl]2

1104

Me

CO2Me

CO2Me

Me

CO2Me

CO2Me

Me

CO2Me

CO2Me

Me

CO2Me

CO2Me

1111

1109

1108

1107

Me Me

30

The use of unstabilized carbon nucleophiles was also cursorily pursued Work by

Evans showed that allylic hexafluoroisopropyl carbonates underwent regio- and

stereoselective alkylation upon treatment with aryl zinc reagents in the presence of

TpRh(C2H4)2 LiBr and dibenzylidene acetone44 However drawbacks to Evansrsquos

system included the need for a labile leaving group and a catalyst that was not

commercially available Gratifyingly Dr Ashfeld showed that treatment of the

enantioenriched allylic methyl carbonate 1102 with the phenyl zinc bromide and

[Rh(CO)2Cl]2 gave an 1112 in excellent yield and regioselectivity (Eq 113) The

product is one of inversion of stereochemistry presumably by nucleophilic attack of the

aryl zinc reagent on the allyl metal center followed by reductive elimination

OCO2Me

1102

[Rh(CO)2Cl]2 PhLi

ZnBr2 THF rt99

regioselectivity gt955

Ph

1112

99 ee 92 ee

(113)

Phenol and aliphatic alcohol nucleophiles were initially explored by Dr Ashfeld

and while aliphatic alcohols and their metal alkoxides did not prove to be effective

nucleophiles success was achieved utilizing phenols as pronucleophiles The use of

ortho-substituted phenols as substrates was of particular interest since the regioselective

etherification of unsymmetrical allylic alcohol derivatives continues pose a synthetic

problem especially for these sterically demanding nucleophiles45 Thus the etherification

of the allylic carbonate 1100 was attempted with ortho-phenyl phenol (1115) using

LiHMDS as base but no etherification products were obtained Work by Evans indicated

that copper alkoxides proved to be better substrates in Rh(I)-catalyzed allylic

31

etherifications than lithium alkoxides and the authors hypothesize that the ldquosofterrdquo nature

of the copper alkoxide led to the increased efficiency of these reactions Upon

application of the above precedent Dr Ashfeld found that copper phenoxides were

excellent nucleophiles (Table 14) For example treatment of the primary allylic

carbonate 1100 with the copper (I) alkoxide 1115 and [Rh(CO)2Cl2] gave a good yield

of 1116 in a highly regioselective fashion (entry 1) Additionally Anna Smith found

that allenes such as 1117 also serve as excellent substrates and the allenic ether 1118

was obtained (entry 2) Dr Ashfeld also showed that the lithium salts of sulfonamides

1119 and 1121 gave the allyl amine products 1120 and 1122 respectively and highly

regioselectively

32

Table 14 Heteroatom Nucleophiles

OCO2MeR1


NucR1

R2R3 R4

+Nuc R4

R3R1 R2

191 1113 1114


majorminor

1OCO2Me

84 928

1100

NucTHFrt

nucleophile

OCu(I)

Ph Ph

O

2OCO2Me

75 gt955

1117

OCu(I)

PhPh

O

1115

1115

1116

1118

3OCO2Me

78 9010

1100

11191120

4OCO2Me

42 8812

1100

11211122

NTsLiTsN Ph

LiTsN TsN

Based on the above results a mechanistic hypothesis was devised which is based

in part on the work of Evans37 Reaction of an allylic carbonate 181 or 184 with the

rhodium catalyst generates enyl intermediates 182 and 185 respectively that can be

intercepted by a nucleophile to generate the resulting allylic alkylation product 183 or

33

186 If the rate of isomerization k1 and k-1 of the two enyl intermediates 182 and 185

is slow compared to the rate of nucleophilic attack k2 or k3 then the product of

nucleophilic attack on the carbon bearing the leaving group will be observed namely

181 rarr 183 and 184 rarr 186 Electron withdrawing ligands such as CO or to a lesser

extent phosphite additives in Evansrsquos case tend to increase the Lewis acidity of rhodium

and thus lead to tighter binding of the alkene in the enyl intermediate and slow

equilibration37 A catalyst which gives high regioselectivity favoring alkylation of the

carbon previously bearing the leaving group would provide a novel complement to

existing allylic alkylation catalysts

Scheme 115

R

Rh(I)

R

Rh(III)

Nuc

R

LG

R

Rh(III)

NucRh(I)

Path A

Path B

R

LG

R

R

R

k1k-1

k2

k3

R

Nuc

R

RNuc

R

181 182 183

184185

186

14 The Pauson-Khand Reaction

141 Introduction

The Pauson-Khand reaction (PKR) is formally a [2+2+1] reaction of an alkyne an

alkene and carbon monoxide to form a cyclopentenone46 The reaction was discovered

by Pauson and Khand in the early 1970rsquos and initial experiments showed that norbornene

(1123) and propyne (1124) react to give the cyclopentenone 1125 when heated in the

34

presence of Co2(CO)8 (Eq 114)47 However the authors found that the efficiency of the

reaction suffered if strained alkenes were not used and often when unsymmetrical

alkenes were utilized mixtures of regioisomers were obtained Furthermore the high

temperatures and long reaction times often necessary to effect the reaction were not

compatible with sensitive substrates By simply tethering the alkene and alkyne in 1981

Schore significantly expanded the scope of the PKR as strained alkenes were no longer

required48 Additionally the intramolecular version of the PKR is regioselective with

respect to the alkene and requires milder temperatures Work by a number of research

groups has since shown that various promoters are capable of accelerating the PKR

including silica gel49 trialkylamine N-oxides50 molecular sieves51 sulfides52 and

sulfoxides53 and often these promoters increase reaction efficiency

MeO

H

H+

Co2(CO)8 ∆

Me1123 1124

1125

(114)

142 Mechanism of the PKR

Dicobaltoctacarbonyl is by far the most common reagent used to effect the PKR

and the mechanism for this transformation was originally proposed by Magnus and has

become widely accepted54 Except for the initially formed dicobalthexacarbonyl-alkyne

complex no intermediates have been isolated and the detailed mechanism is based on

observations of regio- and stereochemistry in a large number of examples Reaction of

the alkyne moiety in 1126 with the cobalt complex gives the hexacarbonyldicobalt-

alkyne complex 1127 (Scheme 116) Loss of a carbon monoxide ligand frees a

35

coordination site on a cobalt atom and facilitates subsequent alkene coordination as in

1128 Irreversible insertion of the alkene from the complexed π-face into a cobalt-

carbon bond forms the metallocycle 1129 and this step is thought to be both rate- and

product-determining55 CO-insertion gives 1130 and carbon-cobalt bond migration to

the electrophilic carbonyl provides 1131 A final reductive elimination of

dicobaltcarbonyl gives the cyclopentenone product 1132

Scheme 116

Co2(CO)8

Co(CO)3(CO)3Co

R-CO

Co(CO)2

Co(CO)3

R

Co

Co(CO)3

R

COCO

Co

Co(CO)3

R

CO

O

(CO)3CoCo(CO)

O

R

O-Co2(CO)4

R

1126 1127 1128 1129

1132 1131 1130

R

143 Scope and Limitations of the PKR

A variety of different alkynes and alkenes have been successfully employed in the

PKR4655 With respect to the intermolecular variant acetylene and terminal alkynes are

the most satisfactory alkynes and internal alkynes tend to give lower yields As noted

above the intermolecular PKR works best with strained cyclic alkenes Also as the

steric hindrance of the alkene substrate increases the yield usually decreases

Unsymmetrical alkenes often give mixtures of regioisomers but Krafft has resolved the

36

issue of regioselectivity as well as poor reactivity of unstrained alkenes by introducing a

sulfide directing group on the alkene partner in the homoallylic position56 For example

ethers were found to be poor ligands and the reaction of 1133 with phenylacetylene

(1134) gave a mixture (32) of 1135 and 1136 in modest yield (Eq 115) When the

MOM-ether is switched to a methyl sulfide as in 1137 then a higher yield and a better

regioselectivity is obtained (Eq 116)

MOMO

PhCo2(CO)8

toluene 100 degC41

11351136 = 32

O

Ph

MOMO

O

Ph

MOMO

+

11341133

+

1135 1136

MeS

PhCo2(CO)8

toluene 100 degC61

11371138 = 181

O

Ph

MeS

O

Ph

MeS

+

11381137

+

1139 1140

(115)

(116)

In the intramolecular case typically 15- and 16- enynes are the most common

substrates57 Cyclization of 17-enynes as well as 14-enynes have generally not been

successful As above internal alkenes and sterically hindered alkenes give reduced

yields In all cases the presence of many varied functional groups is tolerated including

ethers alcohols ketones ketals esters tertiary amines amides thioethers and

heteroaromatic rings provided these are not in the propargyl position as complications

have been noted in these cases57

37

144 The Catalytic Pauson-Khand Reaction

1441 Cobalt-Catalyzed PKR

Efforts toward rendering the PKR catalytic in Co2(CO)8 began with a report by

Pauson in which intermolecular PKRs could be conducted with substoichiometric

Co2(CO)8 (10) but only if strained alkenes norbornene and norbornadiene were used58

The first catalytic PKR of a nonstrained alkene was demonstrated by Rautenstrauch and

in that report 1-heptyne was reacted with ethylene in the presence of only 022 mol

Co2(CO)8 under a CO atmosphere (100 bar) to give 2-pentyl-2cyclopentenone in 47

yield59 The first practical catalytic PKR which did not require elevated CO pressure was

performed by Jeong and coworkers60 They found that a major obstacle in the

development of a catalytic process was the formation of cobalt clusters as well as other

inactive cobalt carbonyl species and they reasoned that addition of the proper ligand

could suppress these deleterious processes In fact utilization of triphenyl phosphite as a

ligand gave 51-94 yields of bicyclopentenenones such as 1141 from 1142 with as little

as 3 mol Co2(CO)8 and balloon pressure (1 atm) of CO (Eq 117)

OEtO2C

EtO2C

Co2(CO)8 (3 mol)P(OPh)3 (10 mol)

CO (1 atm) DME120 degC 82

EtO2C

EtO2C

1141 1142

(117)

Other cobalt-catalyzed PKRs employing high intensity light61 and super critical

fluids as solvent62 have been reported but a sufficiently general method catalytic in

cobalt has not been developed as evidenced by the fact that the vast majority of PKRs

are still conducted with stoichiometric Co2(CO)8 and a promoter of some sort In an

38

effort to simplify the catalytic PKR transition metals other than cobalt have been

examined and success has been achieved with titanium ruthenium and rhodium

catalysts

1442 Titanium-Catalyzed PKR

Buchwald developed the first titanium catalyzed PKR using the titanocene

catalyst Cp2Ti(CO)2 under a CO atmosphere (18 psi) and these conditions gave excellent

yields of fused cyclopentenones such as 1143 (Eq 118)63 Subsequent work using

chiral titanocene catalysts allowed the preparation of 1144 in an enantioselective

fashion64

CO (18 psi)Cp2Ti(CO)2 (5 )

toluene 90 degC92

O

Ph

O

1143 1144

OPh

(118)

1443 Ruthenium- and Rhodium-Catalyzed PKR

The first reports of the use of a late transition metal to catalyze PKRs emerged in

the late 1990rsquos when Murai and Mitsudo virtually simultaneously reported the use of

Ru(CO)12 to catalyze PKRs6566 Under almost identical conditions differing only in the

choice of solvent 1145 smoothly underwent PKR to give 1146 among a number of

other examples (Eq 119)

Me

O

1145 1146

MeEtO2C

EtO2CEtO2C

EtO2C

CO (10-15 atm)Ru(CO)12 (2)

dioxane or DMAc140-150 degC

86-76

(119)

Narasaka and Jeong independently reported the rhodium-catalyzed PKR in the

early 1990rsquos6768 Narasaka showed that [Rh(CO)Cl]2 was an active catalyst and only 1

39

was required to transform the enyne 1147 to the cyclopentenone 1148 under balloon

pressure of CO (Scheme 117) Jeong screened a number of Rh(I) catalysts and found

[RhCl(CO)dppp]2 to be the most efficient giving 1148 in quantitative yield The low

catalyst loadings required and the high yields of these reactions make them quite

attractive alternatives to the corresponding stoichiometric protocol However the

drawbacks are the high temperatures required and the high cost of the rhodium catalysts

Scheme 117

Ph

O

11471148

PhEtO2C

EtO2C

EtO2C

EtO2C

CO (1 atm)[Rh(CO)2Cl]2 (1)Bu2O 130 degC 94

CO (1 atm)[RhCl(CO)dppp]2 (25)

toluene 110 degC 99

145 Application of the Pauson-Khand Reaction in Synthesis

The PKR has been employed in a number of natural product syntheses due to the

high level of complexity that can be generated in the reaction from simple starting

materials46 Magnus was the first to employ the intramolecular PKR in natural product

synthesis and the formal synthesis of (plusmn)-coriolin (1151) relied on the PKR of the

readily available enyne 1148 to give 1149 in 50 yield as well as 15 of the opposite

diastereomer (Scheme 118)69 The cyclopentenone 1149 was further elaborated to the

tricyclic compound 1150 which constituted a formal synthesis of 1151

40

Scheme 118

TBSOMe Co2(CO)8

heptane110 degC (sealed tube)

50

Me

O

TBSO

H

1148 1149

6 steps HO

H

1150

O

OH

H

HO

H

1151

O

OH

H

O

O

H

Application of the PKR to the synthesis of complex alkaloid natural product

targets has received less attention One notable example was reported by Cassayre and

Zard in the total synthesis of (-)-dendrobine (1154)70 The enyne substrate 1152 was

prepared using a nitrogen-centered radical cyclization developed by the authors and

underwent PKR after the initially generated cobalt-alkyne complex was treated with

NMO (Scheme 119) The strained cyclopentenone was unstable but reduction of the

crude enone gave the stable tricyclic product 1153 in moderate yield over three steps

Notably the reaction is completely diastereoselective and the PKR and subsequent

alkene reduction set three key stereocenters Carbonyl reduction and introduction of the

lactone ring completed the synthesis of (-)-dendrobine (1154)

41

Scheme 119

OOAc

N NO

H H

H

i) Co2(CO)8 CH3CNii) NMOH2Oiii) PdC H2

51

1152 1153

N

H H

H

1154

O

9 steps

OAc

The recent synthesis of (+)-conessine (1158) also featured a PKR to assemble the

core of an alkaloid natural product71 PKR of the enyne 1155 using DMSO as a

promoter gave a 67 yield of a mixture (61) of diastereomers favoring 1156 (Scheme

120) A series of reactions which included alkene reduction and inversion of two

stereocenters finally gave the natural product 1158

Scheme 120

N Co2(CO)8DMSO (6 equiv)

THF 65 degC67

11561157 = 611155

MeO MeO1156

N

O

MeO1158

N

7 steps

MeO1157

N

O+

H

42

146 Synthesis of Bridged Structures via Pauson-Khand Reaction

Despite the enormous potential of the PKR to synthesize cyclopentenones the

intramolecular reaction has been overwhelmingly restricted to the synthesis of fused

bicyclo[330]octenones such as 1160 and bicyclo[430]nonenones such as 1161

(Scheme 121)46 However a number of exceptions some in the realm of natural product

synthesis are noteworthy

Scheme 121

O O

1159 n = 1 or 2

PKR

n

1160 1161

or

The first example of the synthesis of a bridged ring system by PKR was reported

by Krafft wherein enyne 1162 was transformed in modest yield to the ten-membered

bridged enone 1163 (Eq 120)72 Shortly thereafter Lovely and coworkers reported a

similar PKR of an aromatic substituted enyne 1164 to form the bridged epoxy ketone

1165 (Eq 121)73 Use of the aromatic backbone was intended to restrict the

conformational degrees of freedom in the substrate in order to preorganize the alkene and

alkyne for cyclization The authors assume that the epoxidation of the initially formed

enone double bond is NMO promoted however they do not offer a detailed mechanistic

hypothesis for this transformation

43

O

Me

MeO

O

Me

Me

O

Co2(CO)8 CH2Cl2

1164 1165

then NMO48

O

O

O

OO

1162 1163

Co2(CO)8 CH2Cl2

then NMO31

(120)

(121)

In their elegant formal synthesis of α-cedrene (1169) and β-cedrene (1170) Kerr

and coworkers were the first to apply a PKR to the synthesis of a bridged structure in the

context of natural product synthesis74 Sulfide promoted PKR of the enyne 1166

afforded the bridged cyclopentenone 1167 in excellent yield as one diastereomer

(Scheme 122) Five additional steps were required to transform the PKR product 1167

to cedrone (1168) which constituted a formal synthesis of both α-cedrene (1169) and β-

cedrene (1170)

Scheme 122

O O

OO

O

DCE 83 degC95

11671166

Co2(CO)8nBuSMe

1170

H

1169

H

1168

O

H

5 steps

44

Recently Winkler and coworkers reported a particularly demanding PKR in their

synthetic approach to ingenol 117675 Alkylation of the dioxanone 1171 which was

rapidly accessed by a key [2+2] photocycloaddition gave the PKR substrate 1173

(Scheme 123) The dihydrate of trimethylamine N-oxide was found to best promote the

PKR to give 1174 and the authors noted that use of the anhydrous reagent gave

considerably reduced yields With the cyclopentenone 1174 in hand retro-aldol reaction

installed the cis-intrabridgehead stereochemistry in 1175 which unfortunately is

opposite to the stereochemistry in the natural product The authors hope to revise their

synthetic route to ameliorate this discrepancy and if successful the rapid synthetic route

to ingenol (1176) would be particularly impressive

Scheme 123

O O

O

H

Co2(CO)8 4 A MStoluene

then Me3NO2H2O60-70

OO

OO

11731174

K2CO3MeOH

55O

CO2Me

O

H

1175

O

H

1176

HO HOHO

HO

H

H

O O

O

H

1171

H

TMS

Br

LDA DMPU THFthen TBAF 82

1172

45

15 Tandem Transition Metal-Catalyzed Reactions

151 Introduction Catalysis of Multiple Mechanistically Different Transformations

Transition metal-catalyzed transformations have become ubiquitous in organic

synthesis and these reactions have become indispensable tools in an organic chemistrsquos

repetoire7a As the field of organometallic chemistry has grown and matured transition

metal catalysts that are increasingly chemoselective have been developed and stringing

multiple transition metal-catalyzed processes in tandem has been an important goal The

catalysis of multiple mechanistically similar reactions with a single transition metal

catalyst is well known and can be accomplished by a specific order of addition of

reagents or by differing reactivity of functional groups76 However as the list of

transition metal-catalyzed reactions continues to become more diverse modern synthetic

organic chemists have begun to pursue the catalysis of multiple fundamentally different

reactions in one pot with a single transition metal catalyst system77

152 Tandem Reactions Involving Alkene Metathesis

Grubbs has been a pioneer in the area of employing a single transition metal

catalyst to mediate multiple fundamentally different transformations78 Utilizing his

second-generation metathesis catalyst 1178 Grubbs catalyzed first the cross metathesis

of the styrene 1176 with methyl acrylate (1177) and upon completion of the reaction an

atmosphere of hydrogen was introduced to reduce the double bond to ultimately give

1179 (Eq 122) The ruthenium catalyst 1178 is also capable of performing transfer

hydrogenation and starting with the alcohol 1180 which is readily available in one step

from (R)-citronellal ring closing metathesis can be accomplished with 1178 (Eq 123)

Following ring closure 3-pentanone and NaOH were added and a ruthenium-catalyzed

46

transfer hydrogenation took place to install the ketone in 1181 Finally an atmosphere of

hydrogen was introduced to reduce the alkene and finally give muscone 1181 In such a

fashion three mechanistically distinct reactions RCM transfer hydrogenation and

alkene reduction can be accomplished in a single reaction vessel with a single transition

metal catalyst simply by modifying the reagents

Cl

CO2Me+

MesN NMes

RuPh

PCy3ClCl

1178

1176 1177

then H2 (100 psi)69

CO2Me

Cl

1179

OOHi) 1178

ii) Et2CO NaOHiii) H2

11801181

56

(122)

(123)

153 Tandem Reactions Which Include a PKR

1531 Chungrsquos PKR[2+2+2] and Reductive PKR

Chung and coworkers have reported two cobalt-catalyzed tandem processes

which both involve PKR as the initial step79 Starting with the 16-diyne 1182 catalytic

PKR employing Co2(CO)8 and a high CO pressure (441 psi) generates an unstable

cyclopentadienone which then undergoes cobalt-catalyzed [2+2+2] cycloaddition in the

presence of two equivalents of phenylacetylene to give the tricyclic product 1183 (Eq

124) A number of additional examples were reported but geminal substitution at the 4-

47

position of the starting material was important for optimal yields The same research

group published the concurrent cobalt nanoparticle catalyzed reductive PKR In this

case as opposed to the metathesisalkene reduction methodology developed by Grubbs

hydrogen could be present throughout the reaction sequence Thus treatment of the

enyne 1184 with cobalt nanoparticles in a H2CO atmosphere with heating gave the

bicycle 1185 in excellent yield (Eq 125) and a number of other examples were also

reported

EtO2C

EtO2C

CO (441 psi)Co2(CO)8 (5 )

CH2Cl2 130 degC68

OEtO2C

EtO2C

PhPh

1182 1183

MeO2C

MeO2C

1184

Co nanoparticles

H2 (73 psi) CO (73 psi)THF 130 degC

98

OMeO2C

MeO2CH

H

1185

(124)

(125)

A significant drawback to the catalytic PKR is the need for a toxic CO

atmosphere often in high pressure Morimoto Kakiuchi and coworkers devised a fusion

of two rhodium-catalyzed reactions in order to replace the CO atmosphere with

formaldehyde80 Rhodium-catalyzed decarbonylation converts the formaldehyde to CO

and H2 followed by a rhodium catalyzed PKR to deliver 1187 from 1186 without the

need for a CO atmosphere (Eq 125) They found that the use of two phosphine ligands

water soluble TPPTS (triphenylphosphane-3-3prime-3primeprime-trisulfonic acid trisodium salt) and

organic soluble dppp (bis(diphenylphosphinopropane)) were essential for high yields

48

The authors hypothesize that the two reactions are partitioned into two phases The

decarbonylation is thought to occur in the aqueous phase and the PKR is thought to occur

in a micellar phase hence the use of two ligands as well as the surfactant SDS (sodium

dodecylsulfate)

MeO2C

MeO2C

1186

OMeO2C

MeO2C

1187

[RhCl(cod)]2 (5)dppp (10) TPPTS (10)

SDS H2O 100 degC

PhPh

O

HH+ (126)

1532 Tandem Allylic AlkylationPauson-Khand Reaction

Evans hoped to utilize the highly regioselective allylic alkylation catalyzed by his

phosphite modified Wilkinsonrsquos catalyst to synthesize enynes that could undergo further

Rh(I)-catalyzed cyclization reaction such as Pauson-Khand reaction (PKR)81 When the

secondary allylic carbonate 168 was treated with the P(OMe)3 modified Wilkinsonrsquos

catalyst and the anion of 1188 the alkylation products 1189 and 1190 were obtained

but no PKR was observed after extended heating under a CO atmosphere (Scheme 124)

A screen of Rh(I) catalysts showed that [RhCl(CO)dppp]2 catalyzed the allylic alkylation

highly efficiently and regioselectively Thus following completion of the allylic

alkylation the reaction mixture was simply heated to reflux and the PKR also proceeded

in high yield and good diastereoselectivity to deliver a mixture of the two

cyclopentenones 1191 and 1192 Notably [RhCl(CO)dppp]2 is capable of catalyzing

highly regioselective allylic alkylations using secondary carbonates such as 168 as

substrates without the need for phosphite modification and perhaps this is due to the

49

ability of the CO ligand to withdraw electron density from the metal center through π-

back bonding81

Scheme 124

∆

Me

OCO2Me [RhCl(CO)dppp]2 (5)

NaH

CO CH3CN 30 degC

CO2MeMeO2C

168

1188

Me

MeO2C

MeO2C

CO2Me

CO2Me

Me+

1189 1190

OMeO2C

MeO2C

Me H

OMeO2C

MeO2C

Me H

+

1191 1192

11891190 = 371 88

11911192 = 71 87

1533 Tandem Rh(I)-Catalyzed Allylic Alkylation-Carbocyclizations

The work of Dr Ashfeld above showed that [Rh(CO)2Cl]2-catalyzed allylic

alkylations can be conducted in a highly regioselective manner and use of substituted

malonate nucleophiles allows for the synthesis of 16-enyne products (vide supra) Not

only is [Rh(CO)2Cl]2 capable of catalyzing allylic alkylations but recent reports outside

of the Martin group have disclosed a number of [Rh(CO)2Cl]2-catalyzed carbocyclization

reactions of 16-enynes such as [5+2]-cycloadditions42 PKR67 and cycloisomerizations41

Dr Brandon Ashfeld and Anna Smith sought to exploit the highly regioselective

50

[Rh(CO)2Cl]2-catalyzed allylic alkylation to synthesize enyne products 1195 that could

serve as starting materials for subsequent [Rh(CO)2Cl]2-catalyzed carbocyclization

reactions such as [5+2]-cycloadditions PKR and cycloisomerizations (Scheme 125)82

Of particular importance the possibility that both reactions could be conducted in one

reaction vessel with a single catalyst was attractive and the goal was to develop reaction

conditions that would facilitate both reactions in a tandem sequence without the need to

add additional reagents or catalysts

Scheme 125

X

+ LG

R

[Rh(CO)2Cl]2X

R

X

R

X O

R

XR

PKR

X = C(CO2Me)2 NTs O

[5+2]

cycloisom

CO

11931194

1195

1196

1197

1198

Before this work only cationic Rh(I) catalysts were reported to facilitate the

cycloisomerization of 16-enynes and the use of neutral Rh(I) catalysts such as

[Rh(CO)2Cl]2 to accomplish the same goal was not assured Smith found that

[Rh(CO)2Cl]2 does in fact catalyze the isomerization of 16-enynes to 14-dienes as vinyl

alkylidene cyclopentanes Smith optimized the reaction of the substituted malonate

nucleophile 1104 with the allylic trifluoroacetate 1199 to give the enyne

cycloisomerization product 1200 in good yield (Scheme 126) Notably the preservation

51

of Z-alkene geometry in the [Rh(CO)2Cl]2-catalyzed allylic alkylation enables the

synthesis of the corresponding Z-enyne and cycloisomerization of Z-enynes are well

known to be more efficient than the corresponding E-enynes83 In another set of

experiments Dr Ashfeld demonstrated the allylic alkylation of the same substituted

malonate 1104 with the cyclopropyl trifluoroacetate 1201 to give an intermediate

cyclopropyl enyne that underwent subsequent [5+2]-cycloaddition by simply increasing

the reaction temperature to provide 1202 These reactions highlight how the high

regioselectivities in the [Rh(CO)2Cl]2-catalyzed allylic alkylations and multifunctional

nature of [Rh(CO)2Cl]2 can both be exploited to synthesize products with a high level of

complexity from relatively simple starting materials in one reaction vessel in an efficient

fashion

Scheme 126

OCOCF3

NaH [Rh(CO)2Cl]2CH3CN -40 then 110 degC

72

MeO2C

MeO2CCO2MeMeO2C

Me

NaH [Rh(CO)2Cl]2CH3CN rt then 80 degC

89

OCOCF3 MeO2C

MeO2C

1200

1202

1104

1199

1201

16 Conclusions

The importance of transition metal catalysis to the modern synthetic organic

chemist cannot be overstated Indeed the report of a complex natural product synthesis

52

without at least one transition metal-catalyzed transformation has become exceedingly

rare Simply transition metal catalysis often offers modes of reactivity and selectivity

that are not possible when compared with all other synthetic organic chemical

methodology catalytic or otherwise

Transition metal-catalyzed allylic alkylations continue to generate interest in the

synthetic organic community due to the high levels of chemo- regio- stereo- and

enantioselectivity available from this powerful reaction Palladium continues to be the

most common choice of allylic alkylation catalysts most likely due to the surge in

research aimed at rendering the palladium-catalyzed allylic alkylation enantioselective

However the complementary regioselectivities exhibited by other transition metal

catalysts allows one to access products that would be difficult or impossible to attain via

palladium catalysis

The Pauson-Khand reaction is a powerful way to quickly assemble

cyclopentenones Since the discovery of the reaction the combined efforts of many

talented chemists have transformed the PKR from an organometallic oddity to a practical

choice for the synthesis of a number of complex natural product targets and research in

the area of improving the catalytic PKR and increasing the enantioselectivity of the PKR

continues to be a fertile field Unfortunately the limitations of the reaction in terms of

substrate scope prevent widespread use of the PKR in complex molecule synthesis

Further as the realm of transition metal-catalyzed transformations continues to

expand the possibility of cascade reaction sequences which include an allylic alkylation

as well as other transition metal catalyzed reactions in one reaction vessel employing a

single catalyst has become a reality

53

Chapter 2 Regioselective Rhodium-Catalyzed Allylic Substitutions of

Unsymmetrical Carbonates and Related Cascade Reactions

21 [Rh(CO)2Cl]2 Catalyzed Transformations-Introduction

Transition metal catalyzed allylic alkylations offer reactivity modes that are

unavailable via simple SN2 chemistry As discussed in the previous chapter allylic

acetates and carbonates are relatively inert to SN2 alkylation chemistry and thus offer a

complementary chemoselectivity when utilized in transition metal-catalyzed allylic

alkylation reactions Further in a stereochemical sense transition metal catalyzed allylic

alkylations give products of net retention whereas SN2 alkylation proceeds through

inversion The enantioselective transition metal-catalyzed allylic alkylation is yet another

illustration of the power of these catalytic transformations to access products unavailable

through simple alkylation chemistry

The [Rh(CO)2Cl]2-catalyzed allylic substitution reaction discovered by Dr

Brandon Ashfeld offers a regioselectivity profile unique among transition metal catalysts

Dr Ashfeld found that [Rh(CO)2Cl]2-catalysis gave products of nucleophilic attack on

the carbon bearing the leaving group in a highly regioselective fashion For example

when primary allylic carbonates such as 21 were employed as substrates alkylation at

the primary carbon is observed preferentially giving 22 (Eq 21) and this

regioselectivity is commonly observed under palladium catalysis Alternatively products

of attack at the more hindered allylic site such as 24 could be obtained simply by

employing a tertiary carbonate 23 as the substrate (Eq 22) and this regiochemistry is

54

typical under a variety of transition metal catalysis including Ru Mo W Ir and Rh

Thus Dr Ashfeldrsquos discovery was important in that one transition metal catalyst

[Rh(CO)2Cl]2 was found to be capable of preferentially providing the product of

nucleophilic attack on the carbon bearing the leaving group regardless of the substitution

at each allylic terminus This reactivity mode stands in stark contrast to previously

disclosed allylic substitution catalysts Of particular note is the fact that this unique

regiochemical profile allows one to access products of varying substitution patterns such

as 22 and 24 with a single catalyst whereas previously palladium catalysis would be

required to obtain 22 from either 21 or 23 and other transition metal catalysts would

give 24 regardless of whether 21 or 23 was employed as a substrate

R

R

OCO2Me

Nuc[Rh(CO)2Cl]2

R

R

Nuc

R

OCO2Me

R

Nuc[Rh(CO)2Cl]2

R

Nuc

R

21 22

23 24

(21)

(22)

[Rh(CO)2Cl]2 has also been reported to mediate a number of carbocyclization

reactions including [5+2]-cycloaddtions42 and PKRs67 Moreover a vast number of

Rh(I)-catalyzed transformations employ substrates that could be assembled in a highly

regioselective fashion via a [Rh(CO)2Cl]2-catalyzed allylic substitution reaction (Scheme

21) Thus we envisioned that [Rh(CO)2Cl]2 could be used to catalyze cascade reaction

sequences in which allylic alkylation would serve as the first step and any of a number of

Rh(I)-catlyzed carbocyclization reactions would be used to access a vast array of

55

polycyclic structures For example allylic etherification utilizing a meta-ketimino copper

phenoxide nucleophile 26 would provide products 27 which could undergo a

subsequent imine directed Rh(I) catalyzed ortho-alkylation84 Similarly 210 could be

synthesized by alkylation of the allyl malonate 29 and a successive Rh(I)-catlayzed

metallo-ene reaction in the same reaction vessel would give 14-dienes as vinyl

alkylidene cyclopentanes such as 21185 Finally the propargyl malonate nucleophile

212 would provide 16-enynes 213 that can undergo Rh(I)-catalyzed PKRs to access

bicyclopentenones 2146768

Scheme 21

O

NBn

Rh(I)

RO

NBn

R

XX

MeO2CO

Rh(I)

X O

R

Rh(I)X

R

MeO2CO R

OCu(I)

NBn

[Rh(CO)2Cl]2

[Rh(CO)2Cl]2

[Rh(CO)2Cl]2

25

26

213 X = C(CO2Me)2 NRH OH

2728




-CO


X


X

56

The following chapter will describe efforts directed toward further probing the

regioselectivity of the [Rh(CO)2Cl]2-catalyzed allylic substitution in systems that were

not thoroughly explored by Dr Ashfeld Particular emphasis was placed on reactions

that yield products that can function as substrates in cyclization reactions especially

Rh(I)-catalyzed transformations with the ultimate goal being the development of a

family of Rh(I)-catalyzed cascade reactions wherein the cyclization substrate is

assembled via a [Rh(CO)2Cl]2-catalyzed allylic substitution

22 [Rh(CO)2Cl]2ndashCatalyzed Allylic Substitution Reactions Scope and Limitations

221 Allylic Alkylations of Substrates With Sterically Similar Allylic Termini

In each of the Rh(I)-catalyzed allylic alkylations explored by Dr Ashfeld the

product of nucleophilic attack on the carbon bearing the leaving group was the major

product regardless of the steric environment at each allylic site39 However we queried

whether the same trend would be observed if the substitution at each allylic site was

virtually identical For example if each allylic site was secondary as in 215 would the

regiochemical trend hold regardless of the nature of the groups R and Rprime (Eq 23)

R R R R215 216

Nuc-[Rh(CO)2Cl]2 (23)

OCO2Me Nuc

Initial allylic alkylation experiments to test this question showed substantial

erosion of regioselectivity compared with the high regioselectivities observed by Dr

Ashfeld For example treating allylic carbonate 217 with the sodium salt of dimethyl

malonate in the presence of [Rh(CO)2Cl]2 provided a good yield of a mixture (7624) of

regioisomers 219 and 220 favoring nucleophilic attack at the carbon previously bearing

57

the leaving group (Scheme 22) However when 218 was allowed to react with the

sodium salt of dimethyl malonate under identical conditions a mixture of 219 and 220

was obtained in which 219 was slightly favored

Scheme 22

OCO2Me

OCO2Me

CH2(CO2Me)2 NaH[Rh(CO)2Cl]2 (10)

THF rtor

218

217

219 220

+

From 217 72 7624 219220From 218 76 5545 219220

CO2MeMeO2C CO2MeMeO2C

As the steric demand adjacent to one allylic terminus began to increase

substantial erosion of the high regioselectivities observed by Dr Ashfeld were observed

Reaction of the allylic carbonate 221 with the sodium salt of dimethyl malonate in the

presence of [Rh(CO)2Cl]2 gave 223 with highly regioselectivity favoring nucleophilic

attack at the carbon bearing the leaving group (Scheme 23) In contrast starting with the

allylically transposed carbonate 222 223 was again the major product In each case

long reaction times (2-3 days) were required to consume starting material Considering

that Dr Ashfeld had observed erosion of regioselectivities upon increasing the reaction

temperature elevated reaction temperatures were avoided

58

Scheme 23

OCO2Me

OCO2Me


THF rtor

222

221

223 224

+

From 221 56 955 223224From 222 58 8614 223224


Further increasing the steric bulk adjacent to one allylic terminus to a tert-butyl

group as in 225 and 226 yielded similar results to those seen in the cases of 221 and

222 but the preference was even more pronounced (Scheme 24) Regardless of whether

225 or 226 was the substrate allylic alkylation favored 227 with high regiochemical

control Both reactions required extended reaction times and the reactions were stopped

after three days Comparison of the yields as the substitution was changed from ethyl

218 to isopropyl 222 to tert-butyl 226 indicated that the yield steadily decreases from

76 to 58 to 21 respectively

Scheme 24


THF rt227 228

+

From 225 29 946 227228From 226 21 919 227228


OCO2Me

OCO2Me

or

226

225

We reasoned that if we could slow the rate of equilibration of the two enyl

intermediates without equally adversely affecting the rate of nucleophilic attack then the

59

ratio would improve Thus the influence of temperature and solvent polarity was

studied We thought that use of the more polar DMF as solvent would increase the rate of

nucleophilic attack while decreasing the temperature would slow the rate of enyl

equilibration In the event DMF as solvent at -20 ˚C proved optimal preferentially

providing regioisomer 220 when 218 underwent allylic alkylation (Table 22) While

the regiochemical ratio was not high these experiments showed that both temperature

and solvent have a significant effect on the regiochemical outcome of the reaction39

Table 21 Optimization of the Alkylation of 218

OCO2Me MeO2C CO2Me MeO2C CO2Me

solvent 0 or -20 degC

[Rh(CO)2Cl]2 +

220 219

CH2(CO2Me)2 NaH

218

entry solvent yield ratio 220219

1

2

3

4

DMSO

CH3CN

THF

DMF

62

62

76

73

2575

3664

4555

6931

Application of the above optimal conditions to the alkylation of 217 resulted in

an even more pronounced effect on the regioselectivity (Eq 24) in that a ratio of 964 of

219220 was obtained favoring 219 These results confirmed that one key to

controlling the regioselectivity of difficult [Rh(CO)2Cl]2-catalyzed allylic alkylations

was decreased temperature and DMF as solvent39

60


DMF -20 degC88

[Rh(CO)2Cl]2 +

219 220

CH2(CO2Me)2 NaH

217

219220 = 964

(24)

Often regioselectivities suffer when the steric bulk of the nucleophile increases

and substituted malonates have been reported to give substantially reduced regiocontrol

in a number of transition metal catalyzed allylic alkylations16 In spite of this trend in

other systems alkylation of the secondary carbonate 217 with the substituted malonate

229 proceeded with high regioselectivity to give a mixture (937) of enynes 230 and

231 (Eq 25) Enynes such as 229 can serve as substrates in other Rh(I)-catalyzed

transformations40-42 and the study of the regioselective preparation of such enynes in the

context of developing domino processes will be addressed in subsequent sections within

this chapter

OCO2Me

217

CO2MeMeO2C

+

229

MeO2C

MeO2C

MeO2C

MeO2C 231

230

+

NaH[Rh(CO)2Cl]2

DMF -20 degC88

230231 = 937

(25)

Applying the above optimized conditions (DMF -20 ˚C) to the allylic alkylation

of 222 and 226 did not improve the yields or regioselectivities (Scheme 25) Extended

reaction times did not yield any allylic alkylation products and only starting material was

recovered The substrates 222 and 226 reacted sluggishly even in THF at room

temperature often requiring a number of days to reach completion Thus the lack of any

61

perceptible reaction at -20 ˚C is not that surprising

Scheme 25

OCO2Me


DMF -20 degC

222

OCO2Me

226

orno reaction

While Dr Ashfeld demonstrated that [Rh(CO)2Cl]2-catalyzed allylic alkylations

preferentially gave the product of nucleophilic attack on the carbon bearing the leaving

group using substates with sterically different allylic termini the above experiments

illustrated that the regiochemical trend can also hold for substrates containing sterically

similar allylic termini Optimal regioselectivites were obtained when DMF was used as

the solvent and the temperature was decreased to -20 ˚C Furthermore as the steric bulk

of the substituents adjacent to the allylic termini increased the allylic alkylation became

increasingly sluggish The above experiments were quite different than the results

reported by Evans as his phosphite modified Wilkinsonrsquos catalyst is unaffected by the

steric environment adjacent to each allylic site (Eq 111 amp 112) while the substitution at

each allylic site had a pronounced impact on the nature of the major product (Scheme

112)37

222 Regioselective Allylic Aminations

The use of amine and lithium salts of sulfonamides as nucleophiles in transition

metal-catalyzed allylic substitution reactions has been examined by a number of

62

researchers as a useful method for the synthesis of functionalized allyl amines2728 but the

unique ability of [Rh(CO)2Cl]2 catalysis to deliver products of nucleophilic attack on the

carbon bearing the leaving group led us to explore the regioselectivity of [Rh(CO)2Cl]2-

catalyzed allylic aminations Initial experiments by Dr Ashfeld found that the lithium

salts of sulfonamides effectively function as nucleophiles but utilization of simple

amines as nucleophiles did not provide any of the corresponding allyl amine products

Instead of employing lithium salts of sulfonamides as nucleophiles amine nucleophiles

would give allyl amine products without the need for a stoichiometric base and without

the need to remove a tosyl protecting group representing a much more atom economical

approach to these important synthetic intermediates To demonstrate the utility of the

allyl amine products we envisioned that the products of highly regioselective Rh(I)-

catalyzed allylic amination reactions could undergo further Rh(I)-catalyzed cyclization

reactions to rapidly build complex alkaloid structures in one reaction vessel (Scheme

21)

To begin our study of amine nucleophiles we chose pyrrolidine (233) as the

nucleophile and the readily available cinnamyl alcohol derived carbonate 232 as the

electrophile (Eq 26) However when 232 was allowed to react with pyrrolidine in the

presence of a catalytic amount of [Rh(CO)2Cl]2 in THF or DMF only starting material

was recovered despite extended reaction times and elevated temperatures

OCO2Me

HN

[Rh(CO)2Cl]2 (10 mol)THF or DMF rt-60 degC

Recovered Starting Material

232

233

(26)

63

Switching solvent from polar aprotic solvents such as THF and DMF to the polar

protic solvent EtOH had a dramatic effect on the yield Inspiration for using a polar

protic solvent was drawn from the work of Taguchi who found that EtOH was an

optimal solvent for [IrCl(cod)]2ndashcatalyzed allylic aminations13 Treatment of the allylic

carbonate 232 with pyrrolidine and catalytic [Rh(CO)2Cl]2 in EtOH gave an almost

quantitative yield of a mixture of the allyl amines 234 and 235 (Eq 27) In contrast to

Taguchirsquos work the reaction proceeded with a complete lack of regioselectivity giving an

equal amount of each isomer 234 and 235

OCO2Me

HN

[Rh(CO)2Cl]2 (10 mol)EtOH rt

96234235 = 11

232

233

234

N

235

N

+(27)

In order to increase the reactivity of the allylic alkylation substrate the use of

allyltrifluoroacetate substrate 236 was explored Unfortunately instead of allylic

amination only amine acylation was observed giving trfiluoroacetyl pyrrolidine 237 and

cinnamyl alcohol 238

OCOCF3

HN

[Rh(CO)2Cl]2 (10 mol)THF or DMF rt-60 degC236

233

N

CF3O

OH

238

+

237

(28)

The work of Lautens and coworkers on [Rh(COD)2Cl]2-catalyzed ring opening

reactions of oxabcyclic alkenes such as 239 with amine nucleophiles provided some

insight as to a potential problem with our desired [Rh(CO)2Cl]2-catalyzed allylic

64

amination (Eq 29)86 Lautens observed that the rhodium-catalyzed ring opening reaction

of 239 was completely inhibited when pyrrolidine 233 was utilized as a nucleophile but

that the addition of TBAI led to a 98 yield of 240 in a matter of hours

O

HN

[Rh(COD)Cl]2 (25 mol)dppf (5 mol)

THF reflux without TBAI no reaction

with TBAI 98 5 h

OH

N

233

239

240

(29)

Based on his results and previous literature precedent85-88 Lautens proposed a

mechanistic rationale (Scheme 26) Nucleophilic attack of the amine on the rhodium

dimer 240 presumably leads to an amine-rhodium complex 241 a reaction that is well

documented87 Thus if the reaction was irreversible the amine-rhodium complex 241

could represent a poisoned catalyst Alternatively reaction of the chloride bridged dimer

240 with iodide sources has been shown to give the iodide bridged species 24288 which

are well known to be less reactive toward cleavage reactions than the corresponding

chloride bridged complexes89 In the presence of halide additives the amine-rhodium

complex 243 could react to provide the dihalorhodate 244 by nucleophilic displacement

of the amine by the added halide ion in an associative process commonly observed in

square planar d8 metal complexes90 Then two monomeric dihalorhodate complexes

could react to reform the dimer 242

65

Scheme 26

RhCl

OC

OC

ClRh

CO

CO

HN

RhClOC

NHOC

241 poisoned catalyst

233

240

I-

RhI

OC

OC

IRh

CO

CO

HN

RhIOC

NHOC

RhI

OC

OC

I

slower

Bu4N+I-

Bu4N+

233

242

243

244-I-

Addition of TBAI to the reaction of pyrrolidine (233) with 232 had a dramatic

effect (Table 21) After screening a number of solvents and varying amounts of TBAI

the optimal conditions were determined to be 20 mol TBAI and 10 mol

[Rh(CO)2Cl]2 in DCE as solvent These optimized conditions provided the allylic

amination product 234 in high yield and excellent regioselectivity39 The secondary

carbonate 248 also reacted efficiently to give a virtually quantitative yield of 249 as one

regioisomer as determined by the 1H NMR spectrum Tertiary carbonate 251 reacted

with benzylmethylamine (250) to deliver 252 but the allylically transposed substrate

253 also gave exclusively 252 The reversal in regioselectivity in the case of 253 was

66

unexpected and perhaps this result suggests that the nature of the halide-rhodium species

has a marked effect on the rate of enyl isomerization

Table 22 Rh(I)-Catalyzed Allylic Aminations

R2

R1 OCO2Me

R3R4 [Rh(CO)2Cl]2 (10 mol)

NHR1R2 (2 eq)DCE rt

R2

R1 NR2

R3R4 R3

R4R2N

R2R1

+

TBAI (20 mol)

Allylic Carbonate Major Product Yield ()Ratio

(majorminor)Nucleophile

HN

HN

NHBn

Me

OCO2Me

OCO2Me

Me

OCO2Me NMe

Bn

N

Me

N 96

99

89

gt955

gt955

gt955

233

233

250

232

248

251

234

249

252

245 246 247

NHBn

MeN

Me

Bn

85 gt955

250 253 252

OCO2Me

Our ultimate goal was to use a highly regioselective [Rh(CO)2Cl]2-catalyzed

allylic amination as the first step in a cascade of [Rh(CO)2Cl]2-catalyzed processes

culminating in the synthesis of complex alkaloid structures In an effort to develop a

cascade allylic amination-PKR the secondary amine 256 was synthesized following a

literature procedure (Scheme 27)91 The phenyl acetylene moiety was chosen due to the

67

observation that these alkynes tend to react more efficiently than alkyl substituted or

terminal alkynes in [Rh(CO)2Cl]2-catalyzed PKRs6768 Conducting the allylic amination

of allyl methyl carbonate (257) with the secondary amine 256 under the optimized

[Rh(CO)2Cl]2-catalyzed allylic amination conditions gave the enyne 258 but heating

258 under a CO atmosphere failed to provide any of the PKR product 259 Based on the

hypothesis that the anion derived from the leaving group was inhibiting the PKR a

number of modifications to the reaction were tried including the addition of acid to

protonate the carbonate anion leaving groups other than carbonate such as acetate and

trifluoroacetate were also examined Employing these modifications failed to yield any

259 and only unreacted 258 was recovered Reaction of the enyne 258 in the presence

of [Rh(CO)2Cl]2 (10 mol) TBAI (20 mol) and CSA (1 equiv) under a CO

atmosphere gave a 63 yield of 259 Taken together these experiments suggest either

that the rhodium complex present after the allylic amination is not capable of promoting a

PKR on 258 or that byproducts from the leaving group are suppressing the subsequent

PKR

68

Scheme 27

BnNH2

Br

64 BnHN

PhI CuIPd(PPh3)4

Et3N82

BnHNPh

254255 256

OCO2Me

257

CO TBAI (20 mol)[Rh(CO)2Cl]2 (10 mol)

DCE rt-reflux86

BnNPh

258

not BnN

Ph

O

259

Amines served as efficient nucleophiles in the [Rh(CO)2Cl]2-catalyzed allylic

substitution reactions but the addition of substoichiometric amounts of iodide was

critical to the success of the reaction Primary secondary and tertiary allyl amine

products can be obtained in excellent yields and regioselectivies In most cases the

product of nucleophilic attack on the carbon previously bearing the leaving group was

observed as the major product The allyl amine products are highly useful synthetic

intermediates that can be isolated and used in subsequent cyclization reaction such as the

PKR of the allyl amine 258

223 Phenol Pronucleophiles

Dr Ashfeld showed that [Rh(CO)2Cl]2-catalyzed allylic etherification proceed

optimally when copper phenoxides were employed as nucleophiles However Dr

Ashfeld only studied the reaction of ortho-phenyl phenol with a single primary carbonate

(vide infra) Thus we hoped to determine whether secondary and tertiary carbonates

could also function as substrates for allylic etherification substrates We were particularly

69

interested in utilizing ortho-substituted phenols that contained functionality that could be

further elaborated For example starting with ortho-substituted phenols 260 wherein R1

was a halide an alkene or an alkyne would give allyl phenyl ethers 261 and these

products could be cyclized to give a number of ring structures based on the nature of R1

(Scheme 28) A Heck reaction of 261 (R = halide) could give substituted benzofurans

such as 262 whereas RCM of 261 (R = alkene or alkyne) would give chromenes such

as 263 Ortho-alkyne substituents in 261 would enable a subsequent PKR to give

structures like 264

Scheme 28

OH

R1260

R1 = halide alkene alkyne

O

R1

R2

R5

R4R3

261


O

O

O

O

R2

R3

R4

R5

R2

R3

R4R5

R2

R3

264

262

263

HeckR1 = halide

RCMR1 = alkene

or alkyne

PKRR1 = alkyne

[Rh(CO)2Cl]2

In order to explore these possibilities the copper phenoxide derived from ortho-

vinyl phenol 267 was allowed to react with the primary allylic carbonate 268 to give

269 in high regioselectivity (Table 22)39 Dr Ashfeld inspired by the work of Evans25

found that transmetallation of lithium phenoxides to their corresponding copper

70

phenoxides led to superior efficiencies in Rh-catalyzed allylic etherifications One can

envision that subsequent ring-closing metathesis of the diene 269 would offer a concise

method for the synthesis of chromenes92 Similarly reaction of the copper alkoxide

derived from ortho-bromo phenol (270) gave the bromoalkene 271 in a highly

regioselective fashion and Heck reaction of 271 could allow access to substituted

benzofurans93 Secondary carbonate 217 was also an effective substrate giving the

isomer 273 albeit in a lower regioselectivity Tertiary carbonates proved to be

recalcitrant etherification substrates and mostly starting material was recovered when

allylic etherification of 251 was attempted with the copper phenoxide derived from 272

under the previously optimized conditions Changing the solvent (DMF CH3CN) andor

temperature (-20-60 ˚C) did not improve the regioselectivities or yields when 217 or 251

were employed as substrates

71

Table 23 Rh(I)-Catalyzed Allylic Etherifications

R2

R1 OCO2Me

R3R4 R2

R1 Nuc

R3R4 R3

R4Nuc

R2R1

+



245 265 266

LiHMDS CuI[Rh(CO)2Cl]2 (10 mol)

THF rt

OH

OH

Br

OH

Ph

+

267

270

272

OCO2Me

268

OCO2Me

268

217

OCO2Me

OH

Ph

272

OCO2Me

251

O

269

O

Br271

O

Ph273

O

Ph274

77 gt955

87 7129

lt10 NA

73 gt955

Nuc

Copper phenoxides functioned as excellent substrates in [Rh(CO)2Cl]2-catalyzed

allylic etherification reactions with primary and secondary carbonates while preliminary

experiments indicated that tertiary carbonates such as 251 react much more sluggishly

Of particular interest was the use of sterically hindered ortho-substituted phenols as

pronucleophiles and incorporation of nascent functionality such as alkenes and aryl

halides allowed for the possibility of further functionalization of the allyl phenyl ether

72

products such as 269 and 271

224 Intramolecular Allylic Alkylations to Synthesize Medium-Sized Lactones

Considering the high level of regioselectivity we observed in the [Rh(CO)2Cl]2-

catalyzed intermolecular alkylations we queried whether the eight-membered ring

lactone 278 could be prepared from β-ketoester 275 (Scheme 29)39 The synthesis of

eight-membered rings continues to be a challenge especially in the field of

intramolecular transition metal catalyzed allylic alkylations20 and we felt that such a

synthetic application of the [Rh(CO)2Cl]2-catalyzed allylic alkylation would be quite

useful Trost has shown that intramolecular palladium-catalyzed allylic alkylation of

substrates containing trans-alkenes gave the corresponding eight-membered rings which

contained cis-alkenes (Eq 13)20 One can rationalize the change in alkene geometry by

noting that palladium catalysis gives a rapidly equibrating Pd π-allyl intermediate which

can ultimately cyclize to give the more stable eight-membered ring containing a cis-

olefin We felt that a cis-alkne such as 275 would be preferred for a [Rh(CO)2Cl]2-

catalyzed intramolecular alkylation because minimal erosion of alkene geometry was

observed in intermolecular [Rh(CO)2Cl]2-catalyzed allylic alkylations Previous

literature precedent showed that palladium-catalyzed cyclization of substrates containing

β-keto ester nucleophiles gave the six-membered products such as 27721 but

considering the high levels of regioselectivity inherent in the [Rh(CO)2Cl]2-catalyzed

intermolecular allylic alkylations eight-membered lactone 278 could be expected from

[Rh(CO)2Cl]2-catalysis While an intramolecular Pd-catalyzed allylic alkylation to

synthesize an eight-membered ring has been reported by Trost a substantially more

73

sterically demanding β-keto sulfone was employed as a tethered nucleophile20

Scheme 29

O

OO

OCO2Me

O

O O

O

OO

catalyst

base

Pd

Rh 275

276

277

278

O

OO

M

The first attempt to synthesize 275 began with THP protection of propargyl

alcohol (279) to give 280 (Scheme 210) Treatment of the lithium acetylide derived

from 280 with ethylene oxide gave the monoprotected diol 281 which was reduced

under standard conditions using Lindlarrsquos catalyst to yield 282 Acylation of the free

alcohol of 282 with diketene allowed access to the desired β-keto ester moiety in 283

Scheme 210

OH OTHP

On-BuLi

HMPA Et2OTHF65

OTHP

HO

H2 Lindlars Cat HOOTHP

OODMAP

O

O O

279

TsOHH2O

O

280 281

282 283

CH2Cl293

EtOAc78

Et2O84 THPO

Removal of the THP-group from 283 followed by conversion of the resulting free

74

alcohol to the corresponding methyl carbonate was now required to obtain cyclization

substrate 275 However standard acidic conditions to remove the THP protecting group

in 283 gave a mixture of the desired alcohol 284 as well as the products of

transesterification 282 and 285 (Scheme 211) While 284 could be isolated in modest

yields (40-50) a more efficient route to 284 was sought which would avoid the

unwanted transesterification reaction

Scheme 211

O

O O

283THPO

conditionsO

O O

284HO

+ HO

282

THPO

HO

285

HO

+

acids PPTS Dowex-50W AcOHsolvents MeOH EtOH THFH2O

Toward this end a silyl ether protecting group was used in lieu of the THP

protecting group and the synthesis of 275 began with the protection of propargyl alcohol

as its tert-butyldimethylsilyl ether 286 (Scheme 212) Ring opening of ethylene oxide

with the lithium acetylide derived from 286 in the presence of BF3Et2O gave the

alcohol 287 in 71 yield Hydrogenation of the alkyne using Lindlarrsquos catalyst afforded

cis-alkene 288 which upon treatment with diketene gave β-ketoester 289 Deprotection

of the silyl ether 289 with TBAF cleanly provided alcohol 290 and subsequent

formation of the carbonate under standard conditions afforded cyclization precursor 275

75

Scheme 212

OH

TBSCl imid

OTBS

On-BuLi

BF3Et2O THF

71OTBS

HO

H2 Lindlars Cat HOOTBS

OO

DMAP

O

O O

OTBS

TBAF THFO

O O

OH

O

O O

OCO2Me

pyr CH2Cl291

279 286 287

288 289

290 275

91

ClCO2Me

DMF99

EtOAc99

Et2O84

Deprotonation of substrate 275 with either NaH or KOtBu followed by treatment

with [Rh(CO)2Cl]2 (10 mol ) gave 278 in moderate to good yields without any six-

membered lactone isomer observed (Table 23)39 To the best of our knowledge this

transformation represents the first synthesis of an eight-membered lactone by

intramolecular transition metal-catalyzed allylic alkylation of a β-ketoester

Optimization revealed that freshly sublimed KOtBu afforded the desired lactone in a

higher yield than when NaH was employed The reaction proved to be more efficient in

DMF and at lower temperatures

76

Table 24 Intramolecular Allylic Alkylation

O

O O

OCO2Me275

O

OO

Conditions

entry base solvent temperature (degC) yield ()

1

2

3

4

5

NaH

NaH

KOtBu

KOtBu

KOtBu

THF

DMF

THF

DMF

DMF

rt

rt

rt

rt

0

20

34

51

54

68

278

[Rh(CO)2Cl]2(10 mol)

In contrast palladium catalysis of the cyclization of the enolate of 275 gave a

mixture (5545) of regioisomers 278 and 277 in moderate yield (Eq 210) Thus it

appears that for the synthesis of medium-sized rings [Rh(CO)2Cl]2ndashcatalysis can provide

superior regioselectivity to that observed with palladium

KOtBu Pd(PPh3)4DIPHOS DMF

O

O O

+O

OO

O

O O

OCO2Me275

278 277

278277 = 5545

55(210)

225 Intramolecular Allylic Alkylations to Synthesize Medium-Sized Carbacycles

We then questioned whether 8-membered carbocycles could also be formed by

77

rhodium-catalyzed cyclizations Toward this goal the synthesis β-ketoester substrate

294 was undertaken (Scheme 213) Conversion of alcohol 288 to bromide 291 was

performed using CBr4 and PPh3 Treatment of bromide 291 with the dianion of methyl

acetoacetate provided β-ketoester 292 Fluoride deprotection followed by carbonate

formation yielded cyclization precursor 294

Scheme 213

HOOTBS

288

CBr4 PPh3

Et3N CH2Cl278

BrOTBS

291

OMe

OO

NaH n-BuLi

MeO

O O

OTBS

TBAF

MeO

O O

OH

pyr CH2Cl283

MeO

O O

OCO2Me

292 293

294

ClCO2Me

THF69

THF63

Reaction of 294 under the previously optimized cyclization conditions using

KOtBu as the base in the presence of [Rh(CO)2Cl]2 (10 mol) at reduced temperature

provided a mixture of carbocycles 295 and 296 where 6-membered ring formation was

the dominant pathway (Eq 211) The increased transannular strain in the 8-membered

carbocycle 295 compared to the 8-membered lactone 278 may account for the poor

regioselectivity observed Alternatively the well known preference of esters to exist in

an s-trans conformation could prevent attack on the internal allylic terminus favoring

78

eight-membered ring formation when 275 was employed as a substrate94

MeO

O O OO

OMe

+

O

OMe

OKOtBu[Rh(CO)2Cl]2

(10 mol)

DMF -20 degC52

294295 296

295296 = 4357

(211)

MeO2CO

While a mixture of regioisomers was obtained in the above case the fact that any

eight-membered product was obtained was noteworthy as Tsuji has reported the Pd-

catalyzed cyclization of allylic ether 251 gave only the six-membered product 250 (Eq

212)21

OPh

CO2Me

O

Pd(OAc)2 PPh3

62

CO2Me

O

297 296

(212)

23 Cascade Reactions Initiated with [Rh(CO)2Cl]2ndashCatalyzed Allylic Alkylation

Reactions

231 Tandem Allylic Alkylation-Ortho-Alkylation

Ellman and coworkers recently developed a Rh(I) catalyzed intramolecular ortho-

alkylation in which allyl phenyl ethers such as 298 can efficiently cyclize to

dihydrobenzofurans such as 299 when heated in the presence of Wilkinsonrsquos catalyst

(Eq 213)84

79

NBn

O

i) Rh(PPh3)3Cl (5 mol) toluene 125 degC

ii) 1 N HCl (aq) 71

O

O

298 299

(213)

Given Ellmanrsquos work we sought to develop a tandem allylic alkylation-ortho-

alkylation reaction in which the benzyl imine of 3-hydroxyacetophenone 2100 serves as

a pronucleophile to generate an allyl phenyl ether 2101 which we expected would

undergo Rh(I)-catalyzed cyclization to give 2102 upon heating (Scheme 214)

Scheme 214

NBn

O

i) [Rh(CO)2Cl]2 ∆

ii) 1 N HCl (aq)

O

O

2101 2102

NBn

OH

2100

[Rh(CO)2Cl]2

OCO2Me

R2

R1

R3 R4

245

R2

R1

R4 R3

R2

R1

R4R3

Before the tandem sequence was attempted each step of the cascade was

evaluated individually The ortho-alkylation of 298 was first examined and replacement

of Wilkinsonrsquos catalyst with [Rh(CO)2Cl]2 for the cyclization of 298 gave the

dihydrobenzofuran 299 in an unoptimized 53 yield (Eq 214) The use of

[Rh(CO)2Cl]2 to catalyze ortho-alkylations was unknown before these experiments and

therefore we were encouraged by this preliminary result

80

NBn

O

298

then HCl53 O

O

299

[Rh(CO)2Cl]2 (10 mol)toluene 125 degC

(214)

To avoid issues of regioselectivity in the optimization of the allylic etherification

of 2103 allyl methyl carbonate 257 was initially explored as the allylic carbonate (Eq

215) Further since we knew that the cyclization of the allyl phenyl ether 298 was

efficient we felt like this would be a good starting point for optimization efforts

Reaction of the sodium phenoxide derived from 2103 with allyl methyl carbonate 257 in

the presence of [Rh(CO)2Cl]2 (10 mol) gave a modest yield of the ether 2104

However transmetalation to the copper phenoxide by adding one equivalent of CuI

substantially increased the yield of the ether 2104 Evans has shown the superiority of

copper alkoxides in Rh(I)-catalyzed allylic etherifications25

O

OH

2103

+ OCO2Me

257

O

O

2104

NaHMDS[Rh(CO)2Cl]2 (10 mol)

THFwithout CuI 33

with CuI 64

(215)

The allylic etherification of the copper phenoxide derived from 2100 was

explored next since Ellman had shown that the imine functionality is essential for the C-

H activation to take place (Eq 216) In the event the imine 298 was obtained in a

moderate yield

81

NBn

OH

2100

+ OCO2Me

257

NBn

O

298

NaHMDS CuI[Rh(CO)2Cl]2 (10 mol)

THF55

(216)

Carrying out the allylic etherification of 2100 and 257 as above and then heating

the reaction to induce the ortho-alkylation did not provide any of the dihydrofuran 299

(Scheme 215) The reaction was attempted in both THF and toluene and in each case

the allylic etherification product 298 was observed by NMR However heating the

reaction to temperatures up to 150 ˚C (sealed tube) only gave the etherification product

298 and extended heating led to slow decomposition of 298 Presumably the leaving

group inhibited the ortho-alkylation of 298 or the catalyst was modified after the allylic

etherification leading to suppression of the subsequent ring-forming C-H activation

Scheme 215

NBn

OH

2100

OCO2Me257

NBn

O

298


THF or toluenert

rt-150 degCX

then HClO

O

299

Considering that each step of the tandem sequence was not high yielding and

repeated attempts to perform the tandem reaction failed to provide any dihydrofuran

product 299 we looked to other Rh(I) cyclization reactions that could be coupled with a

[Rh(CO)2Cl]2-catalyzed allylic substitution reaction for the development of tandem

reaction sequences

82

232 Tandem Allylic Alkylation-Metallo-ene Reaction

Metallo-ene reactions catalyzed by Rh(I) species were first reported and then

developed by Oppolzer and coworkers85 In those reports a number of 16-dienes such as

2105 were cyclized to the corresponding 14-diene cyclopentanes such as 2106 in a

highly efficient fashion with as little as 1 mol of a Rh(I) catalyst Oppolzer screened a

number of Rh(I) catalysts but the use of [Rh(CO)2Cl]2 to catalyze the metallo-ene

reaction of 2105 was not reported

CO2MeMeO2C

MeO2CO

MeO2C CO2Me

2106

2105

CH3CN 80 degC75

[Rh(COD)Cl]2 (1 mol)

(217)

We envisioned that 2105 which is the starting material for a metallo-ene

reaction could be synthesized using a [Rh(CO)2Cl]2-catalyzed allylic alkylation of the

allyl malonate 2107 and the dicarbonate 2108 (Scheme 216) Subsequent heating of the

reaction mixture was expected to provide the metallo-ene product 2106

83

Scheme 216

CO2MeMeO2C+

OCO2Me

OCO2Me2107

2108

CO2MeMeO2C

MeO2CO

[Rh(CO)2Cl]2

[Rh(CO)2Cl]2MeO2C CO2Me

2106

2105

Initial conditions that were examined for the tandem reaction included treatment

of dicarbonate 2118 with the enolate of allyl malonate 2107 in the presence of

[Rh(CO)2Cl]2 (10 mol) in a variety of solvents (Table 24) The screening of solvents

was carried out because researchers have noted a distinct solvent effect in many metallo-

ene reactions85a Each of the reaction conditions gave a mixture of the desired product

2106 as well as the product of dialkylation 2109 In order to minimize the amount of

dialkylation obtained the amount of malonate 2107 was limited to one equivalent and

these conditions most efficiently gave 2106

84

Table 25 Optimization of the Tandem Allylic Alkylation-Metallo-Ene Reaction

CO2MeMeO2C+

OCO2Me

OCO2Me

NaH[Rh(CO)2Cl]2 (10 mol)

solvent rt-reflux

MeO2C CO2Me

equiv 2107

21072108

2106

MeO2CCO2Me

CO2MeMeO2C

+

2109

equiv 2108 equiv NaH solvent yield 2106 () yeild 2109 ()entry

1

2

3

4

5

6

25

25

25

25

15

15

1

1

1

1

1

1

2

2

2

2

1

1

THF

dioxane

toluene

DMF

THF

dioxane

15

23

20

0

20

32

--

24

7

32

17

16

Based on an observation by Dr Ashfeld that allylic acetates generally react more

slowly than allylic carbonates in [Rh(CO)2Cl]2-catalyzed allylic alkylations the tandem

reaction was attempted with the acetatecarbonate 2110 (Eq 218) The hope was that

the carbonate moiety in 2110 would react much faster than the acetate and the

competing pathway of dialkylation would be avoided Unfortunately the acetate 2110

gave very similar results as compared to the dicarbonate 2108

85

CO2MeMeO2C+

OAc

OCO2Me

NaH (1 equiv)[Rh(CO)2Cl]2

(10 mol)

dioxane rt-reflux45

21062109 = 21

MeO2C CO2Me

21072110

2106 MeO2CCO2Me

CO2MeMeO2C

+

2109

15equiv

1equiv

(218)

While the yield was modest a tandem allylic alkylation-metallo-ene reaction was

developed and we showed that [Rh(CO)2Cl]2 was capable of catalyzing metallo-ene

reactions The problem of double allylic alkylation of the dicarbonate starting material

2109 plagued efforts at further optimizing the tandem sequence and efforts were

directed at more efficient tandem reaction sequences

233 Tandem Allylic Alkylation-Pauson Khand Reaction

The [Rh(CO)2Cl]2-catalyzed PKR has recently emerged as a powerful method for

the catalytic synthesis of cyclopentenones6768 The highly regioselective [Rh(CO)2Cl]2-

catalyzed allylic alkylation provides an efficient method for the synthesis of enynes that

might serve as key starting materials for the PKR Sequential catalysis of an allylic

alkylation and PKR with the same [Rh(CO)2Cl]2 catalyst in the same pot would be an

attractive method for the construction of cyclopentenones from simple readily available

starting materials Evansrsquos tandem Rh(I)-catalyzed allylic alkylation-PKR provided an

encouraging precedent81 and we thought that the unique regioselectivity of

[Rh(CO)2Cl]2-catalyzed allylic alkylations would allow access to products unavailable

by Evansrsquos method Evans only studied secondary carbonates 2112 as substrates and as

a result only bicyclopentenones 2113 with substitution at C2 were accessed

86

MeO2C CO2Me+

R

OCO2Me [RhCl(CO)dppp]2O

MeO2C

MeO2C

R

1

23

4

5

67

8

2111 2112

2113

(219)

In contrast to Evansrsquos rhodium-catalyzed allylic alkylation [Rh(CO)2Cl]2

preferentially gives the products of nucleophilic attack on the carbon bearing the leaving

group (Scheme 217) As such linear and branched Pauson-Khand substrates could be

synthesized and cyclized depending on whether 2114 2115 or 2116 were used as

allylic substrates Using [Rh(CO)2Cl]2 catalysis we anticipated that products 2117

2118 and 2119 with substitution on C-2 C-4 or both respectively could be obtained

Scheme 217

+

R

LG

R LG

or

or

[Rh(CO)2Cl]2

OMeO2C

R

4

2115

2114

2119R LG2116

R

R

MeO2C CO2Me

2111

2

MeO2C

OMeO2C

2117

R

2

MeO2C

OMeO2C

R

42118

MeO2C

[Rh(CO)2Cl]2

[Rh(CO)2Cl]2

We chose to use the substituted malonate 2120 and allyl carbonate 257 as

reactants to initiate our study of the tandem allylic alkylationPKR because Koga had

observed that the [Rh(CO)2Cl]2-catalyzed PKR of phenyl acetylenes were more efficient

than those of alkyl substituted or terminal acetylenes (Scheme 218)67 The choice of

allyl methyl carbonate (257) was predicated on the desire avoid regioselectivity issues

87

until the tandem reaction sequence was optimized The allylic alkylation of 257 with the

malonate 2120 gave the enyne 2121 in excellent yield and the PKR of 2121 proceeded

in virtually quantitative yield

Scheme 218

CO2MeMeO2C

Ph

OCO2Me

[Rh(CO)2Cl]2 (10 mol)NaH THF rt

91

PhMeO2C

MeO2C

[Rh(CO)2Cl]2 (10 mol)

THF reflux99

MeO2C

MeO2C

Ph

O

CO (1 atm)

21212120

2122

257

We then turned our attention to the tandem process However simply conducting

the allylic alkylation of 257 with 2120 as above followed by heating the reaction under

reflux in an atmosphere of CO did not provide any PKR product 2122 (Eq 220)

2121

CO2MeMeO2C

PhNaH CO (1 atm)


THF rt - reflux

PhMeO2C

MeO2C

2120

OCO2Me

257

not 2122 (220)

One hypothesis for the inhibition of the Pauson-Khand step was that the leaving

group was binding with the catalyst and shutting down the reaction Such a supposition

seemed reasonable considering that the one difference between the successful PKR of the

isolated enyne 2121 and the attempted PKR following the allylic alkylation of 1120 was

the presence of the leaving group in solution Alternatively the nature of the catalyst

88

could be different following the allylic alkylation leading to suppression of the

subsequent PKR of 2121 In order to determine whether the reaction was affected by the

leaving group the PKR of 2121 was conducted in the presence of NaOMe which has

commonly been invoked as a by product after decarboxylation of the carbonate leaving

group in Rh(I)-catalyzed allylic alkylation reactions (Eq 221)14a The presence of

NaOMe completely inhibited the previously quantitative PKR of 2121 Since allylic

acetates can also function was substrates for [Rh(CO)2Cl]2-catalyzed allylic alkylations

addition of NaOAc to the PKR of 2121 was also explored and this additive also

inhibited the PKR

O

Ph

MeO2C

MeO2C

2122

Ph CO [Rh(CO)2Cl]2 THF reflux

NaOMe or NaOAcX

MeO2C

MeO2C

2121

(221)

A number of research groups have used phosphine ligands95 silver salts96 and

halide additives86 to modify the electronic environment of the metal and often the

rhodium-catalyzed PKR was improved through the use of such additives The addition of

phosphine ligands had no adverse affect on the allylic alkylation of 2120 with 257

typically giving complete allylic alkylation as determined by TLC However none of the

phosphines (PPh3 dppp dppf) that were added either before or after the allylic alkylation

of 2120 facilitated the subsequent PKR (Eq 222) Silver salts such as AgOTf and

AgSbF6 are commonly used to form a ldquocationicrdquo rhodium catalyst that is more

electrophilic As with the phosphines addition of AgOTf or AgSbF6 did not adversely

affect the course of the allylic alkylation of 2120 but no subsequent PKR occurred

89

Lautens and coworkers have noted a halide effect in the rhodium catalyzed ring opening

of oxabicycles and in many cases the addition of TBAI facilitated ring opening reactions

when [Rh(COD)Cl]2 alone failed to promote the reaction86 However the addition of

TBAI before or after the allylic alkylation of 2120 did not lead to PKR product 2122

Interestingly the addition of camphorsulfonic acid (CSA) after the allylic alkylation did

facilitate the PKR and the cyclopentenone 2122 was obtained in 59 yield The

impetus for adding a protic acid was to protonate the methoxide generated from the

leaving group14a and hopefully eliminate the adverse interaction of methoxide with the

rhodium catalyst that was shutting down the reaction Notably the use of benzoic acid

para-nitrobenzoic acid triethylamine hydrochloride HClMeOH and HClTHF did not

promote the PKR

CO2MeMeO2C

Ph

+ OCO2Me

CO NaH[Rh(CO)2Cl]2additive THF

O

Ph

MeO2C

MeO2C

2120

257

2122

additive = phosphines Ag salts TBAI no PKRadditive = CSA 59

or additive after AA step

(222)

The above experiments suggested that interaction of the leaving group with the

catalyst was interfering with the subsequent PKR reaction While the addition of CSA

did allow PKR to take place we hoped to discover a set of conditions that did not require

the addition of reagents halfway through the reaction sequence To test the hypothesis

that the leaving group was adversely interacting with the catalyst the nature of the

leaving group was probed Less basic or more sterically demanding leaving groups were

explored in an attempt to minimize any possible metal-leaving group interaction While

90

allyl acetate allyl tert-butyl carbonate allyl phenyl sulfone did not give any PKR

product allyl trifluoroacetate provided the cyclopentenone 2122 in a 48 yield (Eq

223)

CO2MeMeO2C

Ph

+ LGCO NaH

[Rh(CO)2Cl]2O

Ph

MeO2C

MeO2C2120

2123

2122

LG = -OCO2Me -OCO2tBu -OAc -SO2Ph no PKR

LG = -OCOCF3 48 yield

rt - reflux(223)

The allylic alkylationPKR was explored with a variety of allylic trifluoroacetates

and during the course of these reactions TLC analysis often indicated the presence of the

alcohol from the hydrolyzed trifluoroacetate This species presumably arises from trace

amounts of hydroxide present in the NaH To probe this possibility the sodium salt of

the malonate 2120 formed from NaH and the corresponding malonate was azeotroped

with toluene to remove water before adding to the catalyst and trifluoroacetate 2126 and

the yields of the Pauson-Khand products were significantly improved under this modified

procedure (Scheme 219)82 Good yields were obtained with alkyl aromatic and

hydrogen substituents on the terminus of the alkyne In the case of 2125 when R = Me

higher boiling Bu2O was used as higher temperatures were required for the cyclization

Scheme 219

91

MeO2CCO2Me

OCOCF3 OMeO2C

MeO2C+

R

CO [Rh(CO)2Cl]2

(10 mol )

R

azeotroped wtoluene

2126

2127 R=H = 732122 R=Ph = 682128 R=Me = 67

2124 R = H2120 R = Ph2125 R = Me

THF or Bu2Ort-reflux

In contrast to allyl trifluoroacetate 2126 trifluoroacetates with internal double

bonds such as 2129 failed to undergo the previously optimized allylic alkylation-PKR

tandem sequence Generally the allylic alkylation of 2120 proceeded readily but the

subsequent PKR did not occur The allylic alkylationPKR using the sodium salt of

malonate 2120 and trifluoroacetate 2129 was performed in a variety of solvents (THF

DMF toluene Bu2O) but none of the reactions gave the PKR product 2130 and only

the intermediate enyne was isolated (Scheme 220) The addition of CSA after the allylic

alkylation was not effective in this case nor was increasing the CO pressure to 40 psi

Scheme 220

CO2MeMeO2C

PhCO (1-40 atm)

[Rh(CO)2Cl]2 (10 mol)Base Solvent rt-reflux

Ph

OMeO2C

MeO2C

Et

X

Base NaH KOtBuSolvent THF Bu2O CH3CN DME DCE DMF toluene

2120 2130

OCOCF3

2129

Optimization attempts revealed that the stoichiometry of the allylic alkylation

reaction was exceedingly important (Scheme 221) When an excess of the substituted

malonate nucleophile 2120 was employed in the allylic alkylation reaction as usual then

an excellent yield of the 16-enyne 2131 was obtained To our surprise analogous

92

reaction employing an excess of the allyl trifluoroacetate 2129 led to a precipitous

decline in the isolated yield of the same enyne 2131 based on 2120 being the limiting

reagent

Scheme 221

2120

+OCOCF3

2129

CO NaH [Rh(CO)2Cl]2

(10 mol)THF

MeO2C

MeO2C

2131

MeO2C CO2Me

Ph

2 eq 1 eq

1 eq 2 eq

Ph

Isolated Yield96

24

The above experiments suggested that excess malonate ion was essential to obtain

optimal yields of 2131 Thus the next logical question was whether excess reagents

leftover from the first step of the tandem reaction sequence would have a deleterious

effect on the [Rh(CO)2Cl]2-catalyzed PKR of 16-enynes To test this question two

control experiments were performed to determine whether excess trifluoroacetate 2126

or excess malonate salt derived from 2120 would negatively impact the PKR

[Rh(CO)2Cl]2-catalyzed PKR of the enyne 2121 in the presence of one equivalent of

added allyl trifluoroacetate 2126 had a minimal effect on the efficiency of the cyclization

giving the bicyclopentenone 2122 in 84 yield (Eq 224) However the addition of one

equivalent of the malonate salt 2120 to the PKR of 2121 led to a substantially

diminished yield of 2122 and the reaction required 24 h to reach completion (Eq 225)

93

O

Ph

MeO2C

MeO2C2122

MeO2C

MeO2C

2121

Ph

CO [Rh(CO)2Cl]2

(10 mol) THF reflux+ OCOCF384 6 h

O

Ph

MeO2C

MeO2C

2122

MeO2C

MeO2C

2121

Ph

+51 24 h

2126

(224)

(225)

CO [Rh(CO)2Cl]2

(10 mol) THF reflux

2120

MeO2C CO2Me

Ph

The observation that the sodium salt of the malonate inhibited the PKR suggested

that the substituted malonate 2120 was binding in some way with the catalyst perhaps in

a bidentate fashion similar to well known diketonate Rh(I) complexes97 In fact

Wilkinson has observed that [Rh(CO)2Cl]2 readily forms diketonate 2133 in the

presence of acetylacetone 2132 and a base (Eq 226)97 A similar coordination of the

malonate 2134 with [Rh(CO)2Cl]2 under the reaction conditions would give 2135 (Eq

227) perhaps inhibiting the PKR

[Rh(CO)2Cl]2 +O O

BaCO3O

ORh

CO

CO

[Rh(CO)2Cl]2 +

O

O O

O

Base OMeO

MeOO

RhCO

CO

R R

2132 2133

21342135

(226)

(227)

In order to determine whether sequestration of the catalytically active Rh(I)

species was indeed responsible for the lack of reactivity with respect to substituted

malonates the Meldrumrsquos acid derived nucleophile 2137 was prepared (Scheme 222)

94

Such 13-dicarbonyl compounds are not able to achieve a geometry capable of binding to

transition metals in a bidentate fashion due to their cyclic nature Monoalkylation of

Meldrumrsquos acid is typically problematic in that products of dialkylation are often

obtained As a result a procedure developed by Smith was employed98 and the aldehyde

derived from 2136 was treated with Meldrumrsquos acid in the presence of BH3Me2NH to

give the desired nucleophile 2137 in good yield over two steps However the tandem

allylic alkylationPKR employing 2137 as a nucleophile gave only the allylic alkylation

product 2138 and none of the PKR product 2139 These experiments suggest that

bidentate binding of the nucleophile to the rhodium catalyst is at least not solely

responsible for the inhibition of the PKR step

Scheme 222

O

OO

O

2138

THF rt-reflux

PhOH

1) PCC celite CH2Cl2

2) BH3Me2NH

Meldrums acid MeOH 74 over 2 steps

2136

O O

O O

Ph2137

O

OO

O Ph

O

2139

Ph

not observed

CO NaH [Rh(CO)2Cl]2 (10 mol)

OCOCF3

2129

Despite the above setbacks modest success was achieved when the allylic

alkylation of 2120 with 2129 was performed as previously described (rt THF) and

upon completion the reaction was placed in a microwave reactor and heated to 200 ˚C

95

and 240 psi In the event a 30 yield of the cyclopentenone 2130 was obtained and the

stereochemistry was determined by comparison of the 1H NMR spectral data with the

known PKR product 2140 This reaction highlights the ability of [Rh(CO)2Cl]2 to give

PKR products unavailable by Evansrsquos rhodium catalyst (Scheme 223)

Scheme 223

CO2MeMeO2C

Ph

OCOCF3 Ph

OMeO2C

MeO2C

EtH

21202130

i) CO (1 atm) NaH [Rh(CO)2Cl]2 (10) THF rtii) mwave (200 degC 240 psi) 30

2129

Ph

OEtO2C

EtO2C

MeH

2140

24 Conclusions

The [Rh(CO)2Cl]2-catalyzed allylic alkylations of allylic carbonates and acetates

exhibit a novel regiochemisty wherein nucleophilic substitution occurs preferentially at

the carbon bearing the leaving group Exploration of the regioselectivity showed that

high levels of regiocontrol are present even when the allylic substrate contains sterically

similar allylic termini In addition to malonate and substituted malonate nucleophiles

copper phenoxide and amine nucleophiles can also be employed in allylic substitutions

catalyzed by [Rh(CO)2Cl]2 The first synthesis of an eight-membered lactone by

intramolecular transition metal-catalyzed allylic alkylation of a β-ketoester was reported

providing an useful method for the synthesis of these strained rings

96

Perhaps the most important aspect of the [Rh(CO)2Cl]2-catalyzed allylic

alkylation is that the reaction allows for the regioselective preparation of enyne products

that can undergo subsequent Rh(I)-catalyzed carbocyclizations Toward this end a

tandem allylic alkylationPKR was discovered that may be employed to prepare

bicyclopentenones from substituted malonates and allylic trifluoroacetes While the

tandem rhodium-catalyzed allylic alkylationPKR was previously known81 the novel

regiochemistry of [Rh(CO)2Cl]2 allows access to new substitution patterns in the

cyclopentenone products In addition a tandem allylic alkylationmetallo-ene reaction

was discovered which gives 14-diene cyclopentanes although competitive dialkylation

could not be completely suppressed

97

Chapter 3 The Macroline Alkaloids

31 Introduction

The macroline family is a large class of indole alkaloids comprising more than

100 members99 The alkaloids in the macroline family have been isolated from various

species within the Alstonina Rauwolfia Corynanthe and Strychnos genera and the

interest in these alkaloids originated from extensive use of Alstonia plants in Chinese folk

medicine for the treatment of malaria100 Scientists have since confirmed that many

macroline alkaloids possess marked antiprotozoal activity as well as sedative ganglionic

blocking hypoglycemic antibacterial and anticancer activity101 All of the macroline

alkaloids possess an indole annulated azabicyclo[331] skeleton and alkaloids in the

macroline class are defined as those having the same connectivity as macroline (31)

which lacks a N4-C21 linkage (Figure 31) The macroline alkaloids are biogenetically

related to the sarpagine alkaloids which are defined as those alkaloids having the same

connectivity as sarpagine (32) and notable within this class is presence of an N4-C21

linkage

Figure 31 Macroline and Sarpagine

N

NMe

Me

OH

O

H

H

H

H

macroline (31)

NH

NHO

H

H H

HOH

sarpagine (32)

421

16

4 21

98

311 Alstonerine

Alstonerine (33) is a member of the macroline family of alkaloids and was first

isolated by LeQuesne and Cook in 1969 (Figure 32)102 Indole alkaloids in the macroline

family display an array of biological activities and specifically alstonerine (33) has been

reported to possess cytotoxic activity against two human lung cancer cell lines103 From a

structural perspective 33 contains a number of challenging structural elements including

the indole annulated azabicyclo[331] skeleton and the vinylogous ester moiety in the E-

ring

Figure 32 Alstonerine

N

MeN

Me

O

O

H

H

H

H

33

A BC D

E

32 MacrolineSarpagine Biogenesis

Early studies indicated that macroline and sarpagine alkaloids are biogenetically

related and specifically that macroline alkaloids are biogenetically derived from

sarpagine alkaloids The biosynthesis of the macrolinesarpagine families of alkaloids

begins with the common precursor strictosidine (34) which has been invoked as a

biosynthetic intermediate for all monoterpenoid indole alkaloids (Scheme 31)104 Van

Tamelen has proposed that strictosidine is transformed into 45-dehydrogeissoschizine

(35) by acetal cleavage and condensation of the amine and aldehyde functionalities to

form iminium ion 35105 The iminium ion is intercepted by the pendant enolate to

99

generate the sarpagine skeleton 36 Saponification decarboxylation epimerization and

reduction are thought to finally give 37 the sarpagine core structure

Scheme 31

NH

N

H

H H

HOH

37

NH

NH

34 Strictosidine

O

MeO2C

OGlu

HNH

N

35

OH

MeO2CH

H H

NH

N

H

H H

CHO

CO2Me

36

Lounasmaa and Hanhinen have proposed an alternate sequence of events and

suggest that bond formation between C-5 and C-16 occurs before D-ring formation as

shown below (Scheme 32)106 They argued that the shortest possible distance between

the C-5 and C-16 centers in 35 is about 270 Ǻ which is prohibitively long for bond

formation However in the absence of the D-ring the distance between these two

reactive carbons is only about 150 Ǻ as in 38 They proposed that 39 then undergoes

alkene migration and reductive amination to give 36

100

Scheme 32

NH

NH

34 Strictosidine

O

MeO2C

OGlu

HH N

H

NH

38

OHCHO

MeO2CH

H

NH

NH CHO

H

H H

CHOCO2Me

39

NH

NH CHO

H

H H

CHOCO2Me

310

NH

N

H

H H

CHO

CO2Me

36

Biomemetic syntheses of ajmalene (314) by Van Tamelen105 and N-

methylvellosimine (318) by Martin107 respectively indicated that the presence of the D-

ring does not prevent Mannich cyclization to provide sarpagine alkaloids (Scheme 33)

Van Tamelen generated an iminium ion intermediate 312 by decarbonylation of 311

which cyclized to provide 313 an intermediate in the synthesis of ajmalene (314) In a

similar biomemetic sequence Martin treated the amino nitrile 315 with Lewis acid to

produce the iminium ion 316 which was intercepted by the tethered silyl enol ether to

give 317 and after base-mediated epimerization N-methylvelosimine (318) These

biomemetic syntheses strongly supported the biosynthetic proposal set forth by Van

Tamelen

101

Scheme 33

NH

N

311

OHC

H

CO2H

NH

N

312

OHC

H

DCC PTSA

dioxane

NH

N

H

H H

313

CHO

NMe

N

H H

ajmaline (314)

OHHO

H

H

NMe

N

CN

315

H

TBSO

BF3Et2O

NMe

N

316

H

TBSO

NMe

N

H

H H

317

HCHO

NMe

N

H

H H

N-methylvellosimine (318)

HCHO

KOHMeOH

56

In a series of biomemetic transformations Le Quesne provided support for the

proposition that the macoline alkaloids are biogenetically derived from the sarpagine

alkaoids Le Quesne showed that following protection of 37 as the corresponding silyl

ether 319 multi-step oxidation to 320 and subsequent retro-Michael reaction to

provided macroline 31 (Scheme 34)108 Based on model studies he proposed that

102

macroline (31) then undergoes conversion to the αβ-epoxide internal displacement and

dehydration to yield alstonerine (33)109 Le Quesne thus provided support for the

assertion that the macroline and sarpagine alkaloids are biogenetically related namely

that the macroline alkaloids such as 31 and 33 are biogenetically derived from the

sarpagine alkaloids 37

Scheme 34

N

MeN

Me

OH

O

H

H

H

H

31

N

MeN

Me

O

O

H

H

H

H

33

NH

N

H

H H

HOH

37

NH

N

H

H H

HOTBS

319

TBS-Cl imid

DMF

NH

N

H

H H

HOTBS

320

Oi) Me2SO4 K2CO3

ii) TBAF

33 Cookrsquos Stratagies to Synthesize MacrolineSarpagine Alkaloids

The field of macrolinesarpagine total synthesis has been dominated by Cook and

coworkers110 and their synthetic approach to this entire class of indole alkaloid natural

products centers on a common tetracyclic ketone intermediate 323 (Scheme 35)111 As

described below Cookrsquos strategies toward a number of macrolinesarpagine alkaloids

103

rely on late stage installation of the final E-ring using the ketone moiety in the ABCD-

ring precursor 323 as a functional handle Cookrsquos ability to rapidly assemble 323 in

high enantiomeric purity is an advantage to many of his syntheses However often long

synthetic sequences are required to transform the ketone in 323 to the functionalized E-

ring found in macroline alkaloids such as alstonerine (33) talcarpine (321) and

norsuaveoline (322)

Scheme 35

H

NMe

BnN

O

Dieckmann

Pictet-SpenglerH

323

NH

NH2

CO2H

324

NMe

MeN

OH

H

H

H

alstonerine (33)

O

NMe

MeN

talcarpine (321)

H

H

H

H

OMe

CHO

NH

HN

H

H

N

Et

norsuaveoline (322)

331 Cookrsquos Tetracycylic Ketone 323

Cookrsquos synthesis of the key ABCD-ring intermediate 323 commences with

straightforward N1-methylation and esterification of unnatural D-tryptophan (324) to

provide 325 (Scheme 36) Reductive amination to protect the primary amino group of

325 was somewhat sensitive After stirring 325 with benzaldehyde for two h at room

temperature until imine formation was complete sodium borohydride was added at -5 ˚C

104

and the reaction was stirred for an additional three h Longer reaction times or higher

reaction temperatures resulted in erosion of the ee of 326 under the basic conditions

Pictet-Spengler condensation of 326 with 2-oxopentanedioic acid provided an epimeric

mixture at C3 which in the presence of acidic methanol underwent Fischer esterification

and acid-catalyzed equilibration to the thermodynamically more stable diastereomer 327

Treatment of 327 with sodium methoxide allowed base-induced epimerization to occur

at C5 followed by Dieckmann condensation to provide exclusively the cis-tetracycle

328 The trans isomer 327 is not able attain a conformation suitable for Dieckmann

condensation thus accounting for the complete selectivity The somewhat convoluted

series of equibrations and epimerizations is why Cook started with the unnatural D-

tryptophan (324) The incorrect initial configuration at C5 sets the correct C3

configuration that in turn induces the eventual epimerization at C5 to the correct

stereochemistry Finally decarboxylation of 328 under acidic conditions provided the

key tetracycle 323 in seven steps from D-tryptophan (324) in a 47 overall yield

105

Scheme 36

NH

NH2

CO2H

324

1) NaNH3 MeI

2) HCl MeOH80 (2 steps) N

Me

NH2

CO2Me

325

PhCHO MeOH

NaBH4 -5 degC88 N

Me

NHBn

CO2Me

326

1) C6H6dioxane ∆

HO2C

O

CO2H

2) HClMeOH ∆

80NMe

NBn

CO2Me

CO2Me

327

NaH MeOH

PhMe ∆

92

NMe

BnN

328

O

CO2Me

H

H

AcOHHClH2O

∆ 91NMe

BnN

323

OH

H

3

5

The acid-catalyzed isomerization of the mixture of cis-327 and trans-327 to

provide exclusively trans-327 following Pictet-Spengler cyclization is thought to

proceed through an aryl stabilized cation as shown in Scheme 37 The C3-N4 bond is

protonated to form an equilibrating pair of stabilized cations 329 and 330 The more

thermodynamically stable trans isomer 330 then undergoes C-N bond reformation to

exclusively provide trans-327

106

Scheme 37

N NNMe

H

CO2Me

CO2Me

MeNPh

H

CO2Me

CO2Me

Ph

HNNMe

H

CO2Me

CO2MePh

HNNMe

H

CO2Me

Ph

CO2Me

NMe

NBn

CO2Me

CO2Me

trans-327

cis-327

329 330

HCl

trans-327

332 Cookrsquos Streamlined Synthesis of 323

Cook later significantly streamlined the synthesis of the tetracyclic intermediate

323 by combining a number of steps in one-pot sequences (Scheme 38)112 Starting

with commercially available D-tryptophan methyl ester (324) reductive amination was

again accomplished using benzaldehyde and sodium borohydride at 5˚C followed by

neutralization with TFA The solvent was removed and CH2Cl2 TFA and 44-

dimethoxybutyric acid methyl ester were added leading to 331 Methylation of the

indole nitrogen of 331 was carried out with sodium hydride and methyl iodide to give

107

327 Treatment of 327 with sodium methoxide and quenching with glacial acetic acid

led to epimerization and Dieckmann condensation at which point glacial acetic acid

HCl and water were added to facilitate decarboxylation to access 323 In such a

fashion the previous seven step synthesis was executed in five steps using only three

reaction vessels

Scheme 38

tolueneNaHCH3OHreflux72hHOAcHClH2Oreflux10h

NH

NH2

CO2Me

324

PhCHOCH3OHrt2 hNaBH4-5 degC TFA (24 eq)(CH3O)2CHCH2CH2CO2Me

CH2Cl2 rt 48h

83 NH

NBn

CO2Me

CO2Me

331

NMe

N

323 gt98 ee

OH

H Ph85NMe

NBn

CO2Me

CO2Me

327

NaH MeI

DMF95

333 Cookrsquos Synthesis of the N1-Desmethyl Tetracyclic Ketone

Since many macrolinesarpagine alkaloids lack a methyl group on the indole

nitrogen Cook also prepared the tetracyclic ketone lacking an indole N-methyl group

338113 However the synthesis was not a straightforward application of the chemistry

developed for the N-methyl tetracyclic ketone 323 since lactam 334 formed in good

yield (Scheme 39) When N-benzyl-D-tryptophan methyl ester 332 was treated with α-

ketoglutaric acid (333) under Dean-Stark conditions a mixture (41) of diastereomeric

lactams 326 and 327 was obtained Attempts to induce the acid catalyzed

108

transformation of 335 to 334 were not productive presumably due to the destabilization

of the α-aryl cation intermediate by the lactam Lactam formation could be avoided by

utilizing 44-dimethoxybutyrate (336) which in the presence of TFA gave the Pictet-

Spengler product 331 at room temperature with complete trans selectivity The authors

hypothesize that the trans product 331 was both the kinetically and thermodynamically

preferred product and that any cis-product formed in the reaction was equilibrated to the

preferred trans-product 331 under the acidic conditions They noted that the nature of

the acid used was also critical in that formation of a mixture of lactams 334 and 335

was observed in the Pictet-Spengler reaction of 332 with 336 if pTsOH was employed

as the acid source

Scheme 39

NH

NHBn

CO2Me

332

TFA CH2Cl2 92

MeO CO2Me

OMe 336

NH

NBn

CO2Me

CO2Me

331

HO2C CO2H

O 333

PhHdioxane

pTsOH ∆ 86N

NBn

CO2Me

334 O

+

N

NBn

CO2Me

335 O

41 transcis

109

With the trans-β-carboline 331 in hand Dieckmann cyclization initially formed

the lactam 334 which was converted to the tetracyclic product 337 with extended

reaction time (Scheme 310) Decarboxylation of 337 provided the desired tetracyclic

ketone 338

Scheme 310

NH

NBn

CO2Me

CO2Me

331

N

NBn

CO2Me

334 O

NaOMe

NH

BnN

337

O

CO2Me

H

H NH

BnN

338

OH

H

AcOHHClH2O

∆ 91

334 Synthesis of Talpinine and Talcarpine

Cookrsquos methodology for the synthesis of 323 by Pictet-Spengler chemistry was

applied in the syntheses of the maroline alkaloid talcarpine (321) as well as talpinine

(357) Cookrsquos strategy for the synthesis of the macroline alkaloid talcarpine 321 relied

on a conjugate addition to an αβ-unsaturated aldehyde which arose from acid-mediated

cleavage of the acetal 339 (Scheme 311) The acetal 339 was derived from oxidative

cleavage of 340 which in turn was assembled via a clever oxy-Cope rearrangement

Nucleophilic addition to the αβ-unsaturated aldehyde 341 gave rise to the oxy-Cope

110

substrate and ultimately 340 Cook relied on epoxide rearrangement to obtain 341 from

his tetracyclic intermediate 323

Scheme 311

H

NMe

BnN

O

H

323

NMe

MeN

321

H

H

H

H

OMe

CHO

NMe

BnN

339

H

H

H

H

OOMe

conjugate addn

NMe

BnN

340

H

H

H

H Et

NMe

BnN

341

H

H

CHO

HO R

epoxide rearrangement

acetal formation

oxy-cope

Cook began the synthesis of both talpinine (321) and talcarpine (357) from the

key tetracyclic ketone 323 (Scheme 312)114 Thus 323 was treated with the anion

derived from chloromethanesulfonylbenzene to provide an intermediate epoxide which

underwent rearrangement after treatment with LiClO4 to give the unsaturated aldehyde

341 It was hoped that the unsaturated aldehyde 341 would serve as an electrophile in a

conjugate addition with an organometallic reagent derived from 342 However when the

Grignard reagent derived from the allylic bromide 342 was added to the aldehyde 341 a

mixture (503812) of 12- and 14-addition products 343 344 and 345 was obtained

111

Scheme 312

NMe

BnN

323

OH

H

1) LDA THF ClCH2S(O)Ph then KOH

2) LiClO4 dioxane

∆ 90 NMe

BnN

341

H

H

CHO

Et Et

Br 342

Mg 90

NMe

BnN

343

H

H

HO

Et

Et

+

NMe

BnN

344

H

H

Et

O Et

H

H

NMe

BnN

345

H

H

Et

O Et

H

H+

Cook cleverly solved the problem of the lack of regioselectivity in the conjugate

addition of the Grignard reagent to 341 by performing an oxy-Cope rearrangement on

the unwanted 12-addition product 343 to give 344 and 345 in a 32 ratio (Scheme

313)115116

Scheme 313

NMe

BnN

343

H

H

HO

Et

Et

NMe

BnN

344

H

H

Et

O Et

H

H

NMe

BnN

345

H

H

Et

O Et

H

H+

KH18-crown-6

cumene150 degC 88

Even though Cook could ultimately obtain the products 344 and 345 via the oxy-

Cope rearrangement of 343 only 344 contained the proper stereochemistry to access

talcarpine (321) To overcome this deficiency in the above 12-addition-oxy-Cope

rearrangement strategy Cook examined a slightly altered route Thus treatment of the

112

tetracyclic ketone 341 with the organobarium nucleophile derived from 346 gave

exclusively the 12-addition product 347 (Scheme 314) Oxy-Cope reaction in this case

afforded complete control of the configurations at C15 and C20 and a mixture (14) of

the C16-epimeric aldehydes 348 and 349 was obtained Base mediated epimerization of

348 provided exclusively 349 the presumed thermodynamic product Alternatively the

authors hypothesized that the kinetic product 348 could be obtained by low temperature

quenching of the oxy-Cope rearrangement by protonation of the resulting aldehyde

enolate on the less hindered face In fact quenching the oxy-Cope rearrangement of 347

with 1 N TFA at -100 ˚C gave a mixture (431) of 348 to 349 Thus by judicious choice

of reaction conditions either epimer 348 or 349 could be obtained in high purity

Scheme 314

NMe

BnN

341

H

H

CHO

NMe

BnN

347

H

H

HO

Et

Li-biphenylBaI2 THF

Et Br

346

90

NMe

BnN

348

H

H

Et

OH

H

NMe

BnN

349

H

H

Et

OH

H+

KH18-crown-6

dioxane100 degC 85

MeOK

15 20

1615 20

16

Reduction of the aldehyde in 349 was followed by a two-step oxidative cleavage

sequence to give 350 which was treated with acid to provide the enol ether 351 N-

113

(Phenylseleno)phthalimide in acidic methanol was then used to introduce a selenium and

methoxy group to 353 and oxidation followed by elimination gave a mixture (41) of

alkene isomers 339 and 354

Scheme 315

NMe

BnN

349

H

H

Et

OH

H

NaBH4 MeOH

96NMe

BnN

350

H

H

Et

HOH

H

1) OsO4 THF py then NaHSO3

2) NaIO4 MeOH 78

NMe

BnN

351

H

H

H

H

OOH

Et

pTsOH PhH

95

NMe

BnN

352

H

H

H

H

O

Et

N

O

O

SePh

pTsOH MeOH

NMe

BnN

353

H

H

H

H

O

EtSePh

OMe

NaIO4

H2OTHFMeOH90

NMe

BnN

339

H

H

H

H

OOMe

NMe

BnN

354

H

H

H

H

OOMe

+

Treatment of the Z-alkene isomer 339 with H2SO4 promoted acetal cleavage

which allowed bond rotation and subsequent 14-addition to provide a mixture of epimers

355 and 356 (Scheme 316) Interconversion of the isomers 355 and 356 could be

114

accomplished under basic conditions to access 356 from 355 thereby exploiting the

thermodynamic preference for 355 The thermal conversion of 356 to 355 also

proceeds in good yield however the mechanism for the transformation is not completely

understood117

Scheme 316

NMe

BnN

339

H

H

H

H

OOMe

90NMe

BnN

355

H

H

H

H

OMe

CHO

NMe

BnN

356

H

H

H

H

OMe

CHO+

K2CO3 EtOH 85

01 torr 100 degC 75

H2SO4

The ability to interconvert the two epimers 355 and 356 was particularly useful

in that each could be converted in only one synthetic transformation to either talpinine

(357) or talcarpine (321) respectively (Scheme 317) Talpinine (357) was obtained

simply by hydrogenolysis of 355 followed by cyclization to form the final hemiaminal

ring Alternatively treatment of 356 with PdC in the presence of H2 and MeOH gave

talcarpine (321) presumably via in situ formaldehyde generation

115

Scheme 317

NMe

BnN

355

H

H

H

H

OMe

CHO

NMe

BnN

356

H

H

H

H

OMe

CHO

PdC (10 mol)

H2 EtOH92

NMe

MeN

talcarpine (321)

H

H

H

H

OMe

CHO

H2PdC (xs)

MeOH (15 eq)

90

NMe

N

talpinine (357)

H

OMe

H

HO H

H

Cookrsquos synthesis of talpinine (357) and talcarpine (321) highlight the challenges

inherent in the stereocontrolled syntheses of macroline alkaloids While Cook could

access the ABCD-ring ketone intermediate 323 in five steps he required twelve

additional synthetic steps to assemble the final E-ring in either talpinine (357) or

talcarpine (321) Cook twice resorted to the equilibration of reaction mixtures to obtain

stereochemically pure material detracting from the attractiveness of the overall

syntheses

335 Synthesis of Norsuaveoline

The chemistry developed in the talcarpine (321) synthesis also proved useful for

the preparation of the pyridyl macroline alkaloid norsuaveoline (322)118 specifically the

oxy-Cope rearrangement strategy to obtain 349 (Scheme 314) Starting with the N1-

desmethyl tetracyclic ketone 338 Cook prepared 358 by following the same sequence

of reactions described in Scheme 314 for the synthesis of talcarpine (Scheme 318)

116

From 358 acetal formation and oxidative cleavage gave 359 which was converted to

360 under acidic conditions Treatment of the dialdehyde 360 with hydroxylamine

afforded the pyridine ring in 361 which underwent debenzylation to give norsuaveoline

(322)

Scheme 318

NH

BnN

358

H

H

Et

OH

H

NH

BnN

338

H

H

O

NH

BnN

359

H

H

Et

CHOH

H

O O

pTsOHacetone

95NH

BnN

360

H

H

CHO

Et

CHOH

H

NH2OHHCl

EtOH ∆

88NH

RN

H

H

N

Et

361 R = Bn322 R = H

H2 PdC92

1) HO(CH2)2OH pTsOH

PhH ∆ 90

2) OsO4 pyr then NaHSO33) NaIO4 MeOH 80 (2 steps)

The methodology developed for the syntheses of talcarpine (321) and talpinine

(357) served Cook well in his efficient synthesis of norsuaveoline (322) Specifically

the 12-addition of a organobarium reagent followed by oxy-Cope rearrangement allowed

rapid access to a dialdehyde precursor 360 from which the pyridine ring in 322 could

quickly be built Unfortunately the sterocontrol offered by the 12-additionoxy-Cope

117

sequence was superfluous considering that pyridine ring formation from 360 results in

the loss of three stereocenters

336 Cookrsquos Synthesis of Vellosimine

Although vellosimine (365) is considered a sarpagine alkaloid Cookrsquos synthesis

of vellosimine (365) is also important in the realm of macroline alkaloids because he

later employed 365 as a starting material in a number of biomemetic syntheses of

macroline alkaloids119 Starting with the tetracyclic ketone 338 Cook accomplished a

rapid synthesis of vellosimine (365) using a key intramolecular palladium-catalyzed

coupling reaction of a ketone enolate with a vinyl iodide (Scheme 319) Deprotection

and alkylation of the bridging nitrogen of 338 gave 363 via the secondary amine 362

From 363 the intramolecular palladium coupling of the ketone enolate and the vinyl

iodide gave the vellosimine skeleton 364 in good yield From 364 Wittig reaction

cleavage of the enol ether and epimerization of the resulting aldehyde gave the sarpagine

alkaloid vellosimine (365)

118

Scheme 319

NH

BnN

338

OH

H

5 PdC H2HCl EtOH

rt 5 H94 N

H

NH

362

OH

H

BrI

K2CO3 THF ∆

87

NH

N

363

OH

HI

Pd(OAc)2 PPh3Bu4NBr K2CO3

DMF-H2O 65 degC80

NH

N

H

H H

364

O

NH

N

H

H H

vellosimine (365)

HCHO

KOtBu MeOCH2PPh3ClPhH rt 24 h

2 N HCl(aq) 55 degC 6 h73

The intramolecular palladium-catalyzed enolate coupling from 363 offered

efficient access to the sarpagine core structure and ultimately vellosimine (365) Cook

later employed 365 in a biomemetic synthesis of alstonerine (33) as well as other

macroline alkaloids

34 Other Approaches to the Tetracyclic Core of Macroline Alkaloids

All of Cookrsquos syntheses of the macroline and sarpagine alkaloids relied on the

tetracyclic ketones 323 or 338 and used Pictet-Spengler chemistry to install the

tetracyclic core common to all of the macroline and sarpagine alkaloids However a

number of other sometimes vastly different synthetic strategies have been reported to

assemble the tetracyclic core of common to all macroline and sarpagine alkaloids

119

Notable examples of unique methods for the synthesis of the macrolinesarpagine

tetracyclic core are presented below

341 Martinrsquos Biomimetic Synthesis of N-methyl-vellosimine

Martinrsquos synthesis of N-methylvellosimine (366) significantly differed from

Cookrsquos synthesis of vellosimine (365) (Scheme 320)107 While Cook exploited Pictet-

Spengler chemistry followed by Dieckmann cyclization to build the ABCD-framework of

365 Martin started his synthesis of 366 with an easily available ABC-ring containing

intermediate 368 Starting with 368 allowed Martin to exploit a key vinylogous

Mannich reaction as well as an intramolecular Mannich cyclization to ultimately give

366 in a manner similar to the biosynthesis of 366 proposed by van Tamelen (Scheme

31)105

Scheme 320

NMe

N

CN

367

H

NMe

N

H

H H


HCHO

Mannich reaction

NH

NHCl

CO2H

368OTBS

vinylogous Mannich

Martin started with a vinylogous Mannich reaction of 369 with the dihydro-β-

carboline 368 to access 370 after ester formation (Scheme 321)120 Treatment of the

secondary amine 370 with diketene resulted in N-acylation followed by Michael

cyclization to produce the tetracyclic lactam 371 From 371 ketone reduction and

subsequent elimination gave the αβ-unsaturated amide 372 as one geometric isomer

120

Methylation of the indole nucleus of 372 and amide reduction gave ester 373 which

was treated with acid to selectively cleave the tert-butyl ester to give the carboxylic acid

374

Scheme 321

NH

NHCl

CO2H

368

OMe

TBSO 369

1)

2) Me2C=CH2 H2SO4 59 N

H

NH

CO2tBu

370

CO2Mediketene

DMAP PhMe

KOtBu 86

NH

N

CO2tBu

371

H

OO

MeO2C

1) NaBH4 95

2) NaOMe MeOH then AcCl 89 N

H

N

CO2tBu

372

H

O

MeO2C

1) NaH MeI2) Me3OBF4 26-tBu2py

then NaBH490

NMe

N

CO2tBu

373

H

MeO2C

TFA

PhSMe90

NMe

N

CO2H

374

H

MeO2C

The carboxylic acid of 374 was converted in two steps to the nitrile 375 which

would serve as an iminium ion precursor (Scheme 322) At this point the methyl ester

of 375was converted in two steps to the aldehyde 376 Reaction of 376 with NaH and

TBS-Cl provided the silyl enol ether 367 which was converted to a mixture of epimers

378 upon treatment with BF3Et2O and cyclization with the tethered silyl enol ether

121

Equilibration of 378 under basic conditions gave the natural product N-methyl-

vellosimine (366) as a single isomer

Scheme 322

NMe

N

CO2H

374

H

MeO2C

1) EDCI NH4OH 86

2) TFAA py 90NMe

N

CN

375

H

MeO2C

1) LiBH4 THF 98

2) DMP 83

NMe

N

CN

376

H

OHC

NaH TBS-Cl

NMe

N

CN

367

H

TBSO

BF3Et2O

NMe

N

377

H

TBSO

NMe

N

H

H H

378

HCHO

NMe

N

H

H H


HCHO

KOHMeOH

56

Martinrsquos elegant synthesis provided significant support to the van Tamelen

biosynthetic proposal that the sarpagine skeleton arose from a nucleophilic attack of an

enolate on an iminium ion105 and consequently refuted the proposal of Lounasmaa and

Hanhinen that the final cyclization could not take place with an intact D-ring106 The

intramolecular Mannich approach represented a fundamentally unique method for

assembling the tetracyclic core of the sarpagine alkaloids

122

342 Martinrsquos Ring-Closing Metathesis Approach

One of the most rapid routes to a tetracyclic intermediate was disclosed by Martin

wherein ring-closing enyne metathesis of an ABC-ring substrate 381 was used as a key

bond disconnection (Scheme 323)121 Before Martinrsquos work the synthesis of azabridged

bicyclic structures by ring-closing metathesis (RCM) was unknown and he showed that

the methodology could be useful for the synthesis of a number of natural product

scaffolds Synthesis of the ABC-ring RCM substrate 381 started with treatment of the

readily available dihydro-β-carboline 368 with basic MeOH in the presence of Cbz-Cl to

provide 379 Treatment of 379 with BF3Et2O in the presence of allyl-TMS afforded

380 which was converted to 381 in a one-pot procedure

Scheme 323

NH

NHCl

CO2H

i)Et3N CbzCl

CH2Cl2

ii) MeOH Et3N87 N

H

NCbz

CO2Me

OMe

TMS

BF3Et2O

CH2Cl281

51 cistrans

NH

NCbz

CO2MeDIBAL-H

toluene -78 degC

then MeOH NaOMe(MeO)2P(O)C(=N2)COMe

60NH

NCbz

368 379

380 381

Treatment of the enyne 381 with catalytic Grubbs I catalyst 382 afforded the

diene 383 (Scheme 324) Using a two-step procedure the monosubstituted alkene of

383 could be selectively oxidized to give 384 which is a differentially protected form of

123

the αβ-unsaturated aldehyde reported by Cook in the syntheses of a number of macroline

and sarpagine alkaoids

Scheme 324

NH

NCbz

381

RuPh

Cy3P

PCy3Cl

Cl

CH2Cl2 rt97

NH

CbzN

383

1) AD-mix-α aq t-BuOH

2) NaIO4 aq THF 54

NH

CbzN

384

CHO

382

H

H H

H

Martin utilized ring-closing enyne metathesis to rapidly access the tetracyclic core

of the macroline alkaloids in only four steps The efficient and stereoselective approach

developed by Martin represents one of the quickest ways to assemble the tetracyclic

framework of the macroline alkaloids The RCM approach commences with the natural

L-tryptophan constituting a useful alternative to Cookrsquos Pictet-Spengler methodology

which begins with the more expensive D-tryptophan

343 Kuethersquos Aza-Diels-AlderHeck Approach

Instead of building the tetracyclic core of the macroline alkaloids by sequentially

forming the C-and D-rings from an AB-ring indole substrate Keuthe and coworkers

devised a concise route to the tetracyclic core of the macroline alkaloids utilizing a Heck

reaction of a 2-iodoindole with an alkene to assemble the C-ring in the tetracyclic core

structure 390 from an ABD-ring containing substrate 389 (Scheme 325)122 The indole

385 was iodinated to give 386 and the alcohol moiety was oxidized to the aldehyde to

provide 387 Aza-Diels-Alder reaction utilizing Danishefskyrsquos diene 388 in the

presence of benzylamine allowed formation of the D-ring to give 389 Finally a Heck

124

reaction of 389 using stoichiometric palladium yielded the tetracyclic core 390 common

to the macroline alkaloids Catalytic amounts of palladium did not drive the reaction to

completion presumably due to the lack of a properly disposed β-hydrogen for

elimination Keuthersquos approach represents a unique approach to the macroline core in

that the D-ring is formed before the C-ring However drawbacks to this strategy include

the required use of stoichiometric palladium for the key step and the lack of

enantiocontrol

Scheme 325

NMe

OH1) BuLi

2) I2 NMe

OH

I DMP

57 (3 steps) NMe

CHO

I

TMSO

OMe

388

385 386 387

Zn(OTf)2 BnNH270 N

Me

I

389

N

O

Bn

Pd2Cl2(CH3CN)2 (1 eq)

P(tBu)3 CH3CN ∆

85NMe

N

390

H

H Ph

O

344 Baileyrsquos Strategy and Synthesis of (-)-Raumacline and (-)-Suaveoline

Baileyrsquos route to (-)-raumacline (399)123 and (-)-suaveoline (3104)124 employed a

cis-selective Pictet-Spengler reaction that had been developed in his group rather than

the trans-selective Pictet-Spengler utilized by Cook Baileyrsquos efforts began with natural

L-tryptophan (324) which was reduced with LiAlH4 and the resultant amino-alcohol

was tosylated to provide 391 (Scheme 326) Displacement of the tosylate of 391 with

cyanide ion and reductive removal of the N-tosyl group gave the amino-nitrile 392

125

Pictet-Spengler reaction of 392 with the aldehyde 393 was completely cis-selective

giving 394 as the sole product Interestingly when L-tryptophan methyl ester was

employed in the Pictet-Spengler reaction with 393 only 31 cis-selectivity was observed

Detailed studies of Pictet-Spengler reactions of tryptamines with various aldehydes have

shown that subtle changes in the structure of the aldehyde and tryptamine can have

dramatic effects on the cistrans selectivity125 In a general sense kinetic experimental

conditions typically favor cis products and thermodynamic conditions favor trans

products Straightforward elaboration of 394 gave the benzyl protected cyano-aldehyde

395 which underwent Horner-Wadsworth-Emmons reaction with 396 to provide a

mixture (53) of EZ isomers 397 Cyclization of 397 via intramolecular Michael

reaction assembled the tetracyclic structure 398 which was elaborated to the natural

product raumacline (399) in four additional steps

126

Scheme 326

NH

NH2

CO2H

324

1) LAH 98

2) TsCl py 78 NH

NHTs

391

OTs

1) KCN 86

2) NaNH3(l) THF 88

NH

NH2

392

CN

OHCOTBS

393

3Aring sieves rt 24 h

then CH2Cl2 TFA80

NH

394

NH

CN

OTBS1) BnBr 752) MeI NaH 87

3) TBAF 964) Swern 100

NMe

395

NBn

CN

CHO

NMe

397

NBn

CN

(EtO)2PO

Et

O

OEt

396

NaH 65

Et

CO2Et

LiNEt2 THF

-78 degC 99 NMe

N

398

H

H Ph

CO2EtCN

Et

HH

NMe

NH

399

H

H

OHO

Et

H

H

1) LiBH42) pTSA 88

3) DIBAL-H 504) H2Pd-C 100

The cyano-aldehyde 395 was also used to prepare (-)-suaveoline (3104) (Scheme

327) Horner-Wadsworth-Emmons reaction of 395 with a slightly different

phosphonate 3100 gave 3102 which served as a substrate for an intramolecular Michael

reaction to generate the tetracyclic core 3103 Four additional steps gave (-)-suaveoline

(3104)

127

Scheme 327

NMe

395

NBn

CN

CHO

(EtO)2PO

Et

CN

3100

NaH 83 NMe

3102

NBn

CN

Et

CN

KOtBu THF

67

NMe

N

3103

H

H Ph

CNCN

Et

HH

NMe

NH

H

H

N

Et

3104

1) DIBAL-H2) NH2OHHCl EtOH 53

3) HCl EtOH4) H2Pd-C 66

The cis-selective Pictet-Spengler reaction to give 394 developed by the Bailey

group provided a nice complement to the trans-selective Pictet-Spengler reaction

employed by Cook Baileyrsquos synthetic approaches to raumacline (399) and suaveoline

(3104) are similar to Cookrsquos syntheses of related macroline alkaloids in that Bailey

sequentially assembles the C- D- and E-rings from a tryptophan starting material

However since Bailey tetracyclic intermediates 398 and 3103 are significantly more

functionalized than Cookrsquos tetracyclic ketone 323 Bailey could assemble the final E-

ring much more rapidly Unfortunately in order to install the functionality necessary for

E-ring synthesis the syntheses of the two ABCD-ring intermediates 398 and 3103 each

required eleven steps

345 Ohbarsquos Synthesis of (-)-Suaveoline

Obharsquos synthesis of (-)-suaveoline (3104) showcases an oxazole-olefin Diels-

Alder reaction to form pyridines (Scheme 328)126 Notably Ohbarsquos strategy to

synthesize the tetracyclic core employs a diastereoselective reduction to set the cis-

128

stereochemistry of the β-carboline intermediate 3109 whereas most other approaches

utilize Pictet-Spengler strategies Boc-Protected L-tryptophan methyl ester 3105

underwent oxazole formation without erosion of ee and the Boc-group of 3106 was

removed in order to introduce the N-acyl moiety in 3107 Bischler-Napieralski reaction

of 3107 required six days in neat POCl3 and provided the cyclized product 3108 in

modest yield after neutralization Stereoselective hydrogenation 3108 gave the desired

cis-isomer and Boc-protection gave 3109 With the tricyclic intermediate 3109 in hand

two additional steps introduced the olefin required for the subsequent oxazole-olefin

Diels-Alder reaction Straightforward functional group manipulation gave (-)-suaveoline

(3104) in two additional steps

129

Scheme 328

NH

NHBoc

CO2Me

3105

MeNC nBuLi

82NH

NHBoc

3106

O

N

1) TFA 98

2) EtO2CCH2CO2H (EtO)2P(O)CN Et3N DMF 88

NH

NH

3107

O

N

EtO2C

O 1) POCl3

2) Na2CO3 50

NH

3108

NH

CO2Et

O

N

1) H2Pd(OH)2-C 84

2) Boc2O 87

NH

3109

NBoc

CO2Et

O

N

NMe

NH

H

H

N

Et

3104

1) DIBAL-H 952) Ph3P(CH2)2Br tBuOK 73

3) xylene DBN ∆ 69

4) MeI NaH

5) TFA 80

Ohbarsquos synthesis of 3104 was notable for the stereoselective reduction of 3108

to set the C5-stereochemistry rather than Pictet-Spengler reaction Also Ohba was the

first to build the ABCDE-macroline framework in one step from an ABC-ring precursor

346 Rassatrsquos Fischer Indole Synthesis

Another method to access the macroline tetracyclic core was reported by Rassat

who introduced the indole via Fischer indole synthesis after the formation of the

[331]bicyclic skeleton127 Rassat began by treating the diepoxide 3110 with

benzylamine to provide a mixture of regioisomeric bicyclic structures 3111 and 1112

130

(Scheme 329) The unwanted [421]bicycle 3111 could be quantitiatively converted to

the [331]bicycle 3112 simply by trifluoroacylation and hydrolysis Monoprotection of

the diol 3112 as its corresponding TBS-ether 3113 proceeded in moderate yield In a

two-step sequence the benzyl-group of 3113 was changed to a benzoyl in 3114 which

underwent alcohol oxidation and the silyl ether removal to give 3115 Reaction of 3115

with N-methyl-N-phenylhydrazine formed a tetracycle which underwent reduction of the

benzoyl protecting group to the benzylamine to afford 3116 Finally oxidation of the

free alcohol of 3116 gave the racemic tetracyclic intermediate 323 which has been

utilized in enantioenriched form by Cook to make a number of macrolinesarpagine

alkaloids111

131

Scheme 329

O

O OBnNH2

H2O

NBn

OH

HO

31103111

+

BnN

HO OH

3112

1) TFAA

2) NaOH 95

BnN

HO OH

3112

TBS-Cl DMAPEt3N CH2Cl2

50

BnN

HO OTBS

3113

1) H2 PdC

2) K2CO3 PhCOCl 85

BzN

HO OTBS

3114

1) (COCl)2 DMSO Et3N CH2Cl2 95

2) HF CH3CN 95

BzN

OH

3115

1) H2NN(Me)Ph

MeOH HCl ∆

2) LiAlH4 THF 95

NMe

BnN

3116

OHH

H

(COCl)2 DMSO Et3N CH2Cl2

73NMe

BnN

(plusmn)-323

OH

H

Rassatrsquos approach to 323 is unique in that the A- and B-rings were assembled

after CD-ring formation Such a strategy could be useful in the synthesis of indole

substituted macroline alkaloids but the lengthy synthesis of 323 requiring multiple

protecting group manipulations is not appealing if one desires 323 specifically

35 Previous Syntheses of Alstonerine

Due to its exciting biological profile and challenging azabicyclic framework a

number of synthetic approaches to alstonerine (33) have been reported Alstonerine

132

(33) has succumbed to total synthesis twice and both of these syntheses were reported

by Cook128129 Kwon has reported a formal synthesis intersecting one of Cookrsquos

intermediates although in racemic form130 Craig has also reported a unique approach to

the core of 33 but completion of the synthesis was not reported131

351 Cookrsquos First Synthesis of Alstonerine

The first synthesis of 33 was reported by Cook and coworkers in 1990128 Cook

relied on a Claisen rearrangement to set the C15 stereochemistry and a nucleophilic

displacement to assemble the pyran E-ring in 33 (Scheme 330) Cook ultimately

required eleven steps to install the E-ring in 33 from the tetracyclic intermediate 323

Scheme 330

H

NMe

BnN

O

H

H

HNMe

MeN

O

O

H

33

Nucleophilic Displacement

Claisen Rearrangement

323

From 323 a two step sequence was employed to convert the N-benzyl group of

323 to the required N-methyl group (Scheme 331) Thus treatment of 323 with methyl

triflate provided a quaternary ammonium salt that gave 3118 upon hydrogenolysis

Addition of the anion derived from chloromethanesulfinylbenzene to the ketone moiety

in 3118 provided an intermediate epoxide which provided the unsaturated aldehyde

3119 upon treatment with LiClO4 and P(O)Bu3 Numerous attempts to perform an

intermolecular addition to the β-carbon of the αβ-unsaturated aldehyde of 3119 were not

productive and thus an intramolecular strategy was employed Reduction of the

133

aldehyde 3119 to the alcohol 3120 and conjugate addition using 3121 gave vinylogous

ester 3122 Claisen rearrangement of 3122 yielded 3123 and set the appropriate

stereochemistry at C15

Scheme 331

NMe

BnN

323

OH

H

1) MeOTf

2) H2PdC80 N

Me

MeN

3118

OH

H

1) PhS(O)CH2Cl LDA THF then KOH

2) LiClO4 P(O)Bu3PhMe80

NMe

MeN

3119

H

H

CHO

NMe

MeN

3120

H

H

OH

LiAlH4

Et2O -20 degC90

Me

O

Et3N dioxane90

NMe

MeN

3122

H

H

O

PhH 145 degC

sealed tube65 N

Me

MeN

3123

H

H

CHO

O OH

3121

Completion of the synthesis of 33 proceeded as follows (Scheme 332)

Carbonyl reduction and hydroboration of 3123 gave 3125 via 3124 and selective

tosylation of either primary alcohol of 3125 followed by cyclization provided 3126 A

modified Swern oxidation of 3126 oxidized the alcohol to the desired ketone and also

introduced the double bond of the enone present in 33 Dihydroalstonerine 3127 was

also obtained as a side product in 30 yield

134

Scheme 332

NMe

MeN

3123

H

H

CHO

OH

NaBH4

EtOH86 N

Me

MeN

3124

H

H

OHH

HO

i) 9-BBNTHF rt 20 h

ii) NaOH (3N)H2O2 40 degC 85

NMe

MeN

3125

H

H

OHH

HOHO

TsCl pyr rt

then Et3N60 + 33 RSM

NMe

MeN

3126

H

H

H

O

OH

H

H

(COCl)2 DMSO CH2Cl2

-78 to -10 degC then Et3NNMe

MeN

33 51

H

H

H

O

O

H

NMe

MeN

3127 30

H

H

H

O

O

H

+

The modified Swern oxidation to deliver alstonerine (33) deserves some

additional comment Because dihydroalstonerine (3127) could not be converted to

alstonerine (33) under the same Swern conditions Cook reasoned that carbon-carbon

double bond formation in the dihydropyran ring must have occurred prior to oxidation of

the alcohol (Scheme 333) From 3126 Cook proposed hydride transfer to the pendant

oxidizing agent (CH3-S=CH2) assisted by one of the lone pairs on the oxygen to provide

3128 Tautomerization of 3128 gave 3129 and subsequent oxidation of the secondary

alcohol provides (33)

135

Scheme 333

MeN O

MeN

H HH

H

OH

MeH

N

MeN

Me

O

OH

H

H

H

H

3126

H

3126

excess DMSO(COCl)2

MeN O

MeN

H HH

H

O

MeH

3128

SH MeN O

MeN

H HH

H

OH

MeH

3129

tautomerization

MeN O

MeN

H HH

H

OH

Me

3130

DMSO(COCl)2

MeN O

MeN

H HH

H

O

Me

33

The Claisen rearrangement strategy employed in Cookrsquos first synthesis of 33 was

a clever solution to the difficulty associated with conjugate additions to the αβ-

unsaturated aldehyde 3119 However Cookrsquos synthesis suffers from a number of

deficiencies The Swern oxidation needed to convert 3126 to alstonerine (33) also gives

a significant amount of dihydroalstonerine (3127) which Cook could not directly

convert to 33 More importantly Cook ultimately required eleven steps to install the E-

ring in 33 from the tetracyclic intermediate 323 which was assembled in only five steps

136

352 Cookrsquos Second Generation Synthesis of Alstonerine

Cookrsquos second generation synthesis was inspired by his work on the sarpagine

class of alkaloids and their biogenetic relationship to the macroline alkaloids129

Following the same synthetic employed in the synthesis of vellosimine (Scheme 319)

Cook transformed the tetracyclic ketone 323 to N-methylvellosimine (366) in four steps

Scheme 334

NMe

BnN

323

OH

H NMe

N

H

H H


HCHO

4 steps

Reduction of 366 gave another natural product affisine (3131) which was

protected as the corresponding silyl ether 3132 (Scheme 335) A

hydroborationoxidation protocol was employed in order to oxidize the trisubstituted

olefin of 3132 Oxidation of the secondary alcohol 3133 was difficult due to the

basicity of tertiary amine but Dess-Martin periodane was found to provide the ketone

3134 in high yield Retro-Michael reaction gave TIPS-protected macroline 3135 which

underwent oxidative Wacker cyclization to give alstonerine (33) in modest yield

137

Scheme 335

NMe

N

H

H H

366

HCHO

NaBH4

MeOH 0 degC90 N

Me

N

H

H H

3131

H

OH TIPS-OTf26-lut CH2Cl2

90

NMe

N

H

H H

3132

H

OTIPS i) 9 eq BH3Me2S THF

NaOH H2O2 rt

ii) 2 eq HOAc THF ∆

85

NMe

N

H

H H

3133

H

OTIPS

H

OH

DMP CH2Cl2

82NMe

N

H

H H

3134

H

OTIPS

H

O

MeI THF

KOtBu EtOH THF ∆

90

NMe

MeN

3135

H

H

H

OTIPS

O

H

NMe

MeN

33

H

H

H

O

O

H

40 Na2PdCl4 tBuOOHHOAcH2OtBuOH 80 degC

60

The oxidative Wacker cyclization of 3135 to install the E-ring allowed Cook to

avoid the inefficient Swern reaction strategy employed in the first synthesis However

Cook still required ten steps to assemble the E-ring from the ABCD-ring intermediate

323

138

353 Kwonrsquos Formal Synthesis of Alstonerine

Recently Kwon and coworkers reported a formal racemic synthesis of alstonerine

(33) intersecting Cookrsquos intermediate 3120 showcasing a phosphine mediated [4+2]

annulation of imines and allenoates developed in their research group130 Starting with

commercially available [(alkoxycarbonyl)methylene]triphenylphosphorane 3136

allenonate 3139 was prepared in two steps (Scheme 336) The indole coupling partner

3140 was easily accessed by condensing o-nitrobenzenesulfonamide with N-methyl-

indole-2-carboxaldehyde (3138) The key step in the synthesis was a PBu3-catalyzed

[4+2] annulation of 3140 with 3139 to give 3141 as a mixture (31) of diastereomers

Scheme 336

NMe

CHO

o-NsNH2 TiCl4Et3N CH2Cl2

79

NMe

NNs

Ph3POEt

OCO2EtBr

CHCl3 ∆

Ph3POEt

O

EtO2C

Br

AcCl Et3NCH2Cl2

73

CO2Et

CO2Et

3138

3140

3136

3137

3139

+

PBu3 (30)

CH2Cl2 rt73 31 drN

Me3141

NCO2Et

CO2EtNs

H

Intramolecular Friedel-Crafts acylation of 3141 in the presence of HCl gave the

bridged bicycle 3142 (Scheme 337) Next the nosyl group of 3142 was removed to

give the secondary amine 3143 and Eschweiler-Clarke reaction gave the desired N-

139

methyl compound 3144 Treatment of the ketone of 3144 with NaBH3CN and ZnI2

provided the reduced product 3145 as a cyanoborane complex which was heated in

EtOH to give 3146 Reduction of the ester moiety of 3146 provided the alcohol 3120

an intermediate in Cookrsquos first total synthesis of 33128

Scheme 337

NMe

3141

NCO2Et

CO2EtNs

H

HCl EtOAc

90 NMe

NsN

3142

H

H

CO2EtO

PhSH K2CO3

DMF99

NMe

HN

3143

H

H

CO2EtO

HCHO HCO2H ∆

99NMe

MeN

3144

H

H

CO2EtO

NaBH3CN ZnI2

DCE ∆74

NMe

MeN

3145

H

H

CO2Et

BH2CN

EtOH ∆

98

NMe

MeN

3146

H

H

CO2Et

NMe

MeN

(plusmn)-3120

H

H

OH

DIBAL-H

tol -78 degC92

Kwon formed an ABCD-ring fragment 3120 by cyclization of an ABD-ring

substrate 3141 and this strategy was a departure from the work of Cook Kwonrsquos

synthesis of 3120 required nine steps whereas Cook needed ten steps to access 3120 A

drawback to Kwonrsquos approach is that 3120 was obtained in racemic form and an

enantioselective route to 3120 would be advantageous

140

354 Craigrsquos Synthesis of the Core of Alstonerine

Craig and coworkers recently reported a concise route to the core of alstonerine

(33) utilizing aziridine chemistry and a clever application of the Pictet-Spengler

reaction131 An anion derived from the five-membered ring bis-sulfone 3147 generated

by reductive desulfonylation was added to the aziridine 3148 derived from L-tryptophan

to give a modest yield of 3149 (Scheme 338) Oxidation of the disubstituted olefin of

3149 in the presence of the indole moiety was best achieved by employing in situ

generated tetra-n-butylammoinum permanganate to give the diol 3150 Oxidative

cleavage of 3150 produced a dialdehyde and the pendant sulfonamide selectively formed

a six-membered ring iminium ion 3151 with one of the aldehydes Pictet-Spengler

cyclization upon the cyclic iminium ion 3151 produced the epimeric mixture (11) 3152

Scheme 338

NMe

TsN

3152

H

H

SO2Ph

CHO

PhO2S SO2Ph

NMe

NTs

LiC8H10 THFDMPU -78 degC

55-64NMe

NHTs

PhO2S

KMnO4Bu4NBr

CH2Cl261 N

Me

NHTs

PhO2SOH

OH

1 Pb(OAc)4 NaHCO3 DCE

2 TFA MgSO4 CH2Cl2 94

315031493147

NMe

3151

NTs

PhO2S

CHO

3148

141

From 3152 sulfone elimination and vinylogous silyl enol ether formation

provided the diene 3153 which underwent hetero-Diels-Alder reaction with monomeric

formaldehyde132 to give 3154 in modest yield (Scheme 338) Switching the N-tosyl

group to an N-methyl group and elaboration of the E-ring to include the vinylogous ester

moiety is necessary to complete the synthesis of alstonerine (33)

Scheme 339

NMe

TsN

3152

H

H

SO2Ph

CHO

TBDPS-Cl DMAPDBU CH2Cl2

95 NMe

TsN

3153

H

H

OTBDPS

HCHO (16M in THF)Me2AlCl THF

-78 degC - rt36 N

Me

TsN

3154

H

H

OOTBDPS

H

Pictet-Spengler cyclization to simultaneously form the C- and D-rings defined

Craigrsquos approach to alstonerine (33) While the yield was not optimal the hetero-Diels-

Alder approach for the synthesis of the E-ring was unique and could prove useful if

optimized

36 Conclusions

While the order of ring formation varies virtually all of the approaches to the

syntheses of macroline alkaloids relied on ABCD-ring containing intermediates (Figure

33) While a number of strategies were developed for the synthesis of such ABCD-ring

containing intermediates variations of the Pictet-Spengler reaction were most often

142

utilized by different research groups to build tetracyclic structures 355 From the varied

tetracyclic structures synthesis of the remaining E-ring often presented the most difficult

challenge judging by the lengthy synthetic approaches employed All of Cookrsquos

syntheses relied on the tetracycylic ketone 323 or 338 as an intermediate which he

could rapidly access using Pictet-Spengler chemistry But in order to install the varied

E-rings present in alkaloids such as talcarpine (321) norsuaveoline (322) and

alstonerine (33) Cook resorted to long synthetic sequences of ten to twelve steps In

contrast Bailey could build the E-ring of either (-)-raumacline (399) or (-)-suaveoline

(3104) in only four steps from a functionalized tetracyclic intermediate but the syntheses

of the two ABCD-ring intermediates 398 and 3103 each required eleven steps

Strategies disclosed by Kuethe and Kwon to access the tetracyclic core of the macroline

alkaoids suffered from a lack of enantiocontrol and Rassatrsquos Fischer indole synthesis of

323 was twice as long as previous approaches Certainly the challenges inherent in the

synthesis of macroline alkaloids are apparent by the continued contemporary interest in

this class of alkaloids However many of the problems associated with the synthesis of

macroline alkaloids still have not been addressed as evidenced by the varied and often

lengthy synthetic strategies employed

143

Figure 33 Stratagies for the Synthesis of the ABCD-Core of the Macroline Alkaloids

H

NMe

BnN

Pictet-SpenglerH

H

NMe

BnN

HeckH

O

H

NMe

BnN

H

FischerIndole

O

NMe

NsN

H

H

CO2EtOFriedel-Crafts

3155Cook Bailey Craig

R

390Kuethe

323Rassat

3142Kwon

144

Chapter 4 Synthesis of Azabridged Bicyclic Structures via the Pauson-

Khand Reaction Concise Enantioselective Total Synthesis of (-)-

Alstonerine

41 Introduction

As described in the previous chapter the overwhelming majority of approaches to

the macroline alkaloids involve installation of the E-ring through a long series of

transformations commencing with an ABCD-ring precursor (Scheme 41) For example

Cookrsquos syntheses of alstonerine (41) required either 10 or 11 synthetic steps to assemble

the final acyldihydropyran E-ring from the tetracyclic ketone 42 While Cook could

rapidly access 42 by a Pictet-Spengler reaction followed by a Dieckmann cyclization the

lengthy routes necessary to complete alstonerine (41) from 42 beg the question of

whether such synthetic strategies are optimal Cookrsquos use of the tetracyclic ketone 42 as

a common synthetic intermediate for the synthesis of many macroline alkaloids was in

many ways a double-edged sword The utility of 42 in complex alkaloid synthesis has

been repeatedly demonstrated through the synthesis of many diverse natural products but

in the case of alstonerine (41) the need to transform a ketone in 42 to an

acyldihydropyran ring in 41 suggests a lack of retrosynthetic foresight Perhaps in an

attempt to use 42 as a precursor in the syntheses of many disparate alkaloids such as 41

and others Cook may have been forcing a total synthesis on an intermediate instead of

carefully planning a synthetic strategy appropriate to each target

145

Scheme 41

H

NMe

BnN

O

Diekmann

Pictet-SpenglerH

H

HNMe

MeN

O

O

H

41



H

HNMe

MeN

O

O

H

41

Wacker

Pd-CatalyzedEnolate Coupling

42

E

E

A B

A B

C D

C D

11 steps

10 steps

Instead of relying on an ABCD ring intermediate such as 42 we felt that a

cyclopentenone such as 44 would serve as a superior precursor to 41 for a number of

reasons (Scheme 42) We envisioned that the D- and E-rings in cyclopentenone 44

could be installed in one step by a PKR of an ABC-ring containing enyne 45 and the

chemistry for the synthesis of enynes such as 45 had previously been developed in the

Martin group121 The PKR of 45 would generate three new carbon-carbon bonds and

two new rings quickly building a framework from which 41 could be accessed The

pentacyclic cyclopentenone 44 contains all of the carbon atoms present in the core of

alstonerine (41) and ring expansion of the cyclopentenone in 44 by Baeyer-Villiger

oxidation would constitute a rapid assembly of the pyran E-ring as the lactone 43 From

the lactone 43 reduction and elimination to a dihydropyran followed by acylation would

provide the target 41 Because mild conditions for the acylation of dihydropyrans in the

146

β-position were not well known we felt this would be an excellent opportunity to

develop new chemistry

Scheme 42

H

HNMe

MeN

O

O

H

41

H

H

HNMe

RN

OH

43

H

O

H

HNMe

RN

44

H

O

NMe

NR

45

Acylation

Baeyer-Villiger

PKR

Upon further reflection we realized that the development of PKRs to synthesize

azabicyclic structures would enable concise access to a number of natural product

scaffolds For example the PKR of cis-25-disubstituted pyrrolidines such as 48 would

give the tricyclic core 47 of hederacine B (46) a natural product that exhibits promising

anti-inflammatory and antiviral activity (Scheme 43)133 PKRs of

tetrahydroisoquinoline enynes such as 411 would lead to adducts 410 which could

serve as precursors to tetrahydroisoquinoline antitumor antibiotics such as renieramycin

A (49)134

147

Scheme 43

MeN

H2N

O

O

46

RN

47

PGO

O

RN

PGO

48

410

N

N

OH

O

O

Me

MeO

O

O

MeO

Me

Me

HH

H

O Me

O

Me

N

N

R411

N

NR

R

R

O

49

Surprisingly the use of PKRs to synthesize bridged bicyclic structures as

described in Chapter 1 are rare and the synthesis of azabridged bicyclic structures by

PKR was completely without precedent before our work Given the ability of the PKR to

rapidly build complex molecules from simple enyne substructures we sought to pursue

the PKR as a strategy level reaction for the syntheses of a variety of alkaloid core

structures We first planned to determine the scope of the PKR using cis-25-

disubstituted pyrrolidine substrates and cis-26-disubstituted piperidine substrates The

ultimate application of the PKR to the total synthesis of alstonerine (41) and other

alkaloids was also envisioned

148

42 Hederacine A and 25-cis-Disubstituted Pyrrolidines

421 Introduction

Hederacine A (416) and B (417) have an unprecedented structure containing a

azabicyclo[321]octane fused with a five-membered ring providing a particularly

challenging synthetic target The isolation of hederacine A (46) and B (412) from

Glechoma hederacea was reported by Sarker and coworkers in 2003133 Glechoma

hederacea is a perennial hairy herb with a creeping stem commonly found in temperate

regions of Asia Europe and the United States The plant has been used extensively in

folk medicine to treat abscesses arthritis asthma bronchitis cystisis diabetes diarrhea

hemorrhoids headache inflammation scurvy and tetanus135 Moreover in vitro and

animal studies have shown that the plant possesses anti-inflammatory ulcer-protective

anti-viral and cytotoxic activities133 We envisioned that a PKR of a cis-25-disubstituted

pyrrolidine such as 414 would efficiently provide access of the core structure 413

(Scheme 44) The enyne 414 could be derived from the known hydroxy-proline

derivative 415136

149

Scheme 44

MeN

H2N

O

O

46

MeN

H2N

412

HO

O

HO

BocN

413

TBSO

O

BocN

TBSO

414

BocN

TBSO

CO2Me

415

O

422 Preparation of the PKR Substrate

Following a literature procedure the enyne precursor 415 was obtained in a high

yield in four steps from commercially available trans-4-hydroxy-L-proline 416 (Scheme

45)136 Thus 416 was treated with SOCl2 in MeOH to provide the methyl ester 417 in

nearly quantitative yield The pyrrolidine 417 was protected with Boc2O to give 418 in

70 yield and the free alcohol 418 was converted to the TBS ether 419 The protected

lactam 415 was obtained through catalytic biphasic RuO4-oxidation of the carbamate

419 in excellent yield

150

Scheme 45

HN

HO

CO2H SO2Cl

MeOH99

H2+Cl-

N

HO

CO2Me N

HO

CO2Me

Boc

dioxane70

TBS-Climidazole

N

TBSO

CO2Me

Boc RuO2H2O (20)

NaIO4N

TBSO

CO2Me

Boc

O

416 417 418

419 415

Boc2OiPr2NEtDMAP

DMF96

EtOAc96

To explore the scope of the PKR we elected to synthesize the two enynes 422

and 414 which differ only in alkene substitution (Scheme 46) Both substrates were

desired as olefin substitution often has a marked effect on the efficiency of PKRs A

three-step reaction sequence was employed to convert the exocyclic carbonyl group in

415 to the necessary allyl or methallyl group in 420 and 421 respectively Thus Boc-

protected lactam 415 was sequentially treated with LiBHEt3 acetic anhydride and allyl-

or methallyl-TMS in the presence of BF3Et2O to provide a mixture (31) of allylated

products 420 or the mixture (31) of epimers 421 The mixtures 420 and 421 were then

treated sequentially with DIBAL-H and then the Bestman-Ohira reagent in basic

methanol to give the enynes 422 and 414 Elaboration of 422 would show that the

trans-isomer was the favored diastereomer

151

Scheme 46

N

TBSO

CO2Me

Boc

O N

TBSO

CO2Me

Boc

415

R

420 R=H (42 31 transcis)421 R=Me (62 31 transcis)

1 LiBHEt3 THF2 Ac2O Et3N CH2Cl23 allyl TMS or methallyl TMS BF3

Et2O toluene

N

TBSO

Boc1 DIBAL-H CH2Cl2

2 K2CO3 Bestman-Ohira Reagent MeOH

R

422 R=H 57 (31 transcis)414 R=Me 83 (31 transcis)

In order to determine the stereochemistry of the major isomer from the allylation

of 415 we endeavored to obtain a crystalline derivative Removal of the silyl ether from

414 allowed chromatographic separation of the two epimeric alcohols 422 and 423

(Scheme 47) Acetylation of the major isomer 423 gave a crystalline product 424

which was suitable for x-ray analysis

152

Scheme 47

N

TBSO

Boc

414

TBAF THF N

HO

Boc

N

HO

Boc

+

Ac2O Et3NCH2Cl2 97

92

N

AcO

Boc

422 423

424

The crystal structure showed that the undesired trans-product 424 was the major

isomer (Figure 41) This result was discouraging but we decided to determine whether

we could execute the desired PKR of 414 or 422 and then if successful we could later

optimize the diastereoselectivity of the allylation

153

Figure 41 ORTEP of 424

Various PKR conditions were tried to effect the PKR of cistrans mixture 414

(Scheme 48) Utilizing NMO50 DMSO53 and MeSnBu52 as promoters after treatment of

414 with Co2(CO)8 led to intractable mixtures In addition attempts to use Rh(I)

catalysts also led to decomposition6768 While formation of the Co-alkyne complex 425

derived from 414 was rapid and quantitative reaction of this complex to form 426 did

not occur Extended heating and reaction times led to decomposition of the Co-alkyne

complex 425

154

Scheme 48

N

TBSO

Boc

BocN

TBSO

O

426414

Co2(CO)8 N

TBSO

Boc

425

Co2(CO)6

conditions

conditions NMO DMSO MeSBu

THFX

Enynes which contain monosubstituted alkenes are generally superior PKR

substrates48 In order to determine whether the extra methyl group on 414 was inhibiting

the PKR the PKR of the mixture of epimers 422 was attempted using the same

conditions employed for the PKR of 414 (Scheme 49) Again the cyclization failed and

no 429 could be isolated

Scheme 49

N

TBSO

Boc

BocN

TBSO

O

429422

Co2(CO)8 N

TBSO

Boc

428

Co2(CO)6

conditions


THF

423 Protecting Group Removal

A hypothesis as to the failure of the PKR of 414 or 422 was that the bulky Boc

group blocked the approach of the alkene to the alkyne-Co2(CO)6 complex In order to

test this supposition we sought to convert the Boc-group in 414 to a methyl group

Initial experiments directed toward reducing the Boc-group in 414 to a methyl group

155

using LiAlH4 led to complex mixtures so we turned to a two-step sequence involving

Boc-deprotection of 414 and subsequent methylation Deprotection of the Boc-group in

414 proved to be difficult under protic or Lewis acidic conditions and treatment of 414

with HCl or ZnBr2 only gave 430 (Eq 41) Most likely under these conditions

protonation of the olefin resulted in a tertiary carbocation which was trapped by the

carbamate carbonyl with loss of isobutylene to give the observed product 430

N

TBSO

Boc

HCl or ZnBr2 N

TBSO

O O

414 430

(41)

A mixture (13) of the chromatographically separable amine epimers 431 and

432 was obtained when 414 was adsorbed on silica gel and heated under vacuum

(Scheme 410)137 The cis-isomer 431 was alkylated under standard conditions to

provide the tertiary amine 433

156

Scheme 410

N

TBSO

Boc HN

TBSO

HN

TBSO

+

silica gel100 degC01 torr

414 431 432

N

TBSO

K2CO3 MeIacetone

55

Me

433

88431432 = 13

PKR on the tertiary amine 433 failed to provide the cyclopentenone 435 or any

identifiable product (Scheme 411) Formation of the Co-alkyne complex 434 was

complete as observed by TLC however various promoters and thermal conditions did

not yield any 435 and only baseline material was observed after extended heating Only

starting material was recovered when [Rh(CO)2Cl]2-catalyzed PKR of 433 was

attempted

Scheme 411

N

TBSO

Me

MeN

TBSO

O

435433

Co2(CO)8 N

TBSO

Me

434

Co2(CO)6

conditions


THF

157

While the RCM of cis-25-disubstituted pyrrolidines is well established in the

Martin group as a method for forming azabridged bicyclic structures the PKR of similar

substrates does not proceed as attempted in the presence or absence of a carbamate group

on the pyrrolidine nitrogen in the above cases Perhaps the strain required for the alkene

in 436 to coordinate to a cobalt atom is too great or the intermediate cobalt metallacycle

437 invoked as a mechanistic intermediate in the PKR is too strained to form thereby

suppressing the subsequent PKR Since our synthetic plan for the synthesis of hederacine

A (46) relied on a PKR of 414 as a key step the difficulty associated with effecting the

PKR of 414 led us to explore other natural product scaffolds

Scheme 412

N OBn

O

H

H

Co

Co(CO)3

(CO)2

N OBn

O

H

Co Co

(CO)3 (CO)3

436 437

TBSO TBSO

N

TBSO

Boc

422

Co2(CO)8

N

TBSO

Boc

428

Co2(CO)6

158

43 cis-26-Disubstituted Piperidines

Our plan for the synthesis of alstonerine (41) relied upon the PKR of 45 to give

the key cyclopentenone 44 (Scheme 413) In the context of our planned synthesis of

41 we were more generally interested in pursuing the reactions of cis-26-disubstituted

piperidines such as 438 to give azabridged bicyclic compounds 439 in general

Azabridged bicyclic structures are commonly found in biologically active natural and

unnatural substrances138 and we envisioned that PKR of enynes 439 would represent a

rapid route to these structures By changing m and n in 439 we sought to explore the

scope of the PKR reaction to assemble various ring sizes

Scheme 413

HNMe

RN

O

H

NMe

NR

44 45

PKR

H

PKR

N

R

439

m nRN

O

438

m n

Based on previous literature precedent139 and previous work in the Martin group

by Dr Neipp on RCM of cis-26-disubstituted piperidines121 we reasoned that cis-26-

disubstituted piperidines would prove to be effective substrates for PKRs Such a

159

supposition was based on the well-known preference of cis-26-disubstituted piperidines

such as 440 to exist primarily in a diaxial conformation such as 441 due to the A13-

interactions in the chair conformation 440139 As a result the two alkenes in 441 are

ideally disposed to undergo PKR to give 442

Scheme 414

N

X

R

O

A13-Strain N

X

R

O

m

m

n

n

PKR N R

O

X n

m

440 X = H2 O 441 442

O

431 Initial Studies

Our plan for the synthesis of cis-26-disubstituted piperidine enynes was based on

previous work in the Martin group by Dr Christopher Neipp that had been inspired by

the work of Comins (Scheme 415)121140 Dr Neipp prepared a number of cis-26-

disubstituted piperidine dienes 445 which underwent subsequent RCM to form

azabridged bicyclic structures Addition of a Grignard reagent or zinc reagent to 4-

methoxypyridine (443) in the presence of Cbz-Cl gave enones 444 which were treated

with vinyl cuprate reagents to prepare dienes 445 in good yields and high

diastereoselectivies (201-91) favoring the cis-isomers

160

Scheme 415

N

OMe

R1

MgBrn

(ZnCl2) THF -20 degC

then Cbz-Cl 10 HCl70-86

CbzN

O

R1

n

MgBr

R2

MeLi CuCN (111)

THF -78 degC73-81

CbzN

O

R1

R2

443 444 445

n

Inspired by the work of Dr Neipp the anion derived from trimethylsilyl acetylene

was added to 4-methoxypyridine (443) in the presence of Cbz-Cl to give the enone 446

(Scheme 416) Although we hoped to obtain the enyne 447 by the conjugate addition of

an allyl cuprate to the enone 446 numerous attempts to add allyl cuprates to 446 gave

mixtures of 12- and 14-addition products Such results are not that surprising

considering that allyl cuprates are well known to add to enones in a 12-sense in many

cases141 A common solution to the problem of low regioselectivity in allyl cuprate

conjugate additions is to perform a Sakurai reaction142 Thus treatment of 446 with allyl-

TMS in the presence of TiCl4 cleanly afforded a modest yield of the enone 447 without

any 12-addition products being observed The enyne substrate 448 was obtained after

treatment of 447 with basic methanol

Scheme 416

N

OMe

TMSTHF

then Cbz-Cl 95

N

O

Cbz

N

O

CbzTMS

TiCl4 CH2Cl2-30 degC 30

TMS R

443 446447 R=TMS

448 R=H

K2CO3MeOH75

EtMgBr

161

In order to improve the yield of the enyne 448 enone 446 was treated with allyl

tributyltin in the presence of TBS-OTf as a Lewis acid to afford an intermediate silyl enol

ether which underwent silyl deprotection in the presence of TBAF to give 448 in

excellent yield with complete diastereoselectivity (Eq 42) Namely none of the peaks

corresponding to the presence of a corresponding trans-isomer were observed in the 1H

NMR or 13C spectra of 448 The cis-stereochemistry of 448 was confirmed in

subsequent experiments (vide infra) The conjugate addition of allyl stannanes in the

presence of TBS-OTf has been reported by Kim to be a mild alternative to the use of

stronger Lewis acids such as TiCl4143

N

O

Cbz

N

O

Cbz

SnBu3

TBS-OTf CH2Cl2then TBAF

96

TMS

446 448 gt191 dr

(42)

The high level of diastereoselectivity in this conjugate addition to 446 can be

rationalized by analyzing a stereochemical model similar to that invoked by Dr Neipp

(Scheme 411)121 The half-chair conformation 449 in which the acetylene substituent is

oriented in a pseudoaxial position is preferred due to an adverse steric interaction

between the carbamate protecting group and the silyl acetylene moiety when it occupies

an equatorial conformation as in 450 Axial attack of the nucleophile on the preferred

half-chair conformation 449 results in the formation of the desired cis-26-disubstituted

piperidine 448

162

Scheme 417

NO

TMS

O

O

N

H

TMS

OO

O

Nuc

Nuc

449 450

With the cis-26-disubstituted piperidine 448 in hand the PKR of 448 was

attempted utilizing Co2(CO)8 and a number of promoters The conditions that gave the

most efficient reaction involved treatment of 448 with Co2(CO)8 to give an intermediate

cobalt-complex that was treated with six equivalents of DMSO at elevated temperature to

give the enone 451 in excellent yield as one diastereomer (Scheme 418) Optimization

of this reaction revealed that use of high quality Co2(CO)8 was essential to obtain high

yields Many promoters including NMO BuSMe and 4 Aring molecular sieves were

screened but DMSO proved to be the most efficient This transformation represents the

first synthesis of an azabridged structure via a PKR

Scheme 418

N

O

Cbz

448

Co2(CO)8

DMSO

THF 65 degC89

NCbz

OH

O

451

H

H

N

O

Cbz HH

451

H

O

3

The stereochemistry of the product 451 was determined by obtaining an X-ray

crystal structure (Figure 42) Notably the hydrogen atom at the new stereocenter at C3

163

was oriented trans to the bridging nitrogen atom The stereochemistry of 451 is

important since alstonerine (41) possesses the identical trans relationship between the

bridging nitrogen and the bridgehead hydrogen atom Thus the stereochemical precedent

established in the PKR reaction of 448 boded well for the desired PKR of 45 as a key

step in the synthesis of alstonerine (41)

Figure 42 X-Ray Crystal Structure of 451

The high level of stereocontrol in the PKR of 448 prompted us to devise a

stereochemical model to account for the selectivity Work by Krafft and Schore provided

a framework with which to formulate such a model144 They used molecular modeling to

calculate the energies of the metallacycles such as 453 and 454 that would arise from

the alkyne complex 452 (Scheme 419) Theoretically both the cis-453 and trans-454

metallacycles can be formed but they found that in all cases the cis metallacycles 453

were more stable than the trans metallacycles 454 by 35-71 kcal mol-1 Therefore they

proposed that only cis-metallacycles wherein the hydrogen on the newly formed

stereocenter and the remaining cobalt atom are on the same face of the metallacyclic ring

164

as in 453 are viable intermediates They also showed that if one can determine the

lowest energy cis-metallacycle formed from a given enyne starting material then that

metallacycle typically leads to the major product

Scheme 419

Co(CO)2

(CO)3Co

H

Co(CO)2

Co(CO)3

H(CO)3Co Co(CO)3

+

452

cis-453

trans-454

The mechanism outlined in Scheme 420 puts forth a possible explanation for the

diastereoselectivity in the PKR of enyne 448 in light of the above work by Krafft and

Schore The PKR mechanism involves initial Co-alkyne complex formation followed by

subsequent alkene insertion into a Co-C bond to form a metallacycle (vide supra) Four

metallacycles are theoretically possible but based on the calculations of Krafft and

Schore only the two cis-metallacycles 457 and 458 will be considered These two

metallacycles are formed by alkene insertion into the cobalt-alkyne complex from either

conformation 455 or 456 We propose that the metallacycle 458 is disfavored due to

the fact that the bulky cobalt moiety is in close proximity to the cyclohexanone ring in the

alkene conformation 456 whereas conformation 455 does not contain such an

interaction Thus the transition state leading to metallacycle 457 is lower in energy and

as a result 457 is preferentially formed and 451 is the observed product

165

Scheme 420

N OBn

O

H

H

NCbz

Co2(CO)8

Co

Co

N OBn

O

H

H

Co

N OBn

O

H

H

Co Co

(CO)3 (CO)3

N OBn

O

H

H

O

O

O

O

O

CbzNO

H

H

448

455 456

457 458

451 459

O

HCbzNO

H

HO

H

CoCo

Co

(CO)3(CO)2

(CO)3(CO)2

(CO)3(CO)3

432 Synthesis and PKR of Various cis-26-Disubstituted Piperidine Enynes

The high yield and diastereoselectivity obtained when enyne 448 was employed

as a PKR substrate prompted the investigation of other enyne substrates We next chose

166

to study the PKR of the enyne substrate 462 which is a constitutional isomer of 448

The synthesis of 462 is outlined in Scheme 421 Reaction of 4-methoxypyridine (443)

with the zinc reagent derived from 1-trimethylsilylpropargyl bromide in the presence of

Cbz-Cl gave 460 Interestingly reaction of the 4-methoxypyridine (443) with the

corresponding Grignard reagent derived from 1-trimethylsilylpropargyl bromide did not

afford any of the enone 460 Dr Neipp noted similar problems when allyl Grignard

reagents were employed as nucleophiles121 Conjugate addition of vinyl cuprate to 460

gave 461 which was treated with TBAF to provide the enyne 462 in excellent

diastereoselectivity The diastereoselectivity was determined by integration of the 1H

NMR resonances associated with the hydrogen atom bonded to C6 in 461 and the

corresponding trans isomer and the cis-stereochemistry of the major isomer 461 was

confirmed in a subsequent PKR (vide infra)

Scheme 421

N

OMe

443

TMSBr

Zn dust HgCl2 (1) THFthen Cbz-Cl 10 HCl

77

N

O

Cbz

460

TMS

CuCN MeLi (111)

MgBr

TBAFH2OTHF 69

N

O

Cbz

R

THF -78 degC 96 171 dr

461 R = TMS

462 R = H

6

The PKR of enyne 462 yielded one diastereomer 463 in excellent yield with the

hydrogen atom on C1 in 463 again being oriented trans to the bridging nitrogen atom

(Scheme 422) This stereochemical assignment is based on the magnitude of the

coupling constant associated with the methine protons at C1 and C2 in 463 The DEPT

167

spectrum of 463 allowed identification of the 13C NMR resonances associated with all of

the methine carbons and the 1H NMR resonance associated with each methine carbon

was determined by HSQC The HMBC spectrum of 463 showed that C1-H was coupled

with C2 and the C2-H was coupled with C1 Thus the 1H NMR resonances associated

with C1-H and C2-H were determined Each of these protons appeared as a doublet of

triplets and the magnitude of the coupling constant associated with the doublet 15 Hz

suggested that the angle between the C1-H bond and the C2-H bond was close to 90

degrees Analysis of a molecular model of 463 showed that these two C-H bonds were

close to perpendicular to one another and as a result one would expect a small coupling

constant associated with C1-H and C2-H in 463 Analysis of the molecular model of the

diastereomer with the opposite configuration at C1 showed that the C1-H and C2-H

bonds would be eclipsing one another and a larger coupling constant would be expected

Scheme 422

N

O

Cbz

462

Co2(CO)8

DMSO

THF 65 degC91

N

O

O

CbzH HH

463

N OBn

O

HO

463

H

O

1

2

Analysis of the steric interactions in the two alkene conformations 464 and 465

that lead to the cis-metallacycles 466 and 467 can account for the diastereoselective

formation of 463 from 462 (Scheme 423) Metallacycle formation can occur from

either alkene conformation 464 and 465 however conformation 464 places a large

cobalt atom in close proximity with the cyclohexanone ring The conformation 465

168

lacks such an adverse interaction and as a result conformation 465 is favored From

45 alkene insertion gives metallacycle 467 which can react further to give the observed

product 463 Krafft and Schore have shown that the favored PKR diastereomer arises

from the lower energy metallacycle144 and we assert that the transition state leading to

metallacycle 466 is higher in energy leading to preferential formation of the metallacycle

467

169

Scheme 423

NCbz

Co2(CO)8

N OBn

O

H

O

O

CbzNO

H

H

CbzNO

H

H

462

465

468 463

H

Co

N OBn

O

HO

464

Co

(CO)3(CO)3

HCo Co

(CO)3 (CO)3

H HO O

H

N OBn

O

HO

466

Co(CO)2(Co)3Co

N OBn

O

HO

467

H

(CO)2Co Co(CO)3

In order to access different ring sizes we prepared enyne substrate 470 from

which we envisioned that azabicyclo[321]octanes could be assembled by a PKR

(Scheme 424) The azabicyclo[321]octane skeleton is found in many highly

biologically active alkaloids138 and the PKR of enynes such as 470 would entail a new

170

method with which these important structures could be prepared To access 470

conjugate addition of vinyl cuprate to the enone 446 gave 469 which underwent

subsequent fluoride initiated removal of the silyl group to give 470 PKR of 470

provided a mixture (31) of diastereomers 471 in modest yield and the major

diastereomer was tentatively assigned as possessing the C1-HC2-H trans relationship as

shown in 471 based on the PKR of the vinyl enyne substrate 462 The diastereomeric

ratio was determined by integration of the 1H NMR resonances associated with the C6-H

in each diastereomer Perhaps the additional ring strain associated with the cobalt

metallacycle intermediate formed from enyne 446 as compared with the metallacycles

arising from the previously discussed enyne substrates 462 and 448 leads to the

diminished yield and diastereoselectivity

171

Scheme 424

N

O

CbzTMS

446

CuCN MeLi (111)

MgBr

TBAFH2O THF 53

N

O

Cbz

Co2(CO)8

DMSO

THF 65 degC33 31 dr

THF -78 degC 64 gt19 dr

R

469 R = TMS

470 R = H

N

O

CbzH H

471

N OBn

O

HO

471

H1

2

O

H

O

6

433 Sulfonamide and Amide Substrates

As discussed in section 342 previous studies in the Martin group on ring closing

metathesis of cis-26-disubstituted piperidines showed that carbamates are suitable

substrates and these N-acyl piperidines were chosen as RCM substrates due to their well

known preference to adopt a reactive 26-diaxial conformation (Scheme 414)121 We

were curious whether other nitrogen substituents such as sulfonamides and amides could

also be used to enforce the reactive 26-diaxial conformation To this end the synthesis

of cis-26-disubstituted piperidines bearing sulfonamide and amide nitrogen substituents

was undertaken as these nitrogen protecting groups are often employed in complex

molecule synthesis145 Since standard hydrogenolysis conditions could not be used to

cleave the Cbz group of 448 Lewis acidic conditions were explored (Scheme 425)

172

Unfortunately the strong Lewis acidic conditions (TMS-I) required for Cbz cleavage

were not suitable for deprotection of 448 and only decomposition was observed

Scheme 425

Cbz

N

O

448

H2 PdCor

TMSIX

HN

O

472

Due to the above shortcomings a protecting group that could be removed under

milder conditions was desired and the Alloc group proved to be ideal (Scheme 426)

Reaction of 4-methoxypyridine (443) with the anion derived from trimethylsilyl

acetylene in the presence of Alloc-Cl yielded 473 which was deprotected under standard

conditions to afford an excellent yield of the vinylogous amide 474 Tosylation of 474

gave sulfonamide 475 which was treated with basic methanol to give 476 Sakurai

reaction of 476 provided the requisite enyne 477 as a single diastereomer as determined

by its 1H NMR spectrum

173

Scheme 426

Alloc

Ts Ts

N

OMe

MgBrTMS

THF then Alloc-Cl77

N

O443

TMS HN

O

TMS

dimethyl malonate

Pd(PPh3)4 THF93

nBuLi THF -78 degC

then TsCl50

N

O

R

475 R = TMS

476 R = H

K2CO3MeOH48

TMS

TiCl4 CH2Cl239 gt191 dr

N

O

473 474

477

In order to access the analogous amide substrate 479 the vinylogous amide 474

was deprotonated and N-acylated with benzoyl chloride to give the vinylogous imide 478

(Scheme 427) Treatment of 478 with allyl tributylstannane in the presence of TBS-OTf

resulted in conjugate addition and addition of TBAF gave the amide enyne 479 as one

diastereomer as determined by the 1H NMR spectrum at 100 ˚C

Scheme 427

Bz BzHN

O

TMS

474

nBuLi THF -78 degC

then BzCl98

N

O

TMSSnBu3


91 gt191 dr

N

O

478 479

Sulfonamide 477 and amide 479 both proved to be excellent substrates for the

PKR reaction giving the azabridged bicyclic products 480 and 481 respectively in good

to excellent yields and each product was obtained as a single diastereomer (Scheme

174

428) The stereochemistries of 480 and 481 were assigned based on comparison of

their 1H NMRs with that of 451 the stereochemistry of which was confirmed by x-ray

(Fig 42) Specifically the 1H NMR resonances associated with the diastereotopic C7-

Hs appear in 480 and 481 as a doublet of triplets and a doublet of doublet of doublets

and these splitting patterns match those found in the 1H NMR spectrum of 451 Thus

the scope of the PKR of cis-26-disubsitiuted piperidines was extended to include N-

protected amides and sulfonamides although sulfonamides appear to be inferior

substrates as compared to amides and carbamates The hybridization of sulfonamide

nitrogens can range from sp3 to sp2 and crystal structures displaying each end of the

spectrum have been disclosed146 In light of such observations perhaps the nitrogen atom

of 477 is not as sp2-like as those in the carbamate and amide substrates and as a result

477 does not occupy the reactive 26-diaxial conformation to the same extent as these

other substrates These results will be especially important in the field of natural product

synthesis where maximum flexibility in the choice of protecting group is often

advantageous145

Scheme 428

N

O

R Co2(CO)8

DMSO

THF 65 degCN

O

R HH

H

O

477 R = Ts479 R = Bz

480 R = Ts (61)481 R = Bz (94)

7

175

434 Modification of the C-4 Carbonyl Group

Each of the PKR substrates above contained a carbonyl group at C-4 and in order

to analyze whether the presence of a carbonyl function was necessary a series of

substrates differing in substitution at C-4 were synthesized For example stereoselective

reduction of 448 with a bulky hydride source cleanly gave the alcohol 482 and

protection of the alcohol as the corresponding silyl ether afforded 483 (Scheme 429)

The stereochemical assignment in 482 and 483 is based on the magnitude of the

coupling constants corresponding to the 1H NMR resonance associated with the C4-H of

483 The C4-H of 483 appears as a doublet of triplets in the 1H NMR spectrum with

coupling constants of 44 Hz and 68 Hz which correspond to equatorial-axial and

equatorial-equatorial couplings In addition the stereochemistry associated with the

reduction of 448 is consistent with reduction of other cis-26-disubstituted piperidin-4-

ones with L-selectride147

Scheme 429

CbzN

O

448

L-Selectride

THF -78 degC99

CbzN

OH

482

TBS-Climidazole

DMF81

CbzN

OTBS

483

4 4

The substrate 486 which has a simple methylene group at C4 was also sought

Standard Barton deoxygenation of the xanthate ester 484 led to formation of

unidentifiable products possibly due to radical cyclization onto either the alkene or

alkyne moieties (Scheme 429) The next approach to obtain 486 involved reduction of

the dithiolane 485 Although the dithiolane 485 was readily prepared in good yield

176

reduction of the dithiolane moiety in 485 with Raney nickel was accompanied by alkene

and alkyne reduction Use of Raney nickel that was deactivated by refluxing in EtOH

gave similar results We next sought to convert the ketone moiety in 448 to an

intermediate sulfonyl hydrazine that could be reduced to give 486 However only trace

amounts of 486 were obtained after reaction of 448 with toluenesulfonyl hydrazine

followed by treatment with protic or Lewis acids

Scheme 430

N

Cbz

448

O

H2NNHTs H+ or LA NaBH3CN

BF3Et2O

HSCH2CH2SH

CH2Cl284

N

Cbz

485

S S

N

Cbz

486

Raney NiX

X

N

Cbz

484

O

S

SMeii) NaH CS2 MeI THF 46

XAIBN Bu3SnH

i) L-selectride THF 99

Consequent to these failures other methods for synthesizing 486 were pursued

For example glutarimide (487) was transformed to the aminal 488 which was readily

converted to the known sulfone 489 via a procedure previously established in our

laboratory (Scheme 431)121 Alkylation of 489 provided 490 and introduction of the

Cbz group proceeded in high yield to give 491 Reduction of the more electrophilic

carbonyl group in 491 was accomplished with DIBAL-H and the intermediate

177

hemiaminal was treated with BF3Et2O and allyl TMS to give the enyne 486 after

cleaving the silyl group from the acetylene moiety

Scheme 431

HNO O NaBH4 HCl

EtOH

HNO OEt

HNO SO2Ph

PhSO2ClHCO2H

CH2Cl260

nBuLi

TMS

THF71

487 488 489

HNO

TMSnBuLi

then Cbz-ClTHF81

NO

TMSCbz

490 491

1 DIBAL-H THF

2 Allyl-TMS BF3

Et2O 57

N

RCbz

492 R = TMS

486 R = H

TBAF THF86

The PKR of the silyl ether 483 gave the cyclopentenone product 493 in good

yield as one diastereomer (Scheme 432) and the stereochemistry of 493 was assigned

by comparison of the 1H NMR spectrum of 493 with that of 451 The 1H NMR

resonances associated with the diastereotopic C7-Hrsquos in both 493 and 451 appeared as a

doublet of triplets and a doublet of doublet of doublets However the corresponding

substrate 486 containing a methylene group at C-4 underwent a PKR to give a mixture

(41) of diastereomers in good yield favoring 494 The diastereomeric ratio was

determined by integration of the 1H NMR resonances associated with the C11-H of each

diastereomer and the major diastereomer is tentatively assigned based on comparison of

the 1H NMR spectrum of 494 with that of 451

178

Scheme 432

N

R

Cbz Co2(CO)8

DMSO

THF 65 degCN

R

Cbz HH

H

O

483 R = OTBS486 R = H

493 R = OTBS (69)494 R = H (74 41 dr)

117

The substitution at C4 in 483 and 486 played an important role in determining

the diastereoselectivity of the product of the PKR of each substrate (Scheme 433)

Analysis of the alkene confirmations 495 and 497 leading to the cobalt cis-metallacyle

intermediates 499 and 4101 could account for the divergent diastereoselectivites

Treatment of 483 with Co2(CO)8 can lead to two alkene conformations 495 and 497

and alkene conformation 495 was strongly favored due to the magnitude of the A13-

steric interaction between the large silyl ether and the large cobalt complex in 497 As a

result 493 was obtained as the exclusive product Treatment of 486 with Co2(CO)8 can

give two alkene conformations 496 and 498 which lead to the cis-metallacycles 4100

and 4102 Presumably the difference in the magnitude of the A13-steric interactions in

the alkene conformations 496 and 498 when C4 is a methylene group is not as

pronounced as when an axial silyl ether is present at C4 Thus the transition states

leading to the cis-metallacycles 4100 and 4102 are close in energy and a mixture of

diastereomers 494 and 4104 was obtained However since the A13-interaction between

the axial hydrogen at C4 and the cobalt complex as in 498 is larger than that between the

179

axial hydrogen at C4 and the allyl group in 496 then ultimately 494 is the favored

diastereomer

180

Scheme 433

N OBn

O

H

H

CbzN

H

HO

HCbzN

H

HO

H

H

R

(CO)2Co(CO)3Co

N OBn

O

H

H

R

H

(CO)2Co

Co(CO)3

R R

NCbz

Co2(CO)8

N OBn

O

HH

Co Co

(CO)3 (CO)3

N OBn

O

H

H

CoCo

(CO)3 (CO)3

H

R R

H

R

483 R = OTBS486 R = H

4

495 R = OTBS496 R = H

497 R = OTBS498 R = H

499 R = OTBS4100 R = H

4101 R = OTBS4102 R = H

493 R = OTBS494 R = H

4103 R = OTBS4104 R = H

181

These experiments represent the first application of the PKR to prepare azabicylic

structures and clearly demonstrate that the PKR is a useful tool for the synthesis of these

biologically important ring structures In many cases the PKR is highly

diastereoselective delivering only one of two possible diastereomers The PKR of cis-

26-disustituted piperidine enynes introduces a new cyclopentenone ring as well as a new

stereocenter allowing one to rapidly build complex alkaloid structures from easily

accessed enyne substrates A number of cis-26-disubstituted piperidine enyne substrates

were prepared and cyclized and the PKR of these substrates enabled access to varying

ring sizes and piperidine substitution The piperidine nitrogen atom can be functionalized

as a carbamate amide and sulfonamide and thus a number of N-protected azabicyclic

structures can be efficiently obtained Until our work the application of the PKR in

complex molecule synthesis had been overwhelmingly restricted to the synthesis of fused

ring systems and we anticipate that these new variants of the PKR will find expanded

utility in the realm of target directed synthesis

44 Total Synthesis of (-)-Alstonerine

441 Retrosynthesis

The PKR disconnection leading to 4106 as a key intermediate inspired the

following retrosynthesis (Scheme 434) Alstonerine (41) would ultimately arise by

reduction elimination and acylation of the lactone 4105 which could simply be

obtained via a Baeyer-Villiger oxidation of the cyclopentenone 4106 The

cyclopentenone 4106 was envisioned as coming from a PKR of 4107 which has

previously been prepared in the Martin group from natural L-tryptophan (4108)121 A

particular advantage of this PKR approach to 41 is that the D- and E- rings are

182

simultaneously assembled by the PKR and the cyclopentenone product 4106 contains all

of the carbon atoms in the core of alstonerine (41) Preparation of alstonerine beginning

with natural L-tryptophan (4108) is potentially more economical than Cookrsquos previous

syntheses which commence with the more expensive unnatural D-tryptophan

Scheme 434

H

H

H

HNMe

MeN

O

O

H

H

NH

CbzN

O

H

NMe

CbzN

O

H

O

NH

NCbz

NH

NH2

CO2H

Baeyer-Villiger

414105

4106 4107 4108

PKR

H

H

442 Pauson-Khand Reaction

Following chemistry originally developed by Dr Christopher Neipp121 the enyne

496 was synthesized in four steps (Scheme 435) Namely successive treatment of L-

tryptophan (4108) with formic acidacetic anhydride and then formic acidHCl gave the

dihydro-β-carboline 4109 as the hydrochloride salt The dihydro-β-carboline 4109 was

then treated with Et3N and excess Cbz-Cl followed by addition of methanol and more

Et3N to give the aminal 4110 Treatment of 4110 with allyl TMS in the presence of

BF3Et2O gave a mixture (551) of cistrans allylated compounds from which 4111

could easily be separated by recrystallization or chromatography The stereochemistry of

183

the major isomer 4111 was confirmed in subsequent experiments Reduction of the

methyl ester 4111 to the corresponding aldehyde and subsequent addition of NaOMe and

the Bestmann-Ohira reagent gave the enyne 4107 148

Scheme 435

NH

NH2

CO2H

i) HCO2H Ac2Oii) HCl HCO2H

60 NH

NHCl

CO2H

i)Et3N CbzCl

CH2Cl2

ii) MeOH Et3N87 N

H

NCbz

CO2Me

OMe

TMS

BF3Et2O

CH2Cl281

51 cistrans

NH

NCbz

CO2MeDIBAL-H

toluene -78 degC

then MeOH NaOMe THF(MeO)2P(O)C(=N2)COMe

60NH

NCbz

4108 4109 4110

4111 4107

The yields of 4107 were variable and often suffered on scale-up Because no

other side products were observed in the conversion of 4111 to 4107 we hypothesized

that deprotonation of the free indole moiety in 4111 and subsequent oxidation might be a

likely degradation pathway To test this hypothesis tosyl protected indole substrate

4112 and Boc-protected substrate 4114 were individually treated with DIBAL-H

followed by the Bestmann-Ohira reagent MeOH and a base (Scheme 436) None of

the reaction conditions employed resulted in a marked increase of the isolated yield of the

indole enyne 4113 or 4115 However analysis of the nature of the base used in the

reaction showed that sodium methoxide typically gave yields superior to those of K2CO3

184

Scheme 436

N

NCbz

CO2Me

N

NCbz

R R

4111 R = H4112 R = Ts4114 R = Boc

4107 R = H4113 R = Ts4115 R = Boc

DIBAL-Htoluene -78 degC

then MeOH NaOMe or K2CO3

(MeO)2P(O)C(=N2)COMe

20-60

In the course of investigating other protocols for converting aldehydes to alkynes

such as Corey-Fuchs reaction the aldehyde 4116 was required DIBAL-H reduction of

the methyl ester 4114 and followed by quenching at low temperature furnished the

aldehyde 4116 (Eq 43) but warming to room temperature resulted in rapid

decomposition and the instability of aldehydes with electron withdrawing groups in the

α-position is well documented149

N

NCbz

CO2Me

Boc

N

NCbz

CHO

Boc


rapid decomp at rt

4114 4116

(43)

In light of these observations we sought to minimize the exposure of the

intermediate aldehyde to temperatures in excess of -78 ˚C for any significant period of

time Dr Neipprsquos procedure (Scheme 435) involved addition of the Bestmann-Ohira

reagent as a solution in THF after removal of the dry iceacetone bath but we

hypothesized that on scale up the addition of large volumes of solvent would increase the

reaction temperature to a greater extent Thus the same two-step procedure shown in

185

Scheme 434 was followed to convert 4111 to 4107 but all of the reagents were added

before removal of the dry iceacetone bath The modified reaction conditions led to

reproducible yields of 4107 (Eq 44)

NH

NCbz

CO2MeDIBAL-H

toluene -78 degC


-78 degC -rt60

NH

NCbz

3111 3107

(44)

The PKR of 4107 proceeded smoothly to furnish the cyclopentenone 4106 as a

single stereoisomer in excellent yield (Scheme 437) Since the PKR generated a new

stereocenter we sought to determine its configuration and compare the stereochemistry to

that found in alstonerine (41) Although 4106 was not crystalline Boc protection of the

indole moiety gave 4117 which was a crystalline compound suitable for X-ray analysis

Scheme 437

NH

NCbz

NH

CbzN

O

H

Co2(CO)8DMSO (6 eq)

THF 65 degC92 H

H

NBoc

CbzN

O

H

H

HBoc2ODMAP

CH3CN 99

4117

4107 4106

186

The X-ray structure of 4117 showed that the hydrogen atom on the newly formed

stereocenter at C15 was oriented trans to the bridging nitrogen atom (Figure 43) and this

stereochemical relationship is present in alstonerine (41) as well as all other

macrolinesarpagine alkaloids Thus one can envision that 4117 could serve as a

common intermediate for the synthesis of a variety of other macroline alkaloids such as

talcarpine (360) and raumacline (3111)


NBoc

CbzN

O

H

H

H

4117

15

The high diastereoselectivity in the PKR of 4107 can be rationalized by analysis

of the two alkene conformations 4118 and 4119 that lead to the two cis-metallacycles

4120 and 4121 (Scheme 438) We hypothesize that the conformation 4119 is

disfavored due to the steric interaction between the indole ring and the cobalt complex

As a result the conformer 4118 is preferred which reacts further to give the

metallacycle 4120 and ultimately the observed diastereomer 4106

187

Scheme 438

NH

CbzN

O

H

NH

NCbz

Co2(CO)8

4107

4118

4106 4122

H

H

NH

CbzN

O

H

H

H

CoCbzN

BocN

H

H

H

Co

(CO)3

(CO)3

CbzN

BocN

H

H

H

Co

Co (CO)3

(CO)3

CoCbzN

BocN

H

H

H

Co

(CO)3

(CO)3

CbzN

BocN

H

H

HCo

Co(CO)3

(CO)3

4119

41204121

443 Baeyer-Villiger Approach

The successful PKR of 4107 to give 4106 thus set the stage to evaluate

conditions to effect the desired Baeyer-Villiger reaction of 4106 to access the

188

unsaturated lactone 4105 (Scheme 439) Initially it was hoped that protection of the

indole could be avoided Toward this end the PKR product 4106 was treated with NaH

and MeI to introduce the N-methyl group present in the natural product However all

Baeyer-Villiger conditions attempted on 4123 (mCPBA CF3CO3H) gave complicated

reaction mixtures presumably due to oxidation of the indole ring in 4123

Scheme 439

NH

CbzN

O

4106

H

H

H

NMe

CbzN

O

4123

H

H

H

NaH MeI DMF91

Baeyer-Villiger

X

NMe

CbzN

4105

H

H

H

OO

We then envisioned that protection of the indole moiety of 4106 as the

corresponding carbamate 4117 would attenuate the nucleophilicity of the indole and

suppress side reactions involving indole oxidation (Scheme 440) Utilization of peracid

oxidants mCPBA or peroxytrifluoroacetic acid to effect a Baeyer-Villiger reaction on

4117 did not give the desired unsaturated lactone 4105 but instead the lactoneepoxide

4124 was isolated150 Use of basic hydrogen peroxide a reagent known to induce

Baeyer-Villiger reactions of strained ketones151 only gave the epoxide 4125 The

stereochemistries associated with the epoxides of 4124 and 4125 are tentatively

189

assigned based on subsequent experiments and molecular models which indicated that

the α-face of the alkene of 4117 is the more sterically accessible face

Scheme 440

NBoc

CbzN

O

4117

NBoc

CbzN

O

4125

O

MCPBACH2Cl2 60

orCF3COOOH

Na2HPO4CH2Cl2 99

H2O2NaOH

THFMeOH

H

H

H

H

H

H

NBoc

CbzN

4124

H

H

H

OO

O

78

Although the Baeyer-Villiger reaction of 4117 did not provide the desired

unsaturated lactone 4105 a Baeyer-Villiger reaction did indeed occur the intermediate

enol ether simply oxidized further We then examined whether the unsaturated lactone

4105 might be prepared by deoxygenating the lactoneepoxide 4124 (Eq 45) Lactone

4124 was treated with a number of deoxygenation reagents (Cp2TiCl2 Zn WCl6

nBuLi diazodimethyl malonate Rh(OAc)2 I2 PPh3)152 but all these reactions returned

either starting material or intractable mixtures

190

NBoc

CbzN

4124

H

H

H

OO

O

deoxygenationX

NBoc

CbzN

4105

H

H

H

OO

(45)

444 HydrosilylationOxidative Cleavage Approach

Since we could not access 4105 either by Baeyer-Villiger reaction of 4117 or

deoxygenation of 4124 a modified retrosynthesis for alstonerine (41) was devised

(Scheme 441) The saturated lactone 4127 would arise from reduction of the aldehyde

4128 followed by lactonization The aldehyde 4128 was envisioned as coming from an

oxidative cleavage of the silyl enol ether 4129 which in turn could be accessed from

4106 by a stereoselective hydrosilylation

Scheme 441

HNR

CbzN

O

H

OH

4127

H

HNR

CbzN

CO2RCHO

H

H

4128

H

HNH

CbzN

O

H

4106

H

HNR

CbzN

OSiR3

H

4129

H H

Numerous reaction conditions were screened to obtain the silyl enol ether 4130

from enone 4117 We first tried to access the silyl enol ether 4130 by 14-reduction of

the enone 4117 followed by trapping of the intermediate enolate with TES-Cl (Table

191

41)153 but reaction of 4117 with NaNH3(l) or Li-naphthalenide led to decomposition

Following chemistry developed by Saegusa154 the enone 4117 was treated a ldquoCu-Hrdquo

species which was generated in situ by addition of DIBAL-H to MeCu followed by

addition of TES-Cl Only the saturated ketone 4131 was isolated from these attempts A

small amount of silyl enol ether 4130 was obtained when 4117 was treated with a ldquoCu-

Hrdquo reagent generated from PPh3 CuCl and Et3SiH155 Treatment of 4117 with catalytic

Wilkinsonrsquos catalyst and Et3SiH was ineffective and did not give any 4130 but use of

stoichiometric amounts ofWilkinsonrsquos catalyst and Et3SiH gave a small amount of

4130156

192

Table 41 Reductive Silyl Enol Ether Formation

NBoc

CbzN

OH

H

Hconditions

NBoc

CbzN

OSiEt3H

H

H

Conditions Yield 4121

CuI MeLi HMPADIBAL-H then TES-Cl -------

RhCl(PPh3)3 (100 mol) Et3SiH 23

PPh3 CuCl NaOtBuEt3SiH toluene

25

41304117

Na NH3(l) then TES-Cl

Li naphthalenide TES-Cl

Entry

-------

-------1

2

3

5

4

NBoc

CbzN

OH

H

H

4131

+

H H

ββ-Disubstituted enones are notoriously poor substrates for conjugate additions

and hydrosilylations and the results of the above experiments suggested that a

particularly reactive catalyst was required Johnson and coworkers published a method

for the hydrosilylation of ββ-disubstituted enones using catalytic platinum

divinyltetramethyl disiloxane complex (Karstedtrsquos catalyst) in the presence of bulky

trialkylsilanes157 Gratifyingly treatment of enone 4117 with 01 mol of Karstedtrsquos

catalyst in the presence of five equivalents of iPr3SiH at elevated temperature gave the

TIPS-silyl enol ether 4132 in excellent yield (Scheme 442) Less bulky silanes such as

193

TES-H and TBS-H provided a significant amount of the saturated ketone 4131 (~20-

30) presumably via silane dimerization that formed molecular hydrogen that simply

reduced the alkene in the presence of the platinum catalyst158

Scheme 442

Me2Si

O

Me2Si

2

Pt

iPr3SiH Toluene80 degC 93

NBoc

CbzN

OH

H

H

NBoc

CbzN

OTIPSH

H

H

4132

4117

H

NBoc

CbzN

OH

H

H

4131

H

NBoc

CbzN

OTESH

H

H

4130

HMe2Si

O

Me2Si

2

Pt

Et3SiH Toluenert 99

41304131 = 41

+

In order to determine the stereochemistry of the hydrosilylation of 4117 the silyl

enol ether 4132 cleaved to afford the ketone 4131 which was converted to the

crystalline amino-alcohol 4133 by reduction of the ketone group and removal of the

nitrogen protecting groups (Scheme 443) X-ray analysis of 4133 confirmed that the

relative stereochemistry of 4133 matched that of alstonerine (41) insofar as the

hydrogen atom on the newly formed stereocenter was oriented trans to the bridging

nitrogen atom

194

Scheme 443

NBoc

CbzN

OTIPSH

H

TBAF3H2O

THF 66

NBoc

CbzN

OH

H

NH

HN

OHH

H

1 NaBH4 THF2 Silica gel 80 degC 01 mm Hg

3 H2 PdC EtOAc 45 over 3 steps

H

H

H

H

H

H

4133

4132 4131

Oxidative cleavage of the silyl enol ether 4132 was first attempted via

ozonolysis but the reaction did not proceed to give 4134 as desired (Eq 46) While 1H

NMR resonances consistent with the presence of an aldehyde were observed mass

recovery was low and the reaction mixtures were difficult to purify because numerous

compounds were present Efforts to limit the amount of ozone introduced by preparing

stock solutions or by using Sudan Red as an indicator were not effective While ozone is

a common reagent for the oxidative cleavage of silyl enol ethers the presence of other

oxidizable functional groups can present a problem of selectivity because ozone is a

strong oxidizing agent

195

NBoc

CbzN

OTIPSH

H

H

H

ozonolysis

NBoc

CbzN

CHOH

H

CO2TIPS

4132 4134

X (46)

The failure of the ozonolysis of 4132 to induce clean oxidative cleavage of the

silyl enol ether led us to revise our approach to include more mild cleavage conditions

(Scheme 444) A two step procedure was envisioned in which 4128 could be obtained

by cleavage of the α-hydroxy ketone 4135 which might arise from Rubbottom oxidation

of the silyl enol ether 4136

Scheme 444

HNR

CbzN

OSiR3

H

4136

H H

HNR

CbzN

CO2RCHO

H

H

4128

H

HNR

CbzN

O

H

4135

H HHO

In the event Rubbottom oxidation of 4132 gave low yields of the hydroxy ketone

4137 when mCPBA was utilized as the oxidant and buffering the reaction with NaHCO3

or Na2HPO4 did not improve the yield (Eq 47) In each case the reaction of 4132 was

rather messy giving a multitude of products Oxidation of 4132 with dimethyldioxirane

also was also examined but this reaction too was not clean159

196

HNBoc

CbzN

OTIPS

H

4132

H H

HNBoc

CbzN

O

H

4137

H HHO

mCPBA

CH2Cl20-20

(47)

Although Rubbottom oxidations of TIPS-silyl enol ethers are relatively rare such

oxidations of TMS-silyl enol ethers are much more common Magnus has shown that

oxidation of TIPS-silyl enol ethers generates a stable epoxide intermediates such as

4139 that can react further to give an oxonium ion 4140 which can be trapped with the

m-chlorobenzoate anion to give 4141 (Scheme 445)160 The authors also observed

benzoyl transfer to give 4143 A distribution of the various stable intermediates as well

as the desired hydroxyketone 4137 could account for the complicated reaction mixtures

Scheme 445

O

O

OOCOR

OTIPS mCPBAOTIPS

O

OTIPS

OH

H+

4138 4139 4140

OTIPS

OH

4141

RCO2-

OTIPS

4142

O

ROCOR

4143

Osmium tetroxide is also well known for transforming silyl enol ethers to α-

hydroxy ketones Following the precedent set by McCormick treatment of 4132 with

catalytic OsO4 with NMO as the stoichiometric oxidant gave the desired α-hydroxy

ketone 4137 in low yield with the remainder of the mass balance being recovered silyl

197

enol ether 4132 (Table 42)161 One hypothesis for the low conversion was slow

cleavage of the osmate ester intermediate Acceleration of osmate ester cleavage can be

accomplished by increasing the pH of the solution or by adding an amine base but both

of these modifications completely shut down the reaction162 Addition of methyl

sulfonamide a tactic used by Sharpless to accelerate dihydroxylation reactions slightly

increased the yield of 4137163 Discouraged by the lack of success using catalytic

dihydroxylation conditions 4132 was treated with stoichiometric OsO4 and complete

consumption of starting material was observed Cleavage of the resulting osmate ester

was best achieved by bubbling H2S through the reaction mixture164 and thus a good yield

of the α-hydroxy ketone 4137 was obtained Success of the stoichiometric osmylation

conditions supports the hypothesis that osmate ester cleavage is extremely slow and thus

the catalytic cycle is effectively shut down Perhaps the large TIPS-group blocks the

osmate ester from the nucleophilic displacement necessary to free the osmium and allow

it to reenter the catalytic cycle

198

Table 42 OsO4 Oxidation of 4137

NBoc

CbzN conditions

OTIPSH

H

NBoc

CbzN

OH

H

HO

Conditions

4132 4137

Entry Yield 4137

1 OsO4 (10) NMO (22 eq) THFH2O 23

2 OsO4 (10) NMO (22 eq) K2CO3 (3 eq) THFH2O no reaction after 48 h

3 OsO4 (10) NMO (22 eq) pyridine (22 eq) tBuOHH2O no reaction after 24 h

4 OsO4 (10) NMO (11 eq) CH3SO2NH2 (2 eq) THFH2O 28 5 OsO4 (10) TMANO (11 eq) THFH2O 36

6 OsO4 (11 eq) THF then aq NaHSO3 reflux 61

7 OsO4 (11 eq) THF then H2S 74

H

H

H

H

With the α-hydroxy ketone 4137 in hand we turned to the synthesis of the

lactone 4145 (Scheme 446) Oxidative cleavage of 4137 was effected with Pb(OAc)4

in the presence of MeOH and when the reaction was complete excess NaBH4 was added

to give the hydroxy methyl ester 4144 Because acidic conditions were required to

lactonize the hydroxyester 4144 4144 was treated with catalytic pTsOH to

quantitatively provide the key lactone 4145

199

Scheme 446

NBoc

CbzN

OH

H

HO

4137

H

H

Pb(OAc)4 (2 eq)benzene MeOH

then NaBH4 (10 eq)72

4144

NBoc

CbzN

OH

CO2Me

H

H

HNBoc

CbzN

O

H

OH

4145

H

pTsOH CH2Cl2

99

Despite the success of this approach to the lactone 4145 use of toxic osmium and

lead reagents in stoichiometric amounts prompted us to explore more environmentally

benign routes to 4145 (Scheme 447) While the oxidative cleavage of silyl enol ethers is

well known surprisingly the use of Johnson-Lemeiux conditions to effect such

transformations is rare165 Fortunately we found that the silyl enol ether 4132 was

oxidatively cleaved using a catalytic amount (10 mol) of OsO4 and NaIO4 to give an

intermediate aldehydecarboxylic acid 4146 The crude reaction mixture was then simply

treated with NaBH4 to afford a hydroxylactone that cyclized upon quenching the reaction

with acid to deliver the lactone 4145 in 55 overall yield The one-step Johnson-

Lemeiuxreduction sequence is slightly higher yielding compared with the stoichiometric

osmylationoxidative cleavagelactonization sequence

200

Scheme 447

H

H

4145

NBoc

CbzN

OTIPS

H

HOsO4 (10)NaIO4 (4 eq)

THFH2O 51

NBoc

CbzN

CHO

CO2H

NBoc

CbzNH

H OO

NaBH4 MeOH

then TsOHH2O55 2 steps

H

H

H

H

4132 4146

445 Acylation Strategies

With an efficient route to 4145 it was time to explore tactics to complete the

synthesis of alstonerine (41) Reduction of the lactone 4145 to the corresponding lactol

followed by mesylation and elimination provided the dihydropyran 4147 (Scheme 448)

The dihydropyran 4147 was then treated with LiAlH4 in refluxing THF to reduce the

carbamate to an N-methyl group and remove the N-indole protecting group to provide the

tertiary amine 4148 The indole nitrogen in 4148 was then alkylated under standard

conditions to give 4149

201

Scheme 448

LiAlH4

THF reflux 99

NaHthen MeI

DMF 88

NBoc

CbzNH

H OO

H

H

4145

NBoc

CbzNH

H OH

H

4147

1 DIBAL-H toluene -78 degC 90

2 MsCl Et3N THF 67

NH

MeNH

H OH

H

4148

NMe

MeNH

H OH

H

4149

At this point only acylation of the dihydropyran 4149 remained (Scheme 449)

Methods for acylating dihydropyrans at the β-carbon are few and the most common

method is the Friedel-Crafts reaction However when 4149 was treated with a number

of acylating agents (Ac2O AcCl) and Lewis acids (AlCl3 BF3 ZnCl2)166 the major

product was typically the diacylated product 4150 Only trace amounts of 41 were

obtained

202

Scheme 449

NMe

MeNH

H O

Friedel-Crafts acylation

NMe

MeNH

H O

O

+

NMe

MeNH

H O

O

O

Lewis Acids AlCl3 BF3Me2S ZnCl2

Acetylating Agents AcCl Ac2OBases Di-tBu-PyridineSolvents neat CH2Cl2 DMF

H

H

H

H

H

H

4149

41

4150

The only other common method for appending acyl groups to the β-carbon of

dihydropyrans is the Vilsmeier reaction and procedures using dimethylacetamide and

either POCl3 or the more reactive Tf2O have been disclosed167 However when 4149

was treated with with a ldquoVilsmeierrdquo-type reagent generated from dimethylacetamide and

either POCl3 or Tf2O none of the natural product 41 was observed even after extended

reaction times and heating (Eq 48) In each case only starting material 4149 was

recovered

NMe

MeNH

H OH

H

4149

NMe

MeNH

H O

O

H

H

41

NMe2

O

POCl3 or Tf2OX (48)

We reasoned that the presence of the N-Boc group on the indole would suppress

the formation of side products from acylation of the 5-position of indole that plagued

203

previous Friedel-Crafts attempts However the strong Lewis acids required to activate

the acylating agents toward attack by the dihydropyran 4147 also effected carbamate

deprotection (Scheme 451)

Scheme 450

NBoc

CbzNH

H O


NBoc

CbzNH

H O

O



H

H H

H

4147 4152

Instead of directly introducing an acyl group to 4149 appending a trichloroacyl

group followed by subsequent reduction to the acyl moiety can be envisioned (Scheme

450) Such a strategy could be advantageous because trichloroacyl groups have been

appended to the β-carbon of dihydropyrans by simply heating in the presence of

trichloroacetyl chloride without the need for a Lewis acid168 Unfortunately treatment of

4149 with trichloroacetyl chloride even at room temperature led to decomposition

204

Scheme 451

NMe

MeNH

H OH

H

4149

NMe

MeNH

H O

Cl3CO

H

H

4151

X

[H]

NMe

MeNH

H O

O

H

H

41

Cl3C

O

Cl

Previous experiments in the Martin group conducted in the context of the

preparing yohimboid indole alkaloids showed that reactions of dihydropyrans with

trichloroacetyl chloride led to decomposition products when the substrate contained a

tertiary amine or a free indole168 On the other hand high yields of trichloroacylated

dihydropyrans were obtained if the free amine and indole nucleus were protected as

carbamates Encouraged by these reports the synthetic route was slightly modified and

we attempted introduction of a trichloroacyl group prior to carbamate deprotection In

the event trichloroacylation of the dihydropyran 4147 proceeded most efficiently using

pyridine as solvent at elevated temperatures to provide 4153 (Scheme 452) The crude

trichloroketone 4153 thus obtained was treated with ZnAcOH and the vinylogous ester

4154 was obtained in good yield and high purity over two steps after a single

chromatographic purification This reaction sequence should prove widely useful for the

facile synthesis of C-2 acylated glycals a motif widely found in biologically active

natural products169

205

Scheme 452

NBoc

CbzNH

H OH

H

4147

NBoc

CbzNH

H O

Cl3CO

H

H

4153

NBoc

CbzNH

H O

O

H

H

4152

ClCO2CCl3

pyridine 65 degC

Zn AcOH

75 2 steps

446 Completion of the Total Synthesis

Completion of the synthesis of alstonerine (41) from 4152 required carbamate

deprotection and introduction of the two N-methyl groups For the sake of brevity we

hoped to develop conditions to remove both carbamates in 4152 in one step and then

introduce both N-methyl groups in a second step to deliver 41 Direct reduction of the

carbamates in 4152 as before was not an option due to the presence of the newly

appended acyl group We thus turned to the use of TMS-I to remove both of the

carbamates in 4152 and found that treatment of 4152 with freshly distilled TMS-I in the

dark cleanly gave 4154 (Eq 49)

NBoc

CbzNH

H O

O

H

H

4152

NH

HNH

H O

O

H

H

4154

TMS-I

CH3CN78

(49)

206

The task of introducing the methyl groups was slightly more troublesome If the

substrate 4154 was first treated with NaH followed by MeI then a mixture of alstonerine

(41) as well as varying amounts of the 4155 4156 and 4157 were obtained (Scheme

453) Because these side products differ by only a methyl group isolating each by

chromatography was difficult

Scheme 453

NMe

MeNH

H O

O

H

H

41

NMe

HNH

H O

O

H

H

4155

NH

MeNH

H O

O

H

H

4156

NMe

MeNH

H O

O

H

H

4157

NaH then MeI

DMF

side products

NH

HNH

H O

O

H

H

4154

Eventually we found that the natural product 41 was obtained cleanly when 4154

was treated with MeI in THF to first methylate the bridging secondary amine and then

NaH and additional MeI were added to alkylate the more recalcitrant indole nitrogen

atom (Eq 410) The spectral data for synthetic 41 (1H and 13C NMR)129 were consistent

with those previously reported and the optical rotation ([α]25D = -187 (c 030 EtOH))

was compared favorably to that reported in the literature ([α]25D = -190 (c 032

EtOH))128

207

NMe

MeNH

H O

O

H

H

41

NH

HNH

H O

O

H

H

4154

MeI (2 eq)THF

then NaH (3 eq)MeI (3 eq)

72

(410)

Scheme 454 outlines our total synthesis of alstonerine (41) and this concise

approach to 41 required only 11 steps from the known enyne 4107 and 15 steps from

natural L-tryptophan (4108) in 44 overall yield The PKR of 3107 is the first

application of the PKR toward the synthesis of azabridged bicyclic structures in the realm

of natural product synthesis We expect that the pentacyclic intermediate 4106 will find

use in the syntheses of other biologically active alkaloids because the stereochemistry of

4106 is analogous to that found in the macroline sarpagine and ajmaline families of

alkloids Enone hydrosilylation followed by oxidative cleavage allowed the rapid

preparation of the lactone 4145 from 4117 is only three reaction vessels A mild two-

step protocol was developed to acetylate enol ethers was developed that we expect will

find widespread utility in the preparation of these biologically important compounds169

208

Scheme 454

NH

CbzN

O

H

Co2(CO)8DMSO

THF 65 degC92 H

H

4106

NBoc

CbzN

O

H

H

HBoc2ODMAP

CH3CN99

4117

Me2Si

O

Me2Si

2

Pt


NBoc

CbzN

OTIPSH

H

H

4132

H H

H

4145

1 OsO4 (10) NaIO4 (4 eq)

THFH2O 51

NBoc

CbzNH

H OO

2 NaBH4 MeOH


NBoc

CbzNH

H OH

H

4147


2 MsCl Et3N THF 67

TMS-I

CH3CN78

NBoc

CbzNH

H O

O

H

H

4152

1 Cl3CCOCl pyr 65 degC

2 Zn AcOH 75 2 steps

NH

HNH

H O

O

H

H

4154

NMe

MeNH

H O

O

H

H

41

MeI THF

then NaH MeI72

NH

NH2

CO2H


60 NH

NHCl

CO2H

i)Et3N CbzCl

CH2Cl2

ii) MeOH Et3N87 N

H

NCbz

CO2Me

OMe

TMS

BF3Et2O

CH2Cl281

51 cistrans

NH

NCbz

CO2Me

NH

NCbz

4108 4109 4110

4111 4107



-78 degC -rt60

209

45 Conclusions

Before our work the synthesis of azabridged bicyclic structures via PKR was

unknown and application of the PKR to the synthesis of bridged structures in general

was extremely limited We found that the PKR of cis-26-disubstituted piperidines not

only gave the corresponding azabridged bicyclic structures but these products are

typically obtained in high yield and high diastereoselectivity Thus these experiments

represent the first application of the PKR to synthesize azabridged bicyclic structures

Since azabridged bicycles are present in a large number of biologically active substances

we expect that the PKR strategy will prove useful for the facile preparation of many of

these molecules Preliminary experiments indicated that cis-25-disubstituted

pyrrolidines do not undergo PKR

The utility of the PKR to prepare azabridged bicyclic structures was demonstrated

in the facile enantioselective total synthesis of alstonerine (41) Notably the total

synthesis of alstonerine (41) addressed many of the shortcomings of previous syntheses

of macroline natural products including 41 Specifically PKR of a readily available

enyne 4107 offered rapid access to a versatile cyclopentenone intermediate 4106 which

contained all the carbons in the core of alstonerine (41) and the highly stereoselective

nature of the PKR of 4107 gave a single enantiomer 4106 possessing stereochemistry

analogous to the entire class of macroline alkaloids Thus the PKR could prove to be a

general strategy for the syntheses of a number of members of the macroline family

While previous syntheses of alstonerine (41) required long reaction sequences to install

the acyl-dihydropyran E-ring the PKR approach delivers a cyclopentenone ring that can

easily and quickly be manipulated to ultimately give alstonerine (41) Our synthesis

210

required 15 steps from natural L-tryptophan (4108) to obtain alstonerine (41) in a 44

overall yield whereas Cookrsquos best synthesis gave 41 in 16 steps and 121 overall yield

from the unnatural D-tryptophan methyl ester While Cookrsquos overall yield is slightly

better than ours Cook required more steps to arrive at 41 Also Cookrsquos synthesis began

with D-tryptophan methyl ester ($1082g) which is much more costly than the L-

tryptophan ($046g) we used In lieu of a Baeyer-Villiger oxidationalkene reduction

sequence an equally concise two step hydrosilationoxidative cleavage sequence was

employed to ring expand a cyclopentenone ring to a six-membered lactone A mild

strategy for appending acyl groups to the β-carbon of dihydropyrans was developed

which is a common motif found in a number of biologically active natural products169

We anticipate that the precedent set by the PKR of cis-26-disubstituted piperidines

especially in the context of the synthesis of alstonerine (41) will considerably expand

the use of the PKR in complex alkaloid synthesis

211

Chapter 5 Experimental Procedures

51 General

Unless otherwise noted solvents and regents were used without purification

Methylene chloride (CH2Cl2) was distilled from calcium hydride prior to use

Tetrahydrofuran (THF) was dried by passage through two columns of activated neutral

alumina Ethyl acetate (EtOAc) was distilled from CaH2 and stored over 4 Aring molecular

sieves All solvents were determined to contain less than 50 ppm H2O by Karl Fischer

coulomeric moisture analysis Reactions involving air or moisture sensitive reagents or

intermediates were performed under an inert atmosphere of argon in glassware that had

been oven or flame dried Reagents were purchased from Aldrich and used without

further purification unless indicated otherwise Thin-layer chromatography (TLC) was

performed on EM 250 micro silica gel plates The plates were visualized by staining with

PAA (anisaldehyde) or potassium permanganate Flash chromatography was performed

with ICN Silica gel 60 according to established protocol170

The 1H and 13C NMR spectra were obtained on a Varian MERCURY 400 or a

Varian Unity 300 spectrometer operating at 400 (300) and 100 (75) MHz respectively

Unless indicated otherwise all spectra were run as solutions in CDCl3 The 1H NMR

chemical shifts are reported in parts per million (ppm) downfield from tetramethylsilane

(TMS) and are in all cases referenced to the residual protio-solvent present (δ 724 for

CHCl3) The 13C NMR chemical shifts are reported in ppm relative to the center line of

212

the multiplet for deuterium solvent peaks (δ 770 (t) for CDCl3) 13C spectra were

routinely run with broadband 1H decoupling Coupling constants for all spectra are

reported in Hertz (Hz) Low-resolution chemical ionization (CI) mass spectra were

performed on Finnigan MAT TSQ-70 instrument HRMS were made with a VG

analytical ZAB2-E instrument

52 Compounds

6

51 23

4

78

O

O

O

217

Carbonic acid methyl ester 1-methylpent-2-enyl ester (217) KAM1-194

Methyl chloroformate (945 mg 0772 mL 10 mmol) was added to a solution of hex-3-

en-2-ol (501 mg 5 mmol) and pyridine (791 mg 0806 mL 10 mmol) in CH2Cl2 (10 mL)

at 0 ˚C The reaction was warmed to rt and stirred for 12 h Brine (20 ml) was added and

the layers were separated The aqueous layer was extracted with CH2Cl2 (3 x 15 mL)

The combined organic layers were washed with 1 N HCl (2 x 20 mL) sat NaHCO3 (2 x

20 mL) and brine (2x 20 mL) dried (Na2SO4) and concentrated under reduced pressure

The residual oil was purified by flash chromatography eluting with hexaneether (51) to

give 514 mg (65) of 217 as a colorless oil 1H NMR (300 MHz) δ 568 (dt J = 156

60 Hz 1 H) 535 (dd J = 156 72 Hz 1 H) 504 (app p J = 67 Hz 1 H) 363 (s 3 H)

193 (app p J = 72 Hz 2 H) 122 (d J = 67 Hz 3 H) 087 (t J = 72 Hz 3 H) 13C

213

NMR (75 MHz) δ 1549 1354 1277 752 541 249 201 128 IR (neat) 2964 2876

1747 1443 1331 1267 1039 cm-1 mass spectrum (CI) mz 1570869 [C8H13O3 (M+1)

requires 1570865] 157 (base) 113

NMR Assignments 1H NMR (300 MHz) δ 568 (dt J = 156 60 Hz 1 H C4-

H) 535 (dd J = 156 72 Hz 1 H C3-H) 504 (app p J = 67 Hz 1 H C2-H) 363 (s 3

H C8-H) 193 (app p J = 72 Hz 2 H C5-H) 122 (d J = 67 Hz 3 H C1-H) 087 (t J

= 72 Hz 3 H C6-H) 13C NMR (75 MHz) δ 1549 (C7) 1354 (C3) 1277 (C4) 752

(C2) 541 (C8) 249 (C5) 201 (C1) 128 (C6)

O O

O

1

2

34

56

78

218

Carbonic acid 1-ethylbut-2-enyl ester methyl ester (218) KAM1-184 Methyl

chloroformate (945mg 0772 mL 10 mmol) was added to a solution of hex-4-en-3-ol

(501 mg 5 mmol) and pyridine (791 mg 0806 mL 10 mmol) in CH2Cl2 (10 mL) at 0

˚C and the reaction was stirred for 12 h at rt Brine (20 ml) was added and the aqueous

layer was separated The aqueous layer was extracted with CH2Cl2 (3 x 15 mL) The

combined organic layers were washed with 1 N HCl (2 x 20 mL) sat NaHCO3 (2 x 20

mL) and brine (2x 20 mL) dried (Na2SO4) and concentrated under reduced pressure

The residual oil was purified by flash chromatography eluting with pentaneether (51) to

214

give 599 mg (76) of 218 as a yellow oil 1H NMR (300 MHz) δ 575 (dt J = 153 63

Hz 1 H) 539 (dd J = 153 78 Hz 1 H) 490 (app q J = 69 Hz 1 H) 373 (s 3 H)

168 (d J = 63 Hz 3 H) 14-17 (m 2 H) 088 (t J = 75 Hz 3 H) 13C NMR (75 MHz)

δ 1552 1300 1287 804 542 273 175 93 mass spectrum (CI) mz 1570869

[C8H13O3 (M+1) requires 1570865]


H) 539 (dd J = 153 78 Hz 1 H C3-H) 490 (app q J = 69 Hz 1 H C4-H) 373 (s 3

H C8-H) 168 (d J = 63 Hz 3 H C1-H) 14-17 (m 2H C5-H) 088 (t J = 75 Hz 3

H C6-H) 13C NMR (75 MHz) δ 1552 (C7) 1300 (C3) 1287 (C2) 804 (C4) 542

(C8) 273 (C5) 175 (C1) 93 (C6)

6

6

5 61 2

3

4

78

O

O

O

225

Carbonic acid methyl ester 144-trimethylpent-2-enyl ester (225) (KAM1-

206) Methyl chloroformate (0724 mL 9375mmol) was added to a solution of 55-

dimethyl-hex-3-en-2-ol (600 mg 4687 mmol) and pyridine (0742 ml 9375 mmol) in

CH2Cl2 (10 mL) at 0 ˚C The reaction was warmed to rt and stirred for 12 h Brine (20

ml) was added and the layers were separated The aqueous layer was extracted with

CH2Cl2 (3 x 15 mL) The combined organic layers were washed with 1 N HCl (2 x 20

215

mL) sat NaHCO3 (2 x 20 mL) and brine (2x 20 mL) dried (Na2SO4) and concentrated

under reduced pressure to give a crude oil The crude product was purified by flash

chromatography eluting with hexaneether (51) to give 637 mg (73) of 225 as a

colorless oil 1H NMR (300 MHz) δ 569 (d J = 157 Hz 1 H) 532 (dd J = 157 71 Hz

1 H) 510 (p J = 66 Hz 1 H) 370 (s 3 H) 129 (d J = 66 Hz 3 H) 094 (s 9H) 13C

NMR (75 MHz) δ 1550 1446 1237 757 543 327 291 205

NMR Assignments 1H NMR (300 MHz) δ 569 (d J = 156 Hz 1 H C4-H)

532 (dd J = 159 72 Hz 1 H C3-H) 510 (p J = 69 Hz 1 H C2-H) 370 (s 3 H C8-

H) 129 (d J = 66 Hz 3 H C1-H) 094 (s 9H C6-H) 13C NMR (75 MHz) 1550 (C7)

1446 (C4) 1237 (C3) 757 (C2) 543 (C8) 327 (C5) 291 (C6) 205 (C1)

6

5

6

O O

O

1

2

34 6

78

226

Carbonic acid 1-tert-butylbut-2-enyl ester methyl ester (226) (KAM1-188)

Methyl chloroformate (0772 mL 10mmol) was added to a solution of 22-dimethylhex-

4-en-3-ol (641 mg 5 mmol) and pyridine (0806 ml 10 mmol) in CH2Cl2 (10 mL) at 0

˚C The reaction was warmed to rt and stirred for 12 h Brine (20 ml) was added and the

layers were separated The aqueous layer was extracted with CH2Cl2 (3 x 15 mL) The


216

mL) and brine (2x 20 mL) dried (Na2SO4) and concentrated under reduced pressure to

give a crude oil The crude product was purified by flash chromatography eluting with

hexaneether (51) to give 459 mg (49) of 226 as a colorless oil 1H NMR (400 MHz)

δ 574 (dt J = 138 64 Hz 1 H) 543 (dd J = 138 76 Hz 1 H) 470 (d J = 76 Hz 1

H) 373 (s 3H) 169 (d J = 64 Hz 3 H) 087 (s 9 H) 13C NMR (75 MHz) δ 1554

1313 1260 865 543 342 256 177


H) 543 (qd J = 138 76 Hz 1 H C3-H) 470 (d J = 76 Hz 1 H C4-H) 373 (s 3H

C7-H) 169 (d J = 64 Hz 3 H C1-H) 087 (s 9 H C6-H) 13C NMR (75 MHz) δ 1554

(C7) 1313 (C2) 1260 (C3) 865 (C4) 543 (C8) 342 (C5) 256 (C6) 177 (C1)

6

89

12

34

5

7

O O

OO

219

2-(1-Methylpent-2-enyl)malonic acid dimethyl ester (219) KAM2-066

Dimethyl malonate (825 mg 0071 ml 0625 mmol) was added to a suspension of NaH

(20 mg 60 dispersion in mineral oil 05 mmol) in dry DMF (15 mL) at -20 ˚C In a

separate flask 217 (395 mg 025 mmol) and [Rh(CO)2Cl]2 (97 mg 0025 mmol) were

dissolved in dry DMF (05 mL) The resulting sodium enolate was added via syringe to

the solution of 217 and [Rh(CO)2Cl]2 at -20 ˚C The reaction was stirred for 18 h at -20

217

˚C and the brown solids were removed by filtration through a short pad of silica washing

with Et2O The combined filtrate washings were concentrated under vacuum to give a

brown oil that was purified by chromatography eluting with hexaneEt2O (51) to give 47

mg (88) of 219 as a colorless oil 1H NMR (300 MHz) δ 550 (dt J = 156 63 Hz 1

H) 527 (dd J = 156 81 Hz 1 H) 369 (s 3H) 364 (s 3 H) 323 (d J = 93 Hz 1 H)

285 (comp 1 H) 193 (app p J = 75 Hz 2 H) 102 (d J = 69 Hz 3 H) 089 (t J =

75 3 H) 13C NMR (100 MHz) δ 1688 1687 1334 1301 581 523 521 374 254

186 137


H) 527 (dd J = 156 81 Hz 1 H C3-H) 369 (s 3 H C9-H) 364 (s 3 H C9-H) 323

(d J = 93 Hz 1 H C7-H) 285 (comp 1 H C2-H) 193 (app p J = 75 Hz 2 H C5-H)

102 (d J = 69 Hz 3 H C1-H) 089 (t J = 75 3 H C6-H) 13C NMR (100 MHz) δ

1688 (C8) 1687 (C8) 1334 (C4) 1301 (C3) 581 (C7) 523 (C9) 521 (C9) 374

(C2) 254 (C5) 186 (C1) 137 (C6)

89

12

3 4 5

7

O O

OO

220

6

2-(1-Ethylbut-2-enyl)malonic acid dimethyl ester (220) KAM1-267


218








mg (73) of 220 as a colorless oil in a 6931 regioisomeric ratio 1H NMR (400 MHz) δ

548 (m 1 H) 518 (dd J = 150 93 Hz 1 H) 369 (s 3H) 365 (s 3H) 331 (d J = 90

Hz 1H) 187 (m 1 H) 158 (comp 2 H) 104 (d J = 69 Hz 3 H) 082 (t J = 72 Hz 3

H)

NMR Assignments 1H NMR (400 MHz) δ 548 (m 1 H C5-H) 518 (dd J =

150 93 Hz 1 H C4-H) 369 (s 3H C9-H) 365 (s 3H C9-H) 331 (d J = 90 Hz 1H

C7-H) 187 (m 1 H C3-H) 158 (comp 2 H C2-H) 104 (d J = 69 Hz 3 H C6-H)

082 (t J = 72 Hz 3 H C1-H)

O

O

O

O

12

34

5

78

9

6227

2-(144-Trimethylpent-2-enyl)malonic acid dimethyl ester (227) (KAM1-

193A) Dimethyl malonate (0071 ml 0625 mmol) was added to a suspension of NaH (20

219

mg 60 dispersion in mineral oil 05 mmol) in THF (15 mL) at rt In a separate flask

226 (395 mg 025 mmol) and [Rh(CO)2Cl]2 (97 mg 0025 mmol) were dissolved in

THF (05 mL) Both solutions stirred for 15 min and the anion solution was slowly

added dropwise to the catalystcarbonate mixture The reaction was stirred for 3 d at rt

during which time it turned a deep brown color Solids were removed by filtration

through a short pad of silica and washing with Et2O Combined filtrate washings were

concentrated under vacuum gave a brown oil that was purified by chromatography

eluting with hexaneEt2O(51) to give 438 mg (82) of 227 and 228 as a colorless oil

in a 101 ratio The major isomer 227 1H NMR (300 MHz) 550 (d J = 156 Hz 1 H)

518 (dd J = 156 87 Hz 1 H) 370 (s 3 H) 365 (s 3 H) 324 (d J = 87 Hz 1 H)

284 (m 1 H) 104 (d J = 69 3 H) 093 (s 9 H)

NMR Assignments 1H NMR (300 MHz) 550 (d J = 156 Hz 1 H C4-H) 518

(dd J = 156 87 Hz 1 H C3-H) 370 (s 3 H C9-H) 365 (s 3 H C9-H) 324 (d J =

87 Hz 1 H C7-H) 284 (m 1 H C2-H) 104 (d J = 69 3 H C1-H) 093 (s 9 H C6-

H)

220

1

23

45

6

7

8 9 10 1112

13

230

O

O

O

O

2-But-2-ynyl-2-(1-methylpent-2-enyl)-malonic acid dimethyl ester (230)

(KAM5-296) Malonate 229 (115 mg 0625 mmol) was added to a suspension of NaH

(20 mg 05 mmol 60 dispersion in mineral oil) in DMF (1 mL) and the suspension

was stirred for 15 min In a separate flask [Rh(CO)2Cl]2 (10 mg 0025 mmol) was

added to a solution of carbonate 217 (40 mg 025 mmol) in DMF (15 mL) at -20 ˚C

The solution of the anion was added dropwise to the catalystcarbonate solution over 5

min and the reaction was stirred at -20 ˚C for 24 h EtOAc (10 mL) and H2O (5 mL)

added and the organic layer was separated The aqueous layer was extracted with EtOAc

(2 x 5 mL) and the combined organic layers were dried (Na2SO4) and concentrated

under reduced pressure The residue was purified by flash chromatography eluting with

pentaneEt2O (91) to give 58 mg (88) of 230 as a colorless oil in a 937 regioisomeric

ratio 1H NMR (400 MHz) δ 553 (dt J = 152 60 Hz 1 H) 524 (dd J = 152 92 Hz 1

H) 369 (s 3 H) 368 (s 3 H) 297 (app p J = 72 Hz 1 H) 268 (q J = 28 Hz 2 H)

196 (app p J = 64 Hz 2 H) 171 (t J = 28 Hz 3 H) 108 (d J = 68 Hz 3 H) 092 (t J

= 76 Hz 3 H) 13C NMR (100 MHz) δ 1704 1342 1289 784 741 609 521 402

256 241 169 138 35 IR (neat) 2959 2875 1732 1455 1434 1276 1218 1057

221

970 mass spectrum (CI) mz 2671604 [C15H23O4 (M+1) requires 2671596] 267 (base)

235 206 185


H) 524 (dd J = 152 92 Hz 1 H C4-H) 369 (s 3 H C13-H) 368 (s 3 H C13-H)

297 (app p J = 72 Hz 1 H C5-H) 268 (q J = 28 Hz 2 H C8-H) 196 (app p J = 64

Hz 2 H C2-H) 171 (t J = 28 Hz 3 H C11-H) 108 (d J = 68 Hz 3 H C6-H) 092 (t

J = 76 Hz 3 H C1-H) 13C NMR (100 MHz) δ 1704 (C12) 1342 (C3) 1289 (C4)

784 (C9) 741 (C10) 609 (C5) 521 (C13) 402 (C2) 256 (C7) 241 (C8) 169 (C11)

138 (C6) 35 (C1)

N

249

12

3

4

5

6

7

89

10

3

4

89

1-(1-Methyl-3-phenylallyl)-pyrrolidine (249) (KAM4-035A) Pyrrolidine

(36 mg 050 mmol) was added to a solution of 248 (52 mg 025 mmol) TBAI (19 mg

0050 mmol) and [Rh(CO)2Cl]2 (10 mg 0025 mmol) in DCE (1 mL) The reaction was

stirred 12 h at rt The reaction was concentrated under reduced pressure and hexane (1

mL) was added The heterogeneous mixture was filtered through Celite washing with

hexane and concentrated under reduced pressure The residue was purified by flash

chromatography (silica stabilized with 10 Et3N) eluting with hexanesEtOAc (11) to

222

give 50 mg (99) of 249 as a yellow oil 1H NMR (400 MHz) δ 740-700 (comp 5 H)

645 (d J = 156 Hz 1 H) 622 (dd J = 70 156 Hz 1 H) 288 (dt J = 64 148 Hz 1

H) 256 (comp 4 H) 177 (comp 4 H) 127 (d J = 70 3 H) 13C NMR (100 MHz) δ

1372 1340 1296 1285 1272 1262 631 522 233 210 IR (neat) 2967 2780

1494 1446 1310 1167 965 748 692 MS (CI) mz 2021586 [C14H20N1 (M+1)

requires 2021596]

NMR Assignments 1H NMR (400 MHz) δ 740-700 (comp 5 H C8-H amp C9-H

amp C10-H) 645 (d J = 152 Hz 1 H C6-H) 622 (dd J = 152 70 Hz 1 H C5-H) 288

(dt J = 152 70 Hz 1 H C2-H) 256 (comp 4 H C3-H) 177 (comp 4 H C4-H) 127

(d J = 70 3 H C1-H) 13C NMR (100 MHz) δ 1372 (C6) 1340 (C7) 1296 (C10)

1285 (C8) 1272 (C5) 1262 (C9) 631 (C2) 522 (C3) 233 (C4) 210 (C1)

N

252

3

8

9

3

4

8

9

1

2

5

6

7

10

Benzyl-11-dimethylallylmethylamine (252) (KAM4-031)

Benzylmethylamine (61 mg 050 mmol) was added to a solution of 251 (32 mg 025

mmol) TBAI (19 mg 0050 mmol) and [Rh(CO)2Cl]2 (10 mg 0025 mmol) in DCE (1

mL) The mixture was stirred 12 h at rt The solution was concentrated under reduced

223

pressure and hexane (1 mL) was added The heterogeneous mixture was filtered through

Celite washing with hexane and concentrated under reduced pressure The residue was

purified by flash chromatography eluting with hexanesEtOAc (91) to give 42 mg (89)

of 252 as a colorless oil 1H NMR (300 MHz) δ 760-720 (comp 5 H) 603 (dd J =

177 108 Hz 1 H) 513 (dd J = 177 15 Hz 1 H) 509 (dd J = 105 15 Hz 1 H)

352 (s 2 H) 214 (s 3 H) 125 (s 6H) 13C NMR (75 MHz) δ 1470 1413 1285

1281 1265 1120 586 557 345 228 IR (neat) 2973 2842 2794 1494 1453 1411

1355 1181 1001 914 696 MS (CI) mz 1901591 [C13H20N1 (M+1) requires

1901596]


amp C10-H) 603 (dd J = 177 108 Hz 1 H C2-H) 513 (dd J = 177 15 Hz 1 H C1-


(s 6H C3-H) 13C NMR (75 MHz) δ 1470 (C2) 1413 (C7) 1285 (C8) 1281 (C9)

1265 (C10) 1120 (C1) 586 (C4) 557 (C6) 345 (C5) 228 (C3)

General procedure for the [Rh(CO)2Cl]2-Catalyzed allylic alkylation with phenolic

nucleophiles A 10 M solution of LiHMDS (045 mL 045 mmol) was added to a slurry

of phenol 267 (05 mmol) and CuI (95 mg 05 mmol) in THF (15 mL) at room

temperature The mixture was stirred at room temperature for 30 min In a separate

flask [Rh(CO)2Cl]2 (10 mg 0025 mmol) was dissolved in THF (1 mL) stirred for 5 min

at room temperature then transferred via syringe to the flask containing phenoxide

Allylic carbonate 268 (025 mmol) was then added to the mixture and the reaction was

224

stirred at room temperature for 24 h The mixture was filtered through a short plug of

SiO2 eluting with Et2O (50 mL) The eluent was concentrated under reduced pressure

and the crude residue was purified by flash chromatography eluting with hexaneEtOAc

(51) to provide aryl ether 269

O

269

12

3

45

6 78

9

10

11

12

13

1-Pent-2-enyloxy-2-vinylbenzene (269) KAM5-208 Ether 269 was obtained

in 77 yield (025 mmol scale) in THF after 24 h at room temperature as a clear

colorless oil after chromatography (hexane) in a ge955 regioisomeric ratio 1H NMR

(400 MHz) δ 748 (dd J = 72 16 Hz 1 H) 720 (dt J = 84 16 Hz 1 H) 709 (dd J =

176 112 Hz 1 H) 692 (t J = 76 Hz 1 H) 686 (d J = 84 Hz 1 H) 589 (dt J = 152

64 Hz 1 H) 574 (dd J = 176 16 Hz 1 H) 571 (m 1 H) 524 (dd J = 116 20 Hz 1

H) 449 (dd J = 60 12 Hz 2 H) 211 (app p J = 64 Hz 2 H) 103 (t J = 76 Hz 3 H)

13C NMR (100 MHz) δ 1559 1366 1317 1287 1270 1264 1239 1206 1142

1124 692 253 132 IR (CHCl3) 3033 2967 2934 2874 1625 1597 1485 1452

1239 1107 1003 969 cm-1 mass spectrum (CI) mz 1891278 [C17H19O1 (M+1) requires

1891279] 189 (base) 122 107

NMR Assignments 1H NMR (400 MHz) δ 748 (dd J = 72 16 Hz 1 H C2-

H) 720 (dt J = 84 16 Hz 1 H C4-H) 709 (dd J = 176 112 Hz 1 H C12-H) 692

225

(t J = 76 Hz 1 H C3-H) 686 (d J = 84 Hz 1 H C5-H) 589 (dt J = 152 64 Hz 1

H C8-H) 574 (dd J = 176 16 Hz 1 H C13-H) 571 (m 1 H C9-H) 524 (dd J =

116 20 Hz 1 H C13-H) 449 (dd J = 60 12 Hz 2 H C7-H) 211 (app p J = 64 Hz

2 H C10-H) 103 (t J = 76 Hz 3 H C11-H) 13C NMR (100 MHz) δ 1559 (C6) 1366

(C12) 1317 (C8) 1287 (C9) 1270 (C4) 1264 (C2) 1239 (C1) 1206 (C3) 1142

(C5) 1124 (C13) 692 (C7) 253 (C10) 132 (C11)

Br

O

271

12

3

45

6 78

9

10

11

1-Bromo-2-pent-2-enyloxybenzene (271) (KAM4-299) Ether 271 was

obtained in 73 yield (025 mmol scale) in THF after 24 h at room temperature as a

clear colorless oil after chromatography (hexanes) in a gt955 regioisomeric ratio 1H

NMR (300 MHz) δ 756 (dd J = 78 15 Hz 1 H) 726 (td J = 75 15 Hz 1 H) 692

(dd J = 84 15 Hz 1 H) 685 (td J = 78 15 Hz 1 H) 595 (dt J = 156 60 Hz 1 H)

575 (dt J = 156 57 Hz 1 H) 458 (dd J = 57 09 Hz 2 H) 215 (comp 2 H) 106 (t

J = 75 Hz 3 H) 13C NMR (75 MHz) δ 1551 1370 1332 1283 1232 1218 1137

1123 698 253 131 IR (neat) 2967 2934 2875 1586 1478 1276 1243 1031 970

mass spectrum (CI) mz 2390069 [C11H12OBr (M-1) requires 2390072] 243 (base) 242

241 137

226


H) 726 (td J = 75 15 Hz 1 H C4-H) 692 (dd J = 84 15 Hz 1 H C5-H) 685 (td J

= 78 15 Hz 1 H C3-H) 595 (dt J = 156 60 Hz 1 H C8-H) 575 (dt J = 156 57

Hz 1 H C9-H) 458 (dd J = 57 09 Hz 2 H C7-H) 215 (comp 2 H C10-H) 106 (t


1283 (C3) 1232 (C8) 1218 (C9) 1137 (C5) 1123 (C1) 698 (C7) 253 (C10) 131

(C11)

O

273

12

3

45

6

7 89

1011

12

1314

15

16

2-(1-Methyl-pent-2-enyloxy)biphenyl (273) Ether 273 was obtained in 87

yield (034 mmol scale) in THF after 24 h at room temperature as a clear colorless oil

after chromatography (hexanesEtOAc = 91) in a 7129 regioisomeric ratio 1H NMR

(400 MHz) δ 755-694 (comp 9 H) 557 (dt J = 156 60 Hz 1 H) 539 (dd J = 156

68 Hz 1 H) 462 (app p J = 60 Hz 1 H) 197 (app p J = 68 Hz 2 H) 128 (d J = 64

Hz 3 H) 091 (t J = 64 Hz 3 H) 13C NMR (100 MHz) δ 1550 1389 1339 1320

1308 1300 1296 1281 1278 1266 1210 1160 759 251 216 133 IR (CHCl3)

2966 2359 1479 1433 1260 1228 1047 967 cm-1 mass spectrum (CI) mz 2521512

[C17H19O1 (M+1) requires 2521514] 252 (base)

227

NMR Assignments 1H NMR (400 MHz) δ 755-694 (comp 9 H C2-H C3-H

C4-H C5-H C14-H C15-H amp C16-H) 557 (dt J = 156 60 Hz 1 H C10-H) 539

(dd J = 156 68 Hz 1 H C9-H) 462 (app p J = 60 Hz 1 H C8-H) 197 (app p J =

68 Hz 2 H C11-H) 128 (d J = 64 Hz 3 H C7-H) 091 (t J = 64 Hz 3 H C12-H)

13C NMR (100 MHz) δ 1550 (C6) 1389 (C13) 1339 (C15) 1320 (C9) 1308 (C10)

1300 (C2) 1296 (C4) 1281 (C14) 1278 (C16) 1266 (C1) 1210 (C3) 1160 (C5)

759 (C8) 251 (C11) 216 (C7) 133 (C12)

HOO

1

2

3 4

5

67

8

Si

288

5-(tert-Butyldimethylsilanyloxy)-pent-3-en-1-ol (288) A mixture of 287 (20

g 935 mmol) Lindlarrsquos Catalyst (89 mg 0042 mmol) and quinoline (300 microL 232

mmol) in EtOAc (40 mL) was stirred under an atmosphere of H2 for 2 h The catalyst

was removed by filtration through Celite washing with EtOAc (3 x 20 mL) The

combined filtrate washings were washed with 1 N HCl (3 x 50 mL) sat NaHCO3 (3 x 50

mL) brine (3 x 50 mL) dried (Na2SO4) and concentrated under reduced pressure The

residue was purified by flash chromatography eluting with pentaneEt2O (11) to give

203 g (99 ) of 288 as a pale yellow oil 1H NMR (400 MHz) δ 571 (dt J = 108 64

Hz 1 H) 549 (dt J = 108 64 Hz 1 H) 419 (d J = 64 Hz 2 H) 361 (t J = 64 Hz 2

228

H) 232 (app q J = 64 Hz 2 H) 182 (br s 1 H) 087 (s 9 H) 005 (s 6 H) 13C NMR

(100 MHz) δ 1322 1275 616 590 310 259 183 -52 IR (neat) 3355 2954 2857

1471 1361 1254 1086 836 776 mass spectrum (CI) mz 2171614 [C11H25O2Si (M+1)

requires 2171624] 217 (base) 199 133


H) 549 (dt J = 108 64 Hz 1 H C3-H) 419 (d J = 64 Hz 2 H C5-H) 361 (t J =

64 Hz 2 H C1-H) 232 (app q J = 64 Hz 2 H C2-H) 182 (br s 1 H OH) 087 (s 9

H C8-H) 005 (s 6 H C6-H) 13C NMR (100 MHz) δ 1322 (C4) 1275 (C3) 616

(C5) 590(C1) 310 (C2) 259 (C8) 183(C7) -52 (C6)

O

O O

O9

1011

128

612

34

5 7

Si

289

3-Oxobutyric acid 5-(tert-butyldimethylsilanyloxy)-pent-3-enyl ester (289)

DMAP (30 mg 025 mmol) was added in one portion to a solution of 288 (650 mg 30

mmol) and diketene (302 mg 36 mmol) in Et2O (15 mL) at -20 ˚C The reaction was

stirred for 1 h at -20 ˚C and then 2 h at rt A 01 solution of NaOH was added and the

organic layer was separated The organic layer was washed with 01 NaOH (2 x 15

mL) dried (Na2SO4) and concentrated under reduced pressure The residue was purified

by flash chromatography eluting with hexaneEtOAc (11) to give 917 mg (84) of 289

229

as a pale yellow oil 1H NMR (400 MHz) δ 562 (dt J = 121 84 Hz 1 H) 538 (dt J =

121 56 Hz 1 H) 419 (d J = 64 Hz 2 H) 412 (t J = 68 Hz 2 H) 342 (s 2 H) 239

(dd J = 130 76 Hz 2 H) 224 (s 3 H) 087 (s 9 H) 004 (s 6 H) 13C NMR (100

MHz) δ 2004 1670 1326 1251 645 593 500 301 270 259 183 -52 IR

(neat) 2954 2857 1718 1654 1471 1361 1254 1054 836 778 mass spectrum (CI)

mz 3011838 [C15H29O4Si (M+1) requires 3011835] 301 217 (base) 187 169



68 Hz 2 H C5-H) 342 (s 2 H C3-H) 239 (dd J = 130 76 Hz 2 H C6-H) 224 (s 3

H C1-H) 087 (s 9 H C12-H) 004 (s 6 H C10-H) 13C NMR (100 MHz) δ 2004

(C2) 1670 (C4) 1326 (C8) 1251 (C7) 645 (C9) 593 (C5) 500 (C3) 301 (C6) 270

(C1) 259 (C12) 183 (C11) -52 (C10)

O

O O

OH

8

612

34

5 7

9

290

3-Oxobutyric acid 5-hydroxypent-3-enyl ester (290) TBAF (15 mL 1 M in

THF 15 mmol) was added to a solution of 289 (1911 g 637 mmol) in THF (10 mL) at

0 ˚C and the resulting mixture was stirred for 2 h at rt Water (50 mL) was added and the

organic layer was separated The aqueous layer was extracted with EtOAc (3 x 30 mL)

The organic layers were combined and washed with brine (2 x 50 mL) dried (Na2SO4)

230

and concentrated under reduced pressure The residue was purified by flash

chromatography eluting with hexaneEtOAc (11) to give 101 g (91) of 290 as a

colorless oil 1H NMR (400 MHz) δ 571 (dt J = 112 64 Hz 1 H) 546 (dt J = 112

76 Hz 1 H) 415-412 (comp 4 H) 342 (s 2 H) 245-337 (m 2 H) 222 (s 3 H) 13C

NMR (100 MHz) δ 2009 1669 1317 1270 643 583 499 303 268 MS (CI) mz

1870970 [C9H15O4 (M+1) requires 1870970]


H) 546 (dt J = 112 76 Hz 1 H C7-H) 415-412 (comp 4 H C9-H C5-H) 342 (s 2

H C3-H) 245-237 (m 2 H C6-H) 222 (s 3 H C1-H) 13C NMR (100 MHz) δ 2009

(C2) 1669 (C4) 1317 (C8) 1270 (C7) 643 (C9) 583 (C5) 499 (C3) 303 (C6) 268

(C1)

O

O O

O

861

23

4

5 7

910

11O

O

275

3-Oxobutyric acid 5-methoxycarbonyloxypent-3-enyl ester (275) Methyl

chloroformate (1024 g 1084 mmol) was slowly added to a solution of 290 (101 g 524

mmol) and pyridine (856 mg 1084 mmol) in CH2Cl2 (25 mL) at 0 ˚C The reaction was

stirred for 1 h at 0 ˚C and 1 h at rt The reaction was quenched with brine (10 mL) and



231

50 mL) brine (2 x 50 mL) dried (Na2SO4) and concentrated under reduced pressure

The residue was purified by flash chromatography eluting with pentaneEt2O (11) to

give 117 g (91) of 275 as a colorless oil 1H NMR (400 MHz) δ 556-554 (comp 2

H) 455 (d J = 56 Hz 2 H) 405 (t J = 66 Hz 2 H) 364 (s 3 H) 334 (s 2 H) 237

(dd J = 128 66 Hz 2 H) 213 (s 3 H) 13C NMR (100 MHz) δ 2002 1668 1553

1301 1256 637 630 545 496 298 267 IR (neat) 2955 1802 1747 1714 1442

1268 1172 1082 944 mass spectrum (CI) mz 2451026 [C11H17O6 (M+1) requires

2451025] 245 186 169 (base) 154

NMR Assignments 1H NMR (400 MHz) δ 556-554 (comp 2 H C7-H amp C8-

H) 455 (d J = 56 Hz 2 H C9-H) 405 (t J = 66 Hz 2 H C-5-H) 364 (s 3 H C11-

H) 334 (s 2 H C3-H) 237 (dd J = 128 66 Hz 2 H C-6H) 213 (s 3 H C1-H) 13C

NMR (100 MHz) δ 2002 (C2) 1668 (C4) 1553 (C10) 1301 (C8) 1256 (C7) 637

(C11) 630 (C9) 545 (C5) 496 (C3) 298 (C6) 267 (C1)

O

OO

8

6

7 1 2

3

45

9

278

3-Acetyl-3478-tetrahydrooxocin-2-one (278) 275 (50 mg 022 mmol) was

slowly added via tared syringe to a suspension of KOtBu (37 mg 033 mmol) in DMF (1

mL) and stirred for 10 min This solution was slowly transferred via syringe to a solution

232

of [Rh(CO)2Cl]2 (85 mg 0022 mmol) in DMF (1 mL) at 0 ˚C rinsing with DMF (05

mL) The reaction was stirred for 15 min at 0 ˚C and then sat NaHCO3 (2 mL) was

added The mixture was extracted with Et2O (3 x 3 mL) and the combined organic

layers were washed with brine (2 x 5 mL) dried (Na2CO3) and concentrated under

reduced pressure The residue was purified by flash chromatography eluting with

pentaneEt2O (11) to give 25 mg (68) of 278 as a colorless oil 1H NMR (500 MHz) δ

585-576 (comp 2 H) 431-420 (m 2 H) 365 (dd J = 85 55 Hz 1 H) 284-278 (m 1

H) 251-241 (m 2 H) 228-224 (m 1 H) 224 (s 3 H) 13C NMR (100 MHz) δ 2016

1738 1311 1292 678 632 292 286 269 IR (neat) 2958 1713 1650 1359 1261



H) 431-420 (m 2 H C6-H) 365 (dd J = 85 55 Hz 1 H C6-H) 284-278 (m 1 H

C2-H) 251-241 (m 2 H C5-H) 228-224 (m 1 H C2-H) 224 (s 3 H C9-H) 13C

NMR (100 MHz) δ 2016 (C8) 1738 (C7) 1311 (C4) 1292 (C3) 678 (C6) 632 (C1)

292 (C2) 286 (C5) 269 (C9)

233

8

6 7Br

O1

2

3 4

5Si

291

5-Bromopent-2-enyloxy-tert-butyldimethylsilane (291) Et3N (125 g 174

mL 1251 mmol) 288 (900 mg 416 mmol) and PPh3 (219 g 834 mmol) were added

sequentially to a solution of CBr4 (276 g 834 mmol) in CH2Cl2 (30 mL) The reaction

was stirred at rt for 2 h and water (30 mL) was added The organic layer was separated

and washed with water (2 x 30 mL) brine (2 x 30 mL) dried (Na2SO4) and passed

through a plug of silica gel The silica was washed with Et2O (75 mL) and combined

filtrates were concentrated under reduced pressure The residue was purified by flash

chromatography eluting with hexaneEt2O (31) to give 917 mg (78) of 291 as a

yellow oil 1H NMR (300 MHz) δ 566 (dt J = 110 64 Hz 1 H) 542 (dt J = 110 72

Hz 1 H) 421 (d J = 64 Hz 2 H) 335 (t J = 72 Hz 2 H) 261 (app q J = 72 Hz 2

H) 088 (s 9 H) 005 (s 6 H) 13C NMR (100 MHz) δ 1325 1269 594 322 310

259 183 -52 IR (neat) 3021 2955 2856 1471 1360 1254 1095 837 776 MS (CI)

mz 2790776 [C11H24OSiBr (M+1) requires 2790780]



72 Hz 2 H C1-H) 261 (app q J = 72 Hz 2 H C2-H) 088 (s 9 H C8-H) 005 (s 6

234

H C6H) 13C NMR (100 MHz) δ 1325 (C4) 1269 (C3) 594 (C5) 322 (C1) 310

(C2) 259 (C8) 183 (C7) -52 (C6)

1386

7

12

34

59

10

1211O

O O

OSi

292

9-(tert-Butyldimethylsilanyloxy)-3-oxonon-7-enoic acid methyl ester (292)

Methyl acetoacetate (832 mg 717 mmol) was added dropwise to a suspension of NaH

(287 mg 60 dispersion in mineral oil 717 mmol) in THF (15 mL) at 0 ˚C The

reaction stirred for 15 min and n-BuLi (364 mL 20 M in hexanes 717 mmol) was

added slowly at 0 ˚C The reaction stirred for 15 min and a solution of 291 (100 g 358

mmol) in THF (3 mL) was slowly added The reaction was warmed to rt and stirred for

12 h The reaction was quenched with 1 N HCl (20 mL) and Et2O (20 mL) was added

The layers were separated and the aqueous layer was extracted with Et2O (2 x 20 mL)

Combined organic layers were washed with water (2 x 20 mL) brine (2 x 20 mL) dried

(Na2SO4) and concentrated under reduced pressure The residue was purified by flash

chromatography eluting with hexaneEt2O (21) to give 776 mg (69) of 292 as a pale


Hz 1 H) 417 (d J = 62 2 H) 371 (s 3 H) 342 (s 2 H) 251 (t J = 68 Hz 2 H) 204

(dt J = 74 68 Hz 2 H) 164 (app p J = 68 2 H) 087 (s 9 H) 004 (s 6 H)

235


H) 535 (dt J = 112 74 Hz 1 H C8-H) 417 (d J = 62 2 H C10-H) 371 (s 3 H C1-

H) 342 (s 2 H C3-H) 251 (t J = 68 Hz 2 H C5-H) 204 (dt J = 74 68 Hz 2 H

C7-H) 164 (app p J = 68 2 H C6-H) 087 (s 9 H C13-H) 004 (s 6 H C11-H)

O

O O

OH

86

7

12

34

59

10

293

9-Hydroxy-3-oxonon-7-enoic acid methyl ester (293) TBAF (3 mL 1 M in

THF 3 mmol) was added to a solution of 292 (430 mg 137 mmol) in THF (2 mL) at 0

˚C The reaction was warmed to rt and stirred for 2 h Water (10 mL) was added and the




chromatography eluting with hexaneEtOAc (11) to give 171 mg (63 ) of 293 as a pale

yellow oil 1H NMR (300 MHz) δ 566-538 (comp 2 H) 412 (d J = 72 Hz 2 H) 370

(s 3 H) 341 (s 2 H) 252 (t J = 69 2 H) 206 (app q 72 Hz 2 H) 173 (s 1 H) 165

(app p J = 72 Hz 2 H)


H) 412 (d J = 72 Hz 2 H C10-H) 370 (s 3 H C1-H)) 341 (s 2 H C3-H) 252 (t J

236

= 69 2 H C5-H) 206 (app q 72 Hz 2 H C7-H) 173 (s 1 H OH) 165 (app p J =

72 Hz 2 H C6-H)

O

O O

O

86

7

12

34

59

1011 12O

O

294

9-Methoxycarbonyloxy-3-oxonon-7-enoic acid methyl ester (294) Methyl

chloroformate (163 mg 171 mmol) was slowly added to a solution of 293 (171 mg 086


stirred for 1 h at 0 ˚C and then 1 h at rt The reaction was quenched with brine and the





180 mg (83) of 294 as a colorless oil 1H NMR (400 MHz) δ 571-550 (comp 2 H)

463 (d J = 60 Hz 2 H) 375 (s 3 H) 371 (s 3 H) 342 (s 2 H) 253 (t J = 72 Hz 2

H) 212 (dt J = 72 64 Hz 2 H) 167 (app p J = 72 Hz 2 H) MS (CI) mz 2591181

[C12H19O6 (M+1) requires 2591182]

NMR Assignments 1H NMR (400 MHz) δ 571-550 (comp 2 H C8-H

amp C9-H) 463 (d J = 60 Hz 2 H C10-H) 375 (s 3 H C12-H) 371 (s 3 H C-1-H)

237

342 (s 2 H C3-H) 253 (t J = 72 Hz 2 H C5-H) 212 (dt J = 72 64 Hz 2 H C7-H)

167 (app p J = 72 Hz 2 H C6-H)

10

1 23

9

4

5 67

8

2106

O

O

O

O

3-Methylene-4-vinyl-cyclopentane-11-dicarboxylic acid dimethyl ester

(2106) (KAM1-159) Malonate 2107 (107 mg 0625 mmol) was added to a suspension

of NaH (20 mg 60 dispersion in mineral oil 05 mmol) in THF (15 mL) at 0 ˚C and

the mixture was stirred for 15 min In a second vial dicarbonate 2108 (51 mg 025

mmol) was added to a solution of [Rh(CO)2Cl]2 (97 mg 0025 mmol) in THF (05 mL)

at 0 ˚C and the mixture was stirred for 10 min The anion was slowly added to the

catalystcarbonate mixture and the reaction was warmed to rt and stirred for 16 h The

reaction was heated 65 ˚C for 12 hours and then filtered through a short pad of silica

Concentration gave a crude brown oil purified by chromatography eluting with

hexaneEt2O(51) gave 85 mg (15) of 2106 as a colorless oil and spectral results were

consistent with literature dataError Bookmark not defined

238

O CF3

O

12

34

5 67

2129

Trifluoro-acetic acid pent-2-enyl ester (2129) KAM2-206

Trifluoroacetic anhydride (670 mg 32 mmol) was added to a solution of trans-2-penten-

1-ol (250 mg 29 mmol) in Et2O (5 mL) The reaction was stirred for 2 h Sat NaHCO3

(5 mL) added and the organic layer was separated The organic layer was washed with

sat NaHCO3 (5 mL) brine (5 mL) dried (Na2SO4) and concentrated to give 2129 as a

colorless oil (503 mg 95) 1H NMR (400 MHz) δ 1H NMR (400 MHz) δ 593 (dt J =

156 60 Hz 1 H) 556 (dt J = 156 68 Hz 1 H) 474 (d J = 68 Hz 2 H) 209 (p J =

74 Hz 2 H) 100 (t J = 74 3 H) 13C NMR (100 MHz) δ 1572 1412 1204 1160

688 255 128 IR (neat) 1779 1634 1174 706 cm-1 MS (CI) mz 1830640

[C7H10O2F3 (M+1) requires 1830633]


H)) 556 (dt J = 156 68 Hz 1 H C3-H) 474 (d J = 68 Hz 2 H C5-H) 209 (p J =

74 Hz 2 H C2-H) 100 (t J = 74 3 H C1-H) 13C NMR (100 MHz) δ 1572 (C6)

1412 (C4) 1204 (C3) 1160 (C7) 688 (C5) 255 (C2) 128 (C1)

239

O O

O O

1

3

12

3

4

56

78

910

112137

22-Dimethyl-5-(3-phenylprop-2-ynyl)-[13]-dioxane-46-dione (2137)

KAM3-114 Meldrumrsquos acid (720 mg 5 mmol) was added to a solution of BH3Me2NH

(295 mg 5 mmol) in MeOH (6 mL) and the mixture was stirred until a homogenous

solution was obtained A solution of phenylpropynal (650 mg 5 mmol) in MeOH (6 mL)

was then added over 5 min The reaction was stirred for 15 min whereupon it was

poured into iceH2O (30 mL) Concentrated HCl (12 M) was added until pH = 1-2 and

the precipitate was collected by filtration to give an orange solid Trituration of the solid

with hexane gave an orange solid 2137 (949 mg 74) 1H NMR (300 MHz) δ 740-720

(comp 5 H) 373 (t J = 48 Hz 1 H) 324 (d J = 48 Hz 2 H) 180 (s 3 H) 178 (s 3

H) 13C NMR (100 MHz) δ 1642 1317 1281 1227 1053 846 824 461 284

269 175 IR (neat) 3001 1788 1750 1309 1202 1070 941 758 MS (CI) mz

2580889 [C15H14O4 (M+1) requires 2580892]


amp C11-H) 373 (t J = 48 Hz 1 H C4-H) 324 (d J = 48 Hz 2 H C5-H) 180 (s 3 H

C1-H) 178 (s 3 H C1-H) 13C NMR (100 MHz) δ 1642 (C3) 1317 (C9) 1281 (C10)

1227 (C8) 1053 (C2) 846 (C6) 824 (C7) 461 (C4) 284 (C1) 269 (C1) 175 (C5)

240

12 3 4

567

8

9

10

1112

1314

2130

O

H

O

O

OO

15

16

4-Ethyl-5-oxo-6-phenyl-33a45-tetrahydro-1H-pentalene-22-dicarboxylic

acid dimethyl ester (2130) KAM4-119 Malonate 2120 (50 mg 02 mmol) was

added to a suspension of NaH (12 mg 03 mmol) in THF (1 mL) The reaction was

stirred at rt for 15 min and concentrated under reduced pressure and the residue was

dissolved in toluene (1 mL) and concentrated under reduced pressure (3x) The residue

was dissolved in THF (1 mL) and added to a solution of trifluoroacetate 2129 (91 mg

05 mmol) and [Rh(CO)2Cl]2 (8 mg 002 mmol) in THF (1 mL) under a CO atmosphere

The reaction as stirred at rt for 3 h and then placed in a microwave reactor and heated to

200 ˚C (240 psi) for 5 min and concentrated under reduced pressure The residue was

purified by flash chromatography eluting with hexaneEtOAc (31) to give 15 mg (30)

of 2130 as a yellow oil 1H NMR (400 MHz) δ 760-720 (m 5 H) 382 (s 3 H) 370 (s

3 H) 363 (d J = 195 Hz 1 H) 329 (d J = 195 Hz 1 H) 283 (app q J = 75 Hz 2 H)

230-210 (m 1 H) 210-190 (m 1 H) 181 (app t J = 153 Hz 1 H) 160-140 (m 1

H) 100 (t J = 75 Hz 3 H) IR (CDCl3) 1731 1601 1277 1163 MS (CI) mz 3431554

[C20H23O5 (M+1) requires 3431545]

241

NMR Assignments 1H NMR (400 MHz) δ 760-720 (m 5 H C8-H amp C9-H amp

C10-H) 382 (s 3 H C1-H) 370 (s 3 H C1-H) 363 (d J = 195 Hz 1 H C4-H) 329

(d J = 195 Hz 1 H C4-H) 283 (app q J = 75 Hz 2 H C13-H) 230-210 (m 1 H

C15-H) 210-190 (m 1 H C16-H) 181 (app t J = 153 1 H C12-H) 160-140 (m 1

H C16-H) 100 (t J = 75 Hz 3 H C14-H)

N

O O

O

Si

O

O

420

12

3

4

56

7

8

9

10

1112

13

14

15

5-allyl-4-(R)-(tert-butyldimethylsilanyloxy)-pyrrolidine-12-dicarboxylic acid

1-tert-butyl ester 2-(S)-methyl ester (420) (KAM3-255) LiBHEt3 (0322 mL 1 M

solution in THF 0322 mmol) was added to a solution of 415 (100 mg 0268 mmol) in

THF (2 mL) at -78 ˚C The reaction was stirred for 1 h and saturated NaHCO3 (1 mL)

and H2O2 (4 drops 30 in H2O) were added The mixture stirred for 1 h at rt and was

extracted with Et2O (3 x 3mL) Combined organic layers were dried (Na2SO4) and

concentrated under reduced pressure to give a crude oil The crude hemiaminal was

dissolved in toluene (2 mL) and allyl TMS (61 mg 0536 mmol) was added at -78 ˚C

242

After stirring for 5 min BF3Et2O (76 mg 0536 mmol) was added and the reaction was

stirred at -78 ˚C for 1 h Saturated NaHCO3 (2 mL) was added and the mixture was

extracted with EtOAc (3 x 5 mL) dried (Na2SO4) and concentrated under reduced

pressure The residue was purified by flash chromatography eluting with hexanesEtOAc

(81) to give 44 mg (42) of 420 as a colorless oil as a mixture (31) of diastereomers

1H NMR (DMSO temp = 100 ˚C) (500 MHz) δ 585 (m 1 H) 505 (comp 2 H) 416

(m 1 H) 365 (s 3 H) 250-200 (comp 4 H) 137 (s 9 H) 087 (d J = 185 Hz 9 H)

066 (dd J = 105 35 Hz 6 H) MS (CI) mz 4002536 [C20H38N1O5Si1 (M+1) requires

4002519]

NMR Assignments 1H NMR (DMSO temp = 100 ˚C) (500 MHz) δ 585 (comp

1 H C9-H) 505 (comp 2 H C10-H) 450-400 (comp 3 H C7-H ampC8-H) 365 (s 3 H

C15-H) 250-200 (comp 4 H C4-H C5-H amp C6-H) 137 (s 9 H C1-H) 087 (d J =

185 Hz 9 H C13-H) 066 (dd J = 105 35 Hz 6 H C11-H)

243

N

O O

O

Si

O

O

1

11

2

3

4

56

7

8910

12

14

13

15

16

421

4-(R)-(tert-butyldimethylsilanyloxy)-5-(2-methyl-allyl)-pyrrolidine-12-

dicarboxylic acid 1-tert-butyl ester 2-(S)-methyl ester (421) (KAM4-054) LiBHEt3

(145 mL 1 M solution in THF 145 mmol) was added to a solution of 415 (450 mg

120 mmol) in THF (10 mL) at -78 ˚C The reaction was stirred for 1 h and saturated

NaHCO3 (10 mL) and H2O2 (12 drops 30 in H2O) were added The mixture stirred

for 1 h at rt and was extracted with Et2O (3 x 10mL) Combined organic layers were

dried (Na2SO4) and concentrated under reduced pressure to give a crude oil The crude

hemiaminal was dissolved in CH2Cl2 (15 mL) and Et3N (360 mg 360 mmol) Ac2O

(360 mg 360 mmol) and DMAP (20 mg 014 mmol) were added The reaction was

stirred to 12 h at rt Saturated NaHCO3 (10 mL) was added and the mixture was

extracted with CH2Cl2 (3 x 10 mL) Combined organic layers were dried (Na2SO4) and

concentrated to give a crude oil The oil was dissolved in dry toluene (4 mL) and filtered

through a short pad of silica washing with toluene (4 mL) The solution was cooled to -

78 ˚C and methallyl TMS (614 mg 480 mmol) was added The reaction was stirred for

5 min and BF3Et2O (304 mg 240 mmol) was added slowly dropwise The reaction was

244

stirred 15 h and NaHCO3 (10 mL) was added The mixture was extracted with toluene

(3 x 10 mL) and combined organic layers were dried (Na2SO4) and concentrated under


hexanesEtOAc (91) to give 273 mg (61 over 3 steps) of 421 as a colorless oil as a

mixture (31) of diastereomers 1H NMR (400 MHz) δ 471 (comp 2 H) 448 (m 1 H)

420-400 (comp 2 H) 370 (comp 3 H) 240-160 (comp 7 H) 178 (d J = 148 Hz 9

H) 085 (s 9 H) 003 (s 6 H) IR (neat) 2955 2858 1754 1698 1392 1254 1177 MS

(CI) mz 4142678 [C21H40N1O5Si1 (M+1) requires 4142676]

NMR Assignment 1H NMR (400 MHz) δ 471 (comp 2 H C10-H) 448 (m 1

H C7-H) 420-400 (comp 2 H C8-H) 370 (comp 3 H C16-H) 240-160 (comp 7 H

C4-H C5-H C6-H amp C11-H) 178 (d J = 148 Hz 9 H C1-H) 085 (s 9 H C14-H)

002 (s 6 H C12-H)

14 15N

O O

O

Si

422

12

3

4

56

7

8

9

10

1112

13

2-allyl-3-(R)-(tert-butyldimethylsilanyloxy)-5-(S)-ethynyl-pyrrolidine-1-

carboxylic acid tert-butyl ester (422) (KAM4-044) DIBAL-H (120 mL 1 M

245

solution in hexanes 120 mmol) was added dropwise to a solution of 420 (162 mg 040

mmol) in CH2Cl2 (1 mL) at -78 ˚C The reaction was stirred for 30 min and MeOH (15

mL) was added dropwise over 10 min The reaction was warmed to 0 ˚C with an ice bath

and K2CO3 (331 mg 240 mmol) and Bestman-Ohira reagent (230 mg 120 mmol) was

added The reaction slowly warmed to rt over 12 h Saturated NH4Cl (3 mL) was added

and the mixture was extracted with Et2O (3 x 10 mL) Combined organic layers were

dried (Na2SO4) and concentrated under reduced pressure The residue was purified by

flash chromatography eluting with hexanesEtOAc (91) to give 83 mg (57) of 422 as a

colorless oil as a mixture (31) of diastereomers 1H NMR (400 MHz) δ 579 (m 1 H)

501 (comp 2 H) 450-350 (comp 3 H) 240 (comp 5 H) 145 (s 9 H) 088 (s 9 H)

007 (s 6 H) MS (CI) mz 3662467 [C30H36N1O3Si1 (M+1) requires 3662464]

NMR Assignments 1H NMR (400 MHz) δ 579 (m 1 H C9-H) 501 (comp 2

H C10-H) 450-350 (comp 3 H C7-H amp C8-H) 240 (comp 5 H C4-H C5-H C6-H

C15-H) 145 (s 9 H C1-H) 088 (s 9 H C13-H) 007 (s 6 H C11-H)

246

16N

O O

O

Si

1

11

2

3

4

56

7

89

10

12

14

13

15

414

3-(R)-(tert-Butyldimethylsilanyloxy)-5-(S)-ethynyl-2-(2-methyl-allyl)-

pyrrolidine-1-carboxylic acid tert-butyl ester (414) (KAM4-054) DIBAL-H (726

mL 1 M in hexanes 726 mmol) was added over 10 min to a solution of 421 (10 g 242


mL) was added slowly along the side of the flask over 10 min and the reaction was

warmed to -10 ˚C K2CO3 (200 g 145 mmol) and Bestman-Ohira reagent (140 g 726

mmol) were added and the reaction was slowly warmed to rt over 8 h Rochellersquos salt (20

mL saturated solution in H2O) and Et2O (40 mL) were added and stirred vigorously for 1

h The organic layer was separated and the aqueous layer was extracted with Et2O (50

mL) Combined organic layers were washed with brine (50 mL) dried (Na2SO4) and

concentrated under reduced pressure The residue was purified by flash chromatography

eluting with hexanesEtOAc (91) to give 763 mg (83) of 414 as a colorless oil as a

mixture (31) of diastereomers 1H NMR (DMSO temp = 100 ˚C) (500 MHz) δ 470 (s 2

H) 457 (dt J = 135 65 Hz 1 H) 432 (d J = 80 Hz 1 H) 398 (dd J = 115 50 Hz 1

H) 240-200 (comp 5 H) 174 (s 3 H) 142 (s 9 H) 089 (s 9 H) 009 (s 3 H) 008

247

(s 3 H) IR (neat) 3312 2955 2858 1704 1649 1385 1254 1123 873 776 MS (CI)

mz 3802614 [C21H38N1O3Si1 (M+1) requires 3802621]

NMR Assignments 1H NMR (DMSO temp = 100 ˚C) (500 MHz) δ 470 (s 2

H C10-H) 457 (dt J = 135 65 Hz 1 H C7-H) 432 (d J = 80 Hz 1 H C8-H) 398

(dd J = 115 50 Hz 1 H C8-H) 240-200 (comp 5 H C4-H C5-H C6-H amp C16-H)

174 (s 3 H C11-H) 142 (s 9 H C1-H) 089 (s 9 H C14-H) 009 (s 3 H C12-H)

008 (s 3 H C12-H)

N

O O

O

O

1

12

15

2

3

4

56

7

8910

11

13

14

424

3-(R)-acetoxy-5-(S)-ethynyl-2-(R)-(2-methylallyl)-pyrrolidine-1-carboxylic

acid tert-butyl ester (424) (KAM4-057) Et3N (343 mg 340 mmol) Ac2O (346 mg

340 mmol) and DMAP (50 mg 040 mmol) were added to a solution of 423 (300 mg

113 mmol) in CH2Cl2 (10 mL) The reaction was stirred at rt for 12 h and saturated

NaHCO3 (20 mL) was added The mixture was extracted with CH2Cl2 (3 x 20 mL) and

combined organic layers were dried (Na2SO4) and concentrated under reduced pressure

The residue was purified by flash chromatography eluting with hexanesEtOAc (31) to

248

give 336 mg (97) of 424 as a colorless solid 1H NMR (300 MHz) δ 544 (m 1 H)

468 (d J = 141 Hz 2 H) 460-420 (comp 2 H) 224 (comp 5 H) 196 (s 3 H) 174

(s 3 H) 146 (s 9 H) MS (CI) mz 3081864 [C17H26N1O4 (M+1) requires 3081862]

NMR Assignments 1H NMR (300 MHz) δ 544 (m 1 H C5-H) 468 (d J =

141 Hz 2 H C10-H) 460-420 (comp 2 H C7-H amp C4-H) 224 (comp 5 H C6-H

C8-H amp C15-H) 196 (s 3 H C13-H) 174 (s 3 H C11-H) 146 (s 9 H C1-H)

HN

O

Si

432

1

23

4

567

8

910

11

12 13

3-(R)-(tert-butyldimethylsilanyloxy)-5-(S)-ethynyl-2-(S)-(2-methylallyl)-

pyrrolidine (432) (KAM4-075) Carbamate 414 (200 mg 0580 mmol) adsorbed on

silica gel (20 g) was heated to 80 ˚C under vacuum (~ 01-1 torr) for 12 h The silica

was washed with Et2O (10 mL) filtering with cotton and the filtrate was concentrated


hexanesEtOAc (91) to give 100 mg (62) of 432 as a colorless oil 1H NMR (400

MHz) δ 480 (d J = 64 Hz 2 H) 402 (t J = 70 Hz 1 H) 391 (dd J = 70 40 Hz 1

H) 324 (dd J = 112 70 Hz 1 H) 213 (d J = 70 Hz 2 H) 202 (s 1 H) 192 (comp

2 H) 173 (bs 1 H) 167 (s 3 H) 087 (s 9 H) -008 (s 3 H) -009 (s 3 H) 13C NMR

249

(100 MHz) δ 1439 1117 876 738 701 608 464 439 383 260 229 182 -46 -

49 IR (neat) 3311 2954 2930 2856 1648 1471 1255 1104 889 836 775 MS (CI)



402 (t J = 70 Hz 1 H C4-H) 391 (dd J = 70 40 Hz 1 H C1-H) 324 (dd J = 112

70 Hz 1 H C2-H) 213 (d J = 70 Hz 2 H C5-H) 202 (s 1 H C13-H) 192 (comp 2

H C3-H) 173 (bs 1 H N-H) 167 (s 3 H C8-H) 087 (s 9 H C11-H) -008 (s 3 H

C9-H) -009 (s 3 H C9-H) 13C NMR (100 MHz) δ 1439 (C6) 1117 (C7) 876 (C12)

738 (C2) 701 (C13) 608 (C1) 464 (C4) 439 (C5) 383 (C3) 260 (C8) 229 (C11)

182 (C10) -46 (C9) -49 (C9)

N

Me

O

Si

433

1

2

34

5

678

9

1011

12

13 14

3-(R)-(tert-butyldimethylsilanyloxy)-5-(S)-ethynyl-1-methyl-2-(S)-(2-

methylallyl)-pyrrolidine (433) (KAM4-077) MeI (20 mg 014 mmol) was added to a

solution of 431 (40 mg 014 mmol) and K2CO3 (44 mg 0317 mmol) in acetone (1 mL)

at -10 ˚C The reaction stirred for 3 h and was filtered through silica The filtrate was


250

eluting with hexanesEtOAc (91) to give 23 mg (55) of 433 as a yellow oil 1H NMR

(300 MHz) δ 494 (d J = 165 Hz 2 H) 452 (dd J = 129 69 Hz 1 H) 385 (dt J = 78

21 Hz 1 H) 299 (dd 120 72 Hz 1 H) 260 (dd J = 159 78 Hz 1 H) 248 (s 3 H)

228 (m 2 H) 207 (d J = 27 Hz 1 H) 200 (comp 1 H) 181 (s 3 H) 110 (s 9 H)

006 (s 3 H) 005 (s 3 H) 13C NMR (75 MHz) δ 1443 1108 825 736 723 643

543 420 374 360 260 238 182 -44 -50 MS (CI) mz 2942246

[C17H32N1O1Si1 (M+1) requires 2942253]


452 (dd J = 129 69 Hz 1 H C2-H) 385 (dt J = 78 21 Hz 1 H C5-H) 299 (dd

120 72 Hz 1 H C3-H) 260 (dd J = 159 78 Hz 1 H C6-H) 248 (s 3 H C1-H)

228 (m 2 H C4-H amp C6-H) 207 (d J = 27 Hz 1 H C14-H) 200 (comp 1 H C4-H)


13C NMR (75 MHz) δ 1443 (C7) 1108 (C8) 825 (C13) 736 (C14) 723 (C2) 643

(C5) 543 (C1) 420(C3) 374 (C6) 360 (C4) 260 (C12) 238 (C9) 182 (C11) -44

(C10) -50 (C10)

251

N

O

O OSi

1

2 3 4

5

6

78

910

11

1213

14

446

4-Oxo-2-trimethylsilanylethynyl-34-dihydro-2H-pyridine-1-carboxylic acid

benzyl ester (446) KAM3-236 EtMgBr (235 mL 2 M in THF 47 mol) was added to

a solution of TMS-acetylene (508 mg 517 mmol) in THF (4 mL) at -78 ˚C and the

cooling bath was removed while stirring was continued for 30 min The solution was

added to a solution of 4-methoxypyridine (430 mg 390 mmol) in THF (4 mL) and the

reaction was stirred for 5 min Upon warming to -20 ˚C Cbz-Cl (100 g 590 mmol) was

added The reaction was stirred for an additional 20 min whereupon 10 HCl (6 mL)

was added The ice bath was removed and stirring was continued for 10 min Et2O (6

mL) was added and the aqueous layer was extracted with Et2O (3 x 10 mL) The



give 678 mg (96) of 446 as a colorless oil 1H NMR (400 MHz) δ 771 (m 1 H) 739-

732 (comp 5 H) 541-522 (comp 4 H) 279 (dd J = 164 68 Hz 1 H) 258 (d J =

164 Hz 1 H) 009 (s 9 H) 13C NMR (100 MHz) δ 1911 1348 1288 1287 1286

1281 1077 1003 895 691 456 412 -039 IR (neat) 2960 1732 1677 1609 1329

252

1307 1252 1213 1188 845 MS (CI) mz 328 [C18H22NO3Si (M+1) requires 328] 328

(base) 312 284

NMR Assignments 1H NMR (400 MHz) δ 771 (m 1 H C1-H) 739-732

(comp 5 H C9-H C10-H amp C11-H) 541-522 (comp 4 H C2-H C5-H amp C7-H) 279

(dd J = 164 68 Hz 1 H C4-H) 258 (d J = 164 Hz 1 H C4-H) 009 (s 9 H C14-H)

13C NMR (100 MHz) δ 1911 (C3) 1348 (C8) 1288 (C1) 1287 (C10) 1286 (C9)

1281 (C11) 1077 (C2) 1003 (C12) 895 (C7) 691 (C13) 456 (C4) 412 (C5) -039

(C14)

N

O

OO

1

2 34

5

67

910

11

12

448

8

13

1415

16

2-Allyl-6-ethynyl-4-oxopiperidine-1-carboxylic acid benzyl ester (448)

KAM4-296 TBS-OTf (924 mg 350 mmol) was added to a solution of 446 (950 mg

291 mmol) and allyltributylstannane (115 g 350 mmol) in CH2Cl2 (15 mL) at -78 ˚C

and the solution was stirred for 15 min TBAF (290 g 900 mmol) was added and the

cooling bath was removed After 30 min NH4Cl (15 mL) was added The mixture was

extracted with CH2Cl2 (3 x 20 mL) and the combined organic layers were dried


253

chromatography eluting with hexanesEtOAc (31) to give 830 mg (96) of 448 as a

colorless oil 1H NMR (300 MHz) δ 740-720 (comp 5 H) 580-540 (comp 2 H) 520-

500 (comp 4H) 452 (bs 1 H) 280-240 (comp 6 H) 241 (d J = 27 Hz 1 H) 13C

NMR (75 MHz) δ 2054 1548 1359 1339 1285 1282 1280 1183 825 679 532

451 429 427 395 IR (neat) 3285 3067 3033 2977 1693 1642 1404 1322 1112

1028 920 698 MS (CI) mz 2981439 [C19H19NO3 (M+1) requires 2981443]


amp C3-H) 580-540 (comp 2 H C5-H ) 520-500 (comp 4 H C13-H C14-H amp C11-

H) 452 (bs 1 H C7-H) 280-240 (comp 6 H C8-H C10-H ampC12-H) 241 (d J = 27

Hz 1 H C16-H) 13C NMR (75 MHz) δ 2054 (C9) 1548 (C6) 1359 (C4) 1339

(C13) 1285 (C2) 1282 (C1) 1280 (C3) 1183 (C14) 825 (C15) 737 (C5) 679

(C16) 532 (C8) 451 (C10) 429 (C7) 427 (C11) 395 (C12)

254

N

O

O

O

O

451

17

1

2

3

4

567

8

9 10

11

1213

14

1516

H

Repersentative Procedure for PKR of cis-26-Disubstituted Piperidines

410-Dioxo-12-azatricyclo[631026]dodec-2-ene-12-carboxylic acid benzyl

ester (451) (KAM3-243) Co2(CO)8 (45 mg 0130 mmol) was added to 448 (35 mg

0118 mmol) in THF (1 mL) under an Ar atmosphere The reaction was stirred for 1 h

and complete conversion to the alkyne-Co(CO)6 complex observed by TLC DMSO (55

mg 0708 mmol) was added and the reaction was heated to 50 ˚C for 14 h Et2O (3 mL)

was added and the reaction was filtered through Celite washing with acetone (5 mL)

The combined filtrate and washings were concentrated under reduced pressure to give a

dark oil that was purified by flash chromatography eluting with hexanesEtOAc (11) to

give 34 mg (89) of 451 as a white solid 1H NMR (DMSO temp = 100 ˚C) (500 MHz)

δ 760-720 (comp 5 H) 598 (s 1 H) 557 (d J = 70 Hz 1 H) 517 (s 2 H) 480 (s 1

H) 296 (dd J = 165 70 Hz 2 H) 284 (dd J = 110 75 Hz 2 H) 253 (m 1 H) 235

(d J = 165 Hz 1 H) 219 (ddd J = 135 65 20 Hz 1 H) 192 (dd J = 185 30 Hz 1

H) 160 (dt J = 135 10 Hz 1 H) 13C NMR (DMSO temp = 100 ˚C) (125 MHz) δ

2058 2055 1755 1531 1361 1279 1274 1270 1265 665 502 480 440 437


255

NMR Assignments 1H NMR (DMSO temp = 100 ˚C) (500 MHz) δ 760-720

(comp 5 H C15-H C16-H amp C17-H) 598 (s 1 H C2-H) 557 (d J = 70 Hz 1 H C4-

H) 517 (s 2 H C13-H) 480 (s 1 H C8-H) 296 (dd J = 165 70 Hz 2 H C11-H)

284 (dd J = 110 75 Hz 2 H C5-H) 253 (m 1 H C7-H) 235 (d J = 165 Hz 1 H

C7-H) 219 (ddd J = 135 65 20 Hz 1 H C9-H) 192 (dd J = 185 30 Hz 1 H C10-

H) 160 (dt J = 135 10 Hz 1 H C9-H) 13C NMR (DMSO temp = 100 ˚C) (125

MHz) δ 2058 (C6) 2055 (C1) 1755 (C3) 1531 (C12) 1361 (C14) 1279 (C16)

1274 (C17) 1270 (C15) 1265 (C2) 665 (C13) 502 (C4) 480 (C8) 440 (C11) 437

(C7) 411 (C5) 384 (C9) 328 (C10)

N

O

Si

O O

1

2 3 4

5

6 78 9

10

1112

1314

15

460

4-Oxo-2-(3-trimethylsilanyl-prop-2-ynyl)-34-dihydro-2H-pyridine-1-

carboxylic acid benzyl ester (460) KAM4-191 3-Trimethylsilylpropargyl bromide

(274 g 144 mmol) was added to a mixture of 4-methoxypyridine (752 mg 72 mmol)

Zn dust (187 g 288 mmol) and HgCl2 (30 mg 01 mmol) in THF (50 mL) and the

reaction was heated to reflux for 3 h Upon cooling to rt Cbz-Cl (245 g 144 mmol)

was added dropwise and the reaction was stirred for 10 min The mixture was filtered

256

through a plug of Celite (1 cm) to remove excess Zn dust washing with EtOAc (30 mL)

The filtrate was washed with 1 N HCl (2 x 50 mL) brine (50 mL) dried (Na2SO4) and


eluting with hexanesEtOAc (91-31) to give 190 g (77) of 460 as a yellow oil 1H

NMR (400 MHz) δ 768 (bs 1 H) 734-715 (comp 5 H) 525 (bs 1 H) 520 (s 2 H)

466 (bs 1 H) 269 (d J = 60 Hz 2 H) 250 (d J = 76 Hz 2 H) 009 (s 9 H) 13C

NMR (100 MHz) δ 1917 1410 1346 1285 1281 1271 1266 1009 882 689

647 516 384 219 -04 IR (neat) 2959 2900 1731 1672 1604 1328 1296 1198


342 197 181 (base)

NMR Assignments 1H NMR (400 MHz) δ 768 (bs 1 H C1-H) 734-715

(comp 5 H C13-H C14-H amp C15-H) 525 (bs 1 H C2-H) 520 (s 2 H C11-H) 466

(bs 1 H C5-H) 269 (d J = 60 Hz 2 H C4-H) 250 (d J = 76 Hz 2 H C6-H) 009 (s

9 H C9-H) 13C NMR (100 MHz) δ 1917 (C3) 1410 (C10) 1346 (C12) 1285 (C1)

1281 (C15) 1271 (C13) 1266 (C14) 1009 (C2) 882 (C7) 689 (C11) 647 (C8)

516 (C5) 384 (C4 219 (C6) -04 (C9)

257

N

O O

Si

O

12 3 4

567 8

910

11

1213

1415

16

461

17

4-Oxo-2-(3-trimethylsilanylprop-2-ynyl)-6-vinylpiperidine-1-carboxylic acid

benzyl ester (461) KAM4-266 A solution on MeLi (288 mmol 18 mL 16 M in

hexanes) was slowly added to a suspension of flame dried CuCN (256 mg 288 mmol) at

-78 ˚C The reaction was warmed to 0 ˚C for 1 min and then recooled to -78 ˚C Vinyl

magnesium bromide (288 mmol 288 mL 1 M in THF) was added dropwise over 5 min

and the reaction was stirred for 10 min A solution of 460 (655 mg 192 mmol) in THF

(2 mL) was added and the mixture which turned a deep orangered color was stirred at -

78 ˚C for 15 h The reaction was poured into a solution of NH4ClNH4OH (91 10 mL)

and stirred until all the salts dissolved The aqueous solution was extracted with Et2O (3

x 10 mL) and the combined organic layers were dried (Na2SO4) and concentrated under



MHz d6-DMSO 100 ˚C) δ 740-729 (comp 5 H) 602 (ddd J = 155 105 50 Hz 1

H) 519-510 (comp 5 H) 460 (dt J = 70 60 Hz 1 H) 279 (dd J = 160 75 Hz 1

H) 271 (dd J = 160 75 Hz 1 H) 263-247 (comp 5 H) 012 (s 9 H) 13C NMR (125

MHz d6-DMSO 100 ˚C) δ 2052 1545 1390 1361 1278 1272 1269 1150 1034

258

868 664 526 510 418 417 259 -07 IR (neat) 3089 3034 2959 2900 1698

1607 1403 1326 1250 843 MS (CI) mz 3701848 [C21H28NO3Si (M+1) requires

3701838]

NMR Assignments 1H NMR (500 MHz d6-DMSO 100 ˚C) δ 740-729 (comp

5 H C14-H C15-H amp C16-H) 602 (ddd J = 155 105 50 Hz 1 H C7-H) 519-510

(comp 5 H C1-H C6-H amp C12-H) 460 (dt J = 70 60 Hz 1 H C5-H) 279 (dd J =

160 75 Hz 1 H C8-H) 271 (dd J = 160 75 Hz 1 H C8-H) 263-247 (comp 4 H

C2-H amp C4-H) 012 (s 9 H C11-H) 13C NMR (125 MHz d6-DMSO 100 ˚C) δ 2052

(C3) 1545 (C17) 1390 (C13) 1361 (C7) 1278 (C15) 1272 (C16) 1269 (C14)

1150 (C6) 1034 (C12) 868 (C9) 664 (C10) 526 (C1) 510 (C2) 418 (C4) 417

(C5) 259 (C8) -07 (C11)

N

O O

O

1

2 3 4

567 8

910

1112

1314

15

462

18

4-Oxo-2-prop-2-ynyl-6-vinylpiperidine-1-carboxylic acid benzyl ester (462)

KAM4-267 TBAFH2O (300 mg 0900 mmol) was added in one portion to a stirred

solution of 461 (300 mg 0813 mmol) in THF (5 mL) The reaction was stirred for 5

min and NH4Cl (5 mL) was added The mixture was extracted with Et2O (3 x 5 mL) and

259

the combined organic layers were dried (Na2SO4) and concentrated under reduced


(31) to give 166 mg (69) of 462 as a colorless oil 1H NMR (500 MHz d6-DMSO

100 ˚C) δ 740-729 (comp 5 H) 599 (ddd J = 160 105 45 Hz 1 H) 519-512

(comp 5 H) 461 (dt J = 65 50 Hz 1 H) 280 (dd J = 160 70 Hz 1 H) 274 (dd J =

160 70 Hz 1 H) 269 (dt J = 30 10 Hz 1 H) 259 (ddd J = 192 30 15 Hz 1 H)

253-246 (comp 3 H) 13C NMR (125 MHz d6-DMSO 100 ˚C) δ 2052 1545 1388

1361 1278 1272 1270 1152 803 724 664 527 512 417 416 247 IR (neat)

3307 3035 2959 1694 1407 1320 1271 1114 1057 MS (CI) mz 2981443

[C18H20NO3 (M+1) requires 2981443]




160 70 Hz 1 H C2-H) 274 (dd J = 160 70 Hz 1 H C2-H) 269 (dd J = 30 10

Hz 1 H C10-H) 259 (ddd J = 192 30 15 Hz 1 H C4-H) 253-246 (comp 3 H

C4-H amp C8-H) 13C NMR (125 MHz d6-DMSO 100 ˚C) δ 2052 (C3) 1545 (C16)

1388 (C12) 1361 (C7) 1278 (C14) 1272 (C13) 1270 (C15) 1152 (C6) 803 (C9)

724 (C11) 664 (C10) 527 (C1) 512 (C2) 417 (C4) 416 (C5) 247 (C8)

260

16

17

N

O

H

O

OO

1

2 34

5

6

7

89

10 11

12

13 14

15

463


ester (463) KAM4-270 The PKR of 462 was performed on a scale of 017 mmol

according to the representative procedure and the crude product was purified by flash

chromatography eluting with EtOAc to give 463 in a 91 yield as a colorless oil 1H

NMR (500 MHz d6-DMSO 100 ˚C) δ 742-731 (comp 5 H) 593 (s 1 H) 521 (s 2

H) 494 (dt J = 80 15 Hz 1 H) 485 (t J = 65 Hz 1 H) 315 (dt J = 65 15 Hz 1

H) 283 (d J = 140 Hz 1 H) 274 (dd J = 150 60 Hz 1 H) 268 (dd J = 165 65 Hz

1 H) 254 (dd J = 170 70 Hz 1 H) 241 (dd J = 190 70 Hz 1 H) 228 (t J = 150

Hz 1 H) 210 (dd J = 195 25 Hz 1 H) 13C NMR (125 MHz d6-DMSO 100 ˚C) δ

2050 2043 1735 1533 1361 1317 1279 1273 1270 665 507 474 448 436

387 367 348 IR (neat) 3035 2963 2902 1706 1626 1416 1335 1264 1220 1100

1028 MS (CI) mz 3261392 [C19H20NO4 (M+1) requires 3261392]


5 H C15-H C16-H amp C17-H) 593 (s 1 H C8-H) 521 (s 2 H C13-H) 494 (dt J =

80 15 1 H C1-H) 485 (t J = 65 Hz 1 H C5-H) 315 (dt J = 65 15 Hz C11-H)

283 (d J = 145 Hz 1 H C6-H) 274 (dd J = 145 60 Hz 1 H C6-H) 268 (dd J =

261

165 65 Hz 1 H C10-H) 254 (dd J = 165 70 Hz 1 H C10-H) 241 (dd J = 190

70 Hz 1 H C2-H) 228 (t J = 150 Hz 2 H C4-H) 210 (dd J = 190 25 Hz 1 H C2-

H) 13C NMR (125 MHz d6-DMSO 100 ˚C) δ 2050 (C3) 2043 (C9) 1735 (C7) 1533

(C12) 1361 (C8) 1317 (C14) 1279 (C16) 1273 (C17) 1270 (C15) 665 (C13) 507

(C1) 474 (C5) 448 (C11) 436 (C6) 387 (C10) 367 (C2) 348 (C4)

N

O

O O

469

1

2 34

5

6

78

910

11

1213

14

15

Si

16

4-Oxo-2-trimethylsilanylethynyl-6-vinylpiperidine-1-carboxylic acid benzyl

ester (469) KAM4-169 MeLi (094 mL 16 M in Et2O 15 mmol) was added to a

suspension of CuCN (134 mg 15 mmol) in THF (4 mL) at -78 ˚C The mixture was

cooled to 0 ˚C stirred for 1 min and then recooled to -78 ˚C A solution of vinyl

magnesium bromide (15 mL 1 M in THF 15 mmol) was added dropwise The reaction

was stirred for 20 min whereupon a solution of 446 (327 mg 1 mmol) in THF (2 mL)

was added dropwise The resulting mixture stirred 1 h at -78 ˚C at which point the

reaction was poured into a vigorously stirred mixture (91) of saturated NH4ClNH4OH

The mixture was stirred 30 min until all the solids has dissolved and the solution was

262

extracted with Et2O (3 x 20 mL) The combined organic layers were washed with H2O

(30 mL) brine (30 mL) dried (Na2SO4) and concentrated under reduced pressure The

residue was purified by flash chromatography eluting with hexanesEtOAc (31) to give


607 (ddd J = 168 104 64 Hz 1 H) 549 (bs 1 H) 522-510 (comp 4 H) 488 (bs 1


MHz) δ 2054 1547 1376 1360 1285 1282 1280 1163 1077 1040 907 679

547 453 432 -049 IR (neat) 2959 1704 1403 1309 1250 1224 1054 844 MS

(CI) mz 356 [C20H26NO3Si (M+1) requires 356] 356 (base) 340 312 257 168

NMR Assignments 1H NMR (400 MHz) δ 736-730 (comp 5 H C14-H C15-

H amp C16-H) 607 (ddd J = 168 104 64 Hz 1 H C6-H) 549 (bs 1 H C5-H) 522-

510 (comp 4 H C7-H amp C12-H) 488 (bs 1 H C1-H) 297 (dd J = 156 72 Hz 1 H

C2- or C4-H) 269-258 (comp 3 H C2-H amp C4-H) 012 (s 9 H C10-H) 13C NMR (75

MHz) δ 2054 (C3) 1547 (C11) 1376 (C13) 1360 (C6) 1285 (C15) 1282 (C16)

1280 (C14) 1163 (C7) 1077 (C5) 1040 (C1) 907 (C8) 679 (C12) 547 (C9) 453

(C2) 432 (C4) -049 (C10)

263

N

O

O O

470

1

2 34

5

67

89

10

1112

1314

15

2-Ethynyl-4-oxo-6-vinyl-piperidine-1-carboxylic acid benzyl ester (470)

KAM4-170 TBAF (400 mg 112 mmol) was added in one portion to a solution of 469

(200 mg 056 mmol) in THF (5 mL) The reaction was stirred for 30 min and


eluting with hexanesEtOAc (31) to give 83 mg (53) of 470 as a pale yellow oil 1H

NMR (500 MHz d6-DMSO 100 ˚C) δ 740-730 (comp 5 H) 607 (ddd J = 170 105

60 Hz 1 H) 542 (dt J = 75 25 Hz 1 H) 518 (d J = 170 Hz 1 H) 517 (s 2 H) 510

(d J = 90 Hz 1 H) 500 (dd J = 130 60 Hz 1H) 322 (s 1 H) 287 (dd J = 160 70

Hz 1 H) 280 (dd J = 160 70 Hz 1 H) 265 (dd J = 160 55 Hz 1 H) 247 (m 1 H)

13C NMR (75 MHz) δ 2050 1548 1373 1358 1285 1282 1280 1167 824 738

680 548 449 432 425 IR (neat) 3285 2957 1698 1403 1310 1264 1310 1264

1226 1113 1027 698 MS (CI) mz 2841291 [C17H18NO3 (M+1) requires 2841287]

284 (base) 266 240


5 H C13-H C14-H amp C15-H) 607 (ddd J = 170 105 60 Hz 1 H C6-H) 542 (dt J

= 75 25 Hz 1 H C5-H) 518 (d J = 170 Hz 1 H C7-H) 517 (s 2 H C11-H) 510

264

(d J = 90 Hz 1 H C7-H) 500 (dd J = 130 60 Hz 1H C1-H) 322 (s 1 H C9-H)

287 (dd J = 160 70 Hz 1 H C2-H) 280 (dd J = 160 70 Hz 1 H C4-H) 265 (dd J

= 160 55 Hz 1 H C2-H) 247 (m 1 H C4-H) 13C NMR (75 MHz) δ 2050 (C3)

1548 (C10) 1373 (C6) 1358 (C12) 1285 (C14) 1282 (C15) 1280 (C13) 1167

(C7) 824 (C8) 738 (C11) 680 (C9) 548 (C1) 449 (C5) 432 (C2) 425 (C4)

11

10

1

23

45

6

7

89

12 1314

15

16

N

O

O

O

O

471

H

49-Dioxo-11-azatricyclo[531026]undec-2-ene-11-carboxylic acid benzyl



chromatography eluting with hexanesEtOAc (31-11) to give 14 mg (33) of 471 as a

colorless oil as a mixture (31) of diastereomers 1H NMR (500 MHz d6-DMSO 100

˚C) δ 742-731 (comp 5 H) 609 (s 1 H) 538 (bs 1 H) 520 (s 2 H) 524 (m 1 H)

462 (t J = 60 Hz 1 H) 347 (m 1 H) 291 (dd J = 170 60 Hz 1 H) 281 (comp 1

H) 260 (dd J = 180 60 Hz 1 H) 238 (d J = 180 Hz 1 H) 217 (dd J = 180 30 Hz

1 H) MS (CI) mz 3121234 [C18H18NO4 (M+1) requires 3121236] 312 (base) 268

265


5 H C14-H C15-H amp C16-H) 609 (s 1 H C2-H) 538 (bs 1 H C5-H) 520 (s 2 H

C12-H) 524 (m 1 H C7-H) 462 (t J = 60 Hz 1 H C1-H) 347 (m 1 H C3-H) 291

(dd J = 170 60 Hz 1 H C3-H) 281 (comp 1 H C8-H) 260 (dd J = 180 60 Hz 1

H C8-H) 238 (d J = 180 Hz 1 H C10-H) 217 (dd J = 180 30 Hz 1 H C10-H)

N

O O

O

Si

1

2 3 4

5

6

78

9

1011

12

473


allyl ester (473) KAM4-277 EtMgBr (1215 mL 22 mmol 181 M in THF) was

added to TMS-acetylene (245 g 25 mmol) in THF (10 mL) at -78 ˚C The cooling bath

was removed the reaction warmed to rt and was stirred for 30 min The solution was

added via syringe to a solution of 4-methoxypyridine (20 g 18 mmol) in THF (30 mL) at

-78 ˚C The resultant solution was stirred for 5 min at -78 ˚C and then warmed to -20 ˚C

Alloc-Cl (36 g 30 mmol) was added and the reaction was stirred an additional 20 min

HCl (10 mL 10 in H2O) was added and the ice bath was removed Et2O (20 mL) was

added and the layers were separated The aqueous layer was extracted with Et2O (3 x 15

mL) and the organic layers were dried (Na2SO4) and concentrated under reduced

266


(31) to give 459 g (94) of 473 as a white solid 1H NMR (400 MHz) δ 770 (d J =

84 Hz 1 H) 593 (ddd J = 160 104 48 Hz 1 H) 538 (dd J = 160 60 Hz 1 H)

527 (d J = 108 Hz 1 H) 479 (dd J = 128 52 Hz 1 H) 469 (dd J = 136 60 Hz 1

H) 279 (dd J = 164 68 Hz 1 H) 277 (d J = 64 Hz 1 H) 258 (d J = 164 Hz 1 H)

007 (s 9 H) 13C NMR (100 MHz) δ 1912 1519 1410 1312 1190 1078 1003

895 679 456 413 -04 IR (neat) 3088 2960 2900 1732 1678 1608 1418 1372


2781212]

NMR Assignments 1H NMR (400 MHz) δ 770 (d J = 84 Hz 1 H C1-H) 593

(ddd J = 160 104 48 Hz 1 H C8-H) 538 (dd J = 160 60 Hz 2 H C9-H) 527 (d

J = 108 Hz 2 H C2-H amp C5-H) 479 (dd J = 128 52 Hz 1 H C7-H) 469 (dd J =

136 60 Hz 1 H C7-H) 279 (dd J = 164 68 Hz 1 H C4-H) 277 (d J = 64 Hz 1

H) 258 (d J = 164 Hz 1 H C4-H) 007 (s 9 H C12-H) 13C NMR (100 MHz) δ 1912

(C3) 1519 (C6) 1410 (C8) 1312 (C1) 1190 (C9) 1078 (C2) 1003 (C7) 895 (C10)

679 (C11) 456 (C4) 413 (C5) -04 (C12)

267

HN

O

Si

1

2 3 4

56

7

8

474

2-Trimethylsilanylethynyl-23-dihydro-1H-pyridin-4-one (474) KAM4-278

A solution of 473 (277 mg 1 mmol) dimethyl malonate (528 mg 4 mmol) and

Pd(PPh3)4 (22 mg 002 mmol) in THF (5 mL) was stirred at rt for 1 h The reaction was


eluting with hexanesEtOAc (31-12) to give 179 mg (93) of 474 as a white solid 1H

NMR (400 MHz) δ 664 (comp 1 H) 507 (d J = 76 Hz 1 H) 408 (comp 1 H) 256

(dd J = 156 100 Hz 1 H) 246 (dd J = 156 60 Hz 1 H) 011 (s 9 H) 13C NMR

(100 MHz) δ 1912 1508 1020 992 895 451 418 -03 IR (neat) 3233 3022 2960

1631 1573 1530 1404 1231 843 MS (CI) mz 1941005 [C10H16NOSi (M+1) requires

1941001]

NMR Assignments 1H NMR (400 MHz) δ 664 (comp 1 H C1-H) 507 (d J =

76 Hz 1 H C2-H) 408 (comp 1 H N-H) 256 (dd J = 156 100 Hz 1 H C4-H) 246

(dd J = 156 60 Hz 1 H C4-H) 011 (s 9 H C8-H) 13C NMR (100 MHz) δ 1912

(C3) 1508 (C1) 1020 (C2) 992 (C6) 895 (C7) 451 (C5) 418 (C4) -03 (C8)

268

NSiSO O

O

1

2 3 4

5

67

89

10

1112

13

475

1-(Toluene-4-sulfonyl)-2-trimethylsilanylethynyl-23-dihydro-1H-pyridin-4-

one (475) KAM4-280 A solution of 474 (179 mg 0927 mmol) in THF (5 mL) was

cooled to -78 ˚C and a solution of n-BuLi (0426 mL 0976 mmol 229 M in hexanes)

was slowly added over 15 min The deep red solution was stirred at -78 ˚C for 15 min

and TsCl (213 mg 112 mmol) was added in one portion The reaction turned yellow and

was stirred for 15 min at -78 ˚C and 15 min at rt Saturated NaHCO3 (5 mL) was added

and the mixture was extracted with Et2O (3 x 5 mL) The combined organic layers were


flash chromatography eluting with hexanesEtOAc (91-31) to give 162 mg (50) of

475 as a yellow solid 1H NMR (300 MHz) δ 772 (d J = 81 Hz 2 H) 749 (d J = 84

Hz 1 H) 727 (d J = 84 Hz 2 H) 536 (d J = 84 Hz 1 H) 515 (d J = 63 Hz 1 H)

279 (dd J = 162 60 Hz 1 H) 250 (d J = 159 Hz 1 H) 237 (s 3 H) -014 (s 9 H)

13C NMR (75 MHz) δ 1899 1451 1408 1345 1300 1278 1078 981 912 469

422 215 -075 IR (neat) 3081 2963 1681 1597 1403 1362 1272 1168 846 MS

(CI) mz 3481078 [C17H22NO3SiS (M+1) requires 3481090]

269


(d J = 84 Hz 1 H C1-H) 727 (d J = 81 Hz 2 H C8-H) 536 (d J = 84 Hz 1 H C2-

H) 515 (d J = 60 Hz 1 H C5-H) 279 (dd J = 162 60 Hz 1 H C4-H) 250 (d J =

159 Hz 1 H C4-H) 237 (s 3 H C10-H) -014 (s 9 H C13-H) 13C NMR (75 MHz) δ

1899 (C3) 1451 (C6) 1408 (C1) 1345 (C9) 1299 (C7) 1278 (C8) 1078 (C2) 981

(C11) 912 (C12) 469 (C5) 422 (C4) 215 (C10) -075 (C13)

N

SO O

O

1

2 3 4

5

67

89

10

1112

476

2-Ethynyl-1-(toluene-4-sulfonyl)-23-dihydro-1H-pyridin-4-one (476)

KAM4-288 K2CO3 (182 g 1316 mmol) was added to a solution of 475 (114 g 329

mmol) in MeOH (20 mL) The reaction was stirred for 1 h and H2O (20 mL) was added

The mixture was extracted with CH2Cl2 (3 x 30 mL) and the combined organic layers

were dried (Na2SO4) and concentrated under reduced pressure The residue was purified

by flash chromatography eluting with hexanesEtOAc (31-11) to give 404 mg (48) of

476 as a yellow oil 1H NMR (400 MHz) δ 775 (d J = 84 Hz 2 H) 754 (dd J = 88

16 Hz 1 H) 731 (d J = 84 Hz 2 H) 541 (d J = 88 Hz 1 H) 518 (comp 1 H) 2 79

270

(dd J = 160 64 Hz 1 H) 252 (d J = 164 Hz 1 H) 241 (s 3 H) 199 (d J = 20 Hz 1

H) 13C NMR (100 MHz) δ 1897 1454 1409 1344 1299 1278 1079 741 463

419 384 216 IR (neat) 3280 1676 1596 1363 1275 1167 1052 MS (CI) mz

2760693 [C14H14NO3S (M+1) requires 2760694]


(dd J = 88 16 Hz 1 H C1-H) 731 (d J = 84 Hz 2 H C8-H) 541 (d J = 88 Hz 1

H C2-H) 518 (comp 1 H C5-H) 2 79 (dd J = 162 64 Hz 1 H C4-H) 252 (d J =

162 Hz 1 H C4-H) 241 (s 3 H C10-H) 199 (d J = 20 Hz 1 H C12-H) 13C NMR

(100 MHz) δ 1897 (C3) 1454 (C6) 1409 (C1) 1344 (C9) 1299 (C7) 1278 (C8)

1079 (C2) 741 (C12) 463 (C11) 419 (C5) 384 (C4) 216 (C10)

N

SO O

O

1

2 3 4

5

67

89

10

11

12

13

1415

477

2-Allyl-6-ethynyl-1-(toluene-4-sulfonyl)-piperidin-4-one (477) KAM4-289

TiCl4 (0437 mL 0437 mmol 1 M in hexanes) was added to a solution of allyl

trimethylsilane (83 mg 0728 mmol) and 476 (100 mg 0364 mmol) in CH2Cl2 (5 mL)

at -78 ˚C The reaction was stirred for 2 h at -78 ˚C and then 30 min at rt HCl (5 ml 1

271

M in H2O) was added and the mixture was extracted with CH2Cl2 (3 x 5 mL) The



give 45 mg (39) of 477 as a yellow oil 1H NMR (400 MHz) δ 776 (d J = 80 Hz 2

H) 730 (d J = 80 Hz 2 H) 557 (ddt J = 176 104 72 Hz 1 H) 543 (d J = 76 Hz 1

H) 502 (s 1 H) 498 (d J = 76 Hz 1 H) 442 (dt J = 72 60 Hz 1 H) 265 (dd J =

144 72 Hz 1 H) 253-242 (comp 5 H) 241 (s 3 H) 237 (d J = 28 Hz 1 H) 13C

NMR (75 MHz) δ 2044 1441 1369 1338 1299 1273 1187 815 748 554 457

446 434 388 216 IR (neat) 3305 1723 1356 1162 1094 MS (CI) mz 3181163

[C17H20NO3S (M+1) requires 3181164]


(d J = 80 Hz 2 H C8-H) 557 (ddt J = 176 104 72 Hz 1 H C12-H) 543 (d J = 76

Hz 1 H C5-H) 502 (s 1 H C13-H) 498 (d J = 76 Hz 1 H C13-H) 442 (dt J = 72

60 Hz 1 H C1-H) 265 (dd J = 144 72 Hz 1 H C4-H) 253-242 (comp 5 H C2-H

C4-H amp C11-H) 241 (s 3 H C10-H) 237 (d J = 28 Hz 1 H C15-H) 13C NMR (75

MHz) δ 2044 (C3) 1441 (C6) 1369 (C9) 1338 (C12) 1299 (C7) 1273 (C8) 1187

(C13) 815 (C14) 748 (C15) 554 (C5) 457 (C11) 446 (C4) 434 (C2) 388 (C5)

216 (C10)

272

N

O

SiO

1

2 34

5

67

8

9

10

11

1213

478

1-Benzoyl-2-trimethylsilanylethynyl-23-dihydro-1H-pyridin-4-one (478)

KAM4-294 A solution of 474 (416 mg 216 mmol) in THF (10 mL) was cooled to -78

˚C and a solution of nBuLi (1 mL 229 M in hexanes 229 mmol) was slowly added

dropwise over 15 min The reaction stirred for 15 min and benzoyl chloride (605 mg

432 mmol) was added dropwise After the reaction stirred for 15 min at -78 ˚C the

cooling bath was removed and stirring was continued at rt for 15 min Sat NaHCO3 (10




give 630 mg (98) of 478 as a colorless oil 1H NMR (400 MHz) δ 756 (d J = 72 Hz

1 H) 753 (comp 5 H) 548 (m 1 H) 537 (d 72 Hz 1 H) 285 (dd J = 164 64 Hz 1

H) 264 (d J = 164 Hz 1 H) 008 (s 9 H) 13C NMR (75 MHz) δ 1914 1691 1420

1323 1318 1286 1284 1081 1005 895 456 418 -04 IR (neat) 2962 1668


2981263] 298 (base)

273


(comp 5 H C11-H C12-H amp C13-H) 548 (m 1 H C5-H) 537 (d 72 Hz 1 H C2-H)

285 (dd J = 164 64 Hz 1 H C4-H) 264 (d J = 164 Hz 1 H C4-H) 008 (s 9 H

C8-H) 13C NMR (75 MHz) δ 1914 (C3) 1691 (C9) 1420 (C1) 1323 (C10) 1318

(C13) 1286 (C12) 1284 (C11) 1081 (C2) 1005 (C6) 895 (C7) 456 (C5) 418 (C4)

-04 (C8)

N

O

O

1

2 34

5

67

910

1112

13

479

8

1415

2-Allyl-1-benzoyl-6-ethynylpiperidin-4-one (479) KAM4-295 TBS-OTf (316

mg 12 mmol) was added to a solution of 478 (297 mg 1 mmol) and

allyltributylstannane (400 mg 12 mmol) in CH2Cl2 (5 mL) at -78 ˚C and the solution

was stirred for 15 min TBAF (942 mg 3 mmol) was added and the cooling bath was

removed After 30 min NH4Cl (5 mL) was added The mixture was extracted with

CH2Cl2 (3 x 10 mL) and the combined organic layers were dried (Na2SO4) and


eluting with hexanesEtOAc (31) to give 243 mg (91) of 479 as a colorless oil 1H

NMR (500 MHz DMSO temp = 100 ˚C) δ 751 (comp 5 H) 573 (m 1 H) 536 (bs 1

274

H) 506 (comp 2 H) 467 (bs 1 H) 333 (d J = 15 Hz 1 H) 297 (comp 2 H) 280

(dd J = 150 70 Hz 1H) 271 (m 1 H) 251 (dd J = 150 70 Hz 1 H) 242 (d J =

150 Hz 1 H) 13C NMR (125 MHz DMSO temp = 100 ˚C) δ 2043 1697 1354

1339 1293 1279 1260 1172 827 754 525 447 435 423 379 IR (neat) 3256

2976 1724 1643 1402 1357 1216 MS (CI) mz 268 [C17H18NO2 (M+1) requires 268]

268 (base) 250

NMR Assignments 1H NMR (500 MHz DMSO temp = 100 ˚C) δ 751 (comp

5 H C13-H C14-H amp C15-H) 573 (m 1 H C9-H) 536 (bs 1 H C5-H) 506 (comp 2

H C10-H) 467 (bs 1 H C1-H) 333 (d J = 15 Hz 1 H C7-H) 297 (comp 2 H C8-

H) 280 (dd J = 150 70 Hz 1H C4-H) 271 (m 1 H C2-H) 251 (dd J = 150 70

Hz 1 H C4-H) 242 (d J = 150 Hz 1 H C2-H) 13C NMR (125 MHz DMSO temp =

100 ˚C) δ 2043 (C3) 1697 (C11) 1354 (C12) 1339 (C9) 1293 (C15) 1279 (C14)

1260 (C13) 1172 (C10) 827 (C6) 754 (C7) 525 (C5) 447 (C8) 435 (C1) 423

(C4) 379 (C2)

275

N

O

O

H

SO

O

1

2 3 4

5

67

89

101112

1314

15

16

480

12-(Toluene-4-sulfonyl)-12-azatricyclo[631026]dodec-2-ene-410-dione

(480) KAM4-291 The PKR of 477 was performed on a scale of 014 mmol according

to the representative procedure and the crude product was purified by flash

chromatography eluting with hexanesEtOAc (11) to give 29 mg (61) of 14 as a white

solid 1H NMR (400 MHz) δ 768 (d J = 80 Hz 2 H) 727 (d J = 80 Hz 2 H) 589 (s

1 H) 538 (d J = 60 Hz 1 H) 460 (s 1 H) 298-280 (comp 3 H) 249 (comp 3 H)

240 (s 3 H) 202 (m 1 H) 173 (d J = 188 Hz 1 H) 141 (dt J = 128 48 Hz 1 H)

13C NMR (75 MHz) δ 2059 2056 1736 1445 1367 1300 1280 1271 521 501

459 453 416 385 332 216 IR (neat) 3689 2925 1715 1633 1353 1163 1098

999 MS (CI) mz 3461114 [C18H20NO4S (M+1) requires 3461113]


727 (d J = 80 Hz 2 H C14-H) 589 (s 1 H C7-H) 538 (d J = 60 Hz 1 H C5-H)

460 (s 1 H C1-H) 298-280 (comp 3 H C9-H amp C11-H) 249 (comp 3 H C11-H

C2-H amp C4-H) 240 (s 3 H C16-H) 202 (m 1 H C10-H) 173 (d J = 188 Hz 1 H

C4-H) 141 (dt J = 128 48 Hz 1 H C2-H) 13C NMR (75 MHz) δ 2059 (C3) 2056

(C8) 1736 (C6) 1445 (C12) 1367 (C15) 1300 (C13) 1280 (C7) 1271 (C14) 521

(C5) 501 (C1) 459 (C10) 453 (C9) 416 (C4) 385 (C2) 332 (C11) 216 (C16)

276

N

O

1

2 34

5

6

9

10

11

481

OH

7

8

12 13

O

14

15

16

12-Benzoyl-12-azatricyclo[631026]dodec-2-ene-410-dione (481) KAM6-

193 The PKR of 479 was performed on a scale of 023 mmol according to the general

procedure and the crude product was purified by flash chromatography eluting with

hexanesEtOAc (11-01) to give 481 in a 94 yield as a colorless oil 1H NMR (500

MHz d6-DMSO temp = 100 ˚C) δ 750-747 (comp 5 H) 595 (s 1 H) 563 (bs 1 H)

470 (bs 1 H) 306 (dd J = 165 70 Hz 1 H) 297-288 (comp 3 H) 254 (dd J = 185

65 Hz 1 H) 241 (m 1 H) 219 (dd J = 130 60 Hz 1 H) 199 (dd J = 185 30 Hz 1

H) 168 (dt J = 125 40 Hz 1 H) 13C NMR (125 MHz DMSO temp = 100 ˚C) δ

2058 2056 1754 1685 1348 1294 1280 1266 1260 500 488 441 438 410

384 332 IR (neat) 2917 1713 1633 1410 1338 1217 914 MS (CI) mz 296

[C18H18NO3 (M+1) requires 296] 374 296 (base) 157

NMR Assignments 1H NMR (500 MHz DMSO temp = 100 ˚C) δ 750-747

(comp 5 H C14-H C15-H amp C16-H) 595 (s 1 H C10-H) 563 (bs 1 H C1-H) 470

(bs 1 H C5-H) 306 (dd J = 165 70 Hz 1 H C8-H) 297-288 (comp 3 H C8-H amp

C2-H) 254 (dd J = 185 65 Hz 1 H C4-H) 241 (m 1 H C7-H) 219 (ddd J = 130

60 15 Hz 1 H C6-H) 199 (dd J = 185 30 Hz 1 H C4-H) 168 (dt J = 130 40

277

Hz 1 H C6-H) 13C NMR (125 MHz DMSO temp = 100 ˚C) δ 2058 (C3) 2056 (C9)

1754 (C11) 1685 (C12) 1348 (C10) 1294 (C13) 1280 (C15) 1266 (C16) 1260

(C14) 500 (C1) 488 (C5) 441 (C8) 438 (C2) 410 (C4) 384 (C7) 332 (C6)

N

OH

O O

1

2 3 4

5

6

78 9

10

11

1213

1415

16

482

2-Allyl-6-ethynyl-4-hydroxypiperidine-1-carboxylic acid benzyl ester (482)


˚C and a solution of L-selectride (30 mL 1 M in THF) was added dropwise The

reaction was stirred at -78 ˚C whereupon sat NH4Cl (10 mL) was added The mixture

was extracted with Et2O (3 x 10 mL) and the combined organic layers were dried



colorless oil 1H NMR (400 MHz) δ 736-729 (comp 5 H) 576 (ddt J = 168 100 72

Hz 1 H) 528-496 (comp 5 H) 425 (m 1 H) 283 (t J = 72 Hz 2 H) 263 (d J = 24

Hz 1 H) 221-198 (comp 3 H) 173 (ddd J = 32 72 140 Hz 1 H) IR (neat) 3447

278

3297 2953 1684 1409 1324 1087 1063 990 914 MS (CI) mz 300 [C18H22NO3

(M+1) requires 300] 300 (base) 258 256 238 214


H amp C16-H) 576 (ddt J = 168 100 72 Hz 1 H C7-H) 528-496 (comp 5 H C12-

H C8-H C1-H C9-H) 425 (m 1 H C3-H) 283 (t J = 72 Hz 2 H C6-H) 263 (d J =

24 Hz 1 H C10-H) 221-198 (comp 3 H C2-H C4-H) 173 (ddd J = 32 72 140

Hz 1 H C4-H)

N

O O

12 3 4

5

6

78

11

1213

14

1516

1718

283

OSi

9

10

19

2-Allyl-4-(tert-butyldimethylsilanyloxy)-6-ethynylpiperidine-1-carboxylic

acid benzyl ester (483) KAM6-171 482 (250 mg 084 mmol) was dissolved in DMF

(5 mL) and imidazole (170 mg 25 mmol) and TBS-Cl (151 mg 1 mmol) were added

sequentially The reaction stirred at rt for 12 h and NH4Cl (5 mL) was added The

mixture was extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were

washed with H2O (5 mL) brine (5 mL) dried (Na2SO4) and concentrated under reduced

279


(91) to give 268 mg (81) of 483 as a colorless oil 1H NMR (400 MHz) δ 737-729

(comp 5 H) 577 (ddd J = 172 100 72 Hz 1 H) 515 (s 2 H) 507 (d J = 172 Hz 1

H) 497 (d J = 100 Hz 1 H) 423 (m 1 H) 408 (app p J = 40 Hz 1 H) 373 (dt J =

68 44 Hz 1 H) 284 (m 2 H) 220 (d J = 24 Hz 1 H) 202-167 (comp 4 H) 090 (s

9 H) 007 (s 3 H) 005 (s 3 H) 13C NMR (100 MHz) δ 1555 1366 1365 1284

1279 1278 1168 854 706 673 642 507 391 386 366 336 258 181 -49 -

50 IR (neat) 3307 2953 2856 1694 1640 1407 1335 1312 1255 1093 774 MS (CI)

mz 414 [C24H36NO3Si (M+1) requires 414] 414 (base) 398 372 356 238


H amp C19-H) 577 (ddd J = 172 100 72 Hz 1 H C7-H) 515 (s 2 H C15-H) 507

(d J = 172 Hz 1 H C8-H) 497 (d J = 100 Hz 1 H C8-H) 423 (m 1 H C5-H) 408

(app p J = 40 Hz 1 H C1-H) 373 (dt J = 68 44 Hz 1 H C3-H) 284 (m 2 H C6-

H) 220 (d J = 24 Hz 1 H C13-H) 202-167 (comp 4 H C2-H amp C4-H) 090 (s 9 H

C11-H) 007 (s 3 H C9-H) 005 (s 3 H C9-H) 13C NMR (100 MHz) δ 1555 (C14)

1366 (C7) 1365 (C16) 1284 (C18) 1279 (C19) 1278 (C17) 1168 (C8) 854 (C12)

706 (C15) 673 (C3) 642 (C13) 507 (C1) 391 (C5) 386 (C6) 366 (C2) 336 (C4)

258 (C11) 181 (C10) -49 (C9) -50 (C9)

280

N

O O

O

S

S

484

1

23

4

5

6

78

9

10

1112

13

1415

16

1718

2-Allyl-6-ethynyl-4-methylsulfanylthiocarboxyoxypiperidine-1-carboxylic

acid benzyl ester (484) KAM6-215 NaH (34 mg 60 dispersion in mineral oil 085

mmol) was added to a solution of 482 (170 mg 057 mmol) in THF (3 mL) at rt and the

reaction was stirred for 15 min CS2 (130 mg 171 mmol) was added and after the

reaction was stirred for 15 min MeI (142 mg 10 mmol) was added After an additional

15 min of stirring ice was added until all bubbling ceased H2O (3 mL) was added and

the mixture was extracted with CH2Cl2 (3 x 5 mL) The combined organic layers were


flash chromatography eluting with hexanesEtOAc (91) to give 102 mg (46) of 484 as

a yellow oil 1H NMR (400 MHz) δ 736-728 (comp 5 H) 587 (m 1 H) 571 (ddd J =

168 125 68 Hz 1 H) 522 (m 1 H) 518 (s 2 H) 512 (d J = 168 Hz 1 H) 502 (d

J = 125 Hz 1 H) 432 (m 1 H) 432 (app q J = 70 Hz 1 H) 283 (m 2 H) 258 (s 3

H) 244 (d J =152 Hz 1H) 230 (d J = 24 Hz 1 H) 228 (m 1 H) 206-182 (comp 2

H) 13C NMR (100 MHz) δ 2150 1552 1363 1355 1284 1280 1279 1178 843

751 712 676 496 386 383 328 292 191 IR (neat) 3290 2953 1697 1406

281

1312 1270 1209 1055 MS (ESI) mz 390 [C20H23NO3S2 (M+1) requires 390] 412 390

(base) 346 282


H amp C18-H) 587 (m 1 H C5-H) 571 (ddd J = 168 125 68 Hz 1 H C7-H) 522

(m 1 H C5-H) 518 (s 2 H C140H) 512 (d J = 168 Hz 1 H C8-H) 502 (d J = 125

Hz 1 H C8-H) 432 (m 1 H C1-H) 432 (app q J = 70 Hz 1 H C3-H) 283 (m 2 H

C6-H) 258 (s 3 H C10-H) 244 (d J =152 Hz 1H C4-H) 230 (d J = 24 Hz 1 H

C12-H) 228 (m 1 H C4-H) 206-182 (comp 2 H C2-H) 13C NMR (100 MHz) δ

2150 (C9) 1552 (C13) 1363 (C15) 1355 (C7) 1284 (C17) 1280 (C18) 1279

(C16) 1178 (C8) 843 (C11) 751 (C14) 712 (C3) 676 (C12) 496 (C5) 386 (C1)

383 (C6) 328 (C4) 292 (C2) 191 (C10)

N

S S

O O

1

2 3 4

5

6

78

9 10

1112

13

1415

1617

18

485

7-Allyl-9-ethynyl-14-dithia-8-azaspiro[45]decane-8-carboxylic acid benzyl

ester (485) KAM6-201 BF3Et2O (76 mg 067 mmol) was added to a solution of 448

(10 g 337 mmol) and ethanedithiol (126 g 1348 mmol) in CH2Cl2 (10 mL) at rt and

282

the reaction was stirred for 1 h Additional BF3Et2O (76 mg 067 mmol) was added

and after 30 min 1 M NaOH (10 mL) and CH2Cl2 (10 mL) were added The mixture

was extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were dried

(Na2SO4) and concentrated reduced pressure The residue was purified by flash

chromatography eluting with hexanesEtOAc (91) to give 105 g (84) of 485 as a

colorless oil 1H NMR (300 MHz) 735-729 (comp 5 H) 573 (ddd J = 174 102 75

Hz 1 H) 526 (m 1 H) 517 (s 2 H) 510 (d J = 174 Hz 1 H) 502 (d J = 102 Hz 1

H) 433 (app p J = 69 Hz 1 H) 339-321 (comp 4 H) 285-222 (comp 7 H) 13C

NMR (75 MHz) 1552 1364 1351 1284 1280 1277 1177 841 725 675 619

523 448 418 412 396 385 384 IR (neat) 3288 2923 1698 1406 1318 1262

1057 MS (CI) mz 374 [C20H24NO2S2 (M+1) requires 374] 374 (base) 332 330

NMR Assignments 1H NMR (300 MHz) 735-729 (comp 5 H C16-H C17-H

amp C18-H) 573 (ddd J = 174 102 75 Hz 1 H C7-H) 526 (m 1 H C5-H) 517 (s 2

H C14-H) 510 (d J = 174 Hz 1 H C8-H) 502 (d J = 102 Hz 1 H C8-H) 433 (app

p J = 69 Hz 1 H C1-H) 339-321 (comp 4 H C9-H amp C10-H) 285-222 (comp 7 H

C2-H C4-H C6-H amp C12-H) 13C NMR (75 MHz) 1552 (C13) 1364 (C15) 1351

(C7) 1284 (C17) 1280 (C18) 1277 (C16) 1177 (C8) 841 (C11) 725 (C14) 675

(C12) 619 (C5) 523 (C1) 448 (C3) 418 (C2) 412 (C4) 396 (C6) 385 (C10) 384

(C9)

283

HNO

Si

1

23

4

5 67 8

490

6-Trimethylsilanylethynylpiperidin-2-one (490) KAM6-231 A solution of

TMS-acetylene (323 g 33 mmol) in THF (25 mL) was cooled to -78 ˚C and nBuLi (132

mL 25 M in hexanes 33 mmol) was added dropwise The reaction was warmed to 0 ˚C

and stirred for 10 min The solution was added to a solution of 489 (26 g 109 mmol) in

THF (25 mL) at -78 ˚C and the reaction was stirred for 30 min at -78 ˚C and 30 min at rt

The reaction was quenched with NaHCO3 (30 mL) and the mixture was extracted with

EtOAc (3 x 25 mL) The combined organic layers were dried (Na2SO4) and concentrated


EtOAc to give 152 g (71) of 490 as a white solid mp = 126-127 ˚C 1H NMR (400

MHz) δ 574 (s 1 H) 424 (m 1 H) 234 (comp 2 H) 200 (comp 2 H) 186-170

(comp 2 H) 014 (s 9 H) 13C NMR (100 MHz) δ 1712 1044 881 449 311 288

188 -03 IR (neat) 3190 3077 2956 1687 1649 1405 1309 1252 841 756 MS

(ESI) mz 196 [C10H18NOSi (M+1) requires 196] 391 (base) 196

NMR Assignment 1H NMR (400 MHz) δ 574 (s 1 H N-H) 424 (m 1 H C5-

H) 234 (comp 2 H C2-H) 200 (comp 2 H C4-H) 186-170 (comp 2 H C3-H) 014

(s 9 H) 13C NMR (100 MHz) δ 1712 (C1) 1044 (C6) 881 (C7) 449 (C5) 311 (C2)

288 (C3) 188 (C4) -03 (C8)

284

NO

Si9

1011

1213

14

491

O O

1

23

4

5 67 8

2-Oxo-6-trimethylsilanylethynylpiperidine-1-carboxylic acid benzyl ester

(491) KAM6-233 A solution of 490 (750 mg 385 mmol) in THF (15 mL) was

cooled to -78 ˚C and a solution of nBuLi (186 mL 227 M in hexanes 423 mmol) was

added slowly dropwise over 5 min The reaction was stirred for 30 min whereupon Cbz-

Cl (130 g 770 mmol) was added The cooling bath was removed and the reaction was

stirred for 15 min The reaction was quenched with sat NH4Cl (15 mL) and extracted

with EtOAc (3 x 15 mL) The combined organic layers were dried (Na2SO4) and


eluting with hexanesEtOAc (91-31) to give 102 g (81) of 491 as a white solid mp

= 70-71 ˚C 1H NMR (400 MHz) δ 743-729 (comp 5 H) 528 (comp 2 H) 511 (m 1

H) 275-179 (comp 6 H) 012 (s 9 H) 13H NMR (75 MHz) δ 1703 1529 1351

1283 1280 1277 1031 888 684 483 340 285 175 -04 IR (neat) 3065 2959

2899 1778 1738 1714 1498 1455 1373 1250 1134 1062 843 MS (CI) mz 330

[C18H24NO3Si (M+1) requires 330] 330 286 (base) 270


H amp C14-H) 528 (comp 2 H C10-H) 511 (m 1 H C5-H) 275-179 (comp 6 H C2-

285

H C3-H amp C4-H) 012 (s 9 H C8-H) 13H NMR (75 MHz) δ 1703 (C1) 1529 (C9)

1351 (C11) 1283 (C13) 1280 (C14) 1277 (C12) 1031 (C6) 888 (C10) 684 (C7)

483 (C5) 340 (C2) 285 (C3) 175 (C4) -04 (C8)

N9

10

11

1213

14

486

O O

1

23

4

5

6

78

1516

2-Allyl-6-ethynylpiperidine-1-carboxylic acid benzyl ester (486) KAM6-

240 A solution of 491 (830 mg 252 mmol) in THF (25 mL) was cooled to -78 ˚C and a

solution of DIBAL-H (303 mL 1 M in toluene 303 mmol) was added slowly dropwise

over 5 min The reaction was stirred at -78 ˚C for 30 min and MeOH (05 mL) was

added The reaction was warmed to rt and sat Rochellersquos salt (25 mL) was with vigorous

stirring The mixture was extracted with EtOAc (3 x 15 mL) and the combined organic

layers were dried (Na2SO4) and concentrated under reduced pressure The pale yellow

oil was dissolved in CH2Cl2 (25 mL) and cooled to -78 ˚C whereupon allyl TMS (143 g

126 mmol) and BF3Et2O (177 g 126 mmol) were added sequentially The reaction

was stirred 30 min and warmed to rt NaHCO3 (15 mL) was added and the mixture

stirred for 15 min The solution was extracted with CH2Cl2 (3 x 15 mL) and the


286

to give a crude oil (506 mg) A portion of the oil (200 mg) was dissolved in THF (10

mL) and TBAF (220 mg 0845 mmol) was added The reaction was stirred at rt for 30

min and NH4Cl (5 mL) was added The mixture was extracted with EtOAc (3 x 10 mL)

and the combined organic layers were dried (Na2SO4) and concentrated under reduced



temp = 100 ˚C) δ 738-729 (comp 5 H) 573 (ddd J = 175 100 70 Hz 1 H) 512 (s

2 H) 505 (d J = 175 Hz 1 H) 502 (m 1 H) 498 (d J = 100 Hz 1 H) 420 (m 1 H)

299 (d J = 25 Hz 1 H) 256-148 (comp 8 H) 13C NMR (125 MHz d6-DMSO temp

= 100 ˚C) δ 1542 1363 1355 1277 1272 1269 1160 845 724 660 506 409

360 298 260 140 IR (neat) 3294 3248 2944 1697 1406 1318 1267 1098 MS

(CI) mz 284 [C18H22NO2 (M+1) requires 284] 284 (base) 242 198 176

NMR Assignments 1H NMR (500 MHz d6-DMSO temp = 100 ˚C) δ 738-

729 (comp 5 H C14-H C15-H amp C16-H) 573 (ddd J = 175 100 70 Hz 1 H C7-

H) 512 (s 2 H C12-H) 505 (d J = 175 Hz 1 H C8-H) 502 (m 1 H C5-H) 498 (d

J = 100 Hz 1 H C8-H) 420 (m 1 H C1-H) 299 (d J = 25 Hz 1 H C10-H) 256-

148 (comp 8 H C2-H C3-H C4-H C6-H) 13C NMR (125 MHz d6-DMSO temp =

100 ˚C) δ 1542 (C11) 1363 (C13) 1355 (C7) 1277 (C15) 1272 (C16) 1269 (C14)

1160 (C8) 845 (C9) 724 (C12) 660 (C10) 506 (C6) 409 (C5) 360 (C1) 298 (C5)

260 (C2) 140 (C3)

287

N

O

1

23

4

5

6

9

10

11

494

O

OH

7

8

12 13

14 15

16

17

4-Oxo-12-azatricyclo[631026]dodec-2-ene-12-carboxylic acid benzyl ester



chromatography eluting with hexanesEtOAc (11) to give 494 in a 74 yield as a

colorless oil as a mixture (41) of diastereomers 1H NMR (500 MHz d6-DMSO 100 ˚C)

δ 737-728 (comp 5 H) 589 (bs 1 H) 511 (s 2 H) 436 (m 1 H) 352 (m 1 H) 253

(dd J = 180 60 Hz 1 H) 249 (m 1 H) 215 (dd J = 135 75 Hz 1 H) 208-152

(comp 7 H) 13C NMR (125 MHz d6-DMSO 100 ˚C) δ 2057 1781 1532 1364

1278 1272 1268 1258 659 495 466 432 372 355 276 184 141 IR (neat)

2939 1694 1621 1419 1321 1085 MS (ESI) mz 312 [C19H21NO3 (M+1) requires

312] 334 (base) 312


5 H C15-H C16-H amp C17-H) 589 (bs 1 H C1-H) 511 (s 2 H C13-H) 436 (m 1 H

C5-H) 352 (m 1 H C7-H) 253 (dd J = 180 60 Hz 1 H C8-H) 249 (m 1 H C8-H)

215 (dd J = 135 75 Hz 1 H C6-H) 208-152 (comp 7 H C2-H C3-H C4-H amp C6-

H) 13C NMR (125 MHz d6-DMSO 100 ˚C) δ 2057 (C9) 1781 (C11) 1532 (C12)

288

1364 (C10) 1278 (C14) 1272 (C16) 1268 (C17) 1258 (C15) 659 (C13) 495 (C1)

466 (C5) 432 (C7) 372 (C8) 355 (C6) 276 (C2) 184 (C4) 141 (C3)

N

O

O

OH

OSi

1

2 34

5

67

89

10

11 12

13

14 15

16

1718

1920

493

10-(tert-butyldimethylsilanyloxy)-4-oxo-12-azatricyclo[631026]dodec-2-ene-

12-carboxylic acid benzyl ester (493) KAM6-172 The PKR of 486 was performed

on a scale of 029 mmol according to the representative procedure and the crude product

was purified by flash chromatography eluting with hexanesEtOAc (91-31) to give 493

in a 69 yield as a colorless oil 1H NMR (500 MHz d6-DMSO 100 ˚C) δ 737-728

(comp 5 H) 587 (d J = 20 Hz 1 H) 517 (d J = 75 Hz 1 H) 510 (s 2 H) 454 (m 1

H) 427 (m 1 H) 407 (m 1H) 240 (dd J = 180 65 Hz 1 H) 228 (comp 2 H) 200

(ddd J = 130 70 20 Hz 1 H) 194 (dd 180 30 Hz 1 H) 171-164 (comp 2 H)

153 (dt J = 125 50 Hz 1 H) 085 (s 9 H) 007 (s 3 H) 003 (s 3 H) 13C NMR (125

MHz d6-DMSO 100 ˚C) δ 2059 1790 1532 1363 1278 1272 1268 1256 660

622 480 454 418 371 353 350 326 250 169 -56 -57 IR (neat) 2928 2855

1713 1623 1416 1322 1278 1088 839 MS (CI) mz 442 [C25H36NO4Si (M+1)

requires 442] 442 (base) 308

289


5 H C15-H C16-H amp C17-H) 587 (d J = 20 Hz 1 H C10-H) 517 (d J = 75 Hz 1

H C1-H) 510 (s 2 H C13-H) 454 (m 1 H C5-H) 427 (m 1 H C3-H) 407 (m 1H

C7-H) 240 (dd J = 180 65 Hz 1 H C8-H) 228 (comp 2 H C2-H) 200 (ddd J =

130 70 20 Hz 1 H C6-H) 194 (dd 180 30 Hz 1 H C8-H) 171-164 (comp 2 H

C4-H) 153 (dt J = 125 50 Hz 1 H C6-H) 085 (s 9 H C20-H) 007 (s 3 H C18-H)

003 (s 3 H C18-H) 13C NMR (125 MHz d6-DMSO 100 ˚C) δ 2059 (C9) 1790

(C11) 1532 (C12) 1363 (C14) 1278 (C16) 1272 (C17) 1268 (C15) 1256 (C10)

660 (C13) 622 (C3) 480 (C1) 454 (C5) 418 (C8) 371 (C6) 353 (C2) 350 (C4)

326 (C7) 250 (C20) 169 (C19) -56 (C18) -57 (C18)

N

N

SO O

O

O

OO

12

345

6

78

910

11

1213

1415

1617

18

1920

21

2223

24 25

26

27

4112

1-Allyl-9-(toluene-4-sulfonyl)-1349-tetrahydro-β-carboline-23-dicarboxylic

acid 2-benzyl ester 3-methyl ester (4112) KAM5-133 A solution of 4111 (10 g

248 mmol) in THF (20 mL) was cooled to -78 ˚C and NaHMDS (136 mL 272 mmol

2 M in THF) was slowly added The reaction was stirred for 30 min and TsCl (710 mg

290

372 mmol) was added The reaction was warmed to 0 ˚C and stirring was continued an

additional 30 min Sat NH4Cl (20 mL) was added and the mixture was extracted with

Et2O (3 x 25 mL) The combined organic layers were dried (Na2SO4) and concentrated


hexanesEtOAc (31) to give 120 g (86) of 4112 as a yellow oil 1H NMR (500 MHz

d6-DMSO 100 ˚C) δ 803 (d J = 85 Hz 1 H) 756-731 (comp 9 H) 728 (t J = 75 Hz

1 H) 715 (d J = 80 Hz 2 H) 613 (d J = 75 Hz 1 H) 592 (dddd J = 170 135 100

65 Hz 1 H) 522 (comp 2 H) 507 (comp 2 H) 501 (d J = 100 Hz 1 H) 367 (s 3

H) 313 (m 1 H) 302 (m 1 H) 272 (m 1 H) 240 (dt J = 155 95 Hz 1 H) 225 (s

3 H) 13C NMR (125 MHz d6-DMSO 100 ˚C) δ 1715 1548 1448 1360 1345

1339 1336 1294 1293 1285 1278 1273 1270 1254 1246 1236 1184 1164

1159 1144 669 514 510 508 387 204 203 MS (CI) mz 5591909

[C31H31N2O6S (M+1) requires 5591903]

NMR Assignments 1H NMR (500 MHz d6-DMSO 100 ˚C) δ 803 (d J = 85

Hz 1 H C8-H) 756-731 (comp 9 H C5-H C7-H C16-H C25-H C26-H amp C27-H)

728 (t J = 75 Hz 1 H C6-H) 715 (d J = 80 Hz 2 H C16-H) 613 (d J = 75 Hz 1

H C1-H) 592 (dddd J = 170 135 100 65 Hz 1 H C20-H) 522 (comp 2 H C23-

H) 507 (comp 2 H C11-H amp C21-H) 501 (d J = 100 Hz 1 H C21-H) 367 (s 3 H

C13-H) 313 (m 1 H C19-H) 302 (m 1 H C19-H) 272 (m 1 H C2-H) 240 (dt J =

155 95 Hz 1 H C2-H) 225 (s 3 H C18-H) 13C NMR (125 MHz d6-DMSO 100

˚C) δ 1715 (C12) 1548 (C22) 1448 (C17) 1360 (C24) 1345 (C30) 1339 (C9)

1336 (C10) 1294 (C16) 1293 (C14) 1285 (C4) 1278 (C26) 1273 (C25) 1270

291

(C27) 1254 (C15) 1246 (C6) 1236 (C5) 1184 (C7) 1164 (C21) 1159 (C3) 1144

(C8) 669 (C23) 514 (C1) 510 (C13) 508 (C11) 387 (C19) 204 (C2) 203 (C18)

10

11

12

3

45

6 7

8 912

1314 15

16

1718

1920

21

22

23

24

25

N

N

O

O

OO

OO

4114

1-Allyl-34-dihydro-1H-β-carboline-239-tricarboxylic acid 2-benzyl ester 9-

tert-butyl ester 3-methyl ester (4114) KAM4-183 Di-tert-butyl dicarbonate (16 g

743 mmol) was added to a solution of 4111 (20 g 495 mmol) and DMAP (664 mg

544 mmol) in CH3CN (10 mL) The reaction stirred 1 h and was complete by TLC

Et2O (20 mL) was added and washed with 02 M citric acid (10 mL) saturated NaHCO3

(10 mL) and brine (10 mL) and concentrated under reduced pressure The residue was

purified by flash chromatography eluting with hexanesEtOAc (31) to give 25 g (99)

of 4114 as a white foam 1H NMR (500 MHz) δ 809 (d J = 80 Hz 1 H) 755 (d J =

75 Hz 1 H) 739-729 (comp 6 H) 725 (t J = 70 Hz) 608 (bs 1 H) 585 (ddt J =

170 100 70 Hz 1 H) 520-511 (comp 3 H) 501 (d J = 170 Hz 1 H) 497 (d J =

100 Hz 1 H) 365 (s 3 H) 318 (dq J = 80 160 Hz) 252 (m 1 H) 238 (m 1 H)

159 (s 9 H) 13C NMR (125 MHz) δ 1717 1548 1489 1359 1354 1340 1338

292

1278 1274 1273 1239 1223 1178 1162 1148 1122 841 668 513 512 509

385 273 204 IR (neat) 2954 1736 1693 MS (CI) mz 5052342 [C29H33N2O6 (M+1)

requires 5052339]


(d J = 75 Hz 1 H C5-H) 739-729 (comp 6 H C15 C16 C17 amp C3-H) 725 (t J =

70 Hz C4-H) 608 (bs 1 H C9-H) 585 (ddt J = 170 100 70 Hz 1 H C20-H) 520-

511 (comp 3 H C13-H amp C18-H) 501 (d J = 170 Hz 1 H C21-H (trans)) 497 (d J

= 100 Hz 1 H C21-H (cis)) 365 (s 3 H C11-H) 318 (dq J = 80 160 Hz C19-H)

252 (m 1 H C8-H) 238 (m 1 H C8-H) 159 (s 9 H C25-H) 13C NMR (125 MHz) δ

1717 (C10) 1548 (C23) 1489 (C12) 1359 (C14) 1354 (C1) 1340 (C20) 1338

(C22) 1278 (C16) 1274 (C17) 1273 (C6) 1272 (C15) 1239 (C4) 1223 (C5) 1178

(C3) 1162 (C21) 1148 (C7) 1122 (C2) 841 (13) 668 (C24) 513 (C9) 512 (C11)

509 (C18) 385 (C19) 273 (C25) 204 (C8)

293

N

N

SO O

O

O

12

345

6

78

910

11

1213

1415

1617

18

1920

21

2223

24 25

26

27

4113

1-Allyl-3-ethynyl-9-(toluene-4-sulfonyl)-1349-tetrahydro-β-carboline-2-

carboxylic acid benzyl ester (4113) KAM5-101 A solution of 4112 (986 mg 177

mmol) in toluene (10 mL) was cooled to -78 ˚C and DIBAL-H (30 mL 12 M in

toluene 354 mmol) was slowly added over 10 min The reaction was stirred for 30 min

and iPrOH (10 mL) was slowly added over 10 min The reaction was warmed to 0 ˚C

and Cs2CO3 (232 g 716 mmol) and Bestman-Ohira reagent (687 mg 358 mmol) were

added The reaction was slowly warmed to rt over 12 h Saturated Rochellersquos salt (10

mL) was added and the mixture was stirred vigorously for 1 h The solution was

extracted with Et2O (5 x 25mL) and the combined organic layers were dried (Na2SO4)



yellow oil 1H NMR (500 MHz d6-DMSO 100 ˚C) δ 803 (d J = 80 Hz 1 H) 746-

733 (comp 9 H) 728 (t J = 70 Hz 1 H) 714 (d J = 80 Hz 2 H) 602 (d J = 100

Hz 1 H) 594 (dddd J = 165 100 80 60 Hz 1 H) 564 (dt J = 80 20 Hz 1 H)

524 (d J = 165 Hz 1 H) 519 (s 2 H) 505 (d J = 100 Hz 1 H) 330 (m 1 H) 312 (t

294

J = 25 Hz 1 H) 307 (ddd J = 165 75 15 Hz 1 H) 296 (m 1 H) 291 (m 1 H) 225

(s 3 H) 13C NMR (125 MHz d6-DMSO 100 ˚C) δ 1542 1447 1363 1359 1343

1340 1334 1293 1292 1278 1274 1272 1254 1247 1238 1184 1168 1158

1147 838 736 668 518 384 383 266 203 MS (CI) mz 5251849

[C31H29N2O4S (M+1) requires 5251848]



728 (t J = 70 Hz 1 H C6-H)) 714 (d J = 80 Hz 2 H C16-H) 602 (d J = 100 Hz 1

H C1-H) 594 (dddd J = 165 100 80 60 Hz 1 H C20-H) 564 (dt J = 80 20 Hz

1 H C11-H) 524 (d J = 165 Hz 1 H C21-H) 519 (s 2 H C23-H) 505 (d J = 100

Hz 1 H C21-H) 330 (m 1 H C19-H) 312 (t J = 25 Hz 1 H C13-H) 307 (ddd J =

165 75 15 Hz 1 H C19-H) 296 (m 1 H C2-H) 291 (m 1 H C2-H) 225 (s 3 H

C18-H) 13C NMR (125 MHz d6-DMSO 100 ˚C) δ 1542 (C22) 1447 (C17) 1363

(C24) 1359 (C10) 1343 (C14) 1340 (C15) 1334 (C4) 1293 (C16) 1292 (C26)

1278 (C25) 1274 (C15) 1272 (C27) 1254 (C6) 1247 (C6) 1238 (C5) 1184 (C7)

1168 (C21) 1158 (C8) 1147 (C4) 838 (C12) 736 (C13) 668 (C23) 518 (C1) 384

(C11) 383 (C19) 266 (C2) 203 (C18)

295

12

3

45

6 7

8 910

11

12

1314 15

16

1718

1920

21

22

23

24

25

N

N

O

O

OO

4115

1-Allyl-3-ethynyl-34-dihydro-1H-β-carboline-29-dicarboxylic acid 2-benzyl

ester 9-tert-butyl ester (4115) KAM4-222 A solution of 4114 (100 mg 020 mmol)

in CH2Cl2 (1 mL) was cooled to -78 ˚C and DIBAL-H (400 microL 12 M in toluene 048

mmol) was slowly added over 10 min The reaction stirred for 30 min and was complete

by TLC MeOH (05 mL) was slowly added over 10 min and the reaction was warmed to

0 ˚C K2CO3 (85 mg 060 mmol) and Bestman-Ohira reagent (120 mg 060 mmol) were

added and the reaction was slowly warmed to rt over 12 h Saturated Rochellersquos salt (5


extracted with Et2O (5 x 5mL) and combined organic layers were dried (Na2SO4) and


eluting with hexanesEtOAc (31) to give 60 mg (60) of 4115 as a yellow oil 1H

NMR (500 MHz) δ 808 (d J = 82 Hz 1 H) 751 (d J = 82 Hz 1 H) 743-729 (comp

6 H) 725 (t J = 70 Hz 1 H) 596 (d J = 100 Hz 1 H) 588 (ddt J = 170 105 70

Hz 1 H) 567 (d J = 75 Hz 1 H) 515 (s 2 H) 513 (m 1 H) 501 (d J = 100 Hz 1

H) 330-300 (comp 4 H) 262 (m 1 H) 160 (s 9 H) 13C NMR (125 MHz) δ 1543

1489 1358 1356 1343 1330 1279 1278 1274 1272 1240 1224 1176 1165

296

1148 1119 841 733 668 664 514 386 377 272 265 IR (neat) 3293 3068

2979 2933 1731 1694 MS (CI) mz 4712282 [C29H31N2O3 (M+1) requires 4712284]



70 Hz 1 H C4-H) 596 (d J = 100 Hz 1 H C9-H) 588 (ddt J = 170 105 70 Hz 1

H C20-H) 567 (d J = 75 Hz 1 H C18-H) 515 (s 2 H C13-H) 513 (m 1 H C21-H)

501 (d J = 100 Hz 1 H C21-H) 330-300 (comp 4 H C8-H amp C19-H) 262 (m 1 H

C11-H) 160 (s 9 H C25-H) 13C NMR (125 MHz) δ 1543 (C23) 1489 (C12) 1358

(C14) 1356 (C20) 1343 (C1) 1330 (C22) 1279 (C6) 1278 (C17) 1274 (C16)

1272 (C15) 1240 (C4) 1224 (C5) 1176 (C3) 1165 (C21) 1148 (C7) 1119 (C2)

841 (C10) 733 (C24) 668 (C13) 664 (C11) 514 (C9) 386 (C18) 377 (C19) 272

(C25) 265 (C8)

297

12

1314

151617

18

12

3

45

6 78

9 1011

NH

N

OO

O19

20

21

2223

4106

H

1-[(4aR6S13S13aR)-14a567121313a-hexahydro-7-benzyloxycarbonyl- -

613-imino-cyclooct[12-b]indole (4106) KAM4-161 Co2(CO)8 (177 g 512 mmol)

was added to a solution of 4107 (188 g 508 mmol) in THF (50 mL) The reaction

stirred for 1 h and complete Co-alkyne complex formation was observed by TLC

DMSO (220 g 2792 mmol) was added and stirred at 60 ˚C for 8 h The reaction was

cooled to rt and Et2O (30 mL) was added The purple Co-precipitate was removed via

filteration through silica washing with Et2O (30 mL) and the solution was concentrated


hexanesEtOAc (31-11) to give 186 g (92) of 4106 as a colorless oil 1H NMR (500

MHz) δ 1073 (s 1 H) 739 (d J = 79 Hz 1 H) 735-729 (comp 6 H) 707 (dt 72 13

Hz 1 H) 698 (dt J = 79 10 Hz 1 H) 605 (bs 1 H) 564 (d J = 68 Hz 1 H) 550

(bs 1 H) 515 (comp 2 H) 333 (dd J = 164 69 Hz 1 H) 275 (d J = 164 Hz 1 H)

264 (comp 1 H) 234 (dd J = 183 64 Hz 1 H) 226 (dq J = 62 24 Hz 1 H) 199

(dd 183 30 Hz 1 H) 176 (dt J = 126 38 Hz 1 H) 13C NMR (125 MHz) δ 2058

1774 1534 1361 1356 1323 1278 1273 1270 1265 1258 1206 1182 1172

298

1108 1055 663 493 476 402 371 344 250 IR (neat) 3464 3052 2985 1702

1623 MS (CI) mz 3991710 [C25H23N2O3 (M+1) requires 3991709]

NMR Assignments 1H NMR (500 MHz) δ 1073 (s 1 H N-H) 739 (d J = 79

Hz 1 H C2-H) 735-729 (comp 6 H C21 C22 C23 amp C5-H) 707 (dt 72 13 Hz 1

H C4-H) 698 (dt J = 79 13 Hz 1 H C3-H) 605 (bs 1 H C16-H) 564 (d J = 68

Hz 1 H C9-H) 550 (bs 1 H C11-H) 515 (comp 2 H C19-H) 333 (dd J = 164 69

Hz 1 H C8- H) 275 (d J = 164 Hz 1 H C8-H) 264 (comp 1 H C14-H) 234 (dd J

= 183 64 Hz 1 H C13-H) 226 (dq J = 62 24 Hz 1 H C15-H) 199 (dd 183 30

Hz 1 H C13-H) 176 (dt J = 126 38 Hz 1 H C15-H) 13C NMR (125 MHz) δ 2058

(C12) 1774 (C10) 1534 (C18) 1361 (C20) 1356 (C1) 1323 (C17) 1278 (C22)

1273 (C23) 1270 (C21) 1265 (C11) 1258 (C6) 1206 (C4) 1182 (C5) 1172 (C3)

1108 (C2) 1055 (C7) 663 (C19) 493 (C9) 476 (C16) 402 (C13) 371 (C14) 344

(C15) 250 (C8)

299

12

1314

151617

18

12

3

45

6 78

9 1011

N

N

O

OO

O

O19

20

21

2223

2425

26

4117

1-[(4aR6S13S13aR)-14a567121313a-hexahydro-7-benzyloxycarbonyl-

14-tert-butoxycarbonyl-613-imino-cyclooct[12-b]indole (4117) KAM5-278

(Boc)2O (327 mg 122 mmol) was added to a solution of 4106 (350 mg 088 mmol) and

DMAP (134 mg 088 mmol) in CH3CNCH2Cl2 (20 mL 31) and the reaction was

stirred at rt for 1 h Et2O (20 mL) was added and the reaction was washed with 02 M

citric acid (2 x 10 mL) sat NaHCO3 (10 mL) and brine (10 mL) The organic layer was


flash chromatography eluting with hexanesEtOAc (31) to give 430 mg (99) of 4117

as a white foam 1H NMR (500 MHz) δ 812 (d J = 82 Hz 1 H) 748 (d J = 78 Hz 1

H) 734-728 (comp 6 H) 724 (t J = 67 Hz 1 H) 608 (bs 1 H) 606 (bs 1 H) 566

(d J = 72 Hz 1 H) 515 (s 2 H) 331 (dd J = 171 71 Hz 1 H) 277 (comp 2 H) 241

(comp 1 H) 238 (dd J = 184 65 Hz 1 H) 201 (dd J = 185 30 Hz 1 H) 176 (dt J

= 127 41 Hz 1 H) 162 (s 9 H) 13C NMR (125 MHz) δ 2059 1768 1533 1488

1360 1351 1323 1278 1275 1274 1271 1265 1239 1224 1178 1149 1141

300

841 665 541 481 403 362 339 272 246 IR (neat) 3400 2977 2929 1771

1713 1626 MS (CI) mz 4992211 [C30H30N2O5 (M+1) requires 4982233]



67 Hz 1 H C4-H) 608 (bs 1 H C16-H) 606 (bs 1 H C11-H) 566 (d J = 72 Hz 1

H C9-H) 515 (s 2 H C19-H) 331 (dd J = 171 71 Hz 1 H C8-H) 277 (comp 2 H

C8-H amp C14-H) 241 (comp 1 H C15-H) 238 (dd J = 184 65 Hz 1 H C13-H) 201

(dd J = 185 30 Hz 1 H C13-H) 176 (dt J = 127 41 Hz 1 H C15-H) 162 (s 9 H

C26-H) 13C NMR (125 MHz) δ 2059 (C12) 1768 (C10) 1533 (C24) 1488 (C18)

1360 (C20) 1351 (C1) 1323 (C17) 1278 (C22) 1275 (C23) 1274 (C24) 1271

(C11) 1265 (C6) 1239 (C4) 1224 (C5) 1178 (C3) 1149 (C2) 1141 (C7) 841

(C25) 665 (C19) 541 (C9) 481 (C16) 403 (C13) 362 (C14) 339 (C15) 272 (C26)

246

301

19

N

N

O

OO

OO

H

OO

4124

12

3

45

6 7

8 9 10

11

12

1314

151617

18

20

21

2223

24 25

26


14-tert-butoxycarbonyl-613-imino-711-[27-dioxabicyclo[410]heptan-3-one]-

cyclooct[12-b]indole (4124) KAM4-186 Trifluoroacetic anhydride (15 mg 007

mmol) was added to a mixture of 4117 (10 mg 002 mmol)ureaH2O2 (19 mg 020

mmol) and Na2HPO4 (26 mg 018 mmol) in CH2Cl2 (1 mL) at 0 ˚C and the reaction

was stirred for 3 h The reaction was filtrered through a plug of Celite (1 cm) and


eluting with hexanesEtOAc (31-11) to give 10 mg (94) of 4124 as a colorless oil

1H NMR (500 MHz d6-DMSO 100 ˚C) δ 780 (d J = 80 Hz 1 H) 776 (d J = 75 Hz

1 H) 740 (t J = 80 Hz 1 H) 734 (comp 5 H) 723 (t J = 75 Hz 1 H) 588 (bs 1 H)

532 (d J = 80 Hz 1 H) 509 (s 2 H) 437 (bs 1 H) 370 (bs 1 H) 276 (m 1 H) 262

(dd J = 180 65 Hz 1 H) 232 (d J = 140 Hz 1 H) 209 (dd J = 135 80 Hz 1 H)

197 (dd J = 180 35 Hz 1 H) 170 (m 1 H) 157 (s 9 H) IR (neat) 2955 1791 1764

1710 1632 1421 1307 1252 1150 739 MS (CI) mz 531 [C30H31N2O7 (M+1)

requires 531] 531 463 319 243 (base)

302


Hz 1 H C2-H) 776 (d J = 75 Hz 1 H C5-H) 740 (t J = 80 Hz 1 H C4-H) 734

(comp 5 H C24-H C25-H amp C26-H) 723 (t J = 75 Hz 1 H C3-H) 588 (bs 1 H

C16-H) 532 (d J = 80 Hz 1 H C9-H) 509 (s 2 H C22-H) 437 (bs 1 H C11-H)

370 (bs 1 H C14-H) 276 (m 1 H C8-H) 262 (dd J = 180 65 Hz 1 H C8-H) 232

(d J = 140 Hz 1 H C13-H) 209 (dd J = 135 80 Hz 1 H C13-H) 197 (dd J = 180

35 Hz 1 H C15-H) 170 (m 1 H C15-H) 157 (s 9 H C20-H)

N

N

OO

H

OO

OO

4125

12

3

4

56 7

8 910

11

12

1314

151617

18

19

20

21

22

2324 25

26


14-tert-butoxycarbonyl-613-imino-78-epoxycyclopentane-cyclooct[12-b]indole

(4125) KAM4-226 A solution of NaOH (10 microL 100 mgNaOH1mL H2O 0024

mmol) and a solution of H2O2 (15 microL 30 in H2O 01 mmol) were sequentially added

to a solution of 4117 (10 mg 002 mmol) in THFMeOH (04 mL 11) at -20 ˚C The

reaction was stirred 30 min and the cooling bath was removed A solution of NaOH (10

microL 100 mgNaOH1mL H2O 0024 mmol) was added and the reaction was stirred an

additional 1 h The solution was filtered through a plug of Na2CO3silica (1 cm1 cm)

303


chromatography eluting with hexanesEtOAc (91-31) to give 78 mg (78) of 4125 as

a colorless oil 1H NMR (500 MHz d6-DMSO 100 ˚C) δ 812 (d J = 80 Hz 1 H) 754

(d J = 55 Hz 1 H) 735-725 (comp 7 H) 598 (bs 1 H) 514 (s 2 H) 451 (d J = 65

Hz 1 H) 364 (s 1 H) 316 (dd J = 170 70 Hz 1 H) 292 (d J = 170 Hz 1 H) 244-

232 (comp 3 H) 182-173 (comp 2 H) 162 (s 9 H) 13C NMR (125 MHz d6-DMSO

100 ˚C) δ 2071 1534 1487 1359 1352 1321 1278 1275 1272 1270 1240

1224 1178 1148 1142 841 696 666 613 477 473 376 351 290 272 228

IR (neat) 2977 2928 1750 1730 1703 1455 1417 1360 1326 1156 1012 755 MS

(CI) mz 5152175 [C30H31N2O6 (M+1) requires 5152182]


Hz 1 H C2-H) 754 (d J = 55 Hz 1 H C5-H) 735-725 (comp 7 H C3-H C4-H

C24-H C25-H amp C26-H) 598 (bs 1 H C16-H) 514 (s 2 H C22-H) 451 (d J = 70

Hz 1 H C9-H) 364 (s 1 H C11-H) 316 (dd J = 170 70 Hz 1 H C8-H) 292 (d J =

170 Hz 1 H C8-H) 244-232 (comp 3 H C13-H C14-H) 182-173 (comp 2 H C15-

H) 162 (s 9 H C20-H) 13C NMR (125 MHz d6-DMSO 100 ˚C) δ 2071 (C12) 1534

(C18) 1487 (C21) 1359 (C23) 1352 (C1) 1321 (C17) 1278 (C25) 1275 (C6)

1272 (C26) 1270 (C24) 1240 (C4) 1224 (C5) 1178 (C3) 1148 (C7) 1142 (C2)

841 (C11) 696 (C22) 666 (C19) 613 (C10) 477 (C9) 473 (C16) 376 (C13) 351

(C15) 290 (C14) 272 (C20) 228 (C8)

304

N

N

O

H

H

OO

O O

Si

21

2223

2425

26

27

28

12

3

45

6 7

8 9 10

11 12

1314

151617

18

19

20

4130


14-tert-butoxycarbonyl-613-imino-9-triethylsiloxycyclopent-2-en-cyclooct[12-

b]indole (4130) KAM5-204 Karstedtrsquos catalyst (100 microL 3 in xylene 00079 mmol)

was added to freshly distilled (from CaH2) Et3SiH (464 mg 40 mmol) at rt and the

reaction was stirred for 10 min A solution of 4117 (10 g 20 mmol) in toluene (4 mL)

was added and the reaction was stirred at rt for 24 h and the solvent was removed under

reduced pressure The residue was purified by flash chromatography (neutral alumina)

eluting with 100 hexanes-hexanesEtOAc (91) to give 102 g (80) of 4130 as a

colorless oil and 201 mg (20) of 4131 as a colorless oil 1H NMR (500 MHz d6-

DMSO 100 ˚C) δ 809 (d J = 85 Hz 1 H) 745 (d J = 75 Hz 1 H) 733-726 (comp 6

H) 722 (t J = 80 Hz 1 H) 508 (s 1 H) 511 (s 2 H) 473 (d J = 65 Hz 1 H) 454 (s

1 H) 302 (comp 3 H) 268 (comp 2 H) 244 (m 1 H) 190 (m 1 H) 182 (m 1 H)

174 (m 1 H) 161 (bs 9 H) 094 (t J = 80 Hz 9 H) 065 (q J = 80 Hz 6 H) 13C

NMR (125 MHz d6-DMSO 100 ˚C) δ 1648 1544 1538 1488 1364 1352 1328

1279 1278 1272 1268 1236 1222 1176 1148 1040 838 781 659 466 362

305

304 293 272 262 231 57 40 IR (neat) 2954 1729 1699 1636 1455 1421 1327

1157 746 MS (CI) mz 6153249 [C36H47N2O5Si (M+1) requires 6153261]



C25-H C26-H) 722 (t J = 80 Hz 1 H C4-H) 508 (s 1 H C16-H) 511 (s 2 H C22-

H) 473 (d J = 65 Hz 1 H C11-H) 454 (s 1 H C9-H) 302 (m 1 H C10-H) 268

(comp 2 H C8-H) 244 (m 1 H C13-H) 190 (m 1 H C13-H) 182 (m 1 H C14-H)

174 (m 2 H C15-H) 161 (bs 9 H C20-H) 094 (t J = 80 Hz 9 H C28-H) 065 (q J

= 80 Hz 6 H C27-H) 13C NMR (125 MHz d6-DMSO 100 ˚C) δ 1648 (C21) 1544

(C18) 1538 (C12) 1488 (C23) 1364 (C1) 1352 (C17) 1328 (C6) 1279 (C25)

1278 (C24) 1272 (C26) 1268 (C3) 1236 (C5) 1222 (C4) 1176 (C2) 1148 (C7)

1040 (C11) 838 (C9) 781 (C16) 659 (C22) 466 (C10) 362 (C13) 304 (C19) 293

(C15) 272 (C20) 262 (C8) 231 (C14) 57 (C28) 40 (C27)

306

19

N

N

OO

OO

4132

12

3

45

6 7

8 9

151617

18

20

21

2223

24 25

26

27

28

OSi10

11 12

1314

H

H


14-tert-butoxycarbonyl-613-imino-9-triisopropylsiloxycyclopent-8-ene-cyclooct[12-

b]indole (4132) KAM6-179 Solid 4117 (10 g 20 mmol) was added to a solution of

platinum(0)-13-divinyl-1133-tetramethyldisiloxane complex (050 mL 01 M in

xylenes 005 mmol 25 mol) and iPr3SiH (5 mL 24 mmol) in toluene (5 mL) and the

reaction was heated to 60 ˚C for 18 h The reaction was concentrated under reduced

pressure and the residue was purified by flash chromatography (neutral alumina) eluting

with hexanesEtOAc (10-91) to give 132 g (93) of 4132 as a white foam 1H NMR

(300 MHz) δ 827 (m 1 H) 742-726 (comp 8 H) 603 (s 05 H) 593 (s 05 H) 522

(s 1 H) 517 (s 1 H) 491 (d J = 66 Hz 05 H) 483 (d J = 66 Hz 1 H) 472 (s 05

H) 461 (s 05 H) 320 (m 1 H) 278 (comp 3 H) 208-180 (comp 4 H) 176 (s 45

H) 161 (s 45 H) 129-113 (comp 21 H) 13C NMR (75 MHz) δ 1557 1554 1548

1547 1497 1367 1365 1359 1335 1332 1287 1286 1283 1282 1278 1277

1274 1240 1239 1226 1225 1177 1176 1156 1153 1147 1042 1038 838

836 671 668 480 478 476 474 473 471 407 406 313 309 299 280 279

307

276 270 177 123 IR (neat) 2943 2865 1731 1698 1634 1455 1424 1366 1325

1145 882 MS (CI) mz 657 [C39H53N2O5Si (M+1) requires 657] 657 (base) 601 556

405


(comp 8 H C3-H C4-H C5-H C24-H C25-H amp C26-H) 603 (s 05 H C16-H) 593

(s 05 H C16-H) 522 (s 1 H C22-H) 517 (s 1 H C22-H) 491 (d J = 66 Hz 05 H

C9-H) 483 (d J = 66 Hz 1 H C9-H) 472 (s 05 H C11-H) 461 (s 05 H C11-H)

320 (m 1 H C10-H) 278 (comp 3 H C8-H amp C 14-H) 208-180 (comp 4 H C13-H

amp C15-H) 176 (s 45 H C20-H) 161 (s 45 H C20-H) 129-113 (comp 21 H C27-H

amp C28-H) 13C NMR (75 MHz) δ 1557 (C21) 1554 (C21) 1548 (C18) 1547 (C18)

1497 (C12) 1367 (C1) 1365 (C1) 1359 (C17) 1335 (C6) 1332 (C6) 1287 (C23)

1286 (C23) 1283 (C25) 1282 (C25) 1278 (C26) 1277 (C26) 1274 (C24) 1240

(C2) 1239 (C2) 1226 (C5) 1225 (C5) 1177 (C3) 1176 (C3) 1156 (C4) 1153 (C7)

1147 (C7) 1042 (C11) 1038 (C11) 838 (C19) 836 (C19) 671 (C22) 668 (C22)

480 (C16) 478 (C16) 476 (C9) 474 (C9) 473 (C10) 471 (C10) 407 (C8) 406

(C8) 313 (C13) 309 (C13) 299 (C13) 280 (C20) 279 (C20) 276 (C14) 270 (C14)

177 (C28) 123 (C27)

308

N

N

O

H

H

OO

O O21

2223

2425

26

12

3

4

56 7

8 9 10

11 12

1314

151617

18

1920

4131


14-tert-butoxycarbonyl-613-imino-9-oxycyclopentane-cyclooct[12-b]indole (4131)

KAM5-210 TBAF3H2O (158 mg 05 mmol) was added to a solution of 4132 (153

mg 025 mmol) in CH2Cl2 (10 mL) and the reaction was stirred at rt for 3 h Sat NH4Cl

(10 mL) was added and the layers were separated The aqueous layer was extracted with





1 H) 732-727 (comp 6 H) 724 (t J = 75 Hz 1 H) 594 (s 1 H) 512 (s 2 H) 464 (d

J = 65 Hz 1 H) 314 (dd J = 165 70 Hz 1 H) 274 (d J = 170 Hz 1 H) 246 (m1

H) 228 (dd J = 185 80 Hz 2 H) 210 (comp 2 H) 190 (d J = 180 Hz 2 H) 161 (s

9 H) 154 (td J = 135 45 Hz 1 H) 13C NMR (100 MHz C6D6) δ 2153 1542 1488

1362 1351 1324 1278 1272 1270 1268 1237 1222 1176 1148 1107 839

662 469 446 402 384 291 283 279 272 231 IR (neat) 2953 1731 1701

309

1455 1423 1368 1326 1147 1016 747 MS (CI) mz 501 [C30H32N2O5 (M+1)

requires 501] 400 (base)





165 Hz 1 H C8-H) 246 (m1 H C10-H) 228 (comp 2 H C11-H) 210 (dd J = 180

120 Hz 2 H C13-H) 190 (d J = 180 Hz 2 H C15-H) 161 (s 9 H C20-H) 154 (td

J = 135 45 Hz 1 H C14-H) 13C NMR (100 MHz C6D6) δ 2153 (C12) 1542 (C21)

1488 (C18) 1362 (C23) 1351 (C1) 1324 (C17) 1278 (C25) 1272 (C26) 1270

(C24) 1268 (C26) 1237 (C4) 1222 (C5) 1176 (C3) 1148 (C7) 1107 (C11) 839

(C19) 662 (C22) 469 (C9) 446 (C13) 402 (C16) 384 (C11) 291 (C15) 283 (C10)

279 (C8) 272 (C20) 231 (C14)

NH

HN

OH

H

H

12

3

4

56 7

8 9 10

1112

1314

151617

4133

1-[(4aR6S13S13aR)-14a567121313a-hexahydro-613-imino-9R-

hydroxycyclopentane-cyclooct[12-b]indole (4133) KAM6-071 NaBH4 (34 mg 10

mmol) was added in one portion to a solution of 4131 (200 mg 04 mmol) in THF (10

310

mL) at rt The reaction stirred for 1 h and sat NaHCO3 (5 mL) was added The reaction

was extracted with EtOAc (3 x 5mL) and the combined organic layers were dried and

concentrated under reduced pressure The crude oil was adsorbed on to silica gel (20 g)

and heated at 80 ˚C under vacuum (1 mm Hg) for 6 h The flask was cooled and the

silica was washed with EtOAc (5 mL) to which 10 PdC (20 mg) was added under an

atmosphere of H2 (1 atm) The reaction stirred for 3 h and was filtered through Celite (1

cm) and concentrated to give 53 mg (45) of 4133 as a white solid Slow evaporation

from CH2Cl2MeOH (2 mL) gave white needles suitable for x-ray mp = 200-204 1H

NMR (400 MHz CD3OD) δ 726 (d J = 95 Hz 1 H) 715 (d J = 95 Hz 1 H) 691 (td

J = 85 15 Hz 1 H) 685 (dt J = 85 15 Hz 1 H) 414 (m 1 H) 401 (s 1 H) 328 (d

J = 75 Hz 1 H) 320 (m 1 H) 309 (dd J = 195 80 Hz 1 H) 246 (d J = 195 Hz 1

H) 202-143 (comp 7 H) 117 (dd J = 180 30 Hz 1H) 13C NMR (100 MHz

CD3OD) δ 1376 1355 1286 1217 1196 1184 1118 1082 729 497 455 422

394 354 341 323 300 IR (neat) 3394 29241450 1335 742 MS (CI) mz 270

[C17H21N2O (M+1) requires 270]

NMR Assignments 1H NMR (400 MHz CD3OD) δ 726 (d J = 95 Hz 1 H

C2-H) 715 (d J = 95 Hz 1 H C5-H) 691 (td J = 85 15 Hz 1 H C4-H) 685 (dt J

= 85 15 Hz 1 H C3-H) 414 (m 1 H C16-H) 401 (s 1 H C9-H) 328 (d J = 75 Hz

1 H C8-H) 320 (m 1 H C12-H) 309 (dd J = 195 80 Hz 1 H C8-H) 246 (d J =

195 Hz 1 H C10-H) 202-143 (comp 7 H C11-H C13-H C15-H N-H) 117 (dd J =

180 30 Hz 1H C14-H) 13C NMR (100 MHz CD3OD) δ 1376 (C1) 1355 (C17)

311

1286 (C6) 1217 (C4) 1196 (C5) 1184 (C3) 1118 (C7) 1082 (C2) 729 (C12) 497

(C9) 455 (C16) 422 (C15) 394 (C10) 354 (C13) 341 (C11) 323 (C8) 300 (C14)

N

N

OHO

H

H

OO

O O

20

12

3

4

56 7

8 9 1011 12

1314

151617

18

19

21

2223

2425

26

N

N

OHO

H

H

OO

O O

20

12

3

4

56 7

8 9 1011 12

1314

151617

18

19

21

2223

2425

26

4137a 4137b


14-tert-butoxycarbonyl-613-imino-8R-hydroxy-9-oxycyclopentane-cyclooct[12-

b]indole (4137a) and 1-[(4aR6S13S13aR)-14a567121313a-hexahydro-7-

benzyloxycarbonyl-14-tert-butoxycarbonyl-613-imino-8S-hydroxy-9-

oxycyclopentane-cyclooct[12-b]indole (4137b) KAM5-209 OsO4 (289 mg 118


mL) at rt The reaction was stirred at rt for 12 h and then H2S was bubbled through the

reaction for 15 min The thick black precipitate was removed by filtering through Celite

(1 cm) washing with THF (30 mL) and the solvent was removed under reduced pressure

The residue was purified by flash chromatography eluting with hexanesEtOAc (31-11)

to give 480 mg (71) of a mixture of 4137a and 4137b as a colorless oil major isomer

(4137a) 1H NMR (500 MHz d6-DMSO 100 ˚C) δ 810 (d J = 80 Hz 1 H) 748 (d J

= 80 Hz 1 H) 732-722 (comp 7 H) 596 (s 1 H) 512 (comp 2 H) 486 (d J = 70

312

Hz 1 H) 390 (d J = 105 Hz 1 H) 319 (dd J = 165 70 Hz 1 H) 269 (d J = 165

Hz 1 H) 228 (dd J = 190 80 Hz 1 H) 203 (comp 4 H) 166 (m 1H) 161 (s 9H)

13C NMR (125 MHz d6-DMSO 100 ˚C) δ 2151 1543 1488 1363 1351 1325

1279 1278 1272 1268 1237 1223 1177 1151 1148 839 729 662 472 451

405 390 307 272 257 232 IR (neat) 3436 2976 1729 1699 1456 1424 1360

1328 1153 754



C24-H C25-H C26-H) 596 (s 1 H C16-H) 512 (comp 2 H C22-H) 486 (d J = 70

Hz 1 H C9-H) 390 (d J = 105 Hz 1 H C11-H) 319 (dd J = 165 70 Hz 1 H C8-

H) 269 (d J = 165 Hz 1 H C8-H) 228 (dd J = 190 80 Hz 1 H C13-H) 203

(comp 4 H C10-H C13-H C15-H) 166 (m 1H C14-H) 161 (s 9H C20-H) 13C

NMR (125 MHz d6-DMSO 100 ˚C) δ 2151 (C12) 1543 (C21) 1488 (C18) 1363

(C23) 1351 (C1) 1325 (C17) 1279 (C6) 1278 (C25) 1272 (C26) 1268 (C24)

1237 (C4) 1223 (C5) 1177 (C3) 1151 (C7) 1148 (C2) 839 (C19) 729 (C11) 662

(C22) 472 (C16) 451 (C10) 405 (C13) 390 (C9) 307 (C15) 272 (C20) 257 (C8)

232 (C14)

313

19

N

N

OO

OO

4144

12

3

45

6 7

8 9

1718

2021

22

2324

25 26

1011

1314

15

16

H

HO

O12

27

OH


14-tert-butoxycarbonyl-613-imino-7-hydroxymethyl-11-carboxylic acid methyl

ester-cyclooct[12-b]indole (4144) KAM6-048 Pb(OAc)4 (640 mg 145 mmol) was

added to a solution of 4137 (375 mg 0722 mmol) in MeOHbenzene (10 mL 11) at 0

˚C and the reaction was stirred for 15 min at 0 ˚C NaBH4 (430 mg 10 mmol) was added

in 6 portions over 5 min and the reaction was stirred at 0 ˚C for 15 min NaHCO3 (20

mL) was added and the solution was extracted with EtOAc (3 x 30 mL) The combined

organic layers were washed with brine (20 mL) dried (Na2SO4) and concentrated under



MHz d6-DMSO 100 ˚C) δ 810 (d J = 80 Hz 1 H) 747 (d J = 70 Hz 1 H) 731-722

(comp 7 H) 593 (bs 1 H) 508 (s 2 H) 491 (d J = 75 Hz 1 H) 355 (dd J = 110

50 Hz 1 H) 349 (s 3 H) 348 (m 1 H) 321 (dd J = 175 80 Hz 1 H) 257 (d J =

175 Hz 1 H) 237 (dd J = 155 70 Hz 1 H) 227-217 (comp 2 H) 186 (m 1 H)

176-167 (comp 2 H) 160 (s 9 H) 13C NMR (125 MHz d6-DMSO 100 ˚C) δ 1716

314

1543 1488 1364 1349 1337 1277 1271 1266 1236 1222 1176 1147 837

659 576 503 463 453 360 336 296 272 262 250 231 IR (neat) 2931 1729

1697 1454 1367 1328 1155 1116 912 747 MS (CI) mz 549 [C31H36N2O7 (M+1)

requires 549] 549 (base) 493 449




Hz 1 H C9-H) 355 (dd J = 110 50 Hz 1 H C15-H) 349 (s 3 H C18-H) 348 (m 1

H C15-H) 321 (dd J = 175 80 Hz 1 H C8-H) 257 (d J = 175 Hz 1 H C8-H) 237

(dd J = 155 70 Hz 1 H C16-H) 227-217 (comp 2 H C12-H) 186 (m 1 H C16-H)

176-167 (comp 2 H C10-H amp C11-H) 160 (s 9 H C21-H) 13C NMR (125 MHz d6-

DMSO 100 ˚C) δ 1716 (C17) 1543 (C22) 1488 (C19) 1364 (C1) 1349 (C14) 1337

(C6) 1277 (C24) 1271 (C26) 1269 (C27) 1266 (C25) 1236 (C2) 1222 (C5) 1176

(C4) 1153 (C3) 1147 (C7) 837 (C20) 659 (C23) 576 (C15) 503 (C18) 463 (C13)

453 (C9) 360 (C10) 336 (C16) 296 (C8) 272 (C21) 262 (C12) 231 (C11)

315

19

N

N

OO

OO

4145

12

3

45

6 7

8 9

17

18

20

21

2223

2425

26

10

11

1314

1516

H

H

12OO


14-tert-butoxycarbonyl-613-imino-711-[Tetrahydropyran-2-one]-cyclooct[12-

b]indole (4145) KAM6-209 OsO4 (4 mg 0015 mmol) was added to a slurry of

NaIO4 (130 mg 4 mmol) and 4132 (100 mg 0152 mmol) in THFH2O (15 mL 51)

The reaction was stirred at rt for 48 h and H2O (5 mL) was added The solution was

extracted with CH2Cl2 ( 3 x 3 mL) and the combined organic layers were concentrated to

give a crude black oil The oil was dissolved in MeOH (5 mL) and NaBH4 (6 mg 0152

mmol) was added The reaction stirred at rt for 30 min and TsOHH2O (48 mg 025

mmol) was added and stirred an additional 4 h Sat NaHCO3 (5 mL) was added and the

solution was extracted with CH2Cl2 (3 x 3 mL) The combined organic layers were dried



white foam 1H NMR (500 MHz d6-DMSO 100 ˚C) δ 810 (d J = 80 Hz 1 H) 746 (d

J = 80 Hz 1 H) 731-727 (comp 6 H) 724 (t J = 75 Hz 1 H) 598 (bs 1 H) 511 (s

2 H) 451 (d J = 75 Hz 1 H) 440 (dd J = 115 55 Hz 1 H) 432 (t J = 115 Hz 1

316


1 H) 235 (m 1 H) 221 (dd J = 180 20 Hz 1 H) 212 (m 1 H) 195-186 (comp 2

H) 161 (s 9 H) 13C NMR (125 MHz d6-DMSO 100 ˚C) δ 1689 1539 1487 1362

1352 1324 1278 1272 1269 1259 1222 1176 1149 1107 1064 839 674

662 474 469 368 336 306 299 272 234 IR (neat) 2976 1731 1698 1455

1423 1329 1141 912 733 MS (CI) mz 517 [C30H33N2O6 (M+1) requires 517] 545

517 (base) 417



C25-H amp C26-H) 724 (t J = 75 Hz 1 H C3-H) 598 (bs 1 H C16-H) 511 (s 2 H

C22-H) 451 (d J = 75 Hz 1 H C9-H) 440 (dd J = 115 55 Hz 1 H C11-H) 432 (t

J = 115 Hz 1 H C11-H) 318 (dd J = 170 75 Hz 1 H C8-H) 273 (d J = 170 Hz 1


180 20 Hz 1 H C13-H) 212 (m 1 H C14-H) 195-186 (comp 2 H C15-H) 161 (s

9 H C20-H) 13C NMR (125 MHz d6-DMSO 100 ˚C) δ 1689 (C20) 1539 (C21)

1487 (C18) 1362 (C1) 1352 (C17) 1324 (C6) 1278 (C23) 1272 (C25) 1269

(C26) 1259 (C24) 1222 (C2) 1176 (C5) 1149 (C4) 1107 (C3) 1064 (C7) 839

(C11) 674 (C19) 662 (C22) 474 (C16) 469 (C9) 368 (C8) 336 (C13) 306 (C15)

299 (C10) 272 (C20) 234 (C14)

317

19

N

N

OO

OO

4147

12

3

45

6 7

8 9

17

18

20

21

2223

2425

26

10

11

1314

1516

H

H

12O


14-tert-butoxycarbonyl-613-imino-711-[34-dihydro-2H-pyran]-cyclooct[12-

b]indole (4147) KAM6-080 A solution of 4145 (235 mg 0455 mmol) in toluene (10

mL) was cooled to -78 ˚C and a solution of DIBAL-H (0547 mL 1 M in toluene 0547

mmol) was slowly added dropwise The reaction was stirred for 1 h at -78 ˚C and then

MeOH (05 mL) was added The reaction was warmed to rt and sat Rochellersquos salt (20

mL) was added The solution was extracted with EtOAc (3 x 10 mL) and the combined

organic layers were dried (Na2SO4) and concentrated under reduced pressure The

residue was dissolved in THF (5 mL) and cooled to 0 ˚C Et3N (340 mg 336 mmol) and

MsCl (121 mg 105 mmol) were sequentially added and the reaction was stirred at 0 ˚C

for 30 min Sat NH4Cl (5 mL) was added and the solution was extracted with EtOAc (3

x 5 mL) The combined organic layers were dried (Na2SO4) and concentrated under




(comp 6 H) 723 (t J = 70 Hz 1 H) 630 (d J = 60 Hz 1 H) 593 (bs 1 H) 511 (s 2

318

H) 461 (t J = 55 Hz 1 H) 455 (d J = 75 Hz 1 H) 400 (dd J = 110 25 Hz 1 H)

376 (t J = 110 Hz 1 H) 315 (dd J = 170 75 Hz 1 H) 275 (d J = 170 Hz 1 H)

212-196 (comp 3 H) 176 (m 1 H) 161 (s 9 H) 13C NMR (125 MHz d6-DMSO 100

˚C) δ 1538 1488 1428 1362 1351 1325 1277 1273 1272 1269 1236 1222

1176 1149 1148 1036 838 662 637 475 465 379 320 272 260 233 IR

(neat) 2976 1729 1699 1455 1422 1330 1142 747 MS (CI) mz 500 [C30H32N2O5

(M) requires 500] 500 401 387 (base) 267 229

NMR Assignment 1H NMR (500 MHz d6-DMSO 100 ˚C) δ 810 (d J = 85


C25-H amp C26-H) 723 (t J = 70 Hz 1 H C3-H) 630 (d J = 60 Hz 1 H C12-H) 593

(bs 1 H C16-H) 511 (s 2 H C22-H) 461 (t J = 55 Hz 1 H C13-H) 455 (d J = 75

Hz 1 H C9-H) 400 (dd J = 110 25 Hz 1 H C-11) 376 (t J = 110 Hz 1 H C11-H)

315 (dd J = 170 75 Hz 1 H C8-H) 275 (d J = 170 Hz 1 H C8-H) 212-196

(comp 3 H C15-H amp C10-H) 176 (m 1 H C14-H) 161 (s 9 H C20-H) 13C NMR

(125 MHz d6-DMSO 100 ˚C) δ 1538 (C21) 1488 (C18) 1428 (C12) 1362 (C1)

1351 (C17) 1325 (C6) 1277 (C23) 1273 (C25) 1272 (C26) 1269 (C24) 1236

(C2) 1222 (C5) 1176 (C4) 1149 (C3) 1148 (C7) 1036 (C13) 838 (C19) 662

(C22) 637 (C11) 475 (C16) 465 (C9) 379 (C8) 320 (C15) 272 (C20) 260 (C10)

233 (C14)

319

NH

NH

H O

12

3

4

56 7

8 9 10

11

12

1314

151617

18

4148

1-[(4aR6S13S13aR)-14a567121313a-hexahydro-7-methyl-613-

iminopyrano[3456]cyclooct[12-b]indole (4148) KAM6-081 LiAlH4 (18 mg

048 mmol) was added in one portion to a solution of 4147 (60 mg 012 mmol) in THF

(5 mL) The reaction was heated to reflux for 1 hand cooled to rt MeOH was added

until bubbling ceased (3 drops) and the reaction was filtered through Celite (1 cm)

washing with EtOAc (5 mL) The solvent was removed under reduced pressure and the

residue was purified by flash chromatography eluting with hexanesEtOAc (11-01) to

give 29 mg (86) of 4148 as a white solid mp = 174-175 ˚C 1H NMR (400 MHz

C6D6) δ 759 (m 1 H) 726 (comp 2 H) 711 (m 1 H) 647 (d J = 60 Hz 1 H) 623

(bs 1 H) 448 (dd J = 110 44 Hz 1 H) 442 (d J = 110 Hz 1 H) 391 (d J = 92 Hz

1 H) 329 (s 1 H) 298 (dd J = 168 72 Hz 1 H) 256 (d J = 64 Hz 1 H) 214 (s 3

H) 211 (s 1 H) 199 (td J = 120 36 Hz 1 H) 183 (comp 2 H) 147 (d J = 120 Hz

1 H) 13C NMR (100 MHz C6D6) δ 1441 1362 1320 1285 1216 1197 1185

1111 1072 1050 668 555 549 417 408 358 242 228 IR (neat) 3394 2927

2360 1646 1457 1244 1070 741 668 MS (CI) mz 2811657 [C18H21N2O (M+1)

requires 2811654]

320

NMR Assignments 1H NMR (400 MHz C6D6) δ 759 (m 1 H C2-H) 726

(comp 2 H C5-H C4-H) 711 (m 1 H C3-H) 647 (d J = 60 Hz 1 H C12-H) 623

(bs 1 H N-H) 448 (dd J = 110 60 Hz 1 H C13-H) 442 (d J = 110 Hz 1 H C11-

H) 391 (d J = 110 Hz 1 H C11-H) 329 (s 1 H C16-H) 298 (dd J = 168 68 Hz 1

H C9-H) 256 (d J = 68 Hz 1 H C14-H) 214 (s 3 H C18-H) 211 (s 1 H C10-H)

199 (td J = 120 36 Hz 1 H C15-H) 183 (comp 2 H C8-H) 147 (d J = 120 Hz 1

H C15-H) 13C NMR (100 MHz C6D6) δ 1441 (C12) 1362 (C1) 1320 (C17) 1285

(C6) 1216 (C4) 1197 (C5) 1185 (C3) 1111 (C7) 1072 (C2) 1050 (C13) 668

(C11) 555 (C9) 549 (C16) 417 (C10) 408 (C15) 358 (C18) 242 (C8) 228 (C14)

N

NH

H O

19

12

3

45

6 7

8 9 10

11

12

1314

151617

18

4149

1-[(4aR6S13S13aR)-14a567121313a-hexahydro-714-dimethyl-613-

iminopyrano[3456]cyclooct[12-b]indole (4149) KAM6-082 NaH (12 mg 0311

mmol) was added to a solution of 4148 (29 mg 0104 mmol) in DMF (1 mL) at -5 ˚C

The reaction was stirred for 15 min and MeI (22 mg 0150 mmol) was added The

reaction was stirred for 15 h during which time the temperature had warmed to 5 ˚C

The reaction was quenched with H2Obrine (2 mL 11) and extracted with CH2Cl2 (4 x 5

mL) The combined organic layers were washed with H2O (5 mL) dried (Na2SO4) and

concentrated under reduced pressure The solvent was removed under reduced pressure

321

and the residue was purified by flash chromatography eluting with hexanesEtOAc (11)

to give 29 mg (86) of 4149 as a white solid mp = 192-193 ˚C 1H NMR (400 MHz


(t J = 56 Hz 1 H) 443 (d J = 110 Hz 1 H) 392 (ddd J = 110 40 16 Hz 1 H) 348

(t J = 32 Hz 1 H) 304 (dd J = 164 68 Hz 1 H) 284 (s 3 H) 259 (d J = 68 Hz 1

H) 220 (d J = 164 Hz 1 H) 215 (s 3 H) 199 (dd J = 124 40 Hz 1 H) 188 (m 2

H) 148 (dt J = 124 32 Hz 1 H) 13C NMR (100 MHz) δ 1369 1333 1265 1208

1188 1179 1097 1087 1063 1048 666 552 536 418 405 379 347 237

229 IR (neat) 2925 2360 2340 1644 1467 1379 1070 895 738 668 MS (CI) mz

2931659 [C19H21N2O (M-1) requires 2931654]


(comp 2 H C5-H C4-H) 709 (m 1 H C3-H) 647 (d J = 58 Hz 1 H C12-H) 449 (t

J = 58 Hz 1 H C13-H) 443 (d J = 110 Hz 1 H C11-H) 392 (ddd J = 110 40 16

Hz 1 H C11-H) 348 (t J = 32 Hz 1 H C16-H) 304 (dd J = 164 68 Hz 1 H C9-

H) 284 (s 3 H C19-H) 259 (d J = 68 Hz 1 H C14-H) 220 (d J = 164 Hz 1 H

C10-H) 215 (s 3 H C18-H) 199 (dd J = 124 40 Hz 1 H C15-H) 188 (m 2 H C8-

H) 148 (dt J = 124 32 Hz 1 H C15-H) 13C NMR (100 MHz) δ 1369 (C12) 1333

(C1) 1265 (C17) 1208 (C6) 1188 (C4) 1179 (C5) 1097 (C3) 1087 (C7) 1063

(C2) 1048 (C13) 666 (C11) 552 (C8) 536 (C16) 418 (C10) 405 (C15) 379 (C19)

347 (C18) 237 (C8) 229 (C14)

322

19

N

N

OO

OO

4152

12

3

45

6 7

8 9

17

18

20

21

2223

2425

26

10

11

1314

1516

H

H

12O

O27

28


14-tert-butoxycarbonyl-613-imino-711-[1-(56-dihydro-4H-pyran-3-yl)-ethanone]-

cyclooct[12-b]indole (4152) KAM6-188 Trichloroacetyl chloride (04 mL 36

mmol) was added to a solution of 4147 (170 mg 034 mmol) in pyridine (2 mL) and the


pressure and the residue was dissolved in CH2Cl2 (10 mL) The solution was washed

with NH4Cl (2 x 10 mL) filtered through a silica plug (1 cm) and concentrated to give a

crude yellow oil The oil was dissolved in AcOH (2 mL) and added dropwise to a

suspension of Zn dust (200 mg 30 mmol) in AcOH (2 mL) The reaction was stirred for

30 min and more Zn dust (200 mg 30 mmol) was added The reaction was stirred for an

additional 15 min filtered through Celite (1 cm) and concentrated under reduced



100 ˚C) δ 815 (d J = 80 Hz 1 H) 771 (s 1 H) 747 (d J = 80 Hz 1 H) 733-723


30 Hz 1 H) 394 (t J = 115 Hz 1 H) 320 (dd J = 165 75 Hz 1 H) 277 (d J = 170

323

Hz 1 H) 263 (dt J = 115 45 Hz 1 H) 220 (m 1 H) 205 (m 1 H) 204 (s 3 H) 166

(m 1 H) 160 (s 9 H) 13C NMR (125 MHz d6-DMSO 100 ˚C) δ 1939 1568 1539

1488 1362 1351 1327 1277 1274 1273 1269 1237 1223 1193 1176 1148

1107 838 662 647 477 460 359 299 272 257 242 223 IR (neat) 2913

1721 1691 1612 1427 1318 1090 740 MS (CI) mz 543 [C32H35N2O6 (M+1)

requires 543] 544 543 488 444 (base) 400


Hz 1 H C2-H) 771 (s 1 H C12-H) 747 (d J = 80 Hz 1 H C5-H) 733-723 (comp

7 H C3-H C4-H C24-H C25-H amp C26-H) 593 (bs 1 H C16-H) 512 (s 2 H C22-

H) 462 (d J = 75 Hz 1 H C9-H) 424 (dd J = 110 30 Hz 1 H C11-H) 394 (t J =

115 Hz 1 H C11-H) 320 (dd J = 165 75 Hz 1 H C8-H) 277 (d J = 170 Hz 1 H

C8-H) 263 (dt J = 115 45 Hz 1 H C15-H) 220 (m 1 H C15-H) 205 (m 1 H C10-

H) 204 (s 3 H C28-H) 166 (m 1 H C14-H) 160 (s 9 H C20-H) 13C NMR (125

MHz d6-DMSO 100 ˚C) δ 1939 (C27) 1568 (C21) 1539 (C18) 1488 (C12) 1362

(C1) 1351 (C17) 1327 (C6) 1277 (C23) 1274 (C25) 1273 (C26) 1269 (C24)

1237 (C2) 1223 (C5) 1193 (C4) 1176 (C3) 1148 (C7) 1107 (C13) 838 (C19)

662 (C22) 647 (C11) 477 (C16) 460 (C9) 359 (C8) 299 (C15) 272 (C20) 257

(C10) 242 (C28) 223 (C14)

324

NH

NH

4154

12

3

45

6 7

8 9

17

10

11

14

1516

H

H

12O

O13

1819


imino-711-[1-(56-dihydro-4H-pyran-3-yl)-ethanone]-cyclooct[12-b]indole (4154)

KAM6-159 Freshly distilled TMS-I (19 mg 0093 mmol) was added to a solution of

4152 (12 mg 0022 mmol) in CH3CN (1 mL) at 0 ˚C The reaction was stirred for 30

min at 0 ˚C and 15 min at rt Methanolic HCl (1 mL 1 M) was added and the reaction

was concentrated under reduced pressure The residue was dissolved in aqueous HCl (5

mL 1 M) and extracted with CH2Cl2 (3 x 5 mL) The aqueous layer was basified with

30 NH4OH dropwise until pH~12 and then extracted with CH2Cl2 (3 x 5 mL) The


The residue was purified by flash chromatography eluting with EtOAcMeOH (91) to

give 6 mg (78) of 4154 as a white film 1H NMR (400 MHz) δ 799 (bs 1 H) 753 (s

1 H) 744 (d J = 76 Hz 1 H) 728 (d J = 76 Hz 1 H) 713 (t J = 68 Hz 1 H) 707 (t

J = 76 Hz 1 H) 443 (t J = 116 Hz 1 H) 419 (ddd J = 112 40 16 Hz 1 H) 410

(bs 1 H) 344 (d J = 68 Hz 1 H) 322 (dd J = 160 68 Hz 1 H) 272 (m 1 H) 266

(d J = 164 Hz 1 H) 209 (m 1 H) 208 (s 3 H) 192-170 (comp 4 H) 13C NMR (75

MHz) δ 1955 1575 1356 1355 1272 1215 1213 1193 1177 1112 1079 674

325

483 477 374 323 288 250 237 IR (neat) 2921 1614 1453 1321 1195 738 MS

(CI) mz 309 [C19H21N2O2 (M+1) requires 309] 309 (base)

NMR Assignments 1H NMR (400 MHz) δ 799 (bs 1 H indole N-H) 753 (s 1

H C12-H) 744 (d J = 76 Hz 1 H C2-H) 728 (d J = 76 Hz 1 H C5-H) 713 (t J =

68 Hz 1 H C4-H) 707 (t J = 76 Hz 1 H C3-H) 443 (t J = 116 Hz 1 H C11-H)

419 (ddd J = 112 40 16 Hz 1 H C11-H) 410 (bs 1 H C16-H) 344 (d J = 68 Hz

1 H C8-H) 322 (dd J = 160 68 Hz 1 H C8-H) 272 (m 1 H C9-H) 266 (d J =

164 Hz 1 H C15-H) 209 (m 1 H C15-H) 208 (s 3 H C19-H) 192-170 (comp 3 H

C10-H C14-H N-H) 13C NMR (75 MHz) δ 1955 (C19) 1575 (C12) 1356 (C17)

1355 (C1) 1272 (C6) 1215 (C2) 1213 (C5) 1193 (C4) 1177 (C3) 1112 (C13)

1079 (C7) 674 (C11) 483 (C16) 477 (C9) 374 (C8) 323 (C15) 288 (C10) 250

(C19) 237 (C14)

N

N

41

12

3

45

6 7

8 9

17

10

11

14

1516

H

H

12O

O13

1819

20

21

(-)-Alstonerine (41) KAM6-196 Methyl iodide (7 mg 005 mmol) was added

to 4154 (8 mg 00265 mmol) in THF (025 mL) and the reaction was stirred at rt for 3 h

NaH (3 mg 0075 mmol) was added and the reaction was stirred for 30 min Methyl

iodide (10 mg 0075 mmol) was added and the reaction was stirred at rt for 3 h

326

MeOHEtOAc (19 1 mL) was added and the reaction was filtered through silica The

volatiles were removed under reduced pressure and dissolved in CH2Cl2 (5 mL) and

washed with NaHCO3 (5 mL) The organic layer was dried (Na2SO4) and concentrated


hexanesEtOAc (11-01) to give 6 mg (72) of 41 as a white film 1H NMR (400 MHz)

δ 751 (s 1 H) 745 (d J = 80 Hz 1 H) 729 (d J = 80 Hz 1 H) 717 (t J = 72 Hz 1

H) 707 (t J = 80 Hz 1 H) 439 (t J = 112 Hz 1 H) 415 (ddd J = 108 40 16 Hz 1

H) 386 (t J = 32 Hz 1 H) 363 (s 3 H) 331 (dd J = 164 68 Hz 1 H) 307 (d J =

68 Hz 1 H) 260 (ddd J = 100 44 44 Hz 1 H) 248 (d J = 164 1 H) 230 (s 3 H)

211 (ddd J = 112 46 40 Hz 1 H) 207 (s 3 H) 189 (m 1 H) 180 (dd J = 120 36

Hz 1 H) 13C NMR (75 MHz) δ 1955 1574 1372 1332 1265 1211 1208 1187

1178 1090 1059 678 547 538 418 385 324 291 250 229 228 IR (neat)

2895 2359 1617 1468 1320 1276 1192 911 741 MS (CI) mz 337 [C21H25N2O2

(M+1) requires 337] 337 (base) 336 233 [α]D25 = -187 (c 030 EtOH)

NMR Assignments 1H NMR (400 MHz) δ 751 (s 1 H C12-H) 745 (d J = 80

Hz 1 H C2-H) 729 (d J = 80 Hz 1 H C5-H) 717 (t J = 72 Hz 1 H C4-H) 707 (t

J = 80 Hz 1 H C3-H) 439 (t J = 112 Hz 1 H C11-H) 415 (ddd J = 108 40 16

Hz 1 H C11-H) 386 (t J = 32 Hz 1 H C16-H) 363 (s 3 H C21-H) 331 (dd J =

164 68 Hz 1 H C8-H) 307 (d J = 68 Hz 1 H C10-H) 260 (ddd J = 100 44 44

Hz 1 H C10-H) 248 (d J = 164 1 H C8-H) 230 (s 3 H C20-H) 211 (ddd J = 112

46 40 Hz 1 H C14-H) 207 (s 3 H C19-H) 189 (m 1 H C15-H) 180 (dd J = 120

36 Hz 1 H C15-H) 13C NMR (75 MHz) δ 1955 (C18) 1574 (C12) 1372 (C1) 1332

327

(C17) 1265 (C6) 1211 (C4) 1208 (C5) 1187 (C3) 1178 (C2) 1090 (C13) 1059

(C7) 678 (C11) 547 (C9) 538 (C16) 418 (C21) 385 (C20) 324 (C8) 291 (C10)

250 (C19) 229 (C15) 228 (C14)

328

References

1 (a) Trost B M ldquoAtom Economy-A Challenge for Organic Synthesis Homogeneous Catalysis Leads the Wayrdquo Angew Chem Int Ed Engl 1995 34 259-281 (b) Trost B M ldquoThe Atom Economy-A Search for Synthetic Efficiencyrdquo Science 1991 254 1471-1477

2 Tkatchenko I In Comprehensive Organometallic Chemistry Wilkinson G Ed Pergamon Oxford 1982 Vol 8 101

3 Boor J Ziegler-Natta Catalysts and Polymerization Academic Press New York 1979

4 Brown E S In Organic Synthesis via Metal Carbonyls Wender I Pino P Eds Wiley-Interscience New York 1977 Vol 2 p 655

5 a) Trost B M ldquoOrganopalladium Intermediates in Organic Synthesisrdquo Tetrahedron 1977 33 2615-2649 b) Trost B M Verhoeven T R In Comprehensive Organometallic Chemistry Pergamon Oxford 1982 Vol 8 pp 799-938 c) Godleski S A In Comprehensive Organic Synthesis Fleming I Ed Pergamon Press Oxford 1991 Vol 4 pp 585-661

6 Tsuji J Takahashi H Morikawa M ldquoOrganic Synthesis by Means of Noble Metal Compounds XVII Reaction of π-Allylpalladium Chloride with Nucleophilesrdquo Tetrahedron Lett 1965 4387-4388

7 a) Trost B M In Transition Metals in Organic Synthesis Bolm C Ed Wiley-VCH Weinheim 1998 Vol 1 pp 3-13 b) Trost B M Van Vranken D L ldquoAsymmetric Transition Metal-Catalyzed Allylic Alkylationsrdquo Chem Rev 1996 96 395-422

8 Trost B M Verhoeven T R ldquoAllylic Alkylation Palladium-Catalyzed Substitutions of Allylic Carbonates Stereo- and Regioselectivityrdquo J Am Chem Soc 1980 102 4730-4743

9 Tsuji J Palladium Reagents and Catalysts Innovations in Organic Synthesis John Wiley amp Sons New York 1995

10 (a) Kondo T Ono N Satake N Mitsudo T-A Watanabe Y ldquoNucleophilic and Electrophilic Allylation Reactions Synthesis Structure and Ambiphilic Reactivity of (eta3-Allyl)ruthenium(II) Complexesrdquo Organometallics 1995 14 1945-1953 (b) Morisaki Y Kondo T Mitsudo T-A ldquoRuthenium-Catalyzed Allylic Substitution of Cyclic Allyl Carbonates with Nucleophiles Stereoselectivity and Scope of the Reactionrdquo Organometallics 1999 18 4742-4746 (c) Trost B M Fraisse P L Ball Z T ldquoA Stereospecific Ruthenium-Catalyzed Allylic Alkylationrdquo Angew Chem Int Ed Engl 2002 41 1059-1061

11 a) Trost B M Lautens M ldquoRegiochemical Control in the Molybdenum-Catalyzed Reactions of Trimethylsilyl- and Ester-Substituted Allylic Acetatesrdquo Organometallics 1983 2 1687-1689 b) Trost B M Lautens M ldquoMolybdenum Catalysts for Allylic Alkylationrdquo J Am Chem Soc 1982 105 5543-5545

329

12 Trost B M Hung M-H ldquoTungsten-Catalyzed Allylic Alkylations New

Avenues for Selectivityrdquo J Am Chem Soc 1983 105 7757-7759 13 (a) Takeuchi R ldquoIridium Complex-Catalyzed Highly Selective Organic

Synthesisrdquo Synlett 2002 1954-1965 (b) Takeuchi R Kezuka S ldquoIridium-Catalyzed Formation of Carbon-Carbon and Carbon-Heteroatom Bondsrdquo Synthesis 2006 3349-3366

14 (a) Tsuji J Minami I Shimizu I ldquoAllylation of Carbonucleophiles with Allylic Carbonates Under Neutral Conditions Catalyzed by Rhodium Complexesrdquo Tetrahedron Lett 1984 25 5157-5160 (b) Evans P A Nelson J D ldquoRegioselective Rhodium-Catalyzed Allylic Alkylation with a Modified Wilkinsonrsquos Catalystrdquo Tetrahedron Lett 1998 39 1725-1728 (c) Takeuchi R Kitamura N ldquoRhodium Complex-Catalysed Allylic Alkylation of Allylic Acetatesrdquo New Journal of Chemistry 1998 22 659-660 (d) Hayashi T Okada A Suzuka T Kawatsura M ldquoHigh Enantioselectivity in Rhodium-Catalyzed Allylic Alkylation of 1-Substituted 2-Propenyl Acetatesrdquo Org Lett 2003 5 1713-1715

15 Trost B M Hung M-H ldquoOn the Regiochemistry of Metal-Catalyzed Allylic Alkylation A Modelrdquo J Am Chem Soc 1984 106 6837-6839

16 Trost B M Lautens M ldquoOn the Stereo- and Regioselectivity of Molybdenum-Catalyzed Allylic Alkylations Stereocontrolled Approach to Quaternary Carbons and Tandem Alkylation-Cycloadditionrdquo J Am Chem Soc 1983 105 3343-3344

17 Takeuchi R Kashio M ldquoIridium Complex-Catalyzed Allylic Alkylation of Allylic Esters and Allylic Alcohols Unique Regio- and Stereoselectivityrdquo J Am Chem Soc 1998 120 8647-8655

18 Trost B M ldquoCyclizations via Palladium-Catalyzed Allylic Alkylationrdquo Angew Chem Int Ed Engl 1989 28 1173-1219

19 Trost B M Verhoeven T R ldquoInfluence of a Transition Metal on the Regiochemistry of Ring Closures An Approach to Medium-Ring Compoundsrdquo J Am Chem Soc 1979 101 1595-1597

20 Trost B M Verhoeven T R ldquoCyclization Catalyzed by Palladium (0) Initial Studies and Macrolide Formationrdquo J Am Chem Soc 1980 102 4743-4763

21 Tsuji J J Kobayashi Y Kataoka H Takahashi T ldquoPreparation of Five- and Six-Membered Cyclic Ketones by the Palladium-Catalyzed Cyclization Reaction Application to Methyl Dihydrojasmonate Synthesisrdquo Tetrahedron Lett 1980 21 1475-1478

22 Fiaud J C Malleron J L ldquoA Convenient Procedure for Smooth Palladium-Catalyzed Allylic Alkylation by Sodium Diemthyl Malonate and Cyclopentadiene A New Synthesis of Allylic Substituted Cyclopentadienesrdquo Tetrahedron Lett 1980 21 4437-4440

23 Aleksandrowicz P Piotrowska H Sas W ldquoPalladium-Catalyzed C-Alkylation of Nitroalkanesrdquo Tetrahedron 1982 38 1321-1327

24 Evans P A Leahy D K ldquoRegioselective and Enantiospecific Rhodium-Catalyzed Intermolecular Allylic Etherification with Ortho-Substituted Phenolsrdquo J Am Chem Soc 2000 122 5012-5013

330

25 Evans P A Leahy D K ldquoRegio- and Enantiospecific Rhodium-Catalyzed

Allylic Etherification Reactions Using Copper (I) Alkoxides Influence of the Copper Halide Salt on Selectivityrdquo J Am Chem Soc 2002 124 7882-7883

26 Takacs J M In Comprehensive Organic Chemistry II Wilkinson G Ed Elsevier Science New York 1995 Vol 12 pp 814-817

27 Trost B M Van Vranken D L rdquoA General Synthetic Strategy Toward Aminocyclopenitol Glycosidase Inhibitors Application of Palladium Catalysis to the Synthesis of Allosamizoline and Mannistatin Ardquo J Am Chem Soc 1993 115 444-458

28 Evans P A Robinson J E Nelson J D ldquoEnantiospecific Synthesis of Allylamines via the Regioselective Rhodium-Catalyzed Allylic Amination Reactionrdquo J Am Chem Soc 1999 121 6761-6762

29 Murahashi S-I Tanigawa Y Imada Y Taniguchi Y ldquoPalladium (0) Catalyzed Azidation and Amination of Allyl Acetates Selective Synthesis of Allyl Azides and Primary Allylaminesrdquo Tetrahedron Lett 1985 26 227-230

30 Trost B M Schroeder G M ldquoPalladium-Catalyzed Asymmetric Alkylation of Ketone Enolatesrdquo J Am Chem Soc 1999 121 6759-6760

31 Tsuji J Minami I Shimizu I ldquoPalladium-Catalyzed Allylation of Ketones and Aldehydes with Allylic Carbonates via Silyl Enol Ethers under Neutral Conditionsrdquo Chem Lett 1983 8 1325-1326

32 Tsuji J Takahashi K Minami I Shimizu I rdquoPalladium-Catalyzed Preparation of Allyl Esters and Unsaturated Esters from Saturated Esters via Their Silyl Acetalsrdquo Tetrahedron Lett 1984 25 4783-4786

33 Matsushita H Negishi E ldquoSelective Carbon-Carbon Bond Formation via Transition Metal-Catalysis Part 18 Palladium-Catalyzed Stereo- and Regioslecific Coupling of Allylic Derivatives with Alkenyl- and Arylmetals A Highly Selective Synthesis of 14-Dienesrdquo J Am Chem Soc 1981 103 2882-2884

34 a) Dvorak D Stary I Kocovsky P ldquoStereochemistry of Molybdenum(0)-Catlayzed Allylic Substitution The First Observation of a Syn-Syn Mechanismrdquo J Am Chem Soc 1995 117 6130-6131 b) Lolyd-Jones G C Krska S W Hughes D L Gouriou L Bonnet V D Jack K Sun Y Reamer R A ldquoConclusive Evidence for a Retention-Retention Pathway for the Molybdenum-Catalyzed Asymmetric Alkylationrdquo J Am Chem Soc 2004 126 702-703

35 Hayashi T Yamamoto A Hagihara T ldquoStereo- and Regiochemistry in Palladium-Catalyzed Nucleophilic Substitution of Optically Active (E)- and (Z)-Allyl Acetatesrdquo J Org Chem 1986 51 723-727

36 Kazmaier U Zumpe F L ldquoPalladium-Catalyzed Allylic Alkylations without Isomerization-Dream or Realityrdquo Angew Chem Int Ed Engl 2000 39 802-804

37 Evans P A Nelson J D ldquoConservation of Absolute Configuration in the Acylic Rhodium-Catalyzed Allylic Alkylation Reaction Evidence for an Enyl (σ + π) Organorhodium Intermediaterdquo J Am Chem Soc 1998 120 5581-5582

331

38 Sharp P R In Comprehensive Organometallic Chemistry II Abel E W Stone

F G A Wilkinson G Eds Pergamon Press New York 1995 Chapter 2 p 272

39 (a) Ashfeld B A Miller K A Martin S F ldquoDirect Stereoselective Substitution in [Rh(CO)2Cl]2-Catalyzed Allylic Alkylations of Unsymmetrical Substratesrdquo Org Lett 2004 6 1321-1324 (b) Ashfeld B A Miller K A Smith A J Tran K Martin S F ldquoFeatures and Applications of [Rh(CO)2Cl]2-Catalyzed Alkylations of Unsymmetrical Allylic Substratesrdquo Submitted

40 Park K H Son S U Chung Y K ldquoPausonndashKhand Reactions Catalyzed by Entrapped Rhodium Complexesrdquo Tetrahedron Lett 2003 44 2827-2830

41 (a) Cao P Wang B Zhang X ldquoRh-Catalyzed Enyne Cycloisomerizationrdquo J Am Chem Soc 2000 122 6490-6491 (b) Tong X Li D Zhang Z Zhang X ldquoRhodium-Catalyzed Cycloisomerization of 16-Enynes with an Intramolecular Halogen Shift Reaction Scope and Mechanismrdquo J Am Chem Soc 2004 126 7601-7607

42 Wender P A Dyckman A J ldquoTransition Metal-Catalyzed [5 + 2] Cycloadditions of 2-Substituted-1-vinylcyclopropanes Catalyst Control and Reversal of Regioselectivityrdquo Org Lett 1999 1 2089-2092

43 Diver S T Giessert A J ldquoEnyne Metathesis (Enyne Bond Reorganization)rdquo Chem Rev 2004 104 1317-1382

44 Evans P A Uraguchi D ldquoRegio- and Enantiospecific Rhodium-Catalyzed Arylation of Unsymmetrical Fluorinated Acyclic Allylic Carbonates Inversion of Absolute Configurationrdquo J Am Chem Soc 2003 125 7158-7159

45 Goux C Massacret M Lhoste P Sinou D ldquoStereo- and Regioselectivity in Palladium-Catalyzed Allylic Etherificationrdquo Organometallics 1995 14 4845-4847

46 For Reviews on the Pauson-Khand Reaction see (a) Brummond K M Kent J L ldquoRecent Advances in the Pauson-Khand Reaction and Related [2+2+1] Cycloadditionsrdquo Tetrahedron 2000 56 3263-3283 (b) Bonaga L V R Krafft M E ldquoWhen the Pauson-Khand and Pauson-Khand Type Reactions Go Awry A Plethora of Unexpected Resultsrdquo Tetrahedron 2004 60 9795-9833

47 Pauson P L ldquoThe Khand Reaction A Convenient and General Route to a Wide Range of Cyclopentenone Derivativesrdquo Tetrahedron 1985 41 5855-5860

48 Schore N E Croudace M C ldquoPreparation of Bicyclo[330]oct-1-en-3-one and Bicyclo[430]non-1(9)-en-8-one via Intramolecular Cyclization of AlphaOmega-Enynesrdquo J Org Chem 1981 46 5436-5438

49 Smit V A Simonyan S O Tarasov V A Mikaelyan G S Gybin A S Ibragimov I I Caple R Froen D Kreager A ldquoCyclization of Dicobalthexacarbonyl Complexes of Allyl Propargyl Ethers on the Surface of Shromatography Adsorbents A Convenient Method for the Preparation of Substituted 3-Oxabicyclo[330]Oct-5-en-7-one and 4-(Hydroxymethyl)-2-Cyclopenten-1-one Derivatives from Common Precursorsrdquo Synthesis 1989 472-476

332

50 (a) Shambayati S Crowe W E Schrieber S L ldquoN-Oxide Promoted Pauson-

Khand Cyclizations at Room Temperaturerdquo Tetrahedron Lett 1990 31 5289-5292 (b) Jeong N Chung Y K Lee B Y Lee S H Yoo S-E ldquoA Dramatic Acceleration of the Pauson-Khand Reaction by Trimethyl Amine N-Oxiderdquo Synlett 1991 204-206

51 Perez-Serrano L Casarrubios L Dominguez G Perez-Castells ldquoPauson-Khand Reaction Induced by Molecular Sievesrdquo Org Lett 1999 1 1187-1188

52 Sugihara T Yamada M Yamaguchi M Nishizawa M ldquoThe Intra- and Intermolecular Pauson-Khand Reaction Promoted by Alkyl Methyl Sulfidesrdquo Synlett 1999 771-773

53 Chung Y K Lee B Y Jeong N Hudecek M Pauson P L ldquoPromoters for the (Alkyne)hexacarbonyldicobalt-Based Cyclopentenone Synthesisrdquo Organometallics 1993 12 220-223

54 Magnus P Principe L M ldquoOrigins of 12- and 13-Stereoselectivity in Dicobaltcarbonyl Alkene-Alkyne Cyclizations for the Synthesis of Substituted Bicyclo[330]octenonesrdquo Tetrahedron Lett 1985 26 4851-4854

55 Schore N E Comprehensive Organic Synthesis Trost B M Fleming I Eds Pergamon Oxford 1991 Vol5 p 1037

56 Krafft M E ldquoRegiocontrol in the Intermolecular Cobalt-Catalyzed Olefin-Acetylene Cyclizationrdquo J Am Chem Soc 1988 110 968-970

57 Schore N E ldquoThe Pauson-Khand Cycloaddition Reaction for Synthesis of Cyclopentenonesrdquo Org React 1991 40 1

58 Khand I U Knox G R Pauson P L Watts W E Foreman M I ldquoOrganocobalt Complexes Part II Reaction of Acetylenehexacarbonyldicobalt Complexes (R1C2R2)Co2(CO)6 with Norbornene and Its Derivativesrdquo J Chem Soc Perkin Trans1 1973 977

59 Rautenstrauch V Megard P Conesa J Kuster W ldquo2-Pentylcyclopent-2-en-1-one by Catalytic Pauson-Khand Reactionrdquo Angew Chem Int Ed Engl 1990 29 1413

60 Jeong N Hwang S H Lee Y Chung Y K ldquoCatalytic Version of the Intramolecular Pauson-Khand Reactionrdquo J Am Chem Soc 1994 116 3159-3160

61 Pagenkopf B L Livinghouse T ldquoPhotochemical Promotion of the Intramolecular Pauson-Khand Reaction A New Experimental Protocol for Cobalt-Catalyzed [2+2+1] Cycloadditionsrdquo J Am Chem Soc 1996 118 2285-2286

62 Jeong N Hwang S H Lee Y Lim J S ldquoCatalytic Pauston-Khand Reaction in Super Critical Fluidsrdquo J Am Chem Soc 1997 119 10549-10550

63 Hicks F A Kablaoui N M Buchwald S L ldquoTitanocene-Catalyzed Cyclocarbonylization of Enynes to Cyclopentenonesrdquo J Am Chem Soc 1996 118 9450-9451

64 Hicks F A Buchwald S L ldquoAn Intramolecular Titanium Catalyzed Asymmetric Pauson-Khand Type Reactionrdquo J Am Chem Soc 1999 121 7026-7033

333

65 Morimoto T Chantani N Fukumoto Y Murai S ldquoRu3(CO)12-Catalyzed

Cyclocarbonylation of 16-Enynes to Bicyclo[330]octenonesrdquo J Org Chem 1997 62 3762-3765

66 Kondo T Suzuki N Okada T Mitsudo T ldquoFirst Ruthenium-Catalyzed Intramolecular Pauson-Khand Reactionrdquo J Am Chem Soc 1997 19 6187-6188

67 Koga Y Kobayashi T Narasaka K ldquoRhodium-Catalyzed Intramolecular Pauson-Khand Reactionrdquo Chem Lett 1998 249

68 Jeong N Lee S Sung B K ldquoRhodium(I)-Catalyzed Intramolecular Pauson-Khand Reactionrdquo Organometallics 1998 17 3642-3644

69 Exon C Magnus P ldquoStereoselectivity of Intramolecular Dicobalt Octacarbonyl Alkene-Alkyne Cyclizations Short Synthesis of dl-Coriolinrdquo J Am Chem Soc 1983 105 2477-2478

70 Cassayre J Zard S Z ldquoA Short Synthesis of Dendrobinerdquo J Am Chem Soc 1999 121 6072-6073

71 Jiang B Xu M ldquoHighly Enantioselective Construction of Fused Pyrrolidine Systems that Contain a Quaternary Stereocenter Concise Formal Synthesis of (+)-Conessinerdquo Angew Chem Int Ed Engl 2004 43 2543-2546

72 Krafft M E Fu Z Bonaga L V R rdquoSynthesis of Medium-Sized Rings Using the Intramolecular Pauson-Khand Reactionrdquo Tetrahedron Lett 2001 42 1427-1431

73 Lovely C L Seshadri H Wayland B R Cordes A W ldquoSynthesis fo Bridged Medium-Sized Rings through the Pauson-Khand Reactionrdquo Org Lett 2001 3 2607-2610

74 Kerr W J McLaughlin M Morrison A J Pauson P L ldquoFormal Total Synthesis of (plusmn)-α- and β-Cedrene by Preparation of Cedrone Construction of the Tricyclic Carbon Skeleton by the Use of a Highly Efficient Intramolecular Khand Annulationrdquo Org Lett 2001 3 2945-2948

75 Winkler J D Lee E C Y Nevels L I ldquoA Pauson-Khand Approach to the Synthesis of Ingenolrdquo Org Lett 2005 7 1489-1491

76 For Reviews of Metal-Catalyzed Domino Reactions see (a) Malacria M ldquoSelective Preparation of Complex Polycyclic Molecules from Acyclic Precursors via Radical Mediated- or Transition Metal-Catalyzed Cascade Reactionsrdquo Chem Rev 1996 96 289-306 (b) Molander G A Harris C R ldquoSequencing Reactions with Samarium (II) Iodiderdquo Chem Rev 1996 96 307-338

77 Ajamian A Gleason J L ldquoTwo Birds with One Metallic Stone Single-Pot Catalysis of Fundamentally Different Transformationsrdquo Angew Chem Int Ed Engl 2004 43 3754-3760

78 Louie J Bielawski C W Grubbs R H ldquoTandem Catalysis The Sequential Mediation of Olefin Metathesis Hydrogenation and Hydrogen Transfer with Single-Component Ru Complexesrdquo J Am Chem Soc 2001 123 11312-11313

79 (a) Son S U Choi D S Chung Y K Lee S-G ldquoDicobalt Octacarbonyl-Catalyzed Tandem [2 + 2 + 1] and [2 + 2 + 2] Cycloaddition Reaction of Diynes with Two Phenylacetylenes under COrdquo Org Lett 2000 2 2097-2100 (b) Son S U Park K H Chung Y K ldquoCobalt Nanoparticles on Charcoal A Versatile

334

Catalyst in the Pauson-Khand Reaction Hydrogenation and the Reductive Pauson-Khand Reactionrdquo Org Lett 2002 4 3983-3986

80 Fuji K Morimoto T Tsutsumi K Kakiuchi K ldquoAqueous Catalytic Pauson-Khand-Type Reactions of Enynes with Formaldehyde Transfer Carbonylation Involving an Aqueous Decarbonylation and a Micellar Carbonylationrdquo Angew Chem Int Ed Eng 2003 115 2511-2515

81 Evans P A Robinson J E ldquoRegio- and Diastereoselective Tandem Rhodium-Catalyzed Allylic AlkylationPauston-Khand Annulation Reactionsrdquo J Am Chem Soc 2001 123 4609-4610

82 Ashfeld B A Miller K A Smith A J Tran K Martin S F ldquo[Rh(CO)2Cl]2-Catalyzed Domino Reactions Involving Allylic Substitution and Subsequent Carbocyclization Reactionsrdquo Org Lett 2005 7 1661-1663

83 Cao P Wang B Zhang X ldquoRh-Catalyzed Enyne Cycloisomerizationsrdquo J Am Chem Soc 2000 122 6490-6491

84 Thalji R K Ahrendt K A Bergman R G Ellman J A ldquoAnnulation of Aromatic Imines via Directed C-H Activation with Wilkinsonrsquos Catalystrdquo J Am Chem Soc 2001 123 9692-9693

85 (a) Oppolzer W Gaudin J M ldquoCatalytic Intramolecular Palladium-Ene Reactionsrdquo Helv Chim Acta 1987 70 1477-1481 (b) Oppolzer W Furstner A ldquoRhodium(I)-Catalyzed lsquoMetallo-Enersquo Cyclizationsβ-Eliminationsrdquo Helv Chim Acta 1993 76 2329-2337

86 Lautens M Fagnou K Yang D ldquoRhodium-Catalyzed Asymmetric Ring Opening Reactions of Oxabicyclic Alkenes Application of Halide Effects in the Development of a General Processrdquo J Am Chem Soc 2003 125 14884-14892

87 Vallarino L M Sheargold S W ldquoSolid-State Isomerism and Intermetallic Interactions in Rhodium(I) Carbonyl-Amine Complexesrdquo Inorg Chim Acta 1979 36 243-246

88 Fulford A Hickey C E Maitlis P M ldquoFactors Influencing the Oxidative Addition of Iodomethane to [Rh(CO)2I2] the Key Step in Methanol and Methyl Acetate Carbonylationrdquo J Organomet Chem 1990 398 311-323

89 (a) Widenhofer R A Buchwald S L ldquoHalide and Amine Influence in the Equilibrium Formation of Palladium Tris(o-tolyl)phosphine Mono(amine) Complexes from Palladium Aryl Halide Dimersrdquo Organometallics 1996 15 2755 (b) Widenhofer R A Zhong A H Buchwald S L ldquoSynthesis and Solution Structure of Palladium Tris(o-tolyl)phosphine Mono(amine) Complexesrdquo Organometallics 1996 15 2745-2747 (c) Bennett M A Longstaff P A ldquoReaction of Rhodium Halides with Tri-o-Tolylphosphine and Related Ligands Complexes of Divalent Rhodium and Chelate Complexes Containing Rhodium-Carbon σ and micro Bondsrdquo J Am Chem Soc 1969 91 6266-6280 d) Chatt J Venanzi L M ldquoOlefin Coordination Compounds VI Diene Complexes of Rhodiumrdquo J Chem Soc 1957 2445-2450

90 Hegedus L S In Transition Metals in the Synthesis of Complex Organic Molecules University Science Books Sausalito California 1999 Chapter 2 pp13-15

335

91 Molinaro C Jamison T F ldquoNickel-Catlayzed Coupling of Alkynes and

Epoxidesrdquo J Am Chem Soc 2003 125 8076-8077 92 van Otterlo W A L Ngidi E L Kuzvidza S Morgans G L Moleele S S

de Koning C B ldquoRing-Closing Metathesis for the Synthesis of 2H- and 4H-Chromenesrdquo Tetrahedron 2005 61 9996-10006

93 Cheng C Y Liou J P Lee M J ldquoSynthesis of Morphine Fragments Spiro[Benzofuran-3(2H)4prime-Piperidine] and Octahydro-1H-Benzofuro[32-e]Isoquinoline by Intramolecular Heck Reactionrdquo Tetrahedron Lett 1997 38 4571-4574

94 Eliel E L Wilen S H In Stereochemistry of Organic Compounds John Wiley amp Sons Inc New York 1994 Ch 10 pp 618-619

95 Jeong N Sung B K Choi Y K ldquoRhodium(I)-Catalyzed Asymmetric Intramolecuar Pauson-Khand Type Reactionrdquo J Am Chem Soc 2000 122 6771-6772

96 Brummond K M Chen H Sill P You L ldquoA Rhodium(I)-Catalyzed Formal Allenic Alder Ene Reaction for the Rapid and Stereoselective Assembly of Cross Conjugated Trienesrdquo J Am Chem Soc 2002 124 15186-15187

97 Wilkinson G Bonati F ldquoDicarbonyl-β-diketonato- and Related Complexes of Rhodium(I)rdquo J Chem Soc 1964 3156-3160

98 Hrubowchak D M Smith F X ldquoThe Reductive Alkylation of Meldrumrsquos Acidrdquo Tetrahedron Lett 1983 24 4951-4954

99 Lounasmaa M Hanhinen P Westersund M The Sarpagine Group of Indole Alkaloids In The Alkaloids Cordell G A Ed Academic Press New York 1999 vol 52 p 103-196

100 Burkhill I H A Dictionary of Economic Products of the Malay Peninsula Crown Agents for the Colonies London 1935 p 113

101 Hamaker L K Cook J M The Synthesis of Macroline Related Alkaloids In Alkaloids Chemical and Biological Perspectives Pelletier S W Ed Elsevier Science New York 1995 Vol 9 p 23-84

102 Cook J M LeQuesne P W Elderfield R C ldquoAlstonerine a New Indole Alkaloid from Alstonia muellerianardquo J Chem Soc D 1969 1306-1307

103 Keawpradub N Eno-Amooquaye E Burke P J Houghton P J ldquoCytotoxic Activity of Indole Alkaloids from Alstonia macrophyllardquo Planta Med 1999 65 311-315

104 (a) Stockigt J Zenk M ldquoStrictosidine (Isovincoside) The Key Intermediate in the Biosynthesis of Monoterpenoid Indole Alkaloidsrdquo J Chem Soc Chem Comm 1977 646-348 (b) Rueffer M Nagakura Zenk M H ldquoStrictosidine the Common Precursor for Monoterpenoid Indole Alkaloids with 3 α and 3 β Configurationrdquo Tetrahedron Lett 1978 1593-1596 (c) Luckner M Secondary Metabolism in Microorganisms Plants and Animals 3rd ed p 353 Springer Verlag Berlin 1990

105 (a) van Tamelen E E Oliver L K ldquoBiogenetic-Type Total Synthesis of Ajmalinerdquo J Am Chem Soc 1970 92 2136-2137 (b) van Tammelen E E

336

Haarstad V B Orvis R L ldquoHypohalite-Induced Oxidative Decarboxylation of α-Amino Acidsrdquo Tetrahdron 1968 24 687-704

106 Lounasmaa M Hanhinen P ldquoStudies on the Biomimetic Preparation of the Sarpagan Ring System Attempts to Apply the Spontaneous ldquoBiogenetic-Type Cyclizationrdquo of van Tamelen to Bond Formation Between C-5 and C-16 in the Corynantheine Seriesrdquo Tetrahedron 1996 52 15225-15242

107 Deiters A Chen K Eary C T Martin S F ldquoBiomimetic Entry to the Sarpagan Family of Indole Alkaloids Total Synthesis of (+)-Geissoschizine and (+)-N-Methylvellosiminerdquo J Am Chem Soc 2003 125 4541-4550

108 Esmond R W LeQuesne P W ldquoBiomemetic Synthesis of Macrolinerdquo J Am Chem Soc 1980 102 7116-7117

109 Garnick R L LeQuesne P W ldquoBiomimetic Transformations Among Monomeric Macroline-Related Indole Alkaloidsrdquo J Am Chem Soc 1978 100 4213-4219

110 Lewis S E ldquoRecent Advances in the Chemistry of Macroline Sarpagine and Ajmaline-Related Indole Alkaloidsrdquo Tetrahedron 2006 62 8655-8681

111 Bi Y Hamaker L K Cook J M The Synthesis of Macroline Related Sarpagine Indole Alkaloids In Studies in Natural Products Chemistry Rahman A-ur Basha A Eds Elsevier Amsterdam 1993 Vol 13 p 383

112 Yu P Wang T Li J Cook J M ldquoEnantiospecific Total Syntheis of the Sarpagine Related Indole Alkaloids Talpinine and Talcarpine as Well as the Improved Total Synthesis of Alstonerine and Anhydromacrosalhine-methine via the Asymmetric Pictet-Spengler Reactionrdquo J Org Chem 2000 65 3173-3191

113 Yu P Wang T Yu F Cook J M ldquoGeneral Approach for the Synthesis of MacrolineSarpagine Related Indole Alkaloids Via the Asymmetric Pictet-Spengler Reaction The Enantiospecific Synthesis of the Na-H Azabicyclo[331]Nonone Templaterdquo Tetrahedron Lett 1997 38 6819-6822

114 (a) Li J Cook J M ldquoGeneral Approach to the Synthesis of Sarpagine and Ajmaline Alkaloids Enantiospecific Total Synthesis of (+)-Ajmaline and Alkaloid G via the Asymmetric Pictet-Spengler Reactionrdquo J Org Chem 1998 63 4166-4167 (b) Li J Wang T Yu P Peterson A Weber R Soerens D Grubisha D Bennett D Cook J M ldquoGeneral Approach for the Synthesis of AjmalineSarpagine Indole Alkaloids Enantiospecific Total Synthesis of (+)-Ajmaline Alkaloid G and Norsuaveoline via the Asymmetric Pictet-Spengler Reactionrdquo J Am Chem Soc 1999 121 6998-7010

115 Yu P Cook J M ldquoEnantiospecific Total Synthesis of the Sarpagine Related Indole Alkaloids Talpinine and Talcarpine The Oxyanion-Cope Approachrdquo J Org Chem 1998 63 9160-9161

116 Yu P Wang T Li J Cook J M ldquoEnantiospecific Total Synthesis of the Sarpagine Related Indole Alkaloids Talpinine and Talcarpine as Well as the Improved Total Synthesis of Alstonerine and Anhydromacrosalhine-methine via the Asymmetric Pictet-Spengler Reactionrdquo J Org Chem 2000 65 3173-3191

117 Naranjo J Pinar M Hesse M Schmid H ldquoAlkaloids 145 Indole alkaloids of Pleiocarpa talbotiirdquo Helv Chim Acta 1972 55 752-71

337

118 Wang T Yu P Li J Cook J M ldquoThe Enantiospecific Total Synthesis of

Norsuaveolinerdquo Tetrahedron Lett 1998 39 8009-8012 119 (a) Wang T Cook J M ldquoGeneral Approach for the Synthesis of

SarpagineAjmaline Indole Alkaloids Stereospecific Total Synthesis of the Sarpagine Alkaloid (+)-Vellosiminerdquo Org Lett 2000 2 2057-2059 (b) Yu J Wang T Liu X Deschamps J Flippen-Anderson J Liao X Cook J M ldquoGeneral Approach for the Synthesis of Sarpagine Indole Alkaloids Enantiospecific Total Synthesis of (+)-Vellosimine (+)-Normacusine B (-)-Alkaloid Q3 (-)-Panarine (+)-Na-Methylvellosimine and (+)-Na-Methyl-16-epipericyclivinerdquo J Org Chem 2003 68 7565-7581

120 (a) Martin S F ldquoEvolution of the Vinylogous Mannich Reaction as a Key Construction for Alkaloid Synthesisrdquo Acc Chem Res 2002 35 895 (b) Martin S F Clark C C Corbett J W ldquoApplications of Vinylogous Mannich Reactions Asymmetric Synthesis of the Heteroyohimboid Alkaloids (-)-Ajmalicine (+)-19-epi-Ajmalicine and (-)-Tetrahydroalstoninerdquo J Org Chem 1995 60 3236-3242

121 Neipp C E Martin S F ldquoSynthesis of Bridged Azabicyclic Structures via Ring-Closing Olefin Metathesisrdquo J Org Chem 2003 68 8867-8878

122 Kuethe J T Wong A Davies I W Reider P J ldquoAza-Diels-AlderIntramolecular Heck Cyclization Approach to the Tetrahydro-β-Carboline Skeleton of the AjmalineSarpagine Alkaloidsrdquo Tetrahedron Lett 2002 43 3871-3874

123 Bailey P D Clingan P D Mills T J Price R A Pritchard R G ldquoTotal Synthesis of (-)-Raumaclinerdquo Chem Comm 2003 2800

124 Bailey P D Morgan K M ldquoThe Total Synthesis of (-)-Suaveolinerdquo J Chem Soc Perkin Trans 1 2000 21 3578-3580

125 Alberch L Bailey P D Clingan P D Mills T J Price R A Pritchard R G ldquoThe cis-Specific Pictet-Spengler Reactionrdquo Eur J Org Chem 2004 1887-1890

126 Ohba M Natsutani I Sakuma T ldquoTotal Synthesis of Suaveoline and Norsuaveoline via Intramolecular Oxazole-Olefin Diels-Alder Reactionrdquo Tetrahedron Lett 2004 45 6471-6474

127 (a) Michel P Rassat A ldquoAn Easy Access to 26-Dihydroxy-9-azabicyclo[331]nonane a Versatile Synthonrdquo J Org Chem 2000 65 2572-2573 (b) Gennet D Michel P Rassat A ldquo(endoendo)-9-Benzyl-9-azabicyclo[331]nonane-26-diol An Intermediate for the Preparation of Indole Alkaloids of the MacrolineSarpagine Seriesrdquo Synthesis 2000 447-451

128 (a) Zhang L H Cook J M ldquoGeneral Approach to the Synthesis of Macroline-Related Alkaloids Stereospecific Total Synthesis of (-)-Alstonerinerdquo J Am Chem Soc 1990 112 4088-4090 (b) Bi Y Zhang L H Hamaker L K Cook J M ldquoEnantiospecific Synthesis of (-)-Alstonerine and (+)-Macroline as Well as a Partial Synthesis of (+)-Villalstoninerdquo J Am Chem Soc 1994 116 9027-9041

338

129 (a) Liao X Zhou H Yu J Cook J M ldquoAn Improved Synthesis of (+)-

Macroline and Alstonerine as Well as the Formal Total Synthesis of (-)-Talcarpine and (-)-Anhydromacrosalhine-methinerdquo J Org Chem 2006 71 8884-8890 (b) Liao X Zhou H Wearing X Z Ma J Cook J M ldquoThe First Regiospecific Enantiospecific Total Synthesis of 6-Oxoalstophylline and an Improved Total Synthesis of Alstonerine and Alstophylline as Well as the Bisindole Alkaloid Macralstoninerdquo Org Lett 2005 7 3501-3504

130 Tran Y S Kwon O ldquoAn Application of the Phosphine-Catalyzed [4+2] Annulation in Indole Alkaloid Synthesis Formal Syntheses of (plusmn)-Alstonerine and (plusmn)-Macrolinerdquo Org Lett 2005 7 4289-4291

131 Cox P Craig D Ioannidis S Rahn V S ldquo4-(Phenylsulphonyl)-4-lithiocyclopentene as a Nucleophilic 2-Pentene-15-Dial Synthetic Equivalent An Aziridine-Based Synthetic Approach to (-)-Alstonerinerdquo Tetrahedron Lett 2005 46 4687-4690

132 Schlosser M Coffinet D ldquoSCOOPY-Reaktionen Stereoselektivitaumlt der Allyl-alkohol-Synthese via Betain-Yliderdquo Synthesis 1971 380-381

133 Kumarasamy Y Cox P J Jaspars M Nahar L Sarker S D ldquoIsolation Structure Elucidation and Biological Activity of Hederacine A and B Two Unique Alkaloids from Glechoma Hederaceaerdquo Tetrahedron 2003 59 6403-6407

134 Scott J D Williams R M ldquoThe Chemistry and Biology of the Tetrahydroisoquinoline Antitumor Antibioticsrdquo Chem Rev 2002 102 1669-1730

135 Barnes J Anderson L A Phillipson J D Herbal Medicines Pharmaceutical London 2002 pp 280-281

136 Zhang X Schmitt A C Jiang W ldquoA Convenient and High Yield Method to Prepare 4-Hydroxypyroglutamic Acidsrdquo Tetrahedron Lett 2001 42 5335-5338

137 Apelqvist T Wensbo D ldquoSelective Removal of the N- BOC Protective Group Using Silica Gel at Low Pressurerdquo Tetrahedron Letters 1996 37 1471-1472

138 Cordell G A Introduction to Alkaloids A Biogenetic Approach Wiley-Interscience New York 1981

139 Johnson F ldquoAllylic Strain in Six-Membered Ringsrdquo Chem Rev 1968 68 375-413

140 (a) Brown J D Foley M A Comins D L ldquoA Highly Stereocontrolled Four-Step Synthesis of (+-)-Lasubine IIrdquo J Am Chem Soc 1988 110 7445-7447 (b) Comins D L Joseph S P Goehring R R ldquoAsymmetric Synthesis of 2-Alkyl(Aryl)-23-Dihydro-4-Pyridones by Addition of Grignard Reagents to Chiral 1-Acyl-4-methoxypyridinium Saltsrdquo J Am Chem Soc 1994 116 4719-4728

141 House H O Fischer Jr W F ldquoConjugate Addition Reactions with Lithium Diallylcupraterdquo J Org Chem 1969 34 3615-3618

142 Sakurai H ldquoReactions of Allylsilanes and Application to Organic Synthesisrdquo Pure Appl Chem 1982 54 1-22

143 Kim S Lee J M ldquoTrialkylsilyl Triflate-Promoted Conjugate Addition of Allylstannanes to α β-Enonesrdquo Synth Comm 1991 21 25-29

339

144 Breczinski P M Stumpf A Hope H Krafft M E Casalnuovo J A Schore

N E ldquoStereoselectivity in the Intramolecular Pauson-Khand Reaction Towards a Simple Predictive Modelrdquo Tetrahedron 1999 55 6797-6812

145 Greene T W Wuts P G M Protective Groups in Organic Synthesis Wiley-Interscience New York 1999 pp 1-16

146 Ohwada T Okamoto I Shudo K Yamaguchi K ldquoIntrinsic Pyramidal Nitrogen of N-Sulfonylamidesrdquo Tetrahedron Lett 1998 39 7877-7880 and references therein

147 Heintzelman G R Fang W Keen S P Wallace G A Weinreb S M ldquoStereoselective Total Syntheses and Reassignment of Stereochemistry of the Freshwater Cyanobacterial Hepatotoxins Cylindrospermopsin and 7-Epicylindrospermopsinrdquo J Am Chem Soc 2002 124 3939-3945

148 (a) Ohira S ldquoMethanolysis of Dimethyl (1-Diazo-2-Oxopropyl)Phosphonate Generation of Dimethyl (Diazomethyl)Phosphonate and Reaction with Carbonyl Compoundsrdquo Synth Commun 1989 19 561-564 (b) Muller S Liepold B Roth G J Bestmann H J ldquoAn Improved One-pot Procedure for the Synthesis of Alkynes from Aldehydesrdquo Synlett 1996 521-522

149 Ireland R E Norbeck D W ldquoApplication of the Swern Oxidation to the Manipulation of Highly Reactive Carbonyl Compoundsrdquo J Org Chem 1985 50 2198-2200

150 (a) DeBoer A Ellwanger R E ldquoBaeyer-Villiger Oxidation of ∆1(9)-Octalone-2 and ∆1(8)-Indanonerdquo J Org Chem 1974 39 77-83 (b) Abad A Arno A M Cunat A C Zaragoza R J ldquoSynthesis of (+)-Ambreinolide from Abietic Acidrdquo J Org Chem 1989 54 5123-5125

151 Feldman K S Wu M J Rotela D P ldquoTotal Synthesis of (plusmn)-Dactylol and Related Studiesrdquo J Am Chem Soc 1990 112 8490-8496

152 For various methods for the deoxygenation of epoxides see (Ti) RajanBabu T V Nugent W A Beattie M S ldquoFree Radical Mediated Reduction and Deoxygenation of Epoxidesrdquo J Am Chem Soc 1990 112 6408-6409 (W) Sharpless K B Umbreit M A Nieh M T Flood T C ldquoLower Valent Tungsten Halides A New Class of Reagents for Deoxygenation of Organic Moleculesrdquo J Am Chem Soc 1972 94 6538-6540 (Rh) Martin M G Ganem B ldquoEpoxides as Alkene Protecting Groups A Mild ad Efficient Deoxygenationrdquo Tetrahedron Lett 1984 25 251-254 (I) Paryzek Z Wydra R ldquoReaction of Some Trisubstituted Steroid Epoxides with Triphenylphosphine ndash Iodine Complex Deoxygenation of Epoxidesrdquo Tetrahedron Lett 1984 25 2601-2604

153 Caine D ldquoReduction and Related Reactions of αβ-Unsaturated Carbonyl Compounds with Metals in Liquid Ammoniardquo Org React 1976 23 1-258

154 Tsuda T Hayashi T Satomi H Kawamoto T Saegusa T ldquoMethylcopper(I)-Catalyzed Selective Conjugate Reduction of αβ-Unsaturated Carbonyl Compounds by Diisobutylaluminum Hydride in the Presence of Hexamethylphosphoric Triamiderdquo J Org Chem 1986 51 537-540

155 (a) Jurkauskas V Buchwald S L ldquoDynamic Kinetic Resolution via Asymmetric Conjugate Reduction Enantio- and Diastereoselective Synthesis of

340

24-Dialkyl Cyclopentanonesrdquo J Am Chem Soc 2002 124 2892-2893 (b) Lipshutz B H Frieman B A ldquoCuH in a Bottle A Convenient Reagent for Asymmetric Hydrosilationsrdquo Angew Chem Int Ed Engl 2005 44 6345-6348

156 Ojima I Kogure T ldquoReduction of Carbonyl Compounds via Hydrosilylation 4 Highly Regioselective Reductions of αβ-Unsaturated Carbonyl Compoundsrdquo Organometallics 1982 1 1390-1399

157 Johnson C R Raheja R K ldquoHydrosilylation of Enones Platinum Divinyltetramethyldisiloxane Comple in the Preparation of Triisopropylsilyl and Triphenylsilyl Enol Ethersrdquo J Org Chem 1994 59 2287-2288

158 Denmark S E Forbes D C ldquoA Stereochemical Study on the Intramolecular Hydrosilylation of αβ-Unsaturated Estersrdquo Tetrahedron Lett 1992 33 5037-5040

159 Chenault H K Danishefsky S J ldquoCharacterization of 2-Siloxyoxiranes Formed by Epoxidation of Silyl Enol Ethers with Dimethyldioxiranerdquo J Org Chem 1989 54 4249-4250

160 Magnus P Mugrage B ldquoNew Trialkylsilyl Enol Ether Chemistry Regiospecific and Stereospecific Sequential Electrophilic Additionrdquo J Am Chem Soc 1990 112 462-464

161 McCormick J P Tomasik W Johnson M W ldquoα-Hydroxylation of Ketones Osmium TetroxideN-Methylmorpholine ndashN-Oxide Oxidation of Silyl Enol Ethersrdquo Tetrahedron Lett 1981 22 607-610

162 Sharpless K B Akashi K ldquoOsmium Catalyzed Vicinal Hydroxylation of Olefins by Tert-Butyl Hydroperoxide Under Alkaline Conditionsrdquo J Am Chem Soc 1976 98 1986-1987

163 Hashiyama T Morikawa K Sharpless K B ldquoα-Hydroxy Ketones in High Enantiomeric Purity from Asymmetric Dihydroxylation of Enol Ethersrdquo J Org Chem 1992 57 5067-5068

164 Barton D H R Elad D ldquoColombo Root Bitter Principles II Constitution of Columbinrdquo J Chem Soc 1956 2090-2095

165 Liras J L Lynch V M Anslyn E V ldquoThe Ratio between Endocyclic and Exocyclic Cleavage of Pyranoside Acetals Is Dependent upon the Anomer the Temperature the Aglycon Group and the Solventrdquo J Am Chem Soc 1997 119 8191-8200

166 Priebe W Grynkiewicz G Neamati N ldquoOne Step C-acylation of Glycals and 2-Deoxy-Hexopyranoses at C-2rdquo Tetrahedron Lett 1992 33 7681-7684

167 Lellouche J P Koeller S ldquoThe Particular Sensitivity of Silyl Ethers if D-Glucal toward Two Vilsmeier-Haack Reagents POCl3-DMF and (CF3SO2)2O-DMF Their Unique and Selective Conversion to the Corresponding C(6)-O-Formatesrdquo J Org Chem 2001 66 693-696

168 Martin S F Benage B Geraci L S Hunter J E Montimore M ldquoUnified Strategy for Synthesis of Indole and 2-Oxindole Alkaloidsrdquo J Am Chem Soc 1991 113 6161-6171

169 For Selected Examples of Acylated Glycals Isolated from Nature see (a) Guella G Dini F Tomei A Pietra F ldquoPreuplotin a Putative Biogenetic Precursor of

341

the Euplotins Bioactive Sesquiterpenoids of the Marine Ciliated Protist Euplotes crassusrdquo J Chem Soc Perkin Trans 1 1994 161-166 (b) Hooper G J Davies-Coleman M T ldquoNew Metabolites from the South African Soft Coral Capnella thyrsoideardquo Tetrahedron 1995 51 9973-9984 (c) Kam T-S Jayashankar R Sim K-M Yoganathan K ldquoAngustimaline an Unusual Nitrogenous Compound from Alstonia angustifoliardquo Tetrahedron Lett 1997 38 477-478

170 Still W C Kahn M Mitra A ldquoRapid Chromatographic Technique for Preparative Separations with Moderate Resolutionrdquo J Org Chem 1978 43 2923-2925

342

Vita

Kenneth Aaron Miller was born in Pittsburg Pennsylvania on December 13 1979

to Cynthia and Marshall Miller After attending John S Davidson Fine Arts High

School Augusta Georgia in 1998 he attended the University of Georgia During the

course of his undergraduate education he served as a research assistant in the laboratories

of Professor Timothy M Dore In May 2002 he graduated with a Bachelor of Science in

Chemistry In August of 2002 he entered graduate school at the University of Texas at

Austin and joined the research laboratories of Professor Stephen F Martin

Permanent address 103 W 55th St Austin TX 78751

This dissertation was typed by the author

The Dissertation Committee for Kenneth Aaron Miller Certifies that this is the

approved version of the following dissertation




Committee

Stephen F Martin Supervisor

Eric V Anslyn

Michael J Krische

John T McDevitt

Sean M Kerwin




by


Dissertation




of the Requirements

for the Degree of



May 2007

Dedication

To Stephanie Hall

v

Acknowledgements











work was based

vi




















vii
















viii

Table of Contents

List of Tables xii


List of Schemes xiv




121 Introduction2












141 Introduction33




ix













16 Conclusions51













x

24 Conclusions95


31 Introduction97

311 Alstonerine98





















36 Conclusions141


41 Introduction144


421 Introduction148

xi















45 Conclusions209


51 General 211

52 Compounds 212

References328

Vitahellip342

xii

List of Tables


xiii

List of Figures


xiv

List of Schemes


xv


xvi


xvii


1





















2











121 Introduction













3










Scheme 11

M

X-Nuc-

11

X

12

X

M

13

M

14

Nuc

M

15

Nuc

4













Scheme 12

Br

OAcPd(PPh3)4

THF

DMF

OAc

MeO2C

SO2Ph

Br

+CO2Me

SO2Ph

SO2Ph

CO2Me16 17

18

19





5



Scheme 13

R1 R2

X M

R1 R2

M

110 111

Nuc-Nuc-

a b

R1 R2

Nuc

112

R1 R2

113

Nuc

path a

path b

-X-









used as a substrate

6

Scheme 14

LG Nuc

LG Nuc

Pd

Pd

Ru Mo Rh Ir W

Ru Mo Rh Ir W

+ Nuc

115114

116 117










7

Scheme 15

NaHCH2(CO2Me)

OAc

118NaH

CH2(CO2Me)

Pd(PPh3)4

W(CO)3(MeCN)383

or

119 E = CO2Me

E

E

E E

120 E = CO2Me

+

119 E = CO2Me

E

E

E E

120 E = CO2Me

+

119120 = 8614

119120 = 496









8

Scheme 16

OAc

OAc

NaHCH2(CO2Me)

Mo(CO)6

NaHHCMe(CO2Me)

orE

E

E

EMe

121 122

123 E = CO2Me

124 E = CO2Me

89

84















9


sections

Scheme 17

nPr OAc

THF reflux 19 h66

THF rt 1 h94



[Ir(COD)Cl]2 (2)

nPr

nPr

CO2Me

CO2Me

MeO2C CO2Me

126

125

127

126127 = 8812

+

nPr

nPr

CO2Me

CO2Me

MeO2C CO2Me

126 127

126127 = 397

+








documented1316


Alkylations



10








membered) rings

Scheme 18

LG

Nuc Nuc

M

M

127 128











11



favored (Eq 12)

O

O

OAcH

H

CO2Me

SO2Ph

NaH THF

Pd(PPh3)4 dppe60

O

O

SO2PhCO2Me

H

H

129 130

SO2Ph

OAc

SO2Ph

131

SO2Ph

SO2PhBSA THF

Pd(dppe)244

132

(11)

(12)







12

O

SO2Ph

OO

SO2Ph

O134 135

O

SO2Ph

O

133

OAc

+

NaH Pd(PPh3)4Diphos

THF reflux73

134135 = 928

OPh

CO2Me

O

Pd(OAc)2 PPh3

62

CO2Me

O

136 137

(13)

(14)














13
















14

Scheme 19

soft Nuc-

hard Nuc-

H

Nuc

M

140

M

NucM

142

oxidativeaddition

H

Nuc

141

Nuc

H

M

143


Nuc

H

144

M

139

H

LG

138

M

M












minimize A13-strain

15

Scheme 110

R OAc OAc

R

145 146

R OAc OAc

R

147 148


MLn MLn

syn anti

R Nuc Nuc

R

149 150

Nuc- Nuc-








16

Me

PhOAc


151

Me Ph

CO2MeMeO2C

152THF rt

99

Me

OAc


154

THF rt96

Ph

Me Ph

153

CO2MeMeO2C

Me Ph

CO2MeMeO2C

152

Me Ph

153

CO2MeMeO2C

+

+

152153 = 9010

152153 = 928

(15)

(16)










palladium catalysis

Me

PhOAc

155

TfaN

Zn OOtBu

PPh3 [Pd(allyl)Cl]2

THF -78 degC - rt69

Ph157

tBuO2C

NHTfa

156

(17)

17















Scheme 111

nPr OAcTHF reflux

85

NaCH(CO2Et)2


158

nPr

159

CO2Et

CO2EtnPr

nPr

CO2Me

CO2Me

MeO2C CO2Me

160

161

+

+

159160161 = 9073

18















OCO2Me

OMe

O O

RhH(PPh3)4 (5)PBu3 (10)

CO2Me

O162

163

164

THF rt93

(18)




19











OCO2Me

OMe

O O


O

CO2Me

O

+

165

163

166 167

168

OCO2Me

dioxane 100 degC97

OMe

O O

RhH(PPh3)4 (5)PBu3 (10)

163

dioxane 100 degC81

CO2Me

O

CO2Me

O

+

166 167

166167 = 7228

166167 = 1486

(19)

(110)

20























21




991 91

982 89

OCO2Me

169

R1 R2

170

R1 R2CO2Me

CO2MeR1

171

R2

MeO2C

CO2Me



+


1

2

3

4

5

6

phosphite

H

H

H

Me

Me

Me

Me

nPr

Ph

Me

nPr

Ph

P(OMe)3

P(OMe)3

P(OMe)3

P(OPh)3

P(OPh)3

P(OPh)3

982

gt991

964

gt991

95

89

73

32









22



nucleophilic attack

Scheme 112

OCO2Me

165

168

OCO2Me


P(OMe)3 (20) THF

173172

+

From 168 172173 = 421 99From 165 172173 = 21 83

or

MeO2C CO2Me

CO2Me

CO2Me














23



Me

OCO2Me

MeD

Me MeD

CO2MeMeO2C

Me Me

D

CO2MeMeO2C

+

P(OPh)3 (20) THF92


174 175 176

175176 = gt191

R1

OCO2Me

R2 Me iPr

CO2MeMeO2C

+

P(OPh)3 (20) THF92


179 180

From 177 179180 = 973From 178 179180 = 397

iPrMe

MeO2C CO2Me


(111)

(112)










24

Scheme 113

R

Rh(I)

R

Rh(III)

Nuc

R

LG

R

Rh(III)

NucRh(I)

Path A

Path B

R

LG

R

R

R

k1k-1

k2

k3

R

Nuc

R

RNuc

R

181 182 183

184185

186
















25

Scheme 114

R


P(OMe)3 THF R

OR


R

OAr

R

TsNBnor or

187 188 189 190







Group












26











27


OCO2MeR1


NaCH(CO2Me)2 R1

R2R3 R4

CO2Me

CO2Me

+ MeO2CR4

R3R1 R2

CO2Me191 192

193

THF rt


majorminor

1

2

3

OCO2Me CO2Me

CO2Me

OCO2MeCO2Me

CO2Me

OCO2Me

CO2Me

CO2Me

75

80

86

928

946

991(973 ZE)

OCO2MeCO2Me

CO2Me

4 84 973

Ph OCO2Me PhCO2Me

CO2Me

593 9010

194

196

198

1100

1102

195

197

199

1101

1103






28











29


OCO2MeR1

R2R3 R4

R1

R2R3 R4

CO2Me

CO2Me

+ MeO2CR4

R3R1 R2

MeO2C

191

11051106

THF


majorminor

1

2

3

OCO2Me

OCO2Me

OCO2Me

85

98

98

991

8812

1000(8812 ZE)

OCO2Me4 98 gt955

194

196

198

1110

CO2MeMeO2C

Me

+

NaH[Rh(CO)2Cl]2

1104

Me

CO2Me

CO2Me

Me

CO2Me

CO2Me

Me

CO2Me

CO2Me

Me

CO2Me

CO2Me

1111

1109

1108

1107

Me Me

30











OCO2Me

1102

[Rh(CO)2Cl]2 PhLi

ZnBr2 THF rt99


Ph

1112

99 ee 92 ee

(113)










31










regioselectively

32


OCO2MeR1


NucR1

R2R3 R4

+Nuc R4

R3R1 R2

191 1113 1114


majorminor

1OCO2Me

84 928

1100

NucTHFrt

nucleophile

OCu(I)

Ph Ph

O

2OCO2Me

75 gt955

1117

OCu(I)

PhPh

O

1115

1115

1116

1118

3OCO2Me

78 9010

1100

11191120

4OCO2Me

42 8812

1100

11211122

NTsLiTsN Ph

LiTsN TsN





33










Scheme 115

R

Rh(I)

R

Rh(III)

Nuc

R

LG

R

Rh(III)

NucRh(I)

Path A

Path B

R

LG

R

R

R

k1k-1

k2

k3

R

Nuc

R

RNuc

R

181 182 183

184185

186


141 Introduction





34












MeO

H

H+

Co2(CO)8 ∆

Me1123 1124

1125

(114)









35







Scheme 116

Co2(CO)8

Co(CO)3(CO)3Co

R-CO

Co(CO)2

Co(CO)3

R

Co

Co(CO)3

R

COCO

Co

Co(CO)3

R

CO

O

(CO)3CoCo(CO)

O

R

O-Co2(CO)4

R

1126 1127 1128 1129

1132 1131 1130

R








36







MOMO

PhCo2(CO)8

toluene 100 degC41

11351136 = 32

O

Ph

MOMO

O

Ph

MOMO

+

11341133

+

1135 1136

MeS

PhCo2(CO)8

toluene 100 degC61

11371138 = 181

O

Ph

MeS

O

Ph

MeS

+

11381137

+

1139 1140

(115)

(116)








37
















OEtO2C

EtO2C



EtO2C

EtO2C

1141 1142

(117)





38



catalysts






fashion64


toluene 90 degC92

O

Ph

O

1143 1144

OPh

(118)







Me

O

1145 1146

MeEtO2C

EtO2CEtO2C

EtO2C

CO (10-15 atm)Ru(CO)12 (2)


86-76

(119)



39







Scheme 117

Ph

O

11471148

PhEtO2C

EtO2C

EtO2C

EtO2C



toluene 110 degC 99









40

Scheme 118

TBSOMe Co2(CO)8


50

Me

O

TBSO

H

1148 1149

6 steps HO

H

1150

O

OH

H

HO

H

1151

O

OH

H

O

O

H











41

Scheme 119

OOAc

N NO

H H

H


51

1152 1153

N

H H

H

1154

O

9 steps

OAc






Scheme 120


THF 65 degC67

11561157 = 611155

MeO MeO1156

N

O

MeO1158

N

7 steps

MeO1157

N

O+

H

42







Scheme 121

O O

1159 n = 1 or 2

PKR

n

1160 1161

or










43

O

Me

MeO

O

Me

Me

O

Co2(CO)8 CH2Cl2

1164 1165

then NMO48

O

O

O

OO

1162 1163

Co2(CO)8 CH2Cl2

then NMO31

(120)

(121)







cedrene (1170)

Scheme 122

O O

OO

O

DCE 83 degC95

11671166

Co2(CO)8nBuSMe

1170

H

1169

H

1168

O

H

5 steps

44











Scheme 123

O O

O

H


then Me3NO2H2O60-70

OO

OO

11731174

K2CO3MeOH

55O

CO2Me

O

H

1175

O

H

1176

HO HOHO

HO

H

H

O O

O

H

1171

H

TMS

Br


1172

45
























46






Cl

CO2Me+

MesN NMes

RuPh

PCy3ClCl

1178

1176 1177

then H2 (100 psi)69

CO2Me

Cl

1179

OOHi) 1178


11801181

56

(122)

(123)









47







reported

EtO2C

EtO2C

CO (441 psi)Co2(CO)8 (5 )

CH2Cl2 130 degC68

OEtO2C

EtO2C

PhPh

1182 1183

MeO2C

MeO2C

1184

Co nanoparticles


98

OMeO2C

MeO2CH

H

1185

(124)

(125)









48




dodecylsulfate)

MeO2C

MeO2C

1186

OMeO2C

MeO2C

1187


SDS H2O 100 degC

PhPh

O

HH+ (126)















49


back bonding81

Scheme 124

∆

Me


NaH

CO CH3CN 30 degC

CO2MeMeO2C

168

1188

Me

MeO2C

MeO2C

CO2Me

CO2Me

Me+

1189 1190

OMeO2C

MeO2C

Me H

OMeO2C

MeO2C

Me H

+

1191 1192

11891190 = 371 88

11911192 = 71 87









50








Scheme 125

X

+ LG

R

[Rh(CO)2Cl]2X

R

X

R

X O

R

XR

PKR

X = C(CO2Me)2 NTs O

[5+2]

cycloisom

CO

11931194

1195

1196

1197

1198








51











fashion

Scheme 126

OCOCF3


72

MeO2C

MeO2CCO2MeMeO2C

Me


89

OCOCF3 MeO2C

MeO2C

1200

1202

1104

1199

1201

16 Conclusions



52












palladium catalysis












53






















54











R

R

OCO2Me

Nuc[Rh(CO)2Cl]2

R

R

Nuc

R

OCO2Me

R

Nuc[Rh(CO)2Cl]2

R

Nuc

R

21 22

23 24

(21)

(22)








55









Scheme 21

O

NBn

Rh(I)

RO

NBn

R

XX

MeO2CO

Rh(I)

X O

R

Rh(I)X

R

MeO2CO R

OCu(I)

NBn

[Rh(CO)2Cl]2

[Rh(CO)2Cl]2

[Rh(CO)2Cl]2

25

26


2728




-CO


X


X

56
















R R R R215 216


OCO2Me Nuc






57




Scheme 22

OCO2Me

OCO2Me


THF rtor

218

217

219 220

+

From 217 72 7624 219220From 218 76 5545 219220











58

Scheme 23

OCO2Me

OCO2Me


THF rtor

222

221

223 224

+

From 221 56 955 223224From 222 58 8614 223224










Scheme 24


THF rt227 228

+

From 225 29 946 227228From 226 21 919 227228


OCO2Me

OCO2Me

or

226

225



59











[Rh(CO)2Cl]2 +

220 219

CH2(CO2Me)2 NaH

218


1

2

3

4

DMSO

CH3CN

THF

DMF

62

62

76

73

2575

3664

4555

6931






60


DMF -20 degC88

[Rh(CO)2Cl]2 +

219 220

CH2(CO2Me)2 NaH

217

219220 = 964

(24)









this chapter

OCO2Me

217

CO2MeMeO2C

+

229

MeO2C

MeO2C

MeO2C

MeO2C 231

230

+

NaH[Rh(CO)2Cl]2

DMF -20 degC88

230231 = 937

(25)






61


Scheme 25

OCO2Me


DMF -20 degC

222

OCO2Me

226

orno reaction












112)37




62














21)






OCO2Me

HN



232

233

(26)

63









OCO2Me

HN


96234235 = 11

232

233

234

N

235

N

+(27)





OCOCF3

HN


233

N

CF3O

OH

238

+

237

(28)




64




O

HN



with TBAI 98 5 h

OH

N

233

239

240

(29)













65

Scheme 26

RhCl

OC

OC

ClRh

CO

CO

HN

RhClOC

NHOC


233

240

I-

RhI

OC

OC

IRh

CO

CO

HN

RhIOC

NHOC

RhI

OC

OC

I

slower

Bu4N+I-

Bu4N+

233

242

243

244-I-










66




R2

R1 OCO2Me


NHR1R2 (2 eq)DCE rt

R2

R1 NR2

R3R4 R3

R4R2N

R2R1

+

TBAI (20 mol)



HN

HN

NHBn

Me

OCO2Me

OCO2Me

Me

OCO2Me NMe

Bn

N

Me

N 96

99

89

gt955

gt955

gt955

233

233

250

232

248

251

234

249

252

245 246 247

NHBn

MeN

Me

Bn

85 gt955

250 253 252

OCO2Me






67















PKR

68

Scheme 27

BnNH2

Br

64 BnHN

PhI CuIPd(PPh3)4

Et3N82

BnHNPh

254255 256

OCO2Me

257


DCE rt-reflux86

BnNPh

258

not BnN

Ph

O

259















69








structures like 264

Scheme 28

OH

R1260


O

R1

R2

R5

R4R3

261


O

O

O

O

R2

R3

R4

R5

R2

R3

R4R5

R2

R3

264

262

263

HeckR1 = halide

RCMR1 = alkene

or alkyne

PKRR1 = alkyne

[Rh(CO)2Cl]2





70













71


R2

R1 OCO2Me

R3R4 R2

R1 Nuc

R3R4 R3

R4Nuc

R2R1

+



245 265 266


THF rt

OH

OH

Br

OH

Ph

+

267

270

272

OCO2Me

268

OCO2Me

268

217

OCO2Me

OH

Ph

272

OCO2Me

251

O

269

O

Br271

O

Ph273

O

Ph274

77 gt955

87 7129

lt10 NA

73 gt955

Nuc







72























73


Scheme 29

O

OO

OCO2Me

O

O O

O

OO

catalyst

base

Pd

Rh 275

276

277

278

O

OO

M






Scheme 210

OH OTHP

On-BuLi

HMPA Et2OTHF65

OTHP

HO


OODMAP

O

O O

279

TsOHH2O

O

280 281

282 283

CH2Cl293

EtOAc78

Et2O84 THPO


74







Scheme 211

O

O O

283THPO

conditionsO

O O

284HO

+ HO

282

THPO

HO

285

HO

+










75

Scheme 212

OH

TBSCl imid

OTBS

On-BuLi

BF3Et2O THF

71OTBS

HO


OO

DMAP

O

O O

OTBS

TBAF THFO

O O

OH

O

O O

OCO2Me

pyr CH2Cl291

279 286 287

288 289

290 275

91

ClCO2Me

DMF99

EtOAc99

Et2O84









76


O

O O

OCO2Me275

O

OO

Conditions


1

2

3

4

5

NaH

NaH

KOtBu

KOtBu

KOtBu

THF

DMF

THF

DMF

DMF

rt

rt

rt

rt

0

20

34

51

54

68

278







O

O O

+O

OO

O

O O

OCO2Me275

278 277

278277 = 5545

55(210)



77






Scheme 213

HOOTBS

288

CBr4 PPh3

Et3N CH2Cl278

BrOTBS

291

OMe

OO

NaH n-BuLi

MeO

O O

OTBS

TBAF

MeO

O O

OH

pyr CH2Cl283

MeO

O O

OCO2Me

292 293

294

ClCO2Me

THF69

THF63








78


MeO

O O OO

OMe

+

O

OMe

OKOtBu[Rh(CO)2Cl]2

(10 mol)

DMF -20 degC52

294295 296

295296 = 4357

(211)

MeO2CO




212)21

OPh

CO2Me

O

Pd(OAc)2 PPh3

62

CO2Me

O

297 296

(212)


Reactions





(Eq 213)84

79

NBn

O


ii) 1 N HCl (aq) 71

O

O

298 299

(213)





Scheme 214

NBn

O

i) [Rh(CO)2Cl]2 ∆

ii) 1 N HCl (aq)

O

O

2101 2102

NBn

OH

2100

[Rh(CO)2Cl]2

OCO2Me

R2

R1

R3 R4

245

R2

R1

R4 R3

R2

R1

R4R3







80

NBn

O

298

then HCl53 O

O

299


(214)










O

OH

2103

+ OCO2Me

257

O

O

2104


THFwithout CuI 33

with CuI 64

(215)




moderate yield

81

NBn

OH

2100

+ OCO2Me

257

NBn

O

298


THF55

(216)









Scheme 215

NBn

OH

2100

OCO2Me257

NBn

O

298


THF or toluenert

rt-150 degCX

then HClO

O

299





reaction sequences

82








CO2MeMeO2C

MeO2CO

MeO2C CO2Me

2106

2105

CH3CN 80 degC75


(217)





83

Scheme 216

CO2MeMeO2C+

OCO2Me

OCO2Me2107

2108

CO2MeMeO2C

MeO2CO

[Rh(CO)2Cl]2


2106

2105









84


CO2MeMeO2C+

OCO2Me

OCO2Me


solvent rt-reflux

MeO2C CO2Me

equiv 2107

21072108

2106

MeO2CCO2Me

CO2MeMeO2C

+

2109


1

2

3

4

5

6

25

25

25

25

15

15

1

1

1

1

1

1

2

2

2

2

1

1

THF

dioxane

toluene

DMF

THF

dioxane

15

23

20

0

20

32

--

24

7

32

17

16







85

CO2MeMeO2C+

OAc

OCO2Me


(10 mol)

dioxane rt-reflux45

21062109 = 21

MeO2C CO2Me

21072110

2106 MeO2CCO2Me

CO2MeMeO2C

+

2109

15equiv

1equiv

(218)


















86

MeO2C CO2Me+

R


MeO2C

MeO2C

R

1

23

4

5

67

8

2111 2112

2113

(219)







Scheme 217

+

R

LG

R LG

or

or

[Rh(CO)2Cl]2

OMeO2C

R

4

2115

2114

2119R LG2116

R

R

MeO2C CO2Me

2111

2

MeO2C

OMeO2C

2117

R

2

MeO2C

OMeO2C

R

42118

MeO2C

[Rh(CO)2Cl]2

[Rh(CO)2Cl]2






87




Scheme 218

CO2MeMeO2C

Ph

OCO2Me


91

PhMeO2C

MeO2C


THF reflux99

MeO2C

MeO2C

Ph

O

CO (1 atm)

21212120

2122

257




2121

CO2MeMeO2C

PhNaH CO (1 atm)


THF rt - reflux

PhMeO2C

MeO2C

2120

OCO2Me

257

not 2122 (220)






88









inhibited the PKR

O

Ph

MeO2C

MeO2C

2122


NaOMe or NaOAcX

MeO2C

MeO2C

2121

(221)











89











promote the PKR

CO2MeMeO2C

Ph

+ OCO2Me


O

Ph

MeO2C

MeO2C

2120

257

2122



(222)








90



223)

CO2MeMeO2C

Ph

+ LGCO NaH

[Rh(CO)2Cl]2O

Ph

MeO2C

MeO2C2120

2123

2122



rt - reflux(223)











Scheme 219

91

MeO2CCO2Me

OCOCF3 OMeO2C

MeO2C+

R

CO [Rh(CO)2Cl]2

(10 mol )

R

azeotroped wtoluene

2126

2127 R=H = 732122 R=Ph = 682128 R=Me = 67

2124 R = H2120 R = Ph2125 R = Me










Scheme 220

CO2MeMeO2C

PhCO (1-40 atm)


Ph

OMeO2C

MeO2C

Et

X


2120 2130

OCOCF3

2129





92



reagent

Scheme 221

2120

+OCOCF3

2129

CO NaH [Rh(CO)2Cl]2

(10 mol)THF

MeO2C

MeO2C

2131

MeO2C CO2Me

Ph

2 eq 1 eq

1 eq 2 eq

Ph

Isolated Yield96

24












93

O

Ph

MeO2C

MeO2C2122

MeO2C

MeO2C

2121

Ph

CO [Rh(CO)2Cl]2


O

Ph

MeO2C

MeO2C

2122

MeO2C

MeO2C

2121

Ph

+51 24 h

2126

(224)

(225)

CO [Rh(CO)2Cl]2

(10 mol) THF reflux

2120

MeO2C CO2Me

Ph








[Rh(CO)2Cl]2 +O O

BaCO3O

ORh

CO

CO

[Rh(CO)2Cl]2 +

O

O O

O

Base OMeO

MeOO

RhCO

CO

R R

2132 2133

21342135

(226)

(227)




94











Scheme 222

O

OO

O

2138

THF rt-reflux

PhOH


2) BH3Me2NH


2136

O O

O O

Ph2137

O

OO

O Ph

O

2139

Ph

not observed


OCOCF3

2129




95





Scheme 223

CO2MeMeO2C

Ph

OCOCF3 Ph

OMeO2C

MeO2C

EtH

21202130


2129

Ph

OEtO2C

EtO2C

MeH

2140

24 Conclusions










96











97


31 Introduction













linkage


N

NMe

Me

OH

O

H

H

H

H

macroline (31)

NH

NHO

H

H H

HOH

sarpagine (32)

421

16

4 21

98

311 Alstonerine







ring


N

MeN

Me

O

O

H

H

H

H

33

A BC D

E










99



Scheme 31

NH

N

H

H H

HOH

37

NH

NH

34 Strictosidine

O

MeO2C

OGlu

HNH

N

35

OH

MeO2CH

H H

NH

N

H

H H

CHO

CO2Me

36








100

Scheme 32

NH

NH

34 Strictosidine

O

MeO2C

OGlu

HH N

H

NH

38

OHCHO

MeO2CH

H

NH

NH CHO

H

H H

CHOCO2Me

39

NH

NH CHO

H

H H

CHOCO2Me

310

NH

N

H

H H

CHO

CO2Me

36










Tamelen

101

Scheme 33

NH

N

311

OHC

H

CO2H

NH

N

312

OHC

H

DCC PTSA

dioxane

NH

N

H

H H

313

CHO

NMe

N

H H

ajmaline (314)

OHHO

H

H

NMe

N

CN

315

H

TBSO

BF3Et2O

NMe

N

316

H

TBSO

NMe

N

H

H H

317

HCHO

NMe

N

H

H H


HCHO

KOHMeOH

56






102






Scheme 34

N

MeN

Me

OH

O

H

H

H

H

31

N

MeN

Me

O

O

H

H

H

H

33

NH

N

H

H H

HOH

37

NH

N

H

H H

HOTBS

319

TBS-Cl imid

DMF

NH

N

H

H H

HOTBS

320

Oi) Me2SO4 K2CO3

ii) TBAF






103






norsuaveoline (322)

Scheme 35

H

NMe

BnN

O

Dieckmann

Pictet-SpenglerH

323

NH

NH2

CO2H

324

NMe

MeN

OH

H

H

H

alstonerine (33)

O

NMe

MeN

talcarpine (321)

H

H

H

H

OMe

CHO

NH

HN

H

H

N

Et

norsuaveoline (322)







104















105

Scheme 36

NH

NH2

CO2H

324

1) NaNH3 MeI


Me

NH2

CO2Me

325

PhCHO MeOH

NaBH4 -5 degC88 N

Me

NHBn

CO2Me

326

1) C6H6dioxane ∆

HO2C

O

CO2H

2) HClMeOH ∆

80NMe

NBn

CO2Me

CO2Me

327

NaH MeOH

PhMe ∆

92

NMe

BnN

328

O

CO2Me

H

H

AcOHHClH2O

∆ 91NMe

BnN

323

OH

H

3

5







106

Scheme 37

N NNMe

H

CO2Me

CO2Me

MeNPh

H

CO2Me

CO2Me

Ph

HNNMe

H

CO2Me

CO2MePh

HNNMe

H

CO2Me

Ph

CO2Me

NMe

NBn

CO2Me

CO2Me

trans-327

cis-327

329 330

HCl

trans-327









107





reaction vessels

Scheme 38


NH

NH2

CO2Me

324


CH2Cl2 rt 48h

83 NH

NBn

CO2Me

CO2Me

331

NMe

N

323 gt98 ee

OH

H Ph85NMe

NBn

CO2Me

CO2Me

327

NaH MeI

DMF95









108










as the acid source

Scheme 39

NH

NHBn

CO2Me

332

TFA CH2Cl2 92

MeO CO2Me

OMe 336

NH

NBn

CO2Me

CO2Me

331

HO2C CO2H

O 333

PhHdioxane

pTsOH ∆ 86N

NBn

CO2Me

334 O

+

N

NBn

CO2Me

335 O

41 transcis

109




ketone 338

Scheme 310

NH

NBn

CO2Me

CO2Me

331

N

NBn

CO2Me

334 O

NaOMe

NH

BnN

337

O

CO2Me

H

H NH

BnN

338

OH

H

AcOHHClH2O

∆ 91









110



Scheme 311

H

NMe

BnN

O

H

323

NMe

MeN

321

H

H

H

H

OMe

CHO

NMe

BnN

339

H

H

H

H

OOMe

conjugate addn

NMe

BnN

340

H

H

H

H Et

NMe

BnN

341

H

H

CHO

HO R


acetal formation

oxy-cope









111

Scheme 312

NMe

BnN

323

OH

H


2) LiClO4 dioxane

∆ 90 NMe

BnN

341

H

H

CHO

Et Et

Br 342

Mg 90

NMe

BnN

343

H

H

HO

Et

Et

+

NMe

BnN

344

H

H

Et

O Et

H

H

NMe

BnN

345

H

H

Et

O Et

H

H+




313)115116

Scheme 313

NMe

BnN

343

H

H

HO

Et

Et

NMe

BnN

344

H

H

Et

O Et

H

H

NMe

BnN

345

H

H

Et

O Et

H

H+

KH18-crown-6

cumene150 degC 88





112











Scheme 314

NMe

BnN

341

H

H

CHO

NMe

BnN

347

H

H

HO

Et

Li-biphenylBaI2 THF

Et Br

346

90

NMe

BnN

348

H

H

Et

OH

H

NMe

BnN

349

H

H

Et

OH

H+

KH18-crown-6

dioxane100 degC 85

MeOK

15 20

1615 20

16



113




Scheme 315

NMe

BnN

349

H

H

Et

OH

H

NaBH4 MeOH

96NMe

BnN

350

H

H

Et

HOH

H


2) NaIO4 MeOH 78

NMe

BnN

351

H

H

H

H

OOH

Et

pTsOH PhH

95

NMe

BnN

352

H

H

H

H

O

Et

N

O

O

SePh

pTsOH MeOH

NMe

BnN

353

H

H

H

H

O

EtSePh

OMe

NaIO4

H2OTHFMeOH90

NMe

BnN

339

H

H

H

H

OOMe

NMe

BnN

354

H

H

H

H

OOMe

+




114




understood117

Scheme 316

NMe

BnN

339

H

H

H

H

OOMe

90NMe

BnN

355

H

H

H

H

OMe

CHO

NMe

BnN

356

H

H

H

H

OMe

CHO+

K2CO3 EtOH 85

01 torr 100 degC 75

H2SO4







115

Scheme 317

NMe

BnN

355

H

H

H

H

OMe

CHO

NMe

BnN

356

H

H

H

H

OMe

CHO

PdC (10 mol)

H2 EtOH92

NMe

MeN

talcarpine (321)

H

H

H

H

OMe

CHO

H2PdC (xs)

MeOH (15 eq)

90

NMe

N

talpinine (357)

H

OMe

H

HO H

H







syntheses







116




(322)

Scheme 318

NH

BnN

358

H

H

Et

OH

H

NH

BnN

338

H

H

O

NH

BnN

359

H

H

Et

CHOH

H

O O

pTsOHacetone

95NH

BnN

360

H

H

CHO

Et

CHOH

H

NH2OHHCl

EtOH ∆

88NH

RN

H

H

N

Et

361 R = Bn322 R = H

H2 PdC92

1) HO(CH2)2OH pTsOH

PhH ∆ 90







117















118

Scheme 319

NH

BnN

338

OH

H

5 PdC H2HCl EtOH

rt 5 H94 N

H

NH

362

OH

H

BrI

K2CO3 THF ∆

87

NH

N

363

OH

HI


DMF-H2O 65 degC80

NH

N

H

H H

364

O

NH

N

H

H H

vellosimine (365)

HCHO






macroline alkaloids







119











31)105

Scheme 320

NMe

N

CN

367

H

NMe

N

H

H H


HCHO

Mannich reaction

NH

NHCl

CO2H

368OTBS

vinylogous Mannich






120



374

Scheme 321

NH

NHCl

CO2H

368

OMe

TBSO 369

1)


H

NH

CO2tBu

370

CO2Mediketene

DMAP PhMe

KOtBu 86

NH

N

CO2tBu

371

H

OO

MeO2C

1) NaBH4 95


H

N

CO2tBu

372

H

O

MeO2C


then NaBH490

NMe

N

CO2tBu

373

H

MeO2C

TFA

PhSMe90

NMe

N

CO2H

374

H

MeO2C






121



Scheme 322

NMe

N

CO2H

374

H

MeO2C

1) EDCI NH4OH 86

2) TFAA py 90NMe

N

CN

375

H

MeO2C

1) LiBH4 THF 98

2) DMP 83

NMe

N

CN

376

H

OHC

NaH TBS-Cl

NMe

N

CN

367

H

TBSO

BF3Et2O

NMe

N

377

H

TBSO

NMe

N

H

H H

378

HCHO

NMe

N

H

H H


HCHO

KOHMeOH

56







122











Scheme 323

NH

NHCl

CO2H

i)Et3N CbzCl

CH2Cl2

ii) MeOH Et3N87 N

H

NCbz

CO2Me

OMe

TMS

BF3Et2O

CH2Cl281

51 cistrans

NH

NCbz

CO2MeDIBAL-H

toluene -78 degC


60NH

NCbz

368 379

380 381




123



Scheme 324

NH

NCbz

381

RuPh

Cy3P

PCy3Cl

Cl

CH2Cl2 rt97

NH

CbzN

383


2) NaIO4 aq THF 54

NH

CbzN

384

CHO

382

H

H H

H
















124







enantiocontrol

Scheme 325

NMe

OH1) BuLi

2) I2 NMe

OH

I DMP

57 (3 steps) NMe

CHO

I

TMSO

OMe

388

385 386 387

Zn(OTf)2 BnNH270 N

Me

I

389

N

O

Bn


P(tBu)3 CH3CN ∆

85NMe

N

390

H

H Ph

O








125













126

Scheme 326

NH

NH2

CO2H

324

1) LAH 98

2) TsCl py 78 NH

NHTs

391

OTs

1) KCN 86

2) NaNH3(l) THF 88

NH

NH2

392

CN

OHCOTBS

393


then CH2Cl2 TFA80

NH

394

NH

CN



NMe

395

NBn

CN

CHO

NMe

397

NBn

CN

(EtO)2PO

Et

O

OEt

396

NaH 65

Et

CO2Et

LiNEt2 THF

-78 degC 99 NMe

N

398

H

H Ph

CO2EtCN

Et

HH

NMe

NH

399

H

H

OHO

Et

H

H

1) LiBH42) pTSA 88

3) DIBAL-H 504) H2Pd-C 100





(3104)

127

Scheme 327

NMe

395

NBn

CN

CHO

(EtO)2PO

Et

CN

3100

NaH 83 NMe

3102

NBn

CN

Et

CN

KOtBu THF

67

NMe

N

3103

H

H Ph

CNCN

Et

HH

NMe

NH

H

H

N

Et

3104

















128











129

Scheme 328

NH

NHBoc

CO2Me

3105

MeNC nBuLi

82NH

NHBoc

3106

O

N

1) TFA 98


NH

NH

3107

O

N

EtO2C

O 1) POCl3

2) Na2CO3 50

NH

3108

NH

CO2Et

O

N

1) H2Pd(OH)2-C 84

2) Boc2O 87

NH

3109

NBoc

CO2Et

O

N

NMe

NH

H

H

N

Et

3104



4) MeI NaH

5) TFA 80









130










alkaloids111

131

Scheme 329

O

O OBnNH2

H2O

NBn

OH

HO

31103111

+

BnN

HO OH

3112

1) TFAA

2) NaOH 95

BnN

HO OH

3112


50

BnN

HO OTBS

3113

1) H2 PdC

2) K2CO3 PhCOCl 85

BzN

HO OTBS

3114


2) HF CH3CN 95

BzN

OH

3115

1) H2NN(Me)Ph

MeOH HCl ∆

2) LiAlH4 THF 95

NMe

BnN

3116

OHH

H


73NMe

BnN

(plusmn)-323

OH

H








132










Scheme 330

H

NMe

BnN

O

H

H

HNMe

MeN

O

O

H

33



323









133




Scheme 331

NMe

BnN

323

OH

H

1) MeOTf

2) H2PdC80 N

Me

MeN

3118

OH

H



NMe

MeN

3119

H

H

CHO

NMe

MeN

3120

H

H

OH

LiAlH4

Et2O -20 degC90

Me

O

Et3N dioxane90

NMe

MeN

3122

H

H

O

PhH 145 degC

sealed tube65 N

Me

MeN

3123

H

H

CHO

O OH

3121







134

Scheme 332

NMe

MeN

3123

H

H

CHO

OH

NaBH4

EtOH86 N

Me

MeN

3124

H

H

OHH

HO

i) 9-BBNTHF rt 20 h


NMe

MeN

3125

H

H

OHH

HOHO

TsCl pyr rt


NMe

MeN

3126

H

H

H

O

OH

H

H

(COCl)2 DMSO CH2Cl2


MeN

33 51

H

H

H

O

O

H

NMe

MeN

3127 30

H

H

H

O

O

H

+









135

Scheme 333

MeN O

MeN

H HH

H

OH

MeH

N

MeN

Me

O

OH

H

H

H

H

3126

H

3126

excess DMSO(COCl)2

MeN O

MeN

H HH

H

O

MeH

3128

SH MeN O

MeN

H HH

H

OH

MeH

3129

tautomerization

MeN O

MeN

H HH

H

OH

Me

3130

DMSO(COCl)2

MeN O

MeN

H HH

H

O

Me

33








136






Scheme 334

NMe

BnN

323

OH

H NMe

N

H

H H


HCHO

4 steps








137

Scheme 335

NMe

N

H

H H

366

HCHO

NaBH4

MeOH 0 degC90 N

Me

N

H

H H

3131

H


90

NMe

N

H

H H

3132

H


NaOH H2O2 rt


85

NMe

N

H

H H

3133

H

OTIPS

H

OH

DMP CH2Cl2

82NMe

N

H

H H

3134

H

OTIPS

H

O

MeI THF

KOtBu EtOH THF ∆

90

NMe

MeN

3135

H

H

H

OTIPS

O

H

NMe

MeN

33

H

H

H

O

O

H


60




323

138










Scheme 336

NMe

CHO


79

NMe

NNs

Ph3POEt

OCO2EtBr

CHCl3 ∆

Ph3POEt

O

EtO2C

Br

AcCl Et3NCH2Cl2

73

CO2Et

CO2Et

3138

3140

3136

3137

3139

+

PBu3 (30)

CH2Cl2 rt73 31 drN

Me3141

NCO2Et

CO2EtNs

H




139





Scheme 337

NMe

3141

NCO2Et

CO2EtNs

H

HCl EtOAc

90 NMe

NsN

3142

H

H

CO2EtO

PhSH K2CO3

DMF99

NMe

HN

3143

H

H

CO2EtO

HCHO HCO2H ∆

99NMe

MeN

3144

H

H

CO2EtO

NaBH3CN ZnI2

DCE ∆74

NMe

MeN

3145

H

H

CO2Et

BH2CN

EtOH ∆

98

NMe

MeN

3146

H

H

CO2Et

NMe

MeN

(plusmn)-3120

H

H

OH

DIBAL-H

tol -78 degC92






140












Scheme 338

NMe

TsN

3152

H

H

SO2Ph

CHO

PhO2S SO2Ph

NMe

NTs


55-64NMe

NHTs

PhO2S

KMnO4Bu4NBr

CH2Cl261 N

Me

NHTs

PhO2SOH

OH



315031493147

NMe

3151

NTs

PhO2S

CHO

3148

141






Scheme 339

NMe

TsN

3152

H

H

SO2Ph

CHO


95 NMe

TsN

3153

H

H

OTBDPS


-78 degC - rt36 N

Me

TsN

3154

H

H

OOTBDPS

H




optimized

36 Conclusions





142


















143


H

NMe

BnN

Pictet-SpenglerH

H

NMe

BnN

HeckH

O

H

NMe

BnN

H

FischerIndole

O

NMe

NsN

H

H



R

390Kuethe

323Rassat

3142Kwon

144



Alstonerine

41 Introduction

















145

Scheme 41

H

NMe

BnN

O

Diekmann

Pictet-SpenglerH

H

HNMe

MeN

O

O

H

41



H

HNMe

MeN

O

O

H

41

Wacker


42

E

E

A B

A B

C D

C D

11 steps

10 steps













146



Scheme 42

H

HNMe

MeN

O

O

H

41

H

H

HNMe

RN

OH

43

H

O

H

HNMe

RN

44

H

O

NMe

NR

45

Acylation

Baeyer-Villiger

PKR








A (49)134

147

Scheme 43

MeN

H2N

O

O

46

RN

47

PGO

O

RN

PGO

48

410

N

N

OH

O

O

Me

MeO

O

O

MeO

Me

Me

HH

H

O Me

O

Me

N

N

R411

N

NR

R

R

O

49










148


421 Introduction













derivative 415136

149

Scheme 44

MeN

H2N

O

O

46

MeN

H2N

412

HO

O

HO

BocN

413

TBSO

O

BocN

TBSO

414

BocN

TBSO

CO2Me

415

O









150

Scheme 45

HN

HO

CO2H SO2Cl

MeOH99

H2+Cl-

N

HO

CO2Me N

HO

CO2Me

Boc

dioxane70

TBS-Climidazole

N

TBSO

CO2Me

Boc RuO2H2O (20)

NaIO4N

TBSO

CO2Me

Boc

O

416 417 418

419 415

Boc2OiPr2NEtDMAP

DMF96

EtOAc96












151

Scheme 46

N

TBSO

CO2Me

Boc

O N

TBSO

CO2Me

Boc

415

R



Et2O toluene

N

TBSO

Boc1 DIBAL-H CH2Cl2


R







152

Scheme 47

N

TBSO

Boc

414

TBAF THF N

HO

Boc

N

HO

Boc

+

Ac2O Et3NCH2Cl2 97

92

N

AcO

Boc

422 423

424





153








complex 425

154

Scheme 48

N

TBSO

Boc

BocN

TBSO

O

426414

Co2(CO)8 N

TBSO

Boc

425

Co2(CO)6

conditions


THFX






Scheme 49

N

TBSO

Boc

BocN

TBSO

O

429422

Co2(CO)8 N

TBSO

Boc

428

Co2(CO)6

conditions


THF






155







N

TBSO

Boc

HCl or ZnBr2 N

TBSO

O O

414 430

(41)





156

Scheme 410

N

TBSO

Boc HN

TBSO

HN

TBSO

+


414 431 432

N

TBSO

K2CO3 MeIacetone

55

Me

433

88431432 = 13






attempted

Scheme 411

N

TBSO

Me

MeN

TBSO

O

435433

Co2(CO)8 N

TBSO

Me

434

Co2(CO)6

conditions


THF

157










Scheme 412

N OBn

O

H

H

Co

Co(CO)3

(CO)2

N OBn

O

H

Co Co

(CO)3 (CO)3

436 437

TBSO TBSO

N

TBSO

Boc

422

Co2(CO)8

N

TBSO

Boc

428

Co2(CO)6

158










Scheme 413

HNMe

RN

O

H

NMe

NR

44 45

PKR

H

PKR

N

R

439

m nRN

O

438

m n




159





Scheme 414

N

X

R

O

A13-Strain N

X

R

O

m

m

n

n

PKR N R

O

X n

m

440 X = H2 O 441 442

O

431 Initial Studies









160

Scheme 415

N

OMe

R1

MgBrn



CbzN

O

R1

n

MgBr

R2

MeLi CuCN (111)

THF -78 degC73-81

CbzN

O

R1

R2

443 444 445

n












Scheme 416

N

OMe

TMSTHF

then Cbz-Cl 95

N

O

Cbz

N

O

CbzTMS


TMS R

443 446447 R=TMS

448 R=H

K2CO3MeOH75

EtMgBr

161










N

O

Cbz

N

O

Cbz

SnBu3


96

TMS

446 448 gt191 dr

(42)








piperidine 448

162

Scheme 417

NO

TMS

O

O

N

H

TMS

OO

O

Nuc

Nuc

449 450










Scheme 418

N

O

Cbz

448

Co2(CO)8

DMSO

THF 65 degC89

NCbz

OH

O

451

H

H

N

O

Cbz HH

451

H

O

3



163
















164




Scheme 419

Co(CO)2

(CO)3Co

H

Co(CO)2

Co(CO)3

H(CO)3Co Co(CO)3

+

452

cis-453

trans-454













165

Scheme 420

N OBn

O

H

H

NCbz

Co2(CO)8

Co

Co

N OBn

O

H

H

Co

N OBn

O

H

H

Co Co

(CO)3 (CO)3

N OBn

O

H

H

O

O

O

O

O

CbzNO

H

H

448

455 456

457 458

451 459

O

HCbzNO

H

HO

H

CoCo

Co

(CO)3(CO)2

(CO)3(CO)2

(CO)3(CO)3




166













Scheme 421

N

OMe

443

TMSBr


77

N

O

Cbz

460

TMS

CuCN MeLi (111)

MgBr

TBAFH2OTHF 69

N

O

Cbz

R


461 R = TMS

462 R = H

6





167













Scheme 422

N

O

Cbz

462

Co2(CO)8

DMSO

THF 65 degC91

N

O

O

CbzH HH

463

N OBn

O

HO

463

H

O

1

2






168






467

169

Scheme 423

NCbz

Co2(CO)8

N OBn

O

H

O

O

CbzNO

H

H

CbzNO

H

H

462

465

468 463

H

Co

N OBn

O

HO

464

Co

(CO)3(CO)3

HCo Co

(CO)3 (CO)3

H HO O

H

N OBn

O

HO

466

Co(CO)2(Co)3Co

N OBn

O

HO

467

H

(CO)2Co Co(CO)3





170












171

Scheme 424

N

O

CbzTMS

446

CuCN MeLi (111)

MgBr

TBAFH2O THF 53

N

O

Cbz

Co2(CO)8

DMSO

THF 65 degC33 31 dr


R

469 R = TMS

470 R = H

N

O

CbzH H

471

N OBn

O

HO

471

H1

2

O

H

O

6












172



Scheme 425

Cbz

N

O

448

H2 PdCor

TMSIX

HN

O

472









173

Scheme 426

Alloc

Ts Ts

N

OMe

MgBrTMS

THF then Alloc-Cl77

N

O443

TMS HN

O

TMS

dimethyl malonate

Pd(PPh3)4 THF93

nBuLi THF -78 degC

then TsCl50

N

O

R

475 R = TMS

476 R = H

K2CO3MeOH48

TMS


N

O

473 474

477






Scheme 427

Bz BzHN

O

TMS

474

nBuLi THF -78 degC

then BzCl98

N

O

TMSSnBu3


91 gt191 dr

N

O

478 479




174















advantageous145

Scheme 428

N

O

R Co2(CO)8

DMSO

THF 65 degCN

O

R HH

H

O

477 R = Ts479 R = Bz

480 R = Ts (61)481 R = Bz (94)

7

175














Scheme 429

CbzN

O

448

L-Selectride

THF -78 degC99

CbzN

OH

482

TBS-Climidazole

DMF81

CbzN

OTBS

483

4 4






176







Scheme 430

N

Cbz

448

O


BF3Et2O

HSCH2CH2SH

CH2Cl284

N

Cbz

485

S S

N

Cbz

486

Raney NiX

X

N

Cbz

484

O

S


XAIBN Bu3SnH








177



Scheme 431

HNO O NaBH4 HCl

EtOH

HNO OEt

HNO SO2Ph

PhSO2ClHCO2H

CH2Cl260

nBuLi

TMS

THF71

487 488 489

HNO

TMSnBuLi

then Cbz-ClTHF81

NO

TMSCbz

490 491

1 DIBAL-H THF

2 Allyl-TMS BF3

Et2O 57

N

RCbz

492 R = TMS

486 R = H

TBAF THF86











178

Scheme 432

N

R

Cbz Co2(CO)8

DMSO

THF 65 degCN

R

Cbz HH

H

O

483 R = OTBS486 R = H

493 R = OTBS (69)494 R = H (74 41 dr)

117
















179


diastereomer

180

Scheme 433

N OBn

O

H

H

CbzN

H

HO

HCbzN

H

HO

H

H

R

(CO)2Co(CO)3Co

N OBn

O

H

H

R

H

(CO)2Co

Co(CO)3

R R

NCbz

Co2(CO)8

N OBn

O

HH

Co Co

(CO)3 (CO)3

N OBn

O

H

H

CoCo

(CO)3 (CO)3

H

R R

H

R

483 R = OTBS486 R = H

4

495 R = OTBS496 R = H

497 R = OTBS498 R = H

499 R = OTBS4100 R = H

4101 R = OTBS4102 R = H

493 R = OTBS494 R = H

4103 R = OTBS4104 R = H

181
















441 Retrosynthesis








182





Scheme 434

H

H

H

HNMe

MeN

O

O

H

H

NH

CbzN

O

H

NMe

CbzN

O

H

O

NH

NCbz

NH

NH2

CO2H

Baeyer-Villiger

414105

4106 4107 4108

PKR

H

H










183




Scheme 435

NH

NH2

CO2H


60 NH

NHCl

CO2H

i)Et3N CbzCl

CH2Cl2

ii) MeOH Et3N87 N

H

NCbz

CO2Me

OMe

TMS

BF3Et2O

CH2Cl281

51 cistrans

NH

NCbz

CO2MeDIBAL-H

toluene -78 degC


60NH

NCbz

4108 4109 4110

4111 4107










184

Scheme 436

N

NCbz

CO2Me

N

NCbz

R R

4111 R = H4112 R = Ts4114 R = Boc

4107 R = H4113 R = Ts4115 R = Boc




20-60







N

NCbz

CO2Me

Boc

N

NCbz

CHO

Boc


rapid decomp at rt

4114 4116

(43)







185




NH

NCbz

CO2MeDIBAL-H

toluene -78 degC


-78 degC -rt60

NH

NCbz

3111 3107

(44)






Scheme 437

NH

NCbz

NH

CbzN

O

H

Co2(CO)8DMSO (6 eq)

THF 65 degC92 H

H

NBoc

CbzN

O

H

H

HBoc2ODMAP

CH3CN 99

4117

4107 4106

186








NBoc

CbzN

O

H

H

H

4117

15







187

Scheme 438

NH

CbzN

O

H

NH

NCbz

Co2(CO)8

4107

4118

4106 4122

H

H

NH

CbzN

O

H

H

H

CoCbzN

BocN

H

H

H

Co

(CO)3

(CO)3

CbzN

BocN

H

H

H

Co

Co (CO)3

(CO)3

CoCbzN

BocN

H

H

H

Co

(CO)3

(CO)3

CbzN

BocN

H

H

HCo

Co(CO)3

(CO)3

4119

41204121




188






Scheme 439

NH

CbzN

O

4106

H

H

H

NMe

CbzN

O

4123

H

H

H

NaH MeI DMF91

Baeyer-Villiger

X

NMe

CbzN

4105

H

H

H

OO









189



Scheme 440

NBoc

CbzN

O

4117

NBoc

CbzN

O

4125

O

MCPBACH2Cl2 60

orCF3COOOH

Na2HPO4CH2Cl2 99

H2O2NaOH

THFMeOH

H

H

H

H

H

H

NBoc

CbzN

4124

H

H

H

OO

O

78








190

NBoc

CbzN

4124

H

H

H

OO

O

deoxygenationX

NBoc

CbzN

4105

H

H

H

OO

(45)








Scheme 441

HNR

CbzN

O

H

OH

4127

H

HNR

CbzN

CO2RCHO

H

H

4128

H

HNH

CbzN

O

H

4106

H

HNR

CbzN

OSiR3

H

4129

H H




191









4130156

192


NBoc

CbzN

OH

H

Hconditions

NBoc

CbzN

OSiEt3H

H

H





25

41304117



Entry

-------

-------1

2

3

5

4

NBoc

CbzN

OH

H

H

4131

+

H H









193




Scheme 442

Me2Si

O

Me2Si

2

Pt


NBoc

CbzN

OH

H

H

NBoc

CbzN

OTIPSH

H

H

4132

4117

H

NBoc

CbzN

OH

H

H

4131

H

NBoc

CbzN

OTESH

H

H

4130

HMe2Si

O

Me2Si

2

Pt

Et3SiH Toluenert 99

41304131 = 41

+







nitrogen atom

194

Scheme 443

NBoc

CbzN

OTIPSH

H

TBAF3H2O

THF 66

NBoc

CbzN

OH

H

NH

HN

OHH

H



H

H

H

H

H

H

4133

4132 4131










195

NBoc

CbzN

OTIPSH

H

H

H

ozonolysis

NBoc

CbzN

CHOH

H

CO2TIPS

4132 4134

X (46)






Scheme 444

HNR

CbzN

OSiR3

H

4136

H H

HNR

CbzN

CO2RCHO

H

H

4128

H

HNR

CbzN

O

H

4135

H HHO






196

HNBoc

CbzN

OTIPS

H

4132

H H

HNBoc

CbzN

O

H

4137

H HHO

mCPBA

CH2Cl20-20

(47)








Scheme 445

O

O

OOCOR

OTIPS mCPBAOTIPS

O

OTIPS

OH

H+

4138 4139 4140

OTIPS

OH

4141

RCO2-

OTIPS

4142

O

ROCOR

4143





197















198


NBoc

CbzN conditions

OTIPSH

H

NBoc

CbzN

OH

H

HO

Conditions

4132 4137

Entry Yield 4137

1 OsO4 (10) NMO (22 eq) THFH2O 23






H

H

H

H







199

Scheme 446

NBoc

CbzN

OH

H

HO

4137

H

H



4144

NBoc

CbzN

OH

CO2Me

H

H

HNBoc

CbzN

O

H

OH

4145

H

pTsOH CH2Cl2

99












200

Scheme 447

H

H

4145

NBoc

CbzN

OTIPS

H


THFH2O 51

NBoc

CbzN

CHO

CO2H

NBoc

CbzNH

H OO

NaBH4 MeOH


H

H

H

H

4132 4146









201

Scheme 448

LiAlH4

THF reflux 99

NaHthen MeI

DMF 88

NBoc

CbzNH

H OO

H

H

4145

NBoc

CbzNH

H OH

H

4147


2 MsCl Et3N THF 67

NH

MeNH

H OH

H

4148

NMe

MeNH

H OH

H

4149






obtained

202

Scheme 449

NMe

MeNH

H O


NMe

MeNH

H O

O

+

NMe

MeNH

H O

O

O



H

H

H

H

H

H

4149

41

4150







recovered

NMe

MeNH

H OH

H

4149

NMe

MeNH

H O

O

H

H

41

NMe2

O

POCl3 or Tf2OX (48)



203




Scheme 450

NBoc

CbzNH

H O


NBoc

CbzNH

H O

O



H

H H

H

4147 4152







204

Scheme 451

NMe

MeNH

H OH

H

4149

NMe

MeNH

H O

Cl3CO

H

H

4151

X

[H]

NMe

MeNH

H O

O

H

H

41

Cl3C

O

Cl














natural products169

205

Scheme 452

NBoc

CbzNH

H OH

H

4147

NBoc

CbzNH

H O

Cl3CO

H

H

4153

NBoc

CbzNH

H O

O

H

H

4152

ClCO2CCl3

pyridine 65 degC

Zn AcOH

75 2 steps










NBoc

CbzNH

H O

O

H

H

4152

NH

HNH

H O

O

H

H

4154

TMS-I

CH3CN78

(49)

206






Scheme 453

NMe

MeNH

H O

O

H

H

41

NMe

HNH

H O

O

H

H

4155

NH

MeNH

H O

O

H

H

4156

NMe

MeNH

H O

O

H

H

4157

NaH then MeI

DMF

side products

NH

HNH

H O

O

H

H

4154







EtOH))128

207

NMe

MeNH

H O

O

H

H

41

NH

HNH

H O

O

H

H

4154

MeI (2 eq)THF


72

(410)












208

Scheme 454

NH

CbzN

O

H

Co2(CO)8DMSO

THF 65 degC92 H

H

4106

NBoc

CbzN

O

H

H

HBoc2ODMAP

CH3CN99

4117

Me2Si

O

Me2Si

2

Pt


NBoc

CbzN

OTIPSH

H

H

4132

H H

H

4145

1 OsO4 (10) NaIO4 (4 eq)

THFH2O 51

NBoc

CbzNH

H OO

2 NaBH4 MeOH


NBoc

CbzNH

H OH

H

4147


2 MsCl Et3N THF 67

TMS-I

CH3CN78

NBoc

CbzNH

H O

O

H

H

4152



NH

HNH

H O

O

H

H

4154

NMe

MeNH

H O

O

H

H

41

MeI THF

then NaH MeI72

NH

NH2

CO2H


60 NH

NHCl

CO2H

i)Et3N CbzCl

CH2Cl2

ii) MeOH Et3N87 N

H

NCbz

CO2Me

OMe

TMS

BF3Et2O

CH2Cl281

51 cistrans

NH

NCbz

CO2Me

NH

NCbz

4108 4109 4110

4111 4107



-78 degC -rt60

209

45 Conclusions























210














211


51 General



















212






52 Compounds

6

51 23

4

78

O

O

O

217












213

NMR (75 MHz) δ 1549 1354 1277 752 541 249 201 128 IR (neat) 2964 2876


requires 1570865] 157 (base) 113





(C2) 541 (C8) 249 (C5) 201 (C1) 128 (C6)

O O

O

1

2

34

56

78

218









214





[C8H13O3 (M+1) requires 1570865]





(C8) 273 (C5) 175 (C1) 93 (C6)

6

6

5 61 2

3

4

78

O

O

O

225







215






NMR (75 MHz) δ 1550 1446 1237 757 543 327 291 205




1446 (C4) 1237 (C3) 757 (C2) 543 (C8) 327 (C5) 291 (C6) 205 (C1)

6

5

6

O O

O

1

2

34 6

78

226







216






1313 1260 865 543 342 256 177




(C7) 1313 (C2) 1260 (C3) 865 (C4) 543 (C8) 342 (C5) 256 (C6) 177 (C1)

6

89

12

34

5

7

O O

OO

219







217







75 3 H) 13C NMR (100 MHz) δ 1688 1687 1334 1301 581 523 521 374 254

186 137





1688 (C8) 1687 (C8) 1334 (C4) 1301 (C3) 581 (C7) 523 (C9) 521 (C9) 374

(C2) 254 (C5) 186 (C1) 137 (C6)

89

12

3 4 5

7

O O

OO

220

6



218









548 (m 1 H) 518 (dd J = 150 93 Hz 1 H) 369 (s 3H) 365 (s 3H) 331 (d J = 90


H)




082 (t J = 72 Hz 3 H C1-H)

O

O

O

O

12

34

5

78

9

6227



219











284 (m 1 H) 104 (d J = 69 3 H) 093 (s 9 H)




H)

220

1

23

45

6

7

8 9 10 1112

13

230

O

O

O

O















= 76 Hz 3 H) 13C NMR (100 MHz) δ 1704 1342 1289 784 741 609 521 402

256 241 169 138 35 IR (neat) 2959 2875 1732 1455 1434 1276 1218 1057

221


235 206 185






784 (C9) 741 (C10) 609 (C5) 521 (C13) 402 (C2) 256 (C7) 241 (C8) 169 (C11)

138 (C6) 35 (C1)

N

249

12

3

4

5

6

7

89

10

3

4

89








222




1372 1340 1296 1285 1272 1262 631 522 233 210 IR (neat) 2967 2780

1494 1446 1310 1167 965 748 692 MS (CI) mz 2021586 [C14H20N1 (M+1)

requires 2021596]





1285 (C8) 1272 (C5) 1262 (C9) 631 (C2) 522 (C3) 233 (C4) 210 (C1)

N

252

3

8

9

3

4

8

9

1

2

5

6

7

10





223






352 (s 2 H) 214 (s 3 H) 125 (s 6H) 13C NMR (75 MHz) δ 1470 1413 1285

1281 1265 1120 586 557 345 228 IR (neat) 2973 2842 2794 1494 1453 1411


1901596]





1265 (C10) 1120 (C1) 586 (C4) 557 (C6) 345 (C5) 228 (C3)








224





O

269

12

3

45

6 78

9

10

11

12

13








13C NMR (100 MHz) δ 1559 1366 1317 1287 1270 1264 1239 1206 1142

1124 692 253 132 IR (CHCl3) 3033 2967 2934 2874 1625 1597 1485 1452


1891279] 189 (base) 122 107



225





(C12) 1317 (C8) 1287 (C9) 1270 (C4) 1264 (C2) 1239 (C1) 1206 (C3) 1142

(C5) 1124 (C13) 692 (C7) 253 (C10) 132 (C11)

Br

O

271

12

3

45

6 78

9

10

11







J = 75 Hz 3 H) 13C NMR (75 MHz) δ 1551 1370 1332 1283 1232 1218 1137

1123 698 253 131 IR (neat) 2967 2934 2875 1586 1478 1276 1243 1031 970


241 137

226






1283 (C3) 1232 (C8) 1218 (C9) 1137 (C5) 1123 (C1) 698 (C7) 253 (C10) 131

(C11)

O

273

12

3

45

6

7 89

1011

12

1314

15

16







1308 1300 1296 1281 1278 1266 1210 1160 759 251 216 133 IR (CHCl3)



227





13C NMR (100 MHz) δ 1550 (C6) 1389 (C13) 1339 (C15) 1320 (C9) 1308 (C10)

1300 (C2) 1296 (C4) 1281 (C14) 1278 (C16) 1266 (C1) 1210 (C3) 1160 (C5)

759 (C8) 251 (C11) 216 (C7) 133 (C12)

HOO

1

2

3 4

5

67

8

Si

288










228


(100 MHz) δ 1322 1275 616 590 310 259 183 -52 IR (neat) 3355 2954 2857


requires 2171624] 217 (base) 199 133





(C5) 590(C1) 310 (C2) 259 (C8) 183(C7) -52 (C6)

O

O O

O9

1011

128

612

34

5 7

Si

289








229




MHz) δ 2004 1670 1326 1251 645 593 500 301 270 259 183 -52 IR







(C2) 1670 (C4) 1326 (C8) 1251 (C7) 645 (C9) 593 (C5) 500 (C3) 301 (C6) 270

(C1) 259 (C12) 183 (C11) -52 (C10)

O

O O

OH

8

612

34

5 7

9

290






230





NMR (100 MHz) δ 2009 1669 1317 1270 643 583 499 303 268 MS (CI) mz

1870970 [C9H15O4 (M+1) requires 1870970]




(C2) 1669 (C4) 1317 (C8) 1270 (C7) 643 (C9) 583 (C5) 499 (C3) 303 (C6) 268

(C1)

O

O O

O

861

23

4

5 7

910

11O

O

275







231






1301 1256 637 630 545 496 298 267 IR (neat) 2955 1802 1747 1714 1442


2451025] 245 186 169 (base) 154




NMR (100 MHz) δ 2002 (C2) 1668 (C4) 1553 (C10) 1301 (C8) 1256 (C7) 637

(C11) 630 (C9) 545 (C5) 496 (C3) 298 (C6) 267 (C1)

O

OO

8

6

7 1 2

3

45

9

278




232







585-576 (comp 2 H) 431-420 (m 2 H) 365 (dd J = 85 55 Hz 1 H) 284-278 (m 1


1738 1311 1292 678 632 292 286 269 IR (neat) 2958 1713 1650 1359 1261





NMR (100 MHz) δ 2016 (C8) 1738 (C7) 1311 (C4) 1292 (C3) 678 (C6) 632 (C1)

292 (C2) 286 (C5) 269 (C9)

233

8

6 7Br

O1

2

3 4

5Si

291











H) 088 (s 9 H) 005 (s 6 H) 13C NMR (100 MHz) δ 1325 1269 594 322 310

259 183 -52 IR (neat) 3021 2955 2856 1471 1360 1254 1095 837 776 MS (CI)





234


(C2) 259 (C8) 183 (C7) -52 (C6)

1386

7

12

34

59

10

1211O

O O

OSi

292















235





O

O O

OH

86

7

12

34

59

10

293










(app p J = 72 Hz 2 H)



236


72 Hz 2 H C6-H)

O

O O

O

86

7

12

34

59

1011 12O

O

294












[C12H19O6 (M+1) requires 2591182]



237


167 (app p J = 72 Hz 2 H C6-H)

10

1 23

9

4

5 67

8

2106

O

O

O

O












238

O CF3

O

12

34

5 67

2129








74 Hz 2 H) 100 (t J = 74 3 H) 13C NMR (100 MHz) δ 1572 1412 1204 1160

688 255 128 IR (neat) 1779 1634 1174 706 cm-1 MS (CI) mz 1830640

[C7H10O2F3 (M+1) requires 1830633]




1412 (C4) 1204 (C3) 1160 (C7) 688 (C5) 255 (C2) 128 (C1)

239

O O

O O

1

3

12

3

4

56

78

910

112137










H) 13C NMR (100 MHz) δ 1642 1317 1281 1227 1053 846 824 461 284

269 175 IR (neat) 3001 1788 1750 1309 1202 1070 941 758 MS (CI) mz

2580889 [C15H14O4 (M+1) requires 2580892]




1227 (C8) 1053 (C2) 846 (C6) 824 (C7) 461 (C4) 284 (C1) 269 (C1) 175 (C5)

240

12 3 4

567

8

9

10

1112

1314

2130

O

H

O

O

OO

15

16













230-210 (m 1 H) 210-190 (m 1 H) 181 (app t J = 153 Hz 1 H) 160-140 (m 1


[C20H23O5 (M+1) requires 3431545]

241





H C16-H) 100 (t J = 75 Hz 3 H C14-H)

N

O O

O

Si

O

O

420

12

3

4

56

7

8

9

10

1112

13

14

15









242









4002519]




185 Hz 9 H C13-H) 066 (dd J = 105 35 Hz 6 H C11-H)

243

N

O O

O

Si

O

O

1

11

2

3

4

56

7

8910

12

14

13

15

16

421
















244







H) 085 (s 9 H) 003 (s 6 H) IR (neat) 2955 2858 1754 1698 1392 1254 1177 MS





002 (s 6 H C12-H)

14 15N

O O

O

Si

422

12

3

4

56

7

8

9

10

1112

13



245














C15-H) 145 (s 9 H C1-H) 088 (s 9 H C13-H) 007 (s 6 H C11-H)

246

16N

O O

O

Si

1

11

2

3

4

56

7

89

10

12

14

13

15

414















H) 240-200 (comp 5 H) 174 (s 3 H) 142 (s 9 H) 089 (s 9 H) 009 (s 3 H) 008

247

(s 3 H) IR (neat) 3312 2955 2858 1704 1649 1385 1254 1123 873 776 MS (CI)






008 (s 3 H C12-H)

N

O O

O

O

1

12

15

2

3

4

56

7

8910

11

13

14

424








248







HN

O

Si

432

1

23

4

567

8

910

11

12 13










249

(100 MHz) δ 1439 1117 876 738 701 608 464 439 383 260 229 182 -46 -

49 IR (neat) 3311 2954 2930 2856 1648 1471 1255 1104 889 836 775 MS (CI)







738 (C2) 701 (C13) 608 (C1) 464 (C4) 439 (C5) 383 (C3) 260 (C8) 229 (C11)

182 (C10) -46 (C9) -49 (C9)

N

Me

O

Si

433

1

2

34

5

678

9

1011

12

13 14






250





006 (s 3 H) 005 (s 3 H) 13C NMR (75 MHz) δ 1443 1108 825 736 723 643

543 420 374 360 260 238 182 -44 -50 MS (CI) mz 2942246







13C NMR (75 MHz) δ 1443 (C7) 1108 (C8) 825 (C13) 736 (C14) 723 (C2) 643

(C5) 543 (C1) 420(C3) 374 (C6) 360 (C4) 260 (C12) 238 (C9) 182 (C11) -44

(C10) -50 (C10)

251

N

O

O OSi

1

2 3 4

5

6

78

910

11

1213

14

446














164 Hz 1 H) 009 (s 9 H) 13C NMR (100 MHz) δ 1911 1348 1288 1287 1286

1281 1077 1003 895 691 456 412 -039 IR (neat) 2960 1732 1677 1609 1329

252


(base) 312 284




13C NMR (100 MHz) δ 1911 (C3) 1348 (C8) 1288 (C1) 1287 (C10) 1286 (C9)

1281 (C11) 1077 (C2) 1003 (C12) 895 (C7) 691 (C13) 456 (C4) 412 (C5) -039

(C14)

N

O

OO

1

2 34

5

67

910

11

12

448

8

13

1415

16








253




NMR (75 MHz) δ 2054 1548 1359 1339 1285 1282 1280 1183 825 679 532

451 429 427 395 IR (neat) 3285 3067 3033 2977 1693 1642 1404 1322 1112






(C13) 1285 (C2) 1282 (C1) 1280 (C3) 1183 (C14) 825 (C15) 737 (C5) 679

(C16) 532 (C8) 451 (C10) 429 (C7) 427 (C11) 395 (C12)

254

N

O

O

O

O

451

17

1

2

3

4

567

8

9 10

11

1213

14

1516

H















2058 2055 1755 1531 1361 1279 1274 1270 1265 665 502 480 440 437


255







MHz) δ 2058 (C6) 2055 (C1) 1755 (C3) 1531 (C12) 1361 (C14) 1279 (C16)

1274 (C17) 1270 (C15) 1265 (C2) 665 (C13) 502 (C4) 480 (C8) 440 (C11) 437

(C7) 411 (C5) 384 (C9) 328 (C10)

N

O

Si

O O

1

2 3 4

5

6 78 9

10

1112

1314

15

460







256







NMR (100 MHz) δ 1917 1410 1346 1285 1281 1271 1266 1009 882 689

647 516 384 219 -04 IR (neat) 2959 2900 1731 1672 1604 1328 1296 1198


342 197 181 (base)





1281 (C15) 1271 (C13) 1266 (C14) 1009 (C2) 882 (C7) 689 (C11) 647 (C8)

516 (C5) 384 (C4 219 (C6) -04 (C9)

257

N

O O

Si

O

12 3 4

567 8

910

11

1213

1415

16

461

17
















MHz d6-DMSO 100 ˚C) δ 2052 1545 1390 1361 1278 1272 1269 1150 1034

258

868 664 526 510 418 417 259 -07 IR (neat) 3089 3034 2959 2900 1698


3701838]






(C3) 1545 (C17) 1390 (C13) 1361 (C7) 1278 (C15) 1272 (C16) 1269 (C14)

1150 (C6) 1034 (C12) 868 (C9) 664 (C10) 526 (C1) 510 (C2) 418 (C4) 417

(C5) 259 (C8) -07 (C11)

N

O O

O

1

2 3 4

567 8

910

1112

1314

15

462

18





259




100 ˚C) δ 740-729 (comp 5 H) 599 (ddd J = 160 105 45 Hz 1 H) 519-512




1361 1278 1272 1270 1152 803 724 664 527 512 417 416 247 IR (neat)

3307 3035 2959 1694 1407 1320 1271 1114 1057 MS (CI) mz 2981443

[C18H20NO3 (M+1) requires 2981443]







1388 (C12) 1361 (C7) 1278 (C14) 1272 (C13) 1270 (C15) 1152 (C6) 803 (C9)

724 (C11) 664 (C10) 527 (C1) 512 (C2) 417 (C4) 416 (C5) 247 (C8)

260

16

17

N

O

H

O

OO

1

2 34

5

6

7

89

10 11

12

13 14

15

463










2050 2043 1735 1533 1361 1317 1279 1273 1270 665 507 474 448 436

387 367 348 IR (neat) 3035 2963 2902 1706 1626 1416 1335 1264 1220 1100






261




(C12) 1361 (C8) 1317 (C14) 1279 (C16) 1273 (C17) 1270 (C15) 665 (C13) 507

(C1) 474 (C5) 448 (C11) 436 (C6) 387 (C10) 367 (C2) 348 (C4)

N

O

O O

469

1

2 34

5

6

78

910

11

1213

14

15

Si

16










262







MHz) δ 2054 1547 1376 1360 1285 1282 1280 1163 1077 1040 907 679

547 453 432 -049 IR (neat) 2959 1704 1403 1309 1250 1224 1054 844 MS






MHz) δ 2054 (C3) 1547 (C11) 1376 (C13) 1360 (C6) 1285 (C15) 1282 (C16)

1280 (C14) 1163 (C7) 1077 (C5) 1040 (C1) 907 (C8) 679 (C12) 547 (C9) 453

(C2) 432 (C4) -049 (C10)

263

N

O

O O

470

1

2 34

5

67

89

10

1112

1314

15










13C NMR (75 MHz) δ 2050 1548 1373 1358 1285 1282 1280 1167 824 738

680 548 449 432 425 IR (neat) 3285 2957 1698 1403 1310 1264 1310 1264


284 (base) 266 240




264




1548 (C10) 1373 (C6) 1358 (C12) 1285 (C14) 1282 (C15) 1280 (C13) 1167

(C7) 824 (C8) 738 (C11) 680 (C9) 548 (C1) 449 (C5) 432 (C2) 425 (C4)

11

10

1

23

45

6

7

89

12 1314

15

16

N

O

O

O

O

471

H










265






N

O O

O

Si

1

2 3 4

5

6

78

9

1011

12

473











266






007 (s 9 H) 13C NMR (100 MHz) δ 1912 1519 1410 1312 1190 1078 1003

895 679 456 413 -04 IR (neat) 3088 2960 2900 1732 1678 1608 1418 1372


2781212]






(C3) 1519 (C6) 1410 (C8) 1312 (C1) 1190 (C9) 1078 (C2) 1003 (C7) 895 (C10)

679 (C11) 456 (C4) 413 (C5) -04 (C12)

267

HN

O

Si

1

2 3 4

56

7

8

474








(100 MHz) δ 1912 1508 1020 992 895 451 418 -03 IR (neat) 3233 3022 2960


1941001]




(C3) 1508 (C1) 1020 (C2) 992 (C6) 895 (C7) 451 (C5) 418 (C4) -03 (C8)

268

NSiSO O

O

1

2 3 4

5

67

89

10

1112

13

475













13C NMR (75 MHz) δ 1899 1451 1408 1345 1300 1278 1078 981 912 469

422 215 -075 IR (neat) 3081 2963 1681 1597 1403 1362 1272 1168 846 MS


269





1899 (C3) 1451 (C6) 1408 (C1) 1345 (C9) 1299 (C7) 1278 (C8) 1078 (C2) 981

(C11) 912 (C12) 469 (C5) 422 (C4) 215 (C10) -075 (C13)

N

SO O

O

1

2 3 4

5

67

89

10

1112

476









270


H) 13C NMR (100 MHz) δ 1897 1454 1409 1344 1299 1278 1079 741 463

419 384 216 IR (neat) 3280 1676 1596 1363 1275 1167 1052 MS (CI) mz

2760693 [C14H14NO3S (M+1) requires 2760694]





(100 MHz) δ 1897 (C3) 1454 (C6) 1409 (C1) 1344 (C9) 1299 (C7) 1278 (C8)

1079 (C2) 741 (C12) 463 (C11) 419 (C5) 384 (C4) 216 (C10)

N

SO O

O

1

2 3 4

5

67

89

10

11

12

13

1415

477





271








NMR (75 MHz) δ 2044 1441 1369 1338 1299 1273 1187 815 748 554 457

446 434 388 216 IR (neat) 3305 1723 1356 1162 1094 MS (CI) mz 3181163







MHz) δ 2044 (C3) 1441 (C6) 1369 (C9) 1338 (C12) 1299 (C7) 1273 (C8) 1187

(C13) 815 (C14) 748 (C15) 554 (C5) 457 (C11) 446 (C4) 434 (C2) 388 (C5)

216 (C10)

272

N

O

SiO

1

2 34

5

67

8

9

10

11

1213

478













1323 1318 1286 1284 1081 1005 895 456 418 -04 IR (neat) 2962 1668


2981263] 298 (base)

273




C8-H) 13C NMR (75 MHz) δ 1914 (C3) 1691 (C9) 1420 (C1) 1323 (C10) 1318

(C13) 1286 (C12) 1284 (C11) 1081 (C2) 1005 (C6) 895 (C7) 456 (C5) 418 (C4)

-04 (C8)

N

O

O

1

2 34

5

67

910

1112

13

479

8

1415










274




1339 1293 1279 1260 1172 827 754 525 447 435 423 379 IR (neat) 3256


268 (base) 250






100 ˚C) δ 2043 (C3) 1697 (C11) 1354 (C12) 1339 (C9) 1293 (C15) 1279 (C14)

1260 (C13) 1172 (C10) 827 (C6) 754 (C7) 525 (C5) 447 (C8) 435 (C1) 423

(C4) 379 (C2)

275

N

O

O

H

SO

O

1

2 3 4

5

67

89

101112

1314

15

16

480








13C NMR (75 MHz) δ 2059 2056 1736 1445 1367 1300 1280 1271 521 501

459 453 416 385 332 216 IR (neat) 3689 2925 1715 1633 1353 1163 1098







(C8) 1736 (C6) 1445 (C12) 1367 (C15) 1300 (C13) 1280 (C7) 1271 (C14) 521

(C5) 501 (C1) 459 (C10) 453 (C9) 416 (C4) 385 (C2) 332 (C11) 216 (C16)

276

N

O

1

2 34

5

6

9

10

11

481

OH

7

8

12 13

O

14

15

16









2058 2056 1754 1685 1348 1294 1280 1266 1260 500 488 441 438 410

384 332 IR (neat) 2917 1713 1633 1410 1338 1217 914 MS (CI) mz 296







277


1754 (C11) 1685 (C12) 1348 (C10) 1294 (C13) 1280 (C15) 1266 (C16) 1260

(C14) 500 (C1) 488 (C5) 441 (C8) 438 (C2) 410 (C4) 384 (C7) 332 (C6)

N

OH

O O

1

2 3 4

5

6

78 9

10

11

1213

1415

16

482











278

3297 2953 1684 1409 1324 1087 1063 990 914 MS (CI) mz 300 [C18H22NO3

(M+1) requires 300] 300 (base) 258 256 238 214





Hz 1 H C4-H)

N

O O

12 3 4

5

6

78

11

1213

14

1516

1718

283

OSi

9

10

19







279






9 H) 007 (s 3 H) 005 (s 3 H) 13C NMR (100 MHz) δ 1555 1366 1365 1284

1279 1278 1168 854 706 673 642 507 391 386 366 336 258 181 -49 -

50 IR (neat) 3307 2953 2856 1694 1640 1407 1335 1312 1255 1093 774 MS (CI)








1366 (C7) 1365 (C16) 1284 (C18) 1279 (C19) 1278 (C17) 1168 (C8) 854 (C12)

706 (C15) 673 (C3) 642 (C13) 507 (C1) 391 (C5) 386 (C6) 366 (C2) 336 (C4)

258 (C11) 181 (C10) -49 (C9) -50 (C9)

280

N

O O

O

S

S

484

1

23

4

5

6

78

9

10

1112

13

1415

16

1718











168 125 68 Hz 1 H) 522 (m 1 H) 518 (s 2 H) 512 (d J = 168 Hz 1 H) 502 (d



H) 13C NMR (100 MHz) δ 2150 1552 1363 1355 1284 1280 1279 1178 843

751 712 676 496 386 383 328 292 191 IR (neat) 3290 2953 1697 1406

281


(base) 346 282







2150 (C9) 1552 (C13) 1363 (C15) 1355 (C7) 1284 (C17) 1280 (C18) 1279

(C16) 1178 (C8) 843 (C11) 751 (C14) 712 (C3) 676 (C12) 496 (C5) 386 (C1)

383 (C6) 328 (C4) 292 (C2) 191 (C10)

N

S S

O O

1

2 3 4

5

6

78

9 10

1112

13

1415

1617

18

485




282









NMR (75 MHz) 1552 1364 1351 1284 1280 1277 1177 841 725 675 619

523 448 418 412 396 385 384 IR (neat) 3288 2923 1698 1406 1318 1262







(C7) 1284 (C17) 1280 (C18) 1277 (C16) 1177 (C8) 841 (C11) 725 (C14) 675

(C12) 619 (C5) 523 (C1) 448 (C3) 418 (C2) 412 (C4) 396 (C6) 385 (C10) 384

(C9)

283

HNO

Si

1

23

4

5 67 8

490












188 -03 IR (neat) 3190 3077 2956 1687 1649 1405 1309 1252 841 756 MS





288 (C3) 188 (C4) -03 (C8)

284

NO

Si9

1011

1213

14

491

O O

1

23

4

5 67 8












1283 1280 1277 1031 888 684 483 340 285 175 -04 IR (neat) 3065 2959

2899 1778 1738 1714 1498 1455 1373 1250 1134 1062 843 MS (CI) mz 330




285


1351 (C11) 1283 (C13) 1280 (C14) 1277 (C12) 1031 (C6) 888 (C10) 684 (C7)

483 (C5) 340 (C2) 285 (C3) 175 (C4) -04 (C8)

N9

10

11

1213

14

486

O O

1

23

4

5

6

78

1516













286










= 100 ˚C) δ 1542 1363 1355 1277 1272 1269 1160 845 724 660 506 409

360 298 260 140 IR (neat) 3294 3248 2944 1697 1406 1318 1267 1098 MS







100 ˚C) δ 1542 (C11) 1363 (C13) 1355 (C7) 1277 (C15) 1272 (C16) 1269 (C14)

1160 (C8) 845 (C9) 724 (C12) 660 (C10) 506 (C6) 409 (C5) 360 (C1) 298 (C5)

260 (C2) 140 (C3)

287

N

O

1

23

4

5

6

9

10

11

494

O

OH

7

8

12 13

14 15

16

17







(dd J = 180 60 Hz 1 H) 249 (m 1 H) 215 (dd J = 135 75 Hz 1 H) 208-152


1278 1272 1268 1258 659 495 466 432 372 355 276 184 141 IR (neat)


312] 334 (base) 312






288

1364 (C10) 1278 (C14) 1272 (C16) 1268 (C17) 1258 (C15) 659 (C13) 495 (C1)

466 (C5) 432 (C7) 372 (C8) 355 (C6) 276 (C2) 184 (C4) 141 (C3)

N

O

O

OH

OSi

1

2 34

5

67

89

10

11 12

13

14 15

16

1718

1920

493










MHz d6-DMSO 100 ˚C) δ 2059 1790 1532 1363 1278 1272 1268 1256 660

622 480 454 418 371 353 350 326 250 169 -56 -57 IR (neat) 2928 2855

1713 1623 1416 1322 1278 1088 839 MS (CI) mz 442 [C25H36NO4Si (M+1)


289








(C11) 1532 (C12) 1363 (C14) 1278 (C16) 1272 (C17) 1268 (C15) 1256 (C10)

660 (C13) 622 (C3) 480 (C1) 454 (C5) 418 (C8) 371 (C6) 353 (C2) 350 (C4)

326 (C7) 250 (C20) 169 (C19) -56 (C18) -57 (C18)

N

N

SO O

O

O

OO

12

345

6

78

910

11

1213

1415

1617

18

1920

21

2223

24 25

26

27

4112





290









H) 313 (m 1 H) 302 (m 1 H) 272 (m 1 H) 240 (dt J = 155 95 Hz 1 H) 225 (s


1339 1336 1294 1293 1285 1278 1273 1270 1254 1246 1236 1184 1164

1159 1144 669 514 510 508 387 204 203 MS (CI) mz 5591909

[C31H31N2O6S (M+1) requires 5591903]








˚C) δ 1715 (C12) 1548 (C22) 1448 (C17) 1360 (C24) 1345 (C30) 1339 (C9)

1336 (C10) 1294 (C16) 1293 (C14) 1285 (C4) 1278 (C26) 1273 (C25) 1270

291

(C27) 1254 (C15) 1246 (C6) 1236 (C5) 1184 (C7) 1164 (C21) 1159 (C3) 1144

(C8) 669 (C23) 514 (C1) 510 (C13) 508 (C11) 387 (C19) 204 (C2) 203 (C18)

10

11

12

3

45

6 7

8 912

1314 15

16

1718

1920

21

22

23

24

25

N

N

O

O

OO

OO

4114











100 Hz 1 H) 365 (s 3 H) 318 (dq J = 80 160 Hz) 252 (m 1 H) 238 (m 1 H)

159 (s 9 H) 13C NMR (125 MHz) δ 1717 1548 1489 1359 1354 1340 1338

292

1278 1274 1273 1239 1223 1178 1162 1148 1122 841 668 513 512 509


requires 5052339]







1717 (C10) 1548 (C23) 1489 (C12) 1359 (C14) 1354 (C1) 1340 (C20) 1338

(C22) 1278 (C16) 1274 (C17) 1273 (C6) 1272 (C15) 1239 (C4) 1223 (C5) 1178

(C3) 1162 (C21) 1148 (C7) 1122 (C2) 841 (13) 668 (C24) 513 (C9) 512 (C11)

509 (C18) 385 (C19) 273 (C25) 204 (C8)

293

N

N

SO O

O

O

12

345

6

78

910

11

1213

1415

1617

18

1920

21

2223

24 25

26

27

4113
















294



1340 1334 1293 1292 1278 1274 1272 1254 1247 1238 1184 1168 1158

1147 838 736 668 518 384 383 266 203 MS (CI) mz 5251849

[C31H29N2O4S (M+1) requires 5251848]









(C24) 1359 (C10) 1343 (C14) 1340 (C15) 1334 (C4) 1293 (C16) 1292 (C26)

1278 (C25) 1274 (C15) 1272 (C27) 1254 (C6) 1247 (C6) 1238 (C5) 1184 (C7)

1168 (C21) 1158 (C8) 1147 (C4) 838 (C12) 736 (C13) 668 (C23) 518 (C1) 384

(C11) 383 (C19) 266 (C2) 203 (C18)

295

12

3

45

6 7

8 910

11

12

1314 15

16

1718

1920

21

22

23

24

25

N

N

O

O

OO

4115
















1489 1358 1356 1343 1330 1279 1278 1274 1272 1240 1224 1176 1165

296

1148 1119 841 733 668 664 514 386 377 272 265 IR (neat) 3293 3068








(C14) 1356 (C20) 1343 (C1) 1330 (C22) 1279 (C6) 1278 (C17) 1274 (C16)

1272 (C15) 1240 (C4) 1224 (C5) 1176 (C3) 1165 (C21) 1148 (C7) 1119 (C2)

841 (C10) 733 (C24) 668 (C13) 664 (C11) 514 (C9) 386 (C18) 377 (C19) 272

(C25) 265 (C8)

297

12

1314

151617

18

12

3

45

6 78

9 1011

NH

N

OO

O19

20

21

2223

4106

H















1774 1534 1361 1356 1323 1278 1273 1270 1265 1258 1206 1182 1172

298

1108 1055 663 493 476 402 371 344 250 IR (neat) 3464 3052 2985 1702









(C12) 1774 (C10) 1534 (C18) 1361 (C20) 1356 (C1) 1323 (C17) 1278 (C22)

1273 (C23) 1270 (C21) 1265 (C11) 1258 (C6) 1206 (C4) 1182 (C5) 1172 (C3)

1108 (C2) 1055 (C7) 663 (C19) 493 (C9) 476 (C16) 402 (C13) 371 (C14) 344

(C15) 250 (C8)

299

12

1314

151617

18

12

3

45

6 78

9 1011

N

N

O

OO

O

O19

20

21

2223

2425

26

4117













= 127 41 Hz 1 H) 162 (s 9 H) 13C NMR (125 MHz) δ 2059 1768 1533 1488

1360 1351 1323 1278 1275 1274 1271 1265 1239 1224 1178 1149 1141

300

841 665 541 481 403 362 339 272 246 IR (neat) 3400 2977 2929 1771








C26-H) 13C NMR (125 MHz) δ 2059 (C12) 1768 (C10) 1533 (C24) 1488 (C18)

1360 (C20) 1351 (C1) 1323 (C17) 1278 (C22) 1275 (C23) 1274 (C24) 1271

(C11) 1265 (C6) 1239 (C4) 1224 (C5) 1178 (C3) 1149 (C2) 1141 (C7) 841

(C25) 665 (C19) 541 (C9) 481 (C16) 403 (C13) 362 (C14) 339 (C15) 272 (C26)

246

301

19

N

N

O

OO

OO

H

OO

4124

12

3

45

6 7

8 9 10

11

12

1314

151617

18

20

21

2223

24 25

26














1710 1632 1421 1307 1252 1150 739 MS (CI) mz 531 [C30H31N2O7 (M+1)

requires 531] 531 463 319 243 (base)

302







35 Hz 1 H C15-H) 170 (m 1 H C15-H) 157 (s 9 H C20-H)

N

N

OO

H

OO

OO

4125

12

3

4

56 7

8 910

11

12

1314

151617

18

19

20

21

22

2324 25

26









303







100 ˚C) δ 2071 1534 1487 1359 1352 1321 1278 1275 1272 1270 1240

1224 1178 1148 1142 841 696 666 613 477 473 376 351 290 272 228

IR (neat) 2977 2928 1750 1730 1703 1455 1417 1360 1326 1156 1012 755 MS








(C18) 1487 (C21) 1359 (C23) 1352 (C1) 1321 (C17) 1278 (C25) 1275 (C6)

1272 (C26) 1270 (C24) 1240 (C4) 1224 (C5) 1178 (C3) 1148 (C7) 1142 (C2)

841 (C11) 696 (C22) 666 (C19) 613 (C10) 477 (C9) 473 (C16) 376 (C13) 351

(C15) 290 (C14) 272 (C20) 228 (C8)

304

N

N

O

H

H

OO

O O

Si

21

2223

2425

26

27

28

12

3

45

6 7

8 9 10

11 12

1314

151617

18

19

20

4130














NMR (125 MHz d6-DMSO 100 ˚C) δ 1648 1544 1538 1488 1364 1352 1328

1279 1278 1272 1268 1236 1222 1176 1148 1040 838 781 659 466 362

305

304 293 272 262 231 57 40 IR (neat) 2954 1729 1699 1636 1455 1421 1327









(C18) 1538 (C12) 1488 (C23) 1364 (C1) 1352 (C17) 1328 (C6) 1279 (C25)

1278 (C24) 1272 (C26) 1268 (C3) 1236 (C5) 1222 (C4) 1176 (C2) 1148 (C7)

1040 (C11) 838 (C9) 781 (C16) 659 (C22) 466 (C10) 362 (C13) 304 (C19) 293

(C15) 272 (C20) 262 (C8) 231 (C14) 57 (C28) 40 (C27)

306

19

N

N

OO

OO

4132

12

3

45

6 7

8 9

151617

18

20

21

2223

24 25

26

27

28

OSi10

11 12

1314

H

H













1547 1497 1367 1365 1359 1335 1332 1287 1286 1283 1282 1278 1277

1274 1240 1239 1226 1225 1177 1176 1156 1153 1147 1042 1038 838

836 671 668 480 478 476 474 473 471 407 406 313 309 299 280 279

307

276 270 177 123 IR (neat) 2943 2865 1731 1698 1634 1455 1424 1366 1325


405








1497 (C12) 1367 (C1) 1365 (C1) 1359 (C17) 1335 (C6) 1332 (C6) 1287 (C23)

1286 (C23) 1283 (C25) 1282 (C25) 1278 (C26) 1277 (C26) 1274 (C24) 1240

(C2) 1239 (C2) 1226 (C5) 1225 (C5) 1177 (C3) 1176 (C3) 1156 (C4) 1153 (C7)

1147 (C7) 1042 (C11) 1038 (C11) 838 (C19) 836 (C19) 671 (C22) 668 (C22)

480 (C16) 478 (C16) 476 (C9) 474 (C9) 473 (C10) 471 (C10) 407 (C8) 406

(C8) 313 (C13) 309 (C13) 299 (C13) 280 (C20) 279 (C20) 276 (C14) 270 (C14)

177 (C28) 123 (C27)

308

N

N

O

H

H

OO

O O21

2223

2425

26

12

3

4

56 7

8 9 10

11 12

1314

151617

18

1920

4131














1362 1351 1324 1278 1272 1270 1268 1237 1222 1176 1148 1107 839

662 469 446 402 384 291 283 279 272 231 IR (neat) 2953 1731 1701

309

1455 1423 1368 1326 1147 1016 747 MS (CI) mz 501 [C30H32N2O5 (M+1)









1488 (C18) 1362 (C23) 1351 (C1) 1324 (C17) 1278 (C25) 1272 (C26) 1270

(C24) 1268 (C26) 1237 (C4) 1222 (C5) 1176 (C3) 1148 (C7) 1107 (C11) 839

(C19) 662 (C22) 469 (C9) 446 (C13) 402 (C16) 384 (C11) 291 (C15) 283 (C10)

279 (C8) 272 (C20) 231 (C14)

NH

HN

OH

H

H

12

3

4

56 7

8 9 10

1112

1314

151617

4133




310













CD3OD) δ 1376 1355 1286 1217 1196 1184 1118 1082 729 497 455 422

394 354 341 323 300 IR (neat) 3394 29241450 1335 742 MS (CI) mz 270








311

1286 (C6) 1217 (C4) 1196 (C5) 1184 (C3) 1118 (C7) 1082 (C2) 729 (C12) 497

(C9) 455 (C16) 422 (C15) 394 (C10) 354 (C13) 341 (C11) 323 (C8) 300 (C14)

N

N

OHO

H

H

OO

O O

20

12

3

4

56 7

8 9 1011 12

1314

151617

18

19

21

2223

2425

26

N

N

OHO

H

H

OO

O O

20

12

3

4

56 7

8 9 1011 12

1314

151617

18

19

21

2223

2425

26

4137a 4137b














312



13C NMR (125 MHz d6-DMSO 100 ˚C) δ 2151 1543 1488 1363 1351 1325

1279 1278 1272 1268 1237 1223 1177 1151 1148 839 729 662 472 451

405 390 307 272 257 232 IR (neat) 3436 2976 1729 1699 1456 1424 1360

1328 1153 754








(C23) 1351 (C1) 1325 (C17) 1279 (C6) 1278 (C25) 1272 (C26) 1268 (C24)

1237 (C4) 1223 (C5) 1177 (C3) 1151 (C7) 1148 (C2) 839 (C19) 729 (C11) 662

(C22) 472 (C16) 451 (C10) 405 (C13) 390 (C9) 307 (C15) 272 (C20) 257 (C8)

232 (C14)

313

19

N

N

OO

OO

4144

12

3

45

6 7

8 9

1718

2021

22

2324

25 26

1011

1314

15

16

H

HO

O12

27

OH
















314

1543 1488 1364 1349 1337 1277 1271 1266 1236 1222 1176 1147 837

659 576 503 463 453 360 336 296 272 262 250 231 IR (neat) 2931 1729

1697 1454 1367 1328 1155 1116 912 747 MS (CI) mz 549 [C31H36N2O7 (M+1)

requires 549] 549 (base) 493 449








DMSO 100 ˚C) δ 1716 (C17) 1543 (C22) 1488 (C19) 1364 (C1) 1349 (C14) 1337

(C6) 1277 (C24) 1271 (C26) 1269 (C27) 1266 (C25) 1236 (C2) 1222 (C5) 1176

(C4) 1153 (C3) 1147 (C7) 837 (C20) 659 (C23) 576 (C15) 503 (C18) 463 (C13)

453 (C9) 360 (C10) 336 (C16) 296 (C8) 272 (C21) 262 (C12) 231 (C11)

315

19

N

N

OO

OO

4145

12

3

45

6 7

8 9

17

18

20

21

2223

2425

26

10

11

1314

1516

H

H

12OO
















316




1352 1324 1278 1272 1269 1259 1222 1176 1149 1107 1064 839 674

662 474 469 368 336 306 299 272 234 IR (neat) 2976 1731 1698 1455


517 (base) 417









1487 (C18) 1362 (C1) 1352 (C17) 1324 (C6) 1278 (C23) 1272 (C25) 1269

(C26) 1259 (C24) 1222 (C2) 1176 (C5) 1149 (C4) 1107 (C3) 1064 (C7) 839

(C11) 674 (C19) 662 (C22) 474 (C16) 469 (C9) 368 (C8) 336 (C13) 306 (C15)

299 (C10) 272 (C20) 234 (C14)

317

19

N

N

OO

OO

4147

12

3

45

6 7

8 9

17

18

20

21

2223

2425

26

10

11

1314

1516

H

H

12O

















318




˚C) δ 1538 1488 1428 1362 1351 1325 1277 1273 1272 1269 1236 1222

1176 1149 1148 1036 838 662 637 475 465 379 320 272 260 233 IR

(neat) 2976 1729 1699 1455 1422 1330 1142 747 MS (CI) mz 500 [C30H32N2O5

(M) requires 500] 500 401 387 (base) 267 229








(125 MHz d6-DMSO 100 ˚C) δ 1538 (C21) 1488 (C18) 1428 (C12) 1362 (C1)

1351 (C17) 1325 (C6) 1277 (C23) 1273 (C25) 1272 (C26) 1269 (C24) 1236

(C2) 1222 (C5) 1176 (C4) 1149 (C3) 1148 (C7) 1036 (C13) 838 (C19) 662

(C22) 637 (C11) 475 (C16) 465 (C9) 379 (C8) 320 (C15) 272 (C20) 260 (C10)

233 (C14)

319

NH

NH

H O

12

3

4

56 7

8 9 10

11

12

1314

151617

18

4148













1 H) 13C NMR (100 MHz C6D6) δ 1441 1362 1320 1285 1216 1197 1185

1111 1072 1050 668 555 549 417 408 358 242 228 IR (neat) 3394 2927

2360 1646 1457 1244 1070 741 668 MS (CI) mz 2811657 [C18H21N2O (M+1)

requires 2811654]

320








(C6) 1216 (C4) 1197 (C5) 1185 (C3) 1111 (C7) 1072 (C2) 1050 (C13) 668

(C11) 555 (C9) 549 (C16) 417 (C10) 408 (C15) 358 (C18) 242 (C8) 228 (C14)

N

NH

H O

19

12

3

45

6 7

8 9 10

11

12

1314

151617

18

4149









321








1188 1179 1097 1087 1063 1048 666 552 536 418 405 379 347 237

229 IR (neat) 2925 2360 2340 1644 1467 1379 1070 895 738 668 MS (CI) mz

2931659 [C19H21N2O (M-1) requires 2931654]








(C1) 1265 (C17) 1208 (C6) 1188 (C4) 1179 (C5) 1097 (C3) 1087 (C7) 1063

(C2) 1048 (C13) 666 (C11) 552 (C8) 536 (C16) 418 (C10) 405 (C15) 379 (C19)

347 (C18) 237 (C8) 229 (C14)

322

19

N

N

OO

OO

4152

12

3

45

6 7

8 9

17

18

20

21

2223

2425

26

10

11

1314

1516

H

H

12O

O27

28














100 ˚C) δ 815 (d J = 80 Hz 1 H) 771 (s 1 H) 747 (d J = 80 Hz 1 H) 733-723



323



1488 1362 1351 1327 1277 1274 1273 1269 1237 1223 1193 1176 1148

1107 838 662 647 477 460 359 299 272 257 242 223 IR (neat) 2913

1721 1691 1612 1427 1318 1090 740 MS (CI) mz 543 [C32H35N2O6 (M+1)

requires 543] 544 543 488 444 (base) 400








MHz d6-DMSO 100 ˚C) δ 1939 (C27) 1568 (C21) 1539 (C18) 1488 (C12) 1362

(C1) 1351 (C17) 1327 (C6) 1277 (C23) 1274 (C25) 1273 (C26) 1269 (C24)

1237 (C2) 1223 (C5) 1193 (C4) 1176 (C3) 1148 (C7) 1107 (C13) 838 (C19)

662 (C22) 647 (C11) 477 (C16) 460 (C9) 359 (C8) 299 (C15) 272 (C20) 257

(C10) 242 (C28) 223 (C14)

324

NH

NH

4154

12

3

45

6 7

8 9

17

10

11

14

1516

H

H

12O

O13

1819
















MHz) δ 1955 1575 1356 1355 1272 1215 1213 1193 1177 1112 1079 674

325

483 477 374 323 288 250 237 IR (neat) 2921 1614 1453 1321 1195 738 MS









1355 (C1) 1272 (C6) 1215 (C2) 1213 (C5) 1193 (C4) 1177 (C3) 1112 (C13)

1079 (C7) 674 (C11) 483 (C16) 477 (C9) 374 (C8) 323 (C15) 288 (C10) 250

(C19) 237 (C14)

N

N

41

12

3

45

6 7

8 9

17

10

11

14

1516

H

H

12O

O13

1819

20

21





326










211 (ddd J = 112 46 40 Hz 1 H) 207 (s 3 H) 189 (m 1 H) 180 (dd J = 120 36

Hz 1 H) 13C NMR (75 MHz) δ 1955 1574 1372 1332 1265 1211 1208 1187

1178 1090 1059 678 547 538 418 385 324 291 250 229 228 IR (neat)

2895 2359 1617 1468 1320 1276 1192 911 741 MS (CI) mz 337 [C21H25N2O2










327

(C17) 1265 (C6) 1211 (C4) 1208 (C5) 1187 (C3) 1178 (C2) 1090 (C13) 1059

(C7) 678 (C11) 547 (C9) 538 (C16) 418 (C21) 385 (C20) 324 (C8) 291 (C10)

250 (C19) 229 (C15) 228 (C14)

328

References












329















330















331














332

















333

















334













335

















336














337













338

















339














340
















341



342

Vita













by


Dissertation




of the Requirements

for the Degree of



May 2007

Dedication

To Stephanie Hall

v

Acknowledgements











work was based

vi




















vii
















viii

Table of Contents

List of Tables xii


List of Schemes xiv




121 Introduction2












141 Introduction33




ix













16 Conclusions51













x

24 Conclusions95


31 Introduction97

311 Alstonerine98





















36 Conclusions141


41 Introduction144


421 Introduction148

xi















45 Conclusions209


51 General 211

52 Compounds 212

References328

Vitahellip342

xii

List of Tables


xiii

List of Figures


xiv

List of Schemes


xv


xvi


xvii


1





















2











121 Introduction













3










Scheme 11

M

X-Nuc-

11

X

12

X

M

13

M

14

Nuc

M

15

Nuc

4













Scheme 12

Br

OAcPd(PPh3)4

THF

DMF

OAc

MeO2C

SO2Ph

Br

+CO2Me

SO2Ph

SO2Ph

CO2Me16 17

18

19





5



Scheme 13

R1 R2

X M

R1 R2

M

110 111

Nuc-Nuc-

a b

R1 R2

Nuc

112

R1 R2

113

Nuc

path a

path b

-X-









used as a substrate

6

Scheme 14

LG Nuc

LG Nuc

Pd

Pd

Ru Mo Rh Ir W

Ru Mo Rh Ir W

+ Nuc

115114

116 117










7

Scheme 15

NaHCH2(CO2Me)

OAc

118NaH

CH2(CO2Me)

Pd(PPh3)4

W(CO)3(MeCN)383

or

119 E = CO2Me

E

E

E E

120 E = CO2Me

+

119 E = CO2Me

E

E

E E

120 E = CO2Me

+

119120 = 8614

119120 = 496









8

Scheme 16

OAc

OAc

NaHCH2(CO2Me)

Mo(CO)6

NaHHCMe(CO2Me)

orE

E

E

EMe

121 122

123 E = CO2Me

124 E = CO2Me

89

84















9


sections

Scheme 17

nPr OAc

THF reflux 19 h66

THF rt 1 h94



[Ir(COD)Cl]2 (2)

nPr

nPr

CO2Me

CO2Me

MeO2C CO2Me

126

125

127

126127 = 8812

+

nPr

nPr

CO2Me

CO2Me

MeO2C CO2Me

126 127

126127 = 397

+








documented1316


Alkylations



10








membered) rings

Scheme 18

LG

Nuc Nuc

M

M

127 128











11



favored (Eq 12)

O

O

OAcH

H

CO2Me

SO2Ph

NaH THF

Pd(PPh3)4 dppe60

O

O

SO2PhCO2Me

H

H

129 130

SO2Ph

OAc

SO2Ph

131

SO2Ph

SO2PhBSA THF

Pd(dppe)244

132

(11)

(12)







12

O

SO2Ph

OO

SO2Ph

O134 135

O

SO2Ph

O

133

OAc

+

NaH Pd(PPh3)4Diphos

THF reflux73

134135 = 928

OPh

CO2Me

O

Pd(OAc)2 PPh3

62

CO2Me

O

136 137

(13)

(14)














13
















14

Scheme 19

soft Nuc-

hard Nuc-

H

Nuc

M

140

M

NucM

142

oxidativeaddition

H

Nuc

141

Nuc

H

M

143


Nuc

H

144

M

139

H

LG

138

M

M












minimize A13-strain

15

Scheme 110

R OAc OAc

R

145 146

R OAc OAc

R

147 148


MLn MLn

syn anti

R Nuc Nuc

R

149 150

Nuc- Nuc-








16

Me

PhOAc


151

Me Ph

CO2MeMeO2C

152THF rt

99

Me

OAc


154

THF rt96

Ph

Me Ph

153

CO2MeMeO2C

Me Ph

CO2MeMeO2C

152

Me Ph

153

CO2MeMeO2C

+

+

152153 = 9010

152153 = 928

(15)

(16)










palladium catalysis

Me

PhOAc

155

TfaN

Zn OOtBu

PPh3 [Pd(allyl)Cl]2

THF -78 degC - rt69

Ph157

tBuO2C

NHTfa

156

(17)

17















Scheme 111

nPr OAcTHF reflux

85

NaCH(CO2Et)2


158

nPr

159

CO2Et

CO2EtnPr

nPr

CO2Me

CO2Me

MeO2C CO2Me

160

161

+

+

159160161 = 9073

18















OCO2Me

OMe

O O

RhH(PPh3)4 (5)PBu3 (10)

CO2Me

O162

163

164

THF rt93

(18)




19











OCO2Me

OMe

O O


O

CO2Me

O

+

165

163

166 167

168

OCO2Me

dioxane 100 degC97

OMe

O O

RhH(PPh3)4 (5)PBu3 (10)

163

dioxane 100 degC81

CO2Me

O

CO2Me

O

+

166 167

166167 = 7228

166167 = 1486

(19)

(110)

20























21




991 91

982 89

OCO2Me

169

R1 R2

170

R1 R2CO2Me

CO2MeR1

171

R2

MeO2C

CO2Me



+


1

2

3

4

5

6

phosphite

H

H

H

Me

Me

Me

Me

nPr

Ph

Me

nPr

Ph

P(OMe)3

P(OMe)3

P(OMe)3

P(OPh)3

P(OPh)3

P(OPh)3

982

gt991

964

gt991

95

89

73

32









22



nucleophilic attack

Scheme 112

OCO2Me

165

168

OCO2Me


P(OMe)3 (20) THF

173172

+

From 168 172173 = 421 99From 165 172173 = 21 83

or

MeO2C CO2Me

CO2Me

CO2Me














23



Me

OCO2Me

MeD

Me MeD

CO2MeMeO2C

Me Me

D

CO2MeMeO2C

+

P(OPh)3 (20) THF92


174 175 176

175176 = gt191

R1

OCO2Me

R2 Me iPr

CO2MeMeO2C

+

P(OPh)3 (20) THF92


179 180

From 177 179180 = 973From 178 179180 = 397

iPrMe

MeO2C CO2Me


(111)

(112)










24

Scheme 113

R

Rh(I)

R

Rh(III)

Nuc

R

LG

R

Rh(III)

NucRh(I)

Path A

Path B

R

LG

R

R

R

k1k-1

k2

k3

R

Nuc

R

RNuc

R

181 182 183

184185

186
















25

Scheme 114

R


P(OMe)3 THF R

OR


R

OAr

R

TsNBnor or

187 188 189 190







Group












26











27


OCO2MeR1


NaCH(CO2Me)2 R1

R2R3 R4

CO2Me

CO2Me

+ MeO2CR4

R3R1 R2

CO2Me191 192

193

THF rt


majorminor

1

2

3

OCO2Me CO2Me

CO2Me

OCO2MeCO2Me

CO2Me

OCO2Me

CO2Me

CO2Me

75

80

86

928

946

991(973 ZE)

OCO2MeCO2Me

CO2Me

4 84 973

Ph OCO2Me PhCO2Me

CO2Me

593 9010

194

196

198

1100

1102

195

197

199

1101

1103






28











29


OCO2MeR1

R2R3 R4

R1

R2R3 R4

CO2Me

CO2Me

+ MeO2CR4

R3R1 R2

MeO2C

191

11051106

THF


majorminor

1

2

3

OCO2Me

OCO2Me

OCO2Me

85

98

98

991

8812

1000(8812 ZE)

OCO2Me4 98 gt955

194

196

198

1110

CO2MeMeO2C

Me

+

NaH[Rh(CO)2Cl]2

1104

Me

CO2Me

CO2Me

Me

CO2Me

CO2Me

Me

CO2Me

CO2Me

Me

CO2Me

CO2Me

1111

1109

1108

1107

Me Me

30











OCO2Me

1102

[Rh(CO)2Cl]2 PhLi

ZnBr2 THF rt99


Ph

1112

99 ee 92 ee

(113)










31










regioselectively

32


OCO2MeR1


NucR1

R2R3 R4

+Nuc R4

R3R1 R2

191 1113 1114


majorminor

1OCO2Me

84 928

1100

NucTHFrt

nucleophile

OCu(I)

Ph Ph

O

2OCO2Me

75 gt955

1117

OCu(I)

PhPh

O

1115

1115

1116

1118

3OCO2Me

78 9010

1100

11191120

4OCO2Me

42 8812

1100

11211122

NTsLiTsN Ph

LiTsN TsN





33










Scheme 115

R

Rh(I)

R

Rh(III)

Nuc

R

LG

R

Rh(III)

NucRh(I)

Path A

Path B

R

LG

R

R

R

k1k-1

k2

k3

R

Nuc

R

RNuc

R

181 182 183

184185

186


141 Introduction





34












MeO

H

H+

Co2(CO)8 ∆

Me1123 1124

1125

(114)









35







Scheme 116

Co2(CO)8

Co(CO)3(CO)3Co

R-CO

Co(CO)2

Co(CO)3

R

Co

Co(CO)3

R

COCO

Co

Co(CO)3

R

CO

O

(CO)3CoCo(CO)

O

R

O-Co2(CO)4

R

1126 1127 1128 1129

1132 1131 1130

R








36







MOMO

PhCo2(CO)8

toluene 100 degC41

11351136 = 32

O

Ph

MOMO

O

Ph

MOMO

+

11341133

+

1135 1136

MeS

PhCo2(CO)8

toluene 100 degC61

11371138 = 181

O

Ph

MeS

O

Ph

MeS

+

11381137

+

1139 1140

(115)

(116)








37
















OEtO2C

EtO2C



EtO2C

EtO2C

1141 1142

(117)





38



catalysts






fashion64


toluene 90 degC92

O

Ph

O

1143 1144

OPh

(118)







Me

O

1145 1146

MeEtO2C

EtO2CEtO2C

EtO2C

CO (10-15 atm)Ru(CO)12 (2)


86-76

(119)



39







Scheme 117

Ph

O

11471148

PhEtO2C

EtO2C

EtO2C

EtO2C



toluene 110 degC 99









40

Scheme 118

TBSOMe Co2(CO)8


50

Me

O

TBSO

H

1148 1149

6 steps HO

H

1150

O

OH

H

HO

H

1151

O

OH

H

O

O

H











41

Scheme 119

OOAc

N NO

H H

H


51

1152 1153

N

H H

H

1154

O

9 steps

OAc






Scheme 120


THF 65 degC67

11561157 = 611155

MeO MeO1156

N

O

MeO1158

N

7 steps

MeO1157

N

O+

H

42







Scheme 121

O O

1159 n = 1 or 2

PKR

n

1160 1161

or










43

O

Me

MeO

O

Me

Me

O

Co2(CO)8 CH2Cl2

1164 1165

then NMO48

O

O

O

OO

1162 1163

Co2(CO)8 CH2Cl2

then NMO31

(120)

(121)







cedrene (1170)

Scheme 122

O O

OO

O

DCE 83 degC95

11671166

Co2(CO)8nBuSMe

1170

H

1169

H

1168

O

H

5 steps

44











Scheme 123

O O

O

H


then Me3NO2H2O60-70

OO

OO

11731174

K2CO3MeOH

55O

CO2Me

O

H

1175

O

H

1176

HO HOHO

HO

H

H

O O

O

H

1171

H

TMS

Br


1172

45
























46






Cl

CO2Me+

MesN NMes

RuPh

PCy3ClCl

1178

1176 1177

then H2 (100 psi)69

CO2Me

Cl

1179

OOHi) 1178


11801181

56

(122)

(123)









47







reported

EtO2C

EtO2C

CO (441 psi)Co2(CO)8 (5 )

CH2Cl2 130 degC68

OEtO2C

EtO2C

PhPh

1182 1183

MeO2C

MeO2C

1184

Co nanoparticles


98

OMeO2C

MeO2CH

H

1185

(124)

(125)









48




dodecylsulfate)

MeO2C

MeO2C

1186

OMeO2C

MeO2C

1187


SDS H2O 100 degC

PhPh

O

HH+ (126)















49


back bonding81

Scheme 124

∆

Me


NaH

CO CH3CN 30 degC

CO2MeMeO2C

168

1188

Me

MeO2C

MeO2C

CO2Me

CO2Me

Me+

1189 1190

OMeO2C

MeO2C

Me H

OMeO2C

MeO2C

Me H

+

1191 1192

11891190 = 371 88

11911192 = 71 87









50








Scheme 125

X

+ LG

R

[Rh(CO)2Cl]2X

R

X

R

X O

R

XR

PKR

X = C(CO2Me)2 NTs O

[5+2]

cycloisom

CO

11931194

1195

1196

1197

1198








51











fashion

Scheme 126

OCOCF3


72

MeO2C

MeO2CCO2MeMeO2C

Me


89

OCOCF3 MeO2C

MeO2C

1200

1202

1104

1199

1201

16 Conclusions



52












palladium catalysis












53






















54











R

R

OCO2Me

Nuc[Rh(CO)2Cl]2

R

R

Nuc

R

OCO2Me

R

Nuc[Rh(CO)2Cl]2

R

Nuc

R

21 22

23 24

(21)

(22)








55









Scheme 21

O

NBn

Rh(I)

RO

NBn

R

XX

MeO2CO

Rh(I)

X O

R

Rh(I)X

R

MeO2CO R

OCu(I)

NBn

[Rh(CO)2Cl]2

[Rh(CO)2Cl]2

[Rh(CO)2Cl]2

25

26


2728




-CO


X


X

56
















R R R R215 216


OCO2Me Nuc






57




Scheme 22

OCO2Me

OCO2Me


THF rtor

218

217

219 220

+

From 217 72 7624 219220From 218 76 5545 219220











58

Scheme 23

OCO2Me

OCO2Me


THF rtor

222

221

223 224

+

From 221 56 955 223224From 222 58 8614 223224










Scheme 24


THF rt227 228

+

From 225 29 946 227228From 226 21 919 227228


OCO2Me

OCO2Me

or

226

225



59











[Rh(CO)2Cl]2 +

220 219

CH2(CO2Me)2 NaH

218


1

2

3

4

DMSO

CH3CN

THF

DMF

62

62

76

73

2575

3664

4555

6931






60


DMF -20 degC88

[Rh(CO)2Cl]2 +

219 220

CH2(CO2Me)2 NaH

217

219220 = 964

(24)









this chapter

OCO2Me

217

CO2MeMeO2C

+

229

MeO2C

MeO2C

MeO2C

MeO2C 231

230

+

NaH[Rh(CO)2Cl]2

DMF -20 degC88

230231 = 937

(25)






61


Scheme 25

OCO2Me


DMF -20 degC

222

OCO2Me

226

orno reaction












112)37




62














21)






OCO2Me

HN



232

233

(26)

63









OCO2Me

HN


96234235 = 11

232

233

234

N

235

N

+(27)





OCOCF3

HN


233

N

CF3O

OH

238

+

237

(28)




64




O

HN



with TBAI 98 5 h

OH

N

233

239

240

(29)













65

Scheme 26

RhCl

OC

OC

ClRh

CO

CO

HN

RhClOC

NHOC


233

240

I-

RhI

OC

OC

IRh

CO

CO

HN

RhIOC

NHOC

RhI

OC

OC

I

slower

Bu4N+I-

Bu4N+

233

242

243

244-I-










66




R2

R1 OCO2Me


NHR1R2 (2 eq)DCE rt

R2

R1 NR2

R3R4 R3

R4R2N

R2R1

+

TBAI (20 mol)



HN

HN

NHBn

Me

OCO2Me

OCO2Me

Me

OCO2Me NMe

Bn

N

Me

N 96

99

89

gt955

gt955

gt955

233

233

250

232

248

251

234

249

252

245 246 247

NHBn

MeN

Me

Bn

85 gt955

250 253 252

OCO2Me






67















PKR

68

Scheme 27

BnNH2

Br

64 BnHN

PhI CuIPd(PPh3)4

Et3N82

BnHNPh

254255 256

OCO2Me

257


DCE rt-reflux86

BnNPh

258

not BnN

Ph

O

259















69








structures like 264

Scheme 28

OH

R1260


O

R1

R2

R5

R4R3

261


O

O

O

O

R2

R3

R4

R5

R2

R3

R4R5

R2

R3

264

262

263

HeckR1 = halide

RCMR1 = alkene

or alkyne

PKRR1 = alkyne

[Rh(CO)2Cl]2





70













71


R2

R1 OCO2Me

R3R4 R2

R1 Nuc

R3R4 R3

R4Nuc

R2R1

+



245 265 266


THF rt

OH

OH

Br

OH

Ph

+

267

270

272

OCO2Me

268

OCO2Me

268

217

OCO2Me

OH

Ph

272

OCO2Me

251

O

269

O

Br271

O

Ph273

O

Ph274

77 gt955

87 7129

lt10 NA

73 gt955

Nuc







72























73


Scheme 29

O

OO

OCO2Me

O

O O

O

OO

catalyst

base

Pd

Rh 275

276

277

278

O

OO

M






Scheme 210

OH OTHP

On-BuLi

HMPA Et2OTHF65

OTHP

HO


OODMAP

O

O O

279

TsOHH2O

O

280 281

282 283

CH2Cl293

EtOAc78

Et2O84 THPO


74







Scheme 211

O

O O

283THPO

conditionsO

O O

284HO

+ HO

282

THPO

HO

285

HO

+










75

Scheme 212

OH

TBSCl imid

OTBS

On-BuLi

BF3Et2O THF

71OTBS

HO


OO

DMAP

O

O O

OTBS

TBAF THFO

O O

OH

O

O O

OCO2Me

pyr CH2Cl291

279 286 287

288 289

290 275

91

ClCO2Me

DMF99

EtOAc99

Et2O84









76


O

O O

OCO2Me275

O

OO

Conditions


1

2

3

4

5

NaH

NaH

KOtBu

KOtBu

KOtBu

THF

DMF

THF

DMF

DMF

rt

rt

rt

rt

0

20

34

51

54

68

278







O

O O

+O

OO

O

O O

OCO2Me275

278 277

278277 = 5545

55(210)



77






Scheme 213

HOOTBS

288

CBr4 PPh3

Et3N CH2Cl278

BrOTBS

291

OMe

OO

NaH n-BuLi

MeO

O O

OTBS

TBAF

MeO

O O

OH

pyr CH2Cl283

MeO

O O

OCO2Me

292 293

294

ClCO2Me

THF69

THF63








78


MeO

O O OO

OMe

+

O

OMe

OKOtBu[Rh(CO)2Cl]2

(10 mol)

DMF -20 degC52

294295 296

295296 = 4357

(211)

MeO2CO




212)21

OPh

CO2Me

O

Pd(OAc)2 PPh3

62

CO2Me

O

297 296

(212)


Reactions





(Eq 213)84

79

NBn

O


ii) 1 N HCl (aq) 71

O

O

298 299

(213)





Scheme 214

NBn

O

i) [Rh(CO)2Cl]2 ∆

ii) 1 N HCl (aq)

O

O

2101 2102

NBn

OH

2100

[Rh(CO)2Cl]2

OCO2Me

R2

R1

R3 R4

245

R2

R1

R4 R3

R2

R1

R4R3







80

NBn

O

298

then HCl53 O

O

299


(214)










O

OH

2103

+ OCO2Me

257

O

O

2104


THFwithout CuI 33

with CuI 64

(215)




moderate yield

81

NBn

OH

2100

+ OCO2Me

257

NBn

O

298


THF55

(216)









Scheme 215

NBn

OH

2100

OCO2Me257

NBn

O

298


THF or toluenert

rt-150 degCX

then HClO

O

299





reaction sequences

82








CO2MeMeO2C

MeO2CO

MeO2C CO2Me

2106

2105

CH3CN 80 degC75


(217)





83

Scheme 216

CO2MeMeO2C+

OCO2Me

OCO2Me2107

2108

CO2MeMeO2C

MeO2CO

[Rh(CO)2Cl]2


2106

2105









84


CO2MeMeO2C+

OCO2Me

OCO2Me


solvent rt-reflux

MeO2C CO2Me

equiv 2107

21072108

2106

MeO2CCO2Me

CO2MeMeO2C

+

2109


1

2

3

4

5

6

25

25

25

25

15

15

1

1

1

1

1

1

2

2

2

2

1

1

THF

dioxane

toluene

DMF

THF

dioxane

15

23

20

0

20

32

--

24

7

32

17

16







85

CO2MeMeO2C+

OAc

OCO2Me


(10 mol)

dioxane rt-reflux45

21062109 = 21

MeO2C CO2Me

21072110

2106 MeO2CCO2Me

CO2MeMeO2C

+

2109

15equiv

1equiv

(218)


















86

MeO2C CO2Me+

R


MeO2C

MeO2C

R

1

23

4

5

67

8

2111 2112

2113

(219)







Scheme 217

+

R

LG

R LG

or

or

[Rh(CO)2Cl]2

OMeO2C

R

4

2115

2114

2119R LG2116

R

R

MeO2C CO2Me

2111

2

MeO2C

OMeO2C

2117

R

2

MeO2C

OMeO2C

R

42118

MeO2C

[Rh(CO)2Cl]2

[Rh(CO)2Cl]2






87




Scheme 218

CO2MeMeO2C

Ph

OCO2Me


91

PhMeO2C

MeO2C


THF reflux99

MeO2C

MeO2C

Ph

O

CO (1 atm)

21212120

2122

257




2121

CO2MeMeO2C

PhNaH CO (1 atm)


THF rt - reflux

PhMeO2C

MeO2C

2120

OCO2Me

257

not 2122 (220)






88









inhibited the PKR

O

Ph

MeO2C

MeO2C

2122


NaOMe or NaOAcX

MeO2C

MeO2C

2121

(221)











89











promote the PKR

CO2MeMeO2C

Ph

+ OCO2Me


O

Ph

MeO2C

MeO2C

2120

257

2122



(222)








90



223)

CO2MeMeO2C

Ph

+ LGCO NaH

[Rh(CO)2Cl]2O

Ph

MeO2C

MeO2C2120

2123

2122



rt - reflux(223)











Scheme 219

91

MeO2CCO2Me

OCOCF3 OMeO2C

MeO2C+

R

CO [Rh(CO)2Cl]2

(10 mol )

R

azeotroped wtoluene

2126

2127 R=H = 732122 R=Ph = 682128 R=Me = 67

2124 R = H2120 R = Ph2125 R = Me










Scheme 220

CO2MeMeO2C

PhCO (1-40 atm)


Ph

OMeO2C

MeO2C

Et

X


2120 2130

OCOCF3

2129





92



reagent

Scheme 221

2120

+OCOCF3

2129

CO NaH [Rh(CO)2Cl]2

(10 mol)THF

MeO2C

MeO2C

2131

MeO2C CO2Me

Ph

2 eq 1 eq

1 eq 2 eq

Ph

Isolated Yield96

24












93

O

Ph

MeO2C

MeO2C2122

MeO2C

MeO2C

2121

Ph

CO [Rh(CO)2Cl]2


O

Ph

MeO2C

MeO2C

2122

MeO2C

MeO2C

2121

Ph

+51 24 h

2126

(224)

(225)

CO [Rh(CO)2Cl]2

(10 mol) THF reflux

2120

MeO2C CO2Me

Ph








[Rh(CO)2Cl]2 +O O

BaCO3O

ORh

CO

CO

[Rh(CO)2Cl]2 +

O

O O

O

Base OMeO

MeOO

RhCO

CO

R R

2132 2133

21342135

(226)

(227)




94











Scheme 222

O

OO

O

2138

THF rt-reflux

PhOH


2) BH3Me2NH


2136

O O

O O

Ph2137

O

OO

O Ph

O

2139

Ph

not observed


OCOCF3

2129




95





Scheme 223

CO2MeMeO2C

Ph

OCOCF3 Ph

OMeO2C

MeO2C

EtH

21202130


2129

Ph

OEtO2C

EtO2C

MeH

2140

24 Conclusions










96











97


31 Introduction













linkage


N

NMe

Me

OH

O

H

H

H

H

macroline (31)

NH

NHO

H

H H

HOH

sarpagine (32)

421

16

4 21

98

311 Alstonerine







ring


N

MeN

Me

O

O

H

H

H

H

33

A BC D

E










99



Scheme 31

NH

N

H

H H

HOH

37

NH

NH

34 Strictosidine

O

MeO2C

OGlu

HNH

N

35

OH

MeO2CH

H H

NH

N

H

H H

CHO

CO2Me

36








100

Scheme 32

NH

NH

34 Strictosidine

O

MeO2C

OGlu

HH N

H

NH

38

OHCHO

MeO2CH

H

NH

NH CHO

H

H H

CHOCO2Me

39

NH

NH CHO

H

H H

CHOCO2Me

310

NH

N

H

H H

CHO

CO2Me

36










Tamelen

101

Scheme 33

NH

N

311

OHC

H

CO2H

NH

N

312

OHC

H

DCC PTSA

dioxane

NH

N

H

H H

313

CHO

NMe

N

H H

ajmaline (314)

OHHO

H

H

NMe

N

CN

315

H

TBSO

BF3Et2O

NMe

N

316

H

TBSO

NMe

N

H

H H

317

HCHO

NMe

N

H

H H


HCHO

KOHMeOH

56






102






Scheme 34

N

MeN

Me

OH

O

H

H

H

H

31

N

MeN

Me

O

O

H

H

H

H

33

NH

N

H

H H

HOH

37

NH

N

H

H H

HOTBS

319

TBS-Cl imid

DMF

NH

N

H

H H

HOTBS

320

Oi) Me2SO4 K2CO3

ii) TBAF






103






norsuaveoline (322)

Scheme 35

H

NMe

BnN

O

Dieckmann

Pictet-SpenglerH

323

NH

NH2

CO2H

324

NMe

MeN

OH

H

H

H

alstonerine (33)

O

NMe

MeN

talcarpine (321)

H

H

H

H

OMe

CHO

NH

HN

H

H

N

Et

norsuaveoline (322)







104















105

Scheme 36

NH

NH2

CO2H

324

1) NaNH3 MeI


Me

NH2

CO2Me

325

PhCHO MeOH

NaBH4 -5 degC88 N

Me

NHBn

CO2Me

326

1) C6H6dioxane ∆

HO2C

O

CO2H

2) HClMeOH ∆

80NMe

NBn

CO2Me

CO2Me

327

NaH MeOH

PhMe ∆

92

NMe

BnN

328

O

CO2Me

H

H

AcOHHClH2O

∆ 91NMe

BnN

323

OH

H

3

5







106

Scheme 37

N NNMe

H

CO2Me

CO2Me

MeNPh

H

CO2Me

CO2Me

Ph

HNNMe

H

CO2Me

CO2MePh

HNNMe

H

CO2Me

Ph

CO2Me

NMe

NBn

CO2Me

CO2Me

trans-327

cis-327

329 330

HCl

trans-327









107





reaction vessels

Scheme 38


NH

NH2

CO2Me

324


CH2Cl2 rt 48h

83 NH

NBn

CO2Me

CO2Me

331

NMe

N

323 gt98 ee

OH

H Ph85NMe

NBn

CO2Me

CO2Me

327

NaH MeI

DMF95









108










as the acid source

Scheme 39

NH

NHBn

CO2Me

332

TFA CH2Cl2 92

MeO CO2Me

OMe 336

NH

NBn

CO2Me

CO2Me

331

HO2C CO2H

O 333

PhHdioxane

pTsOH ∆ 86N

NBn

CO2Me

334 O

+

N

NBn

CO2Me

335 O

41 transcis

109




ketone 338

Scheme 310

NH

NBn

CO2Me

CO2Me

331

N

NBn

CO2Me

334 O

NaOMe

NH

BnN

337

O

CO2Me

H

H NH

BnN

338

OH

H

AcOHHClH2O

∆ 91









110



Scheme 311

H

NMe

BnN

O

H

323

NMe

MeN

321

H

H

H

H

OMe

CHO

NMe

BnN

339

H

H

H

H

OOMe

conjugate addn

NMe

BnN

340

H

H

H

H Et

NMe

BnN

341

H

H

CHO

HO R


acetal formation

oxy-cope









111

Scheme 312

NMe

BnN

323

OH

H


2) LiClO4 dioxane

∆ 90 NMe

BnN

341

H

H

CHO

Et Et

Br 342

Mg 90

NMe

BnN

343

H

H

HO

Et

Et

+

NMe

BnN

344

H

H

Et

O Et

H

H

NMe

BnN

345

H

H

Et

O Et

H

H+




313)115116

Scheme 313

NMe

BnN

343

H

H

HO

Et

Et

NMe

BnN

344

H

H

Et

O Et

H

H

NMe

BnN

345

H

H

Et

O Et

H

H+

KH18-crown-6

cumene150 degC 88





112











Scheme 314

NMe

BnN

341

H

H

CHO

NMe

BnN

347

H

H

HO

Et

Li-biphenylBaI2 THF

Et Br

346

90

NMe

BnN

348

H

H

Et

OH

H

NMe

BnN

349

H

H

Et

OH

H+

KH18-crown-6

dioxane100 degC 85

MeOK

15 20

1615 20

16



113




Scheme 315

NMe

BnN

349

H

H

Et

OH

H

NaBH4 MeOH

96NMe

BnN

350

H

H

Et

HOH

H


2) NaIO4 MeOH 78

NMe

BnN

351

H

H

H

H

OOH

Et

pTsOH PhH

95

NMe

BnN

352

H

H

H

H

O

Et

N

O

O

SePh

pTsOH MeOH

NMe

BnN

353

H

H

H

H

O

EtSePh

OMe

NaIO4

H2OTHFMeOH90

NMe

BnN

339

H

H

H

H

OOMe

NMe

BnN

354

H

H

H

H

OOMe

+




114




understood117

Scheme 316

NMe

BnN

339

H

H

H

H

OOMe

90NMe

BnN

355

H

H

H

H

OMe

CHO

NMe

BnN

356

H

H

H

H

OMe

CHO+

K2CO3 EtOH 85

01 torr 100 degC 75

H2SO4







115

Scheme 317

NMe

BnN

355

H

H

H

H

OMe

CHO

NMe

BnN

356

H

H

H

H

OMe

CHO

PdC (10 mol)

H2 EtOH92

NMe

MeN

talcarpine (321)

H

H

H

H

OMe

CHO

H2PdC (xs)

MeOH (15 eq)

90

NMe

N

talpinine (357)

H

OMe

H

HO H

H







syntheses







116




(322)

Scheme 318

NH

BnN

358

H

H

Et

OH

H

NH

BnN

338

H

H

O

NH

BnN

359

H

H

Et

CHOH

H

O O

pTsOHacetone

95NH

BnN

360

H

H

CHO

Et

CHOH

H

NH2OHHCl

EtOH ∆

88NH

RN

H

H

N

Et

361 R = Bn322 R = H

H2 PdC92

1) HO(CH2)2OH pTsOH

PhH ∆ 90







117















118

Scheme 319

NH

BnN

338

OH

H

5 PdC H2HCl EtOH

rt 5 H94 N

H

NH

362

OH

H

BrI

K2CO3 THF ∆

87

NH

N

363

OH

HI


DMF-H2O 65 degC80

NH

N

H

H H

364

O

NH

N

H

H H

vellosimine (365)

HCHO






macroline alkaloids







119











31)105

Scheme 320

NMe

N

CN

367

H

NMe

N

H

H H


HCHO

Mannich reaction

NH

NHCl

CO2H

368OTBS

vinylogous Mannich






120



374

Scheme 321

NH

NHCl

CO2H

368

OMe

TBSO 369

1)


H

NH

CO2tBu

370

CO2Mediketene

DMAP PhMe

KOtBu 86

NH

N

CO2tBu

371

H

OO

MeO2C

1) NaBH4 95


H

N

CO2tBu

372

H

O

MeO2C


then NaBH490

NMe

N

CO2tBu

373

H

MeO2C

TFA

PhSMe90

NMe

N

CO2H

374

H

MeO2C






121



Scheme 322

NMe

N

CO2H

374

H

MeO2C

1) EDCI NH4OH 86

2) TFAA py 90NMe

N

CN

375

H

MeO2C

1) LiBH4 THF 98

2) DMP 83

NMe

N

CN

376

H

OHC

NaH TBS-Cl

NMe

N

CN

367

H

TBSO

BF3Et2O

NMe

N

377

H

TBSO

NMe

N

H

H H

378

HCHO

NMe

N

H

H H


HCHO

KOHMeOH

56







122











Scheme 323

NH

NHCl

CO2H

i)Et3N CbzCl

CH2Cl2

ii) MeOH Et3N87 N

H

NCbz

CO2Me

OMe

TMS

BF3Et2O

CH2Cl281

51 cistrans

NH

NCbz

CO2MeDIBAL-H

toluene -78 degC


60NH

NCbz

368 379

380 381




123



Scheme 324

NH

NCbz

381

RuPh

Cy3P

PCy3Cl

Cl

CH2Cl2 rt97

NH

CbzN

383


2) NaIO4 aq THF 54

NH

CbzN

384

CHO

382

H

H H

H
















124







enantiocontrol

Scheme 325

NMe

OH1) BuLi

2) I2 NMe

OH

I DMP

57 (3 steps) NMe

CHO

I

TMSO

OMe

388

385 386 387

Zn(OTf)2 BnNH270 N

Me

I

389

N

O

Bn


P(tBu)3 CH3CN ∆

85NMe

N

390

H

H Ph

O








125













126

Scheme 326

NH

NH2

CO2H

324

1) LAH 98

2) TsCl py 78 NH

NHTs

391

OTs

1) KCN 86

2) NaNH3(l) THF 88

NH

NH2

392

CN

OHCOTBS

393


then CH2Cl2 TFA80

NH

394

NH

CN



NMe

395

NBn

CN

CHO

NMe

397

NBn

CN

(EtO)2PO

Et

O

OEt

396

NaH 65

Et

CO2Et

LiNEt2 THF

-78 degC 99 NMe

N

398

H

H Ph

CO2EtCN

Et

HH

NMe

NH

399

H

H

OHO

Et

H

H

1) LiBH42) pTSA 88

3) DIBAL-H 504) H2Pd-C 100





(3104)

127

Scheme 327

NMe

395

NBn

CN

CHO

(EtO)2PO

Et

CN

3100

NaH 83 NMe

3102

NBn

CN

Et

CN

KOtBu THF

67

NMe

N

3103

H

H Ph

CNCN

Et

HH

NMe

NH

H

H

N

Et

3104

















128











129

Scheme 328

NH

NHBoc

CO2Me

3105

MeNC nBuLi

82NH

NHBoc

3106

O

N

1) TFA 98


NH

NH

3107

O

N

EtO2C

O 1) POCl3

2) Na2CO3 50

NH

3108

NH

CO2Et

O

N

1) H2Pd(OH)2-C 84

2) Boc2O 87

NH

3109

NBoc

CO2Et

O

N

NMe

NH

H

H

N

Et

3104



4) MeI NaH

5) TFA 80









130










alkaloids111

131

Scheme 329

O

O OBnNH2

H2O

NBn

OH

HO

31103111

+

BnN

HO OH

3112

1) TFAA

2) NaOH 95

BnN

HO OH

3112


50

BnN

HO OTBS

3113

1) H2 PdC

2) K2CO3 PhCOCl 85

BzN

HO OTBS

3114


2) HF CH3CN 95

BzN

OH

3115

1) H2NN(Me)Ph

MeOH HCl ∆

2) LiAlH4 THF 95

NMe

BnN

3116

OHH

H


73NMe

BnN

(plusmn)-323

OH

H








132










Scheme 330

H

NMe

BnN

O

H

H

HNMe

MeN

O

O

H

33



323









133




Scheme 331

NMe

BnN

323

OH

H

1) MeOTf

2) H2PdC80 N

Me

MeN

3118

OH

H



NMe

MeN

3119

H

H

CHO

NMe

MeN

3120

H

H

OH

LiAlH4

Et2O -20 degC90

Me

O

Et3N dioxane90

NMe

MeN

3122

H

H

O

PhH 145 degC

sealed tube65 N

Me

MeN

3123

H

H

CHO

O OH

3121







134

Scheme 332

NMe

MeN

3123

H

H

CHO

OH

NaBH4

EtOH86 N

Me

MeN

3124

H

H

OHH

HO

i) 9-BBNTHF rt 20 h


NMe

MeN

3125

H

H

OHH

HOHO

TsCl pyr rt


NMe

MeN

3126

H

H

H

O

OH

H

H

(COCl)2 DMSO CH2Cl2


MeN

33 51

H

H

H

O

O

H

NMe

MeN

3127 30

H

H

H

O

O

H

+









135

Scheme 333

MeN O

MeN

H HH

H

OH

MeH

N

MeN

Me

O

OH

H

H

H

H

3126

H

3126

excess DMSO(COCl)2

MeN O

MeN

H HH

H

O

MeH

3128

SH MeN O

MeN

H HH

H

OH

MeH

3129

tautomerization

MeN O

MeN

H HH

H

OH

Me

3130

DMSO(COCl)2

MeN O

MeN

H HH

H

O

Me

33








136






Scheme 334

NMe

BnN

323

OH

H NMe

N

H

H H


HCHO

4 steps








137

Scheme 335

NMe

N

H

H H

366

HCHO

NaBH4

MeOH 0 degC90 N

Me

N

H

H H

3131

H


90

NMe

N

H

H H

3132

H


NaOH H2O2 rt


85

NMe

N

H

H H

3133

H

OTIPS

H

OH

DMP CH2Cl2

82NMe

N

H

H H

3134

H

OTIPS

H

O

MeI THF

KOtBu EtOH THF ∆

90

NMe

MeN

3135

H

H

H

OTIPS

O

H

NMe

MeN

33

H

H

H

O

O

H


60




323

138










Scheme 336

NMe

CHO


79

NMe

NNs

Ph3POEt

OCO2EtBr

CHCl3 ∆

Ph3POEt

O

EtO2C

Br

AcCl Et3NCH2Cl2

73

CO2Et

CO2Et

3138

3140

3136

3137

3139

+

PBu3 (30)

CH2Cl2 rt73 31 drN

Me3141

NCO2Et

CO2EtNs

H




139





Scheme 337

NMe

3141

NCO2Et

CO2EtNs

H

HCl EtOAc

90 NMe

NsN

3142

H

H

CO2EtO

PhSH K2CO3

DMF99

NMe

HN

3143

H

H

CO2EtO

HCHO HCO2H ∆

99NMe

MeN

3144

H

H

CO2EtO

NaBH3CN ZnI2

DCE ∆74

NMe

MeN

3145

H

H

CO2Et

BH2CN

EtOH ∆

98

NMe

MeN

3146

H

H

CO2Et

NMe

MeN

(plusmn)-3120

H

H

OH

DIBAL-H

tol -78 degC92






140












Scheme 338

NMe

TsN

3152

H

H

SO2Ph

CHO

PhO2S SO2Ph

NMe

NTs


55-64NMe

NHTs

PhO2S

KMnO4Bu4NBr

CH2Cl261 N

Me

NHTs

PhO2SOH

OH



315031493147

NMe

3151

NTs

PhO2S

CHO

3148

141






Scheme 339

NMe

TsN

3152

H

H

SO2Ph

CHO


95 NMe

TsN

3153

H

H

OTBDPS


-78 degC - rt36 N

Me

TsN

3154

H

H

OOTBDPS

H




optimized

36 Conclusions





142


















143


H

NMe

BnN

Pictet-SpenglerH

H

NMe

BnN

HeckH

O

H

NMe

BnN

H

FischerIndole

O

NMe

NsN

H

H



R

390Kuethe

323Rassat

3142Kwon

144



Alstonerine

41 Introduction

















145

Scheme 41

H

NMe

BnN

O

Diekmann

Pictet-SpenglerH

H

HNMe

MeN

O

O

H

41



H

HNMe

MeN

O

O

H

41

Wacker


42

E

E

A B

A B

C D

C D

11 steps

10 steps













146



Scheme 42

H

HNMe

MeN

O

O

H

41

H

H

HNMe

RN

OH

43

H

O

H

HNMe

RN

44

H

O

NMe

NR

45

Acylation

Baeyer-Villiger

PKR








A (49)134

147

Scheme 43

MeN

H2N

O

O

46

RN

47

PGO

O

RN

PGO

48

410

N

N

OH

O

O

Me

MeO

O

O

MeO

Me

Me

HH

H

O Me

O

Me

N

N

R411

N

NR

R

R

O

49










148


421 Introduction













derivative 415136

149

Scheme 44

MeN

H2N

O

O

46

MeN

H2N

412

HO

O

HO

BocN

413

TBSO

O

BocN

TBSO

414

BocN

TBSO

CO2Me

415

O









150

Scheme 45

HN

HO

CO2H SO2Cl

MeOH99

H2+Cl-

N

HO

CO2Me N

HO

CO2Me

Boc

dioxane70

TBS-Climidazole

N

TBSO

CO2Me

Boc RuO2H2O (20)

NaIO4N

TBSO

CO2Me

Boc

O

416 417 418

419 415

Boc2OiPr2NEtDMAP

DMF96

EtOAc96












151

Scheme 46

N

TBSO

CO2Me

Boc

O N

TBSO

CO2Me

Boc

415

R



Et2O toluene

N

TBSO

Boc1 DIBAL-H CH2Cl2


R







152

Scheme 47

N

TBSO

Boc

414

TBAF THF N

HO

Boc

N

HO

Boc

+

Ac2O Et3NCH2Cl2 97

92

N

AcO

Boc

422 423

424





153








complex 425

154

Scheme 48

N

TBSO

Boc

BocN

TBSO

O

426414

Co2(CO)8 N

TBSO

Boc

425

Co2(CO)6

conditions


THFX






Scheme 49

N

TBSO

Boc

BocN

TBSO

O

429422

Co2(CO)8 N

TBSO

Boc

428

Co2(CO)6

conditions


THF






155







N

TBSO

Boc

HCl or ZnBr2 N

TBSO

O O

414 430

(41)





156

Scheme 410

N

TBSO

Boc HN

TBSO

HN

TBSO

+


414 431 432

N

TBSO

K2CO3 MeIacetone

55

Me

433

88431432 = 13






attempted

Scheme 411

N

TBSO

Me

MeN

TBSO

O

435433

Co2(CO)8 N

TBSO

Me

434

Co2(CO)6

conditions


THF

157










Scheme 412

N OBn

O

H

H

Co

Co(CO)3

(CO)2

N OBn

O

H

Co Co

(CO)3 (CO)3

436 437

TBSO TBSO

N

TBSO

Boc

422

Co2(CO)8

N

TBSO

Boc

428

Co2(CO)6

158










Scheme 413

HNMe

RN

O

H

NMe

NR

44 45

PKR

H

PKR

N

R

439

m nRN

O

438

m n




159





Scheme 414

N

X

R

O

A13-Strain N

X

R

O

m

m

n

n

PKR N R

O

X n

m

440 X = H2 O 441 442

O

431 Initial Studies









160

Scheme 415

N

OMe

R1

MgBrn



CbzN

O

R1

n

MgBr

R2

MeLi CuCN (111)

THF -78 degC73-81

CbzN

O

R1

R2

443 444 445

n












Scheme 416

N

OMe

TMSTHF

then Cbz-Cl 95

N

O

Cbz

N

O

CbzTMS


TMS R

443 446447 R=TMS

448 R=H

K2CO3MeOH75

EtMgBr

161










N

O

Cbz

N

O

Cbz

SnBu3


96

TMS

446 448 gt191 dr

(42)








piperidine 448

162

Scheme 417

NO

TMS

O

O

N

H

TMS

OO

O

Nuc

Nuc

449 450










Scheme 418

N

O

Cbz

448

Co2(CO)8

DMSO

THF 65 degC89

NCbz

OH

O

451

H

H

N

O

Cbz HH

451

H

O

3



163
















164




Scheme 419

Co(CO)2

(CO)3Co

H

Co(CO)2

Co(CO)3

H(CO)3Co Co(CO)3

+

452

cis-453

trans-454













165

Scheme 420

N OBn

O

H

H

NCbz

Co2(CO)8

Co

Co

N OBn

O

H

H

Co

N OBn

O

H

H

Co Co

(CO)3 (CO)3

N OBn

O

H

H

O

O

O

O

O

CbzNO

H

H

448

455 456

457 458

451 459

O

HCbzNO

H

HO

H

CoCo

Co

(CO)3(CO)2

(CO)3(CO)2

(CO)3(CO)3




166













Scheme 421

N

OMe

443

TMSBr


77

N

O

Cbz

460

TMS

CuCN MeLi (111)

MgBr

TBAFH2OTHF 69

N

O

Cbz

R


461 R = TMS

462 R = H

6





167













Scheme 422

N

O

Cbz

462

Co2(CO)8

DMSO

THF 65 degC91

N

O

O

CbzH HH

463

N OBn

O

HO

463

H

O

1

2






168






467

169

Scheme 423

NCbz

Co2(CO)8

N OBn

O

H

O

O

CbzNO

H

H

CbzNO

H

H

462

465

468 463

H

Co

N OBn

O

HO

464

Co

(CO)3(CO)3

HCo Co

(CO)3 (CO)3

H HO O

H

N OBn

O

HO

466

Co(CO)2(Co)3Co

N OBn

O

HO

467

H

(CO)2Co Co(CO)3





170












171

Scheme 424

N

O

CbzTMS

446

CuCN MeLi (111)

MgBr

TBAFH2O THF 53

N

O

Cbz

Co2(CO)8

DMSO

THF 65 degC33 31 dr


R

469 R = TMS

470 R = H

N

O

CbzH H

471

N OBn

O

HO

471

H1

2

O

H

O

6












172



Scheme 425

Cbz

N

O

448

H2 PdCor

TMSIX

HN

O

472









173

Scheme 426

Alloc

Ts Ts

N

OMe

MgBrTMS

THF then Alloc-Cl77

N

O443

TMS HN

O

TMS

dimethyl malonate

Pd(PPh3)4 THF93

nBuLi THF -78 degC

then TsCl50

N

O

R

475 R = TMS

476 R = H

K2CO3MeOH48

TMS


N

O

473 474

477






Scheme 427

Bz BzHN

O

TMS

474

nBuLi THF -78 degC

then BzCl98

N

O

TMSSnBu3


91 gt191 dr

N

O

478 479




174















advantageous145

Scheme 428

N

O

R Co2(CO)8

DMSO

THF 65 degCN

O

R HH

H

O

477 R = Ts479 R = Bz

480 R = Ts (61)481 R = Bz (94)

7

175














Scheme 429

CbzN

O

448

L-Selectride

THF -78 degC99

CbzN

OH

482

TBS-Climidazole

DMF81

CbzN

OTBS

483

4 4






176







Scheme 430

N

Cbz

448

O


BF3Et2O

HSCH2CH2SH

CH2Cl284

N

Cbz

485

S S

N

Cbz

486

Raney NiX

X

N

Cbz

484

O

S


XAIBN Bu3SnH








177



Scheme 431

HNO O NaBH4 HCl

EtOH

HNO OEt

HNO SO2Ph

PhSO2ClHCO2H

CH2Cl260

nBuLi

TMS

THF71

487 488 489

HNO

TMSnBuLi

then Cbz-ClTHF81

NO

TMSCbz

490 491

1 DIBAL-H THF

2 Allyl-TMS BF3

Et2O 57

N

RCbz

492 R = TMS

486 R = H

TBAF THF86











178

Scheme 432

N

R

Cbz Co2(CO)8

DMSO

THF 65 degCN

R

Cbz HH

H

O

483 R = OTBS486 R = H

493 R = OTBS (69)494 R = H (74 41 dr)

117
















179


diastereomer

180

Scheme 433

N OBn

O

H

H

CbzN

H

HO

HCbzN

H

HO

H

H

R

(CO)2Co(CO)3Co

N OBn

O

H

H

R

H

(CO)2Co

Co(CO)3

R R

NCbz

Co2(CO)8

N OBn

O

HH

Co Co

(CO)3 (CO)3

N OBn

O

H

H

CoCo

(CO)3 (CO)3

H

R R

H

R

483 R = OTBS486 R = H

4

495 R = OTBS496 R = H

497 R = OTBS498 R = H

499 R = OTBS4100 R = H

4101 R = OTBS4102 R = H

493 R = OTBS494 R = H

4103 R = OTBS4104 R = H

181
















441 Retrosynthesis








182





Scheme 434

H

H

H

HNMe

MeN

O

O

H

H

NH

CbzN

O

H

NMe

CbzN

O

H

O

NH

NCbz

NH

NH2

CO2H

Baeyer-Villiger

414105

4106 4107 4108

PKR

H

H










183




Scheme 435

NH

NH2

CO2H


60 NH

NHCl

CO2H

i)Et3N CbzCl

CH2Cl2

ii) MeOH Et3N87 N

H

NCbz

CO2Me

OMe

TMS

BF3Et2O

CH2Cl281

51 cistrans

NH

NCbz

CO2MeDIBAL-H

toluene -78 degC


60NH

NCbz

4108 4109 4110

4111 4107










184

Scheme 436

N

NCbz

CO2Me

N

NCbz

R R

4111 R = H4112 R = Ts4114 R = Boc

4107 R = H4113 R = Ts4115 R = Boc




20-60







N

NCbz

CO2Me

Boc

N

NCbz

CHO

Boc


rapid decomp at rt

4114 4116

(43)







185




NH

NCbz

CO2MeDIBAL-H

toluene -78 degC


-78 degC -rt60

NH

NCbz

3111 3107

(44)






Scheme 437

NH

NCbz

NH

CbzN

O

H

Co2(CO)8DMSO (6 eq)

THF 65 degC92 H

H

NBoc

CbzN

O

H

H

HBoc2ODMAP

CH3CN 99

4117

4107 4106

186








NBoc

CbzN

O

H

H

H

4117

15







187

Scheme 438

NH

CbzN

O

H

NH

NCbz

Co2(CO)8

4107

4118

4106 4122

H

H

NH

CbzN

O

H

H

H

CoCbzN

BocN

H

H

H

Co

(CO)3

(CO)3

CbzN

BocN

H

H

H

Co

Co (CO)3

(CO)3

CoCbzN

BocN

H

H

H

Co

(CO)3

(CO)3

CbzN

BocN

H

H

HCo

Co(CO)3

(CO)3

4119

41204121




188






Scheme 439

NH

CbzN

O

4106

H

H

H

NMe

CbzN

O

4123

H

H

H

NaH MeI DMF91

Baeyer-Villiger

X

NMe

CbzN

4105

H

H

H

OO









189



Scheme 440

NBoc

CbzN

O

4117

NBoc

CbzN

O

4125

O

MCPBACH2Cl2 60

orCF3COOOH

Na2HPO4CH2Cl2 99

H2O2NaOH

THFMeOH

H

H

H

H

H

H

NBoc

CbzN

4124

H

H

H

OO

O

78








190

NBoc

CbzN

4124

H

H

H

OO

O

deoxygenationX

NBoc

CbzN

4105

H

H

H

OO

(45)








Scheme 441

HNR

CbzN

O

H

OH

4127

H

HNR

CbzN

CO2RCHO

H

H

4128

H

HNH

CbzN

O

H

4106

H

HNR

CbzN

OSiR3

H

4129

H H




191









4130156

192


NBoc

CbzN

OH

H

Hconditions

NBoc

CbzN

OSiEt3H

H

H





25

41304117



Entry

-------

-------1

2

3

5

4

NBoc

CbzN

OH

H

H

4131

+

H H









193




Scheme 442

Me2Si

O

Me2Si

2

Pt


NBoc

CbzN

OH

H

H

NBoc

CbzN

OTIPSH

H

H

4132

4117

H

NBoc

CbzN

OH

H

H

4131

H

NBoc

CbzN

OTESH

H

H

4130

HMe2Si

O

Me2Si

2

Pt

Et3SiH Toluenert 99

41304131 = 41

+







nitrogen atom

194

Scheme 443

NBoc

CbzN

OTIPSH

H

TBAF3H2O

THF 66

NBoc

CbzN

OH

H

NH

HN

OHH

H



H

H

H

H

H

H

4133

4132 4131










195

NBoc

CbzN

OTIPSH

H

H

H

ozonolysis

NBoc

CbzN

CHOH

H

CO2TIPS

4132 4134

X (46)






Scheme 444

HNR

CbzN

OSiR3

H

4136

H H

HNR

CbzN

CO2RCHO

H

H

4128

H

HNR

CbzN

O

H

4135

H HHO






196

HNBoc

CbzN

OTIPS

H

4132

H H

HNBoc

CbzN

O

H

4137

H HHO

mCPBA

CH2Cl20-20

(47)








Scheme 445

O

O

OOCOR

OTIPS mCPBAOTIPS

O

OTIPS

OH

H+

4138 4139 4140

OTIPS

OH

4141

RCO2-

OTIPS

4142

O

ROCOR

4143





197















198


NBoc

CbzN conditions

OTIPSH

H

NBoc

CbzN

OH

H

HO

Conditions

4132 4137

Entry Yield 4137

1 OsO4 (10) NMO (22 eq) THFH2O 23






H

H

H

H







199

Scheme 446

NBoc

CbzN

OH

H

HO

4137

H

H



4144

NBoc

CbzN

OH

CO2Me

H

H

HNBoc

CbzN

O

H

OH

4145

H

pTsOH CH2Cl2

99












200

Scheme 447

H

H

4145

NBoc

CbzN

OTIPS

H


THFH2O 51

NBoc

CbzN

CHO

CO2H

NBoc

CbzNH

H OO

NaBH4 MeOH


H

H

H

H

4132 4146









201

Scheme 448

LiAlH4

THF reflux 99

NaHthen MeI

DMF 88

NBoc

CbzNH

H OO

H

H

4145

NBoc

CbzNH

H OH

H

4147


2 MsCl Et3N THF 67

NH

MeNH

H OH

H

4148

NMe

MeNH

H OH

H

4149






obtained

202

Scheme 449

NMe

MeNH

H O


NMe

MeNH

H O

O

+

NMe

MeNH

H O

O

O



H

H

H

H

H

H

4149

41

4150







recovered

NMe

MeNH

H OH

H

4149

NMe

MeNH

H O

O

H

H

41

NMe2

O

POCl3 or Tf2OX (48)



203




Scheme 450

NBoc

CbzNH

H O


NBoc

CbzNH

H O

O



H

H H

H

4147 4152







204

Scheme 451

NMe

MeNH

H OH

H

4149

NMe

MeNH

H O

Cl3CO

H

H

4151

X

[H]

NMe

MeNH

H O

O

H

H

41

Cl3C

O

Cl














natural products169

205

Scheme 452

NBoc

CbzNH

H OH

H

4147

NBoc

CbzNH

H O

Cl3CO

H

H

4153

NBoc

CbzNH

H O

O

H

H

4152

ClCO2CCl3

pyridine 65 degC

Zn AcOH

75 2 steps










NBoc

CbzNH

H O

O

H

H

4152

NH

HNH

H O

O

H

H

4154

TMS-I

CH3CN78

(49)

206






Scheme 453

NMe

MeNH

H O

O

H

H

41

NMe

HNH

H O

O

H

H

4155

NH

MeNH

H O

O

H

H

4156

NMe

MeNH

H O

O

H

H

4157

NaH then MeI

DMF

side products

NH

HNH

H O

O

H

H

4154







EtOH))128

207

NMe

MeNH

H O

O

H

H

41

NH

HNH

H O

O

H

H

4154

MeI (2 eq)THF


72

(410)












208

Scheme 454

NH

CbzN

O

H

Co2(CO)8DMSO

THF 65 degC92 H

H

4106

NBoc

CbzN

O

H

H

HBoc2ODMAP

CH3CN99

4117

Me2Si

O

Me2Si

2

Pt


NBoc

CbzN

OTIPSH

H

H

4132

H H

H

4145

1 OsO4 (10) NaIO4 (4 eq)

THFH2O 51

NBoc

CbzNH

H OO

2 NaBH4 MeOH


NBoc

CbzNH

H OH

H

4147


2 MsCl Et3N THF 67

TMS-I

CH3CN78

NBoc

CbzNH

H O

O

H

H

4152



NH

HNH

H O

O

H

H

4154

NMe

MeNH

H O

O

H

H

41

MeI THF

then NaH MeI72

NH

NH2

CO2H


60 NH

NHCl

CO2H

i)Et3N CbzCl

CH2Cl2

ii) MeOH Et3N87 N

H

NCbz

CO2Me

OMe

TMS

BF3Et2O

CH2Cl281

51 cistrans

NH

NCbz

CO2Me

NH

NCbz

4108 4109 4110

4111 4107



-78 degC -rt60

209

45 Conclusions























210














211


51 General



















212






52 Compounds

6

51 23

4

78

O

O

O

217












213

NMR (75 MHz) δ 1549 1354 1277 752 541 249 201 128 IR (neat) 2964 2876


requires 1570865] 157 (base) 113





(C2) 541 (C8) 249 (C5) 201 (C1) 128 (C6)

O O

O

1

2

34

56

78

218









214





[C8H13O3 (M+1) requires 1570865]





(C8) 273 (C5) 175 (C1) 93 (C6)

6

6

5 61 2

3

4

78

O

O

O

225







215






NMR (75 MHz) δ 1550 1446 1237 757 543 327 291 205




1446 (C4) 1237 (C3) 757 (C2) 543 (C8) 327 (C5) 291 (C6) 205 (C1)

6

5

6

O O

O

1

2

34 6

78

226







216






1313 1260 865 543 342 256 177




(C7) 1313 (C2) 1260 (C3) 865 (C4) 543 (C8) 342 (C5) 256 (C6) 177 (C1)

6

89

12

34

5

7

O O

OO

219







217







75 3 H) 13C NMR (100 MHz) δ 1688 1687 1334 1301 581 523 521 374 254

186 137





1688 (C8) 1687 (C8) 1334 (C4) 1301 (C3) 581 (C7) 523 (C9) 521 (C9) 374

(C2) 254 (C5) 186 (C1) 137 (C6)

89

12

3 4 5

7

O O

OO

220

6



218









548 (m 1 H) 518 (dd J = 150 93 Hz 1 H) 369 (s 3H) 365 (s 3H) 331 (d J = 90


H)




082 (t J = 72 Hz 3 H C1-H)

O

O

O

O

12

34

5

78

9

6227



219











284 (m 1 H) 104 (d J = 69 3 H) 093 (s 9 H)




H)

220

1

23

45

6

7

8 9 10 1112

13

230

O

O

O

O















= 76 Hz 3 H) 13C NMR (100 MHz) δ 1704 1342 1289 784 741 609 521 402

256 241 169 138 35 IR (neat) 2959 2875 1732 1455 1434 1276 1218 1057

221


235 206 185






784 (C9) 741 (C10) 609 (C5) 521 (C13) 402 (C2) 256 (C7) 241 (C8) 169 (C11)

138 (C6) 35 (C1)

N

249

12

3

4

5

6

7

89

10

3

4

89








222




1372 1340 1296 1285 1272 1262 631 522 233 210 IR (neat) 2967 2780

1494 1446 1310 1167 965 748 692 MS (CI) mz 2021586 [C14H20N1 (M+1)

requires 2021596]





1285 (C8) 1272 (C5) 1262 (C9) 631 (C2) 522 (C3) 233 (C4) 210 (C1)

N

252

3

8

9

3

4

8

9

1

2

5

6

7

10





223






352 (s 2 H) 214 (s 3 H) 125 (s 6H) 13C NMR (75 MHz) δ 1470 1413 1285

1281 1265 1120 586 557 345 228 IR (neat) 2973 2842 2794 1494 1453 1411


1901596]





1265 (C10) 1120 (C1) 586 (C4) 557 (C6) 345 (C5) 228 (C3)








224





O

269

12

3

45

6 78

9

10

11

12

13








13C NMR (100 MHz) δ 1559 1366 1317 1287 1270 1264 1239 1206 1142

1124 692 253 132 IR (CHCl3) 3033 2967 2934 2874 1625 1597 1485 1452


1891279] 189 (base) 122 107



225





(C12) 1317 (C8) 1287 (C9) 1270 (C4) 1264 (C2) 1239 (C1) 1206 (C3) 1142

(C5) 1124 (C13) 692 (C7) 253 (C10) 132 (C11)

Br

O

271

12

3

45

6 78

9

10

11







J = 75 Hz 3 H) 13C NMR (75 MHz) δ 1551 1370 1332 1283 1232 1218 1137

1123 698 253 131 IR (neat) 2967 2934 2875 1586 1478 1276 1243 1031 970


241 137

226






1283 (C3) 1232 (C8) 1218 (C9) 1137 (C5) 1123 (C1) 698 (C7) 253 (C10) 131

(C11)

O

273

12

3

45

6

7 89

1011

12

1314

15

16







1308 1300 1296 1281 1278 1266 1210 1160 759 251 216 133 IR (CHCl3)



227





13C NMR (100 MHz) δ 1550 (C6) 1389 (C13) 1339 (C15) 1320 (C9) 1308 (C10)

1300 (C2) 1296 (C4) 1281 (C14) 1278 (C16) 1266 (C1) 1210 (C3) 1160 (C5)

759 (C8) 251 (C11) 216 (C7) 133 (C12)

HOO

1

2

3 4

5

67

8

Si

288










228


(100 MHz) δ 1322 1275 616 590 310 259 183 -52 IR (neat) 3355 2954 2857


requires 2171624] 217 (base) 199 133





(C5) 590(C1) 310 (C2) 259 (C8) 183(C7) -52 (C6)

O

O O

O9

1011

128

612

34

5 7

Si

289








229




MHz) δ 2004 1670 1326 1251 645 593 500 301 270 259 183 -52 IR







(C2) 1670 (C4) 1326 (C8) 1251 (C7) 645 (C9) 593 (C5) 500 (C3) 301 (C6) 270

(C1) 259 (C12) 183 (C11) -52 (C10)

O

O O

OH

8

612

34

5 7

9

290






230





NMR (100 MHz) δ 2009 1669 1317 1270 643 583 499 303 268 MS (CI) mz

1870970 [C9H15O4 (M+1) requires 1870970]




(C2) 1669 (C4) 1317 (C8) 1270 (C7) 643 (C9) 583 (C5) 499 (C3) 303 (C6) 268

(C1)

O

O O

O

861

23

4

5 7

910

11O

O

275







231






1301 1256 637 630 545 496 298 267 IR (neat) 2955 1802 1747 1714 1442


2451025] 245 186 169 (base) 154




NMR (100 MHz) δ 2002 (C2) 1668 (C4) 1553 (C10) 1301 (C8) 1256 (C7) 637

(C11) 630 (C9) 545 (C5) 496 (C3) 298 (C6) 267 (C1)

O

OO

8

6

7 1 2

3

45

9

278




232







585-576 (comp 2 H) 431-420 (m 2 H) 365 (dd J = 85 55 Hz 1 H) 284-278 (m 1


1738 1311 1292 678 632 292 286 269 IR (neat) 2958 1713 1650 1359 1261





NMR (100 MHz) δ 2016 (C8) 1738 (C7) 1311 (C4) 1292 (C3) 678 (C6) 632 (C1)

292 (C2) 286 (C5) 269 (C9)

233

8

6 7Br

O1

2

3 4

5Si

291











H) 088 (s 9 H) 005 (s 6 H) 13C NMR (100 MHz) δ 1325 1269 594 322 310

259 183 -52 IR (neat) 3021 2955 2856 1471 1360 1254 1095 837 776 MS (CI)





234


(C2) 259 (C8) 183 (C7) -52 (C6)

1386

7

12

34

59

10

1211O

O O

OSi

292















235





O

O O

OH

86

7

12

34

59

10

293










(app p J = 72 Hz 2 H)



236


72 Hz 2 H C6-H)

O

O O

O

86

7

12

34

59

1011 12O

O

294












[C12H19O6 (M+1) requires 2591182]



237


167 (app p J = 72 Hz 2 H C6-H)

10

1 23

9

4

5 67

8

2106

O

O

O

O












238

O CF3

O

12

34

5 67

2129








74 Hz 2 H) 100 (t J = 74 3 H) 13C NMR (100 MHz) δ 1572 1412 1204 1160

688 255 128 IR (neat) 1779 1634 1174 706 cm-1 MS (CI) mz 1830640

[C7H10O2F3 (M+1) requires 1830633]




1412 (C4) 1204 (C3) 1160 (C7) 688 (C5) 255 (C2) 128 (C1)

239

O O

O O

1

3

12

3

4

56

78

910

112137










H) 13C NMR (100 MHz) δ 1642 1317 1281 1227 1053 846 824 461 284

269 175 IR (neat) 3001 1788 1750 1309 1202 1070 941 758 MS (CI) mz

2580889 [C15H14O4 (M+1) requires 2580892]




1227 (C8) 1053 (C2) 846 (C6) 824 (C7) 461 (C4) 284 (C1) 269 (C1) 175 (C5)

240

12 3 4

567

8

9

10

1112

1314

2130

O

H

O

O

OO

15

16













230-210 (m 1 H) 210-190 (m 1 H) 181 (app t J = 153 Hz 1 H) 160-140 (m 1


[C20H23O5 (M+1) requires 3431545]

241





H C16-H) 100 (t J = 75 Hz 3 H C14-H)

N

O O

O

Si

O

O

420

12

3

4

56

7

8

9

10

1112

13

14

15









242









4002519]




185 Hz 9 H C13-H) 066 (dd J = 105 35 Hz 6 H C11-H)

243

N

O O

O

Si

O

O

1

11

2

3

4

56

7

8910

12

14

13

15

16

421
















244







H) 085 (s 9 H) 003 (s 6 H) IR (neat) 2955 2858 1754 1698 1392 1254 1177 MS





002 (s 6 H C12-H)

14 15N

O O

O

Si

422

12

3

4

56

7

8

9

10

1112

13



245














C15-H) 145 (s 9 H C1-H) 088 (s 9 H C13-H) 007 (s 6 H C11-H)

246

16N

O O

O

Si

1

11

2

3

4

56

7

89

10

12

14

13

15

414















H) 240-200 (comp 5 H) 174 (s 3 H) 142 (s 9 H) 089 (s 9 H) 009 (s 3 H) 008

247

(s 3 H) IR (neat) 3312 2955 2858 1704 1649 1385 1254 1123 873 776 MS (CI)






008 (s 3 H C12-H)

N

O O

O

O

1

12

15

2

3

4

56

7

8910

11

13

14

424








248







HN

O

Si

432

1

23

4

567

8

910

11

12 13










249

(100 MHz) δ 1439 1117 876 738 701 608 464 439 383 260 229 182 -46 -

49 IR (neat) 3311 2954 2930 2856 1648 1471 1255 1104 889 836 775 MS (CI)







738 (C2) 701 (C13) 608 (C1) 464 (C4) 439 (C5) 383 (C3) 260 (C8) 229 (C11)

182 (C10) -46 (C9) -49 (C9)

N

Me

O

Si

433

1

2

34

5

678

9

1011

12

13 14






250





006 (s 3 H) 005 (s 3 H) 13C NMR (75 MHz) δ 1443 1108 825 736 723 643

543 420 374 360 260 238 182 -44 -50 MS (CI) mz 2942246







13C NMR (75 MHz) δ 1443 (C7) 1108 (C8) 825 (C13) 736 (C14) 723 (C2) 643

(C5) 543 (C1) 420(C3) 374 (C6) 360 (C4) 260 (C12) 238 (C9) 182 (C11) -44

(C10) -50 (C10)

251

N

O

O OSi

1

2 3 4

5

6

78

910

11

1213

14

446














164 Hz 1 H) 009 (s 9 H) 13C NMR (100 MHz) δ 1911 1348 1288 1287 1286

1281 1077 1003 895 691 456 412 -039 IR (neat) 2960 1732 1677 1609 1329

252


(base) 312 284




13C NMR (100 MHz) δ 1911 (C3) 1348 (C8) 1288 (C1) 1287 (C10) 1286 (C9)

1281 (C11) 1077 (C2) 1003 (C12) 895 (C7) 691 (C13) 456 (C4) 412 (C5) -039

(C14)

N

O

OO

1

2 34

5

67

910

11

12

448

8

13

1415

16








253




NMR (75 MHz) δ 2054 1548 1359 1339 1285 1282 1280 1183 825 679 532

451 429 427 395 IR (neat) 3285 3067 3033 2977 1693 1642 1404 1322 1112






(C13) 1285 (C2) 1282 (C1) 1280 (C3) 1183 (C14) 825 (C15) 737 (C5) 679

(C16) 532 (C8) 451 (C10) 429 (C7) 427 (C11) 395 (C12)

254

N

O

O

O

O

451

17

1

2

3

4

567

8

9 10

11

1213

14

1516

H















2058 2055 1755 1531 1361 1279 1274 1270 1265 665 502 480 440 437


255







MHz) δ 2058 (C6) 2055 (C1) 1755 (C3) 1531 (C12) 1361 (C14) 1279 (C16)

1274 (C17) 1270 (C15) 1265 (C2) 665 (C13) 502 (C4) 480 (C8) 440 (C11) 437

(C7) 411 (C5) 384 (C9) 328 (C10)

N

O

Si

O O

1

2 3 4

5

6 78 9

10

1112

1314

15

460







256







NMR (100 MHz) δ 1917 1410 1346 1285 1281 1271 1266 1009 882 689

647 516 384 219 -04 IR (neat) 2959 2900 1731 1672 1604 1328 1296 1198


342 197 181 (base)





1281 (C15) 1271 (C13) 1266 (C14) 1009 (C2) 882 (C7) 689 (C11) 647 (C8)

516 (C5) 384 (C4 219 (C6) -04 (C9)

257

N

O O

Si

O

12 3 4

567 8

910

11

1213

1415

16

461

17
















MHz d6-DMSO 100 ˚C) δ 2052 1545 1390 1361 1278 1272 1269 1150 1034

258

868 664 526 510 418 417 259 -07 IR (neat) 3089 3034 2959 2900 1698


3701838]






(C3) 1545 (C17) 1390 (C13) 1361 (C7) 1278 (C15) 1272 (C16) 1269 (C14)

1150 (C6) 1034 (C12) 868 (C9) 664 (C10) 526 (C1) 510 (C2) 418 (C4) 417

(C5) 259 (C8) -07 (C11)

N

O O

O

1

2 3 4

567 8

910

1112

1314

15

462

18





259




100 ˚C) δ 740-729 (comp 5 H) 599 (ddd J = 160 105 45 Hz 1 H) 519-512




1361 1278 1272 1270 1152 803 724 664 527 512 417 416 247 IR (neat)

3307 3035 2959 1694 1407 1320 1271 1114 1057 MS (CI) mz 2981443

[C18H20NO3 (M+1) requires 2981443]







1388 (C12) 1361 (C7) 1278 (C14) 1272 (C13) 1270 (C15) 1152 (C6) 803 (C9)

724 (C11) 664 (C10) 527 (C1) 512 (C2) 417 (C4) 416 (C5) 247 (C8)

260

16

17

N

O

H

O

OO

1

2 34

5

6

7

89

10 11

12

13 14

15

463










2050 2043 1735 1533 1361 1317 1279 1273 1270 665 507 474 448 436

387 367 348 IR (neat) 3035 2963 2902 1706 1626 1416 1335 1264 1220 1100






261




(C12) 1361 (C8) 1317 (C14) 1279 (C16) 1273 (C17) 1270 (C15) 665 (C13) 507

(C1) 474 (C5) 448 (C11) 436 (C6) 387 (C10) 367 (C2) 348 (C4)

N

O

O O

469

1

2 34

5

6

78

910

11

1213

14

15

Si

16










262







MHz) δ 2054 1547 1376 1360 1285 1282 1280 1163 1077 1040 907 679

547 453 432 -049 IR (neat) 2959 1704 1403 1309 1250 1224 1054 844 MS






MHz) δ 2054 (C3) 1547 (C11) 1376 (C13) 1360 (C6) 1285 (C15) 1282 (C16)

1280 (C14) 1163 (C7) 1077 (C5) 1040 (C1) 907 (C8) 679 (C12) 547 (C9) 453

(C2) 432 (C4) -049 (C10)

263

N

O

O O

470

1

2 34

5

67

89

10

1112

1314

15










13C NMR (75 MHz) δ 2050 1548 1373 1358 1285 1282 1280 1167 824 738

680 548 449 432 425 IR (neat) 3285 2957 1698 1403 1310 1264 1310 1264


284 (base) 266 240




264




1548 (C10) 1373 (C6) 1358 (C12) 1285 (C14) 1282 (C15) 1280 (C13) 1167

(C7) 824 (C8) 738 (C11) 680 (C9) 548 (C1) 449 (C5) 432 (C2) 425 (C4)

11

10

1

23

45

6

7

89

12 1314

15

16

N

O

O

O

O

471

H










265






N

O O

O

Si

1

2 3 4

5

6

78

9

1011

12

473











266






007 (s 9 H) 13C NMR (100 MHz) δ 1912 1519 1410 1312 1190 1078 1003

895 679 456 413 -04 IR (neat) 3088 2960 2900 1732 1678 1608 1418 1372


2781212]






(C3) 1519 (C6) 1410 (C8) 1312 (C1) 1190 (C9) 1078 (C2) 1003 (C7) 895 (C10)

679 (C11) 456 (C4) 413 (C5) -04 (C12)

267

HN

O

Si

1

2 3 4

56

7

8

474








(100 MHz) δ 1912 1508 1020 992 895 451 418 -03 IR (neat) 3233 3022 2960


1941001]




(C3) 1508 (C1) 1020 (C2) 992 (C6) 895 (C7) 451 (C5) 418 (C4) -03 (C8)

268

NSiSO O

O

1

2 3 4

5

67

89

10

1112

13

475













13C NMR (75 MHz) δ 1899 1451 1408 1345 1300 1278 1078 981 912 469

422 215 -075 IR (neat) 3081 2963 1681 1597 1403 1362 1272 1168 846 MS


269





1899 (C3) 1451 (C6) 1408 (C1) 1345 (C9) 1299 (C7) 1278 (C8) 1078 (C2) 981

(C11) 912 (C12) 469 (C5) 422 (C4) 215 (C10) -075 (C13)

N

SO O

O

1

2 3 4

5

67

89

10

1112

476









270


H) 13C NMR (100 MHz) δ 1897 1454 1409 1344 1299 1278 1079 741 463

419 384 216 IR (neat) 3280 1676 1596 1363 1275 1167 1052 MS (CI) mz

2760693 [C14H14NO3S (M+1) requires 2760694]





(100 MHz) δ 1897 (C3) 1454 (C6) 1409 (C1) 1344 (C9) 1299 (C7) 1278 (C8)

1079 (C2) 741 (C12) 463 (C11) 419 (C5) 384 (C4) 216 (C10)

N

SO O

O

1

2 3 4

5

67

89

10

11

12

13

1415

477





271








NMR (75 MHz) δ 2044 1441 1369 1338 1299 1273 1187 815 748 554 457

446 434 388 216 IR (neat) 3305 1723 1356 1162 1094 MS (CI) mz 3181163







MHz) δ 2044 (C3) 1441 (C6) 1369 (C9) 1338 (C12) 1299 (C7) 1273 (C8) 1187

(C13) 815 (C14) 748 (C15) 554 (C5) 457 (C11) 446 (C4) 434 (C2) 388 (C5)

216 (C10)

272

N

O

SiO

1

2 34

5

67

8

9

10

11

1213

478













1323 1318 1286 1284 1081 1005 895 456 418 -04 IR (neat) 2962 1668


2981263] 298 (base)

273




C8-H) 13C NMR (75 MHz) δ 1914 (C3) 1691 (C9) 1420 (C1) 1323 (C10) 1318

(C13) 1286 (C12) 1284 (C11) 1081 (C2) 1005 (C6) 895 (C7) 456 (C5) 418 (C4)

-04 (C8)

N

O

O

1

2 34

5

67

910

1112

13

479

8

1415










274




1339 1293 1279 1260 1172 827 754 525 447 435 423 379 IR (neat) 3256


268 (base) 250






100 ˚C) δ 2043 (C3) 1697 (C11) 1354 (C12) 1339 (C9) 1293 (C15) 1279 (C14)

1260 (C13) 1172 (C10) 827 (C6) 754 (C7) 525 (C5) 447 (C8) 435 (C1) 423

(C4) 379 (C2)

275

N

O

O

H

SO

O

1

2 3 4

5

67

89

101112

1314

15

16

480








13C NMR (75 MHz) δ 2059 2056 1736 1445 1367 1300 1280 1271 521 501

459 453 416 385 332 216 IR (neat) 3689 2925 1715 1633 1353 1163 1098







(C8) 1736 (C6) 1445 (C12) 1367 (C15) 1300 (C13) 1280 (C7) 1271 (C14) 521

(C5) 501 (C1) 459 (C10) 453 (C9) 416 (C4) 385 (C2) 332 (C11) 216 (C16)

276

N

O

1

2 34

5

6

9

10

11

481

OH

7

8

12 13

O

14

15

16









2058 2056 1754 1685 1348 1294 1280 1266 1260 500 488 441 438 410

384 332 IR (neat) 2917 1713 1633 1410 1338 1217 914 MS (CI) mz 296







277


1754 (C11) 1685 (C12) 1348 (C10) 1294 (C13) 1280 (C15) 1266 (C16) 1260

(C14) 500 (C1) 488 (C5) 441 (C8) 438 (C2) 410 (C4) 384 (C7) 332 (C6)

N

OH

O O

1

2 3 4

5

6

78 9

10

11

1213

1415

16

482











278

3297 2953 1684 1409 1324 1087 1063 990 914 MS (CI) mz 300 [C18H22NO3

(M+1) requires 300] 300 (base) 258 256 238 214





Hz 1 H C4-H)

N

O O

12 3 4

5

6

78

11

1213

14

1516

1718

283

OSi

9

10

19







279






9 H) 007 (s 3 H) 005 (s 3 H) 13C NMR (100 MHz) δ 1555 1366 1365 1284

1279 1278 1168 854 706 673 642 507 391 386 366 336 258 181 -49 -

50 IR (neat) 3307 2953 2856 1694 1640 1407 1335 1312 1255 1093 774 MS (CI)








1366 (C7) 1365 (C16) 1284 (C18) 1279 (C19) 1278 (C17) 1168 (C8) 854 (C12)

706 (C15) 673 (C3) 642 (C13) 507 (C1) 391 (C5) 386 (C6) 366 (C2) 336 (C4)

258 (C11) 181 (C10) -49 (C9) -50 (C9)

280

N

O O

O

S

S

484

1

23

4

5

6

78

9

10

1112

13

1415

16

1718











168 125 68 Hz 1 H) 522 (m 1 H) 518 (s 2 H) 512 (d J = 168 Hz 1 H) 502 (d



H) 13C NMR (100 MHz) δ 2150 1552 1363 1355 1284 1280 1279 1178 843

751 712 676 496 386 383 328 292 191 IR (neat) 3290 2953 1697 1406

281


(base) 346 282







2150 (C9) 1552 (C13) 1363 (C15) 1355 (C7) 1284 (C17) 1280 (C18) 1279

(C16) 1178 (C8) 843 (C11) 751 (C14) 712 (C3) 676 (C12) 496 (C5) 386 (C1)

383 (C6) 328 (C4) 292 (C2) 191 (C10)

N

S S

O O

1

2 3 4

5

6

78

9 10

1112

13

1415

1617

18

485




282









NMR (75 MHz) 1552 1364 1351 1284 1280 1277 1177 841 725 675 619

523 448 418 412 396 385 384 IR (neat) 3288 2923 1698 1406 1318 1262







(C7) 1284 (C17) 1280 (C18) 1277 (C16) 1177 (C8) 841 (C11) 725 (C14) 675

(C12) 619 (C5) 523 (C1) 448 (C3) 418 (C2) 412 (C4) 396 (C6) 385 (C10) 384

(C9)

283

HNO

Si

1

23

4

5 67 8

490












188 -03 IR (neat) 3190 3077 2956 1687 1649 1405 1309 1252 841 756 MS





288 (C3) 188 (C4) -03 (C8)

284

NO

Si9

1011

1213

14

491

O O

1

23

4

5 67 8












1283 1280 1277 1031 888 684 483 340 285 175 -04 IR (neat) 3065 2959

2899 1778 1738 1714 1498 1455 1373 1250 1134 1062 843 MS (CI) mz 330




285


1351 (C11) 1283 (C13) 1280 (C14) 1277 (C12) 1031 (C6) 888 (C10) 684 (C7)

483 (C5) 340 (C2) 285 (C3) 175 (C4) -04 (C8)

N9

10

11

1213

14

486

O O

1

23

4

5

6

78

1516













286










= 100 ˚C) δ 1542 1363 1355 1277 1272 1269 1160 845 724 660 506 409

360 298 260 140 IR (neat) 3294 3248 2944 1697 1406 1318 1267 1098 MS







100 ˚C) δ 1542 (C11) 1363 (C13) 1355 (C7) 1277 (C15) 1272 (C16) 1269 (C14)

1160 (C8) 845 (C9) 724 (C12) 660 (C10) 506 (C6) 409 (C5) 360 (C1) 298 (C5)

260 (C2) 140 (C3)

287

N

O

1

23

4

5

6

9

10

11

494

O

OH

7

8

12 13

14 15

16

17







(dd J = 180 60 Hz 1 H) 249 (m 1 H) 215 (dd J = 135 75 Hz 1 H) 208-152


1278 1272 1268 1258 659 495 466 432 372 355 276 184 141 IR (neat)


312] 334 (base) 312






288

1364 (C10) 1278 (C14) 1272 (C16) 1268 (C17) 1258 (C15) 659 (C13) 495 (C1)

466 (C5) 432 (C7) 372 (C8) 355 (C6) 276 (C2) 184 (C4) 141 (C3)

N

O

O

OH

OSi

1

2 34

5

67

89

10

11 12

13

14 15

16

1718

1920

493










MHz d6-DMSO 100 ˚C) δ 2059 1790 1532 1363 1278 1272 1268 1256 660

622 480 454 418 371 353 350 326 250 169 -56 -57 IR (neat) 2928 2855

1713 1623 1416 1322 1278 1088 839 MS (CI) mz 442 [C25H36NO4Si (M+1)


289








(C11) 1532 (C12) 1363 (C14) 1278 (C16) 1272 (C17) 1268 (C15) 1256 (C10)

660 (C13) 622 (C3) 480 (C1) 454 (C5) 418 (C8) 371 (C6) 353 (C2) 350 (C4)

326 (C7) 250 (C20) 169 (C19) -56 (C18) -57 (C18)

N

N

SO O

O

O

OO

12

345

6

78

910

11

1213

1415

1617

18

1920

21

2223

24 25

26

27

4112





290









H) 313 (m 1 H) 302 (m 1 H) 272 (m 1 H) 240 (dt J = 155 95 Hz 1 H) 225 (s


1339 1336 1294 1293 1285 1278 1273 1270 1254 1246 1236 1184 1164

1159 1144 669 514 510 508 387 204 203 MS (CI) mz 5591909

[C31H31N2O6S (M+1) requires 5591903]








˚C) δ 1715 (C12) 1548 (C22) 1448 (C17) 1360 (C24) 1345 (C30) 1339 (C9)

1336 (C10) 1294 (C16) 1293 (C14) 1285 (C4) 1278 (C26) 1273 (C25) 1270

291

(C27) 1254 (C15) 1246 (C6) 1236 (C5) 1184 (C7) 1164 (C21) 1159 (C3) 1144

(C8) 669 (C23) 514 (C1) 510 (C13) 508 (C11) 387 (C19) 204 (C2) 203 (C18)

10

11

12

3

45

6 7

8 912

1314 15

16

1718

1920

21

22

23

24

25

N

N

O

O

OO

OO

4114











100 Hz 1 H) 365 (s 3 H) 318 (dq J = 80 160 Hz) 252 (m 1 H) 238 (m 1 H)

159 (s 9 H) 13C NMR (125 MHz) δ 1717 1548 1489 1359 1354 1340 1338

292

1278 1274 1273 1239 1223 1178 1162 1148 1122 841 668 513 512 509


requires 5052339]







1717 (C10) 1548 (C23) 1489 (C12) 1359 (C14) 1354 (C1) 1340 (C20) 1338

(C22) 1278 (C16) 1274 (C17) 1273 (C6) 1272 (C15) 1239 (C4) 1223 (C5) 1178

(C3) 1162 (C21) 1148 (C7) 1122 (C2) 841 (13) 668 (C24) 513 (C9) 512 (C11)

509 (C18) 385 (C19) 273 (C25) 204 (C8)

293

N

N

SO O

O

O

12

345

6

78

910

11

1213

1415

1617

18

1920

21

2223

24 25

26

27

4113
















294



1340 1334 1293 1292 1278 1274 1272 1254 1247 1238 1184 1168 1158

1147 838 736 668 518 384 383 266 203 MS (CI) mz 5251849

[C31H29N2O4S (M+1) requires 5251848]









(C24) 1359 (C10) 1343 (C14) 1340 (C15) 1334 (C4) 1293 (C16) 1292 (C26)

1278 (C25) 1274 (C15) 1272 (C27) 1254 (C6) 1247 (C6) 1238 (C5) 1184 (C7)

1168 (C21) 1158 (C8) 1147 (C4) 838 (C12) 736 (C13) 668 (C23) 518 (C1) 384

(C11) 383 (C19) 266 (C2) 203 (C18)

295

12

3

45

6 7

8 910

11

12

1314 15

16

1718

1920

21

22

23

24

25

N

N

O

O

OO

4115
















1489 1358 1356 1343 1330 1279 1278 1274 1272 1240 1224 1176 1165

296

1148 1119 841 733 668 664 514 386 377 272 265 IR (neat) 3293 3068








(C14) 1356 (C20) 1343 (C1) 1330 (C22) 1279 (C6) 1278 (C17) 1274 (C16)

1272 (C15) 1240 (C4) 1224 (C5) 1176 (C3) 1165 (C21) 1148 (C7) 1119 (C2)

841 (C10) 733 (C24) 668 (C13) 664 (C11) 514 (C9) 386 (C18) 377 (C19) 272

(C25) 265 (C8)

297

12

1314

151617

18

12

3

45

6 78

9 1011

NH

N

OO

O19

20

21

2223

4106

H















1774 1534 1361 1356 1323 1278 1273 1270 1265 1258 1206 1182 1172

298

1108 1055 663 493 476 402 371 344 250 IR (neat) 3464 3052 2985 1702









(C12) 1774 (C10) 1534 (C18) 1361 (C20) 1356 (C1) 1323 (C17) 1278 (C22)

1273 (C23) 1270 (C21) 1265 (C11) 1258 (C6) 1206 (C4) 1182 (C5) 1172 (C3)

1108 (C2) 1055 (C7) 663 (C19) 493 (C9) 476 (C16) 402 (C13) 371 (C14) 344

(C15) 250 (C8)

299

12

1314

151617

18

12

3

45

6 78

9 1011

N

N

O

OO

O

O19

20

21

2223

2425

26

4117













= 127 41 Hz 1 H) 162 (s 9 H) 13C NMR (125 MHz) δ 2059 1768 1533 1488

1360 1351 1323 1278 1275 1274 1271 1265 1239 1224 1178 1149 1141

300

841 665 541 481 403 362 339 272 246 IR (neat) 3400 2977 2929 1771








C26-H) 13C NMR (125 MHz) δ 2059 (C12) 1768 (C10) 1533 (C24) 1488 (C18)

1360 (C20) 1351 (C1) 1323 (C17) 1278 (C22) 1275 (C23) 1274 (C24) 1271

(C11) 1265 (C6) 1239 (C4) 1224 (C5) 1178 (C3) 1149 (C2) 1141 (C7) 841

(C25) 665 (C19) 541 (C9) 481 (C16) 403 (C13) 362 (C14) 339 (C15) 272 (C26)

246

301

19

N

N

O

OO

OO

H

OO

4124

12

3

45

6 7

8 9 10

11

12

1314

151617

18

20

21

2223

24 25

26














1710 1632 1421 1307 1252 1150 739 MS (CI) mz 531 [C30H31N2O7 (M+1)

requires 531] 531 463 319 243 (base)

302







35 Hz 1 H C15-H) 170 (m 1 H C15-H) 157 (s 9 H C20-H)

N

N

OO

H

OO

OO

4125

12

3

4

56 7

8 910

11

12

1314

151617

18

19

20

21

22

2324 25

26









303







100 ˚C) δ 2071 1534 1487 1359 1352 1321 1278 1275 1272 1270 1240

1224 1178 1148 1142 841 696 666 613 477 473 376 351 290 272 228

IR (neat) 2977 2928 1750 1730 1703 1455 1417 1360 1326 1156 1012 755 MS








(C18) 1487 (C21) 1359 (C23) 1352 (C1) 1321 (C17) 1278 (C25) 1275 (C6)

1272 (C26) 1270 (C24) 1240 (C4) 1224 (C5) 1178 (C3) 1148 (C7) 1142 (C2)

841 (C11) 696 (C22) 666 (C19) 613 (C10) 477 (C9) 473 (C16) 376 (C13) 351

(C15) 290 (C14) 272 (C20) 228 (C8)

304

N

N

O

H

H

OO

O O

Si

21

2223

2425

26

27

28

12

3

45

6 7

8 9 10

11 12

1314

151617

18

19

20

4130














NMR (125 MHz d6-DMSO 100 ˚C) δ 1648 1544 1538 1488 1364 1352 1328

1279 1278 1272 1268 1236 1222 1176 1148 1040 838 781 659 466 362

305

304 293 272 262 231 57 40 IR (neat) 2954 1729 1699 1636 1455 1421 1327









(C18) 1538 (C12) 1488 (C23) 1364 (C1) 1352 (C17) 1328 (C6) 1279 (C25)

1278 (C24) 1272 (C26) 1268 (C3) 1236 (C5) 1222 (C4) 1176 (C2) 1148 (C7)

1040 (C11) 838 (C9) 781 (C16) 659 (C22) 466 (C10) 362 (C13) 304 (C19) 293

(C15) 272 (C20) 262 (C8) 231 (C14) 57 (C28) 40 (C27)

306

19

N

N

OO

OO

4132

12

3

45

6 7

8 9

151617

18

20

21

2223

24 25

26

27

28

OSi10

11 12

1314

H

H













1547 1497 1367 1365 1359 1335 1332 1287 1286 1283 1282 1278 1277

1274 1240 1239 1226 1225 1177 1176 1156 1153 1147 1042 1038 838

836 671 668 480 478 476 474 473 471 407 406 313 309 299 280 279

307

276 270 177 123 IR (neat) 2943 2865 1731 1698 1634 1455 1424 1366 1325


405








1497 (C12) 1367 (C1) 1365 (C1) 1359 (C17) 1335 (C6) 1332 (C6) 1287 (C23)

1286 (C23) 1283 (C25) 1282 (C25) 1278 (C26) 1277 (C26) 1274 (C24) 1240

(C2) 1239 (C2) 1226 (C5) 1225 (C5) 1177 (C3) 1176 (C3) 1156 (C4) 1153 (C7)

1147 (C7) 1042 (C11) 1038 (C11) 838 (C19) 836 (C19) 671 (C22) 668 (C22)

480 (C16) 478 (C16) 476 (C9) 474 (C9) 473 (C10) 471 (C10) 407 (C8) 406

(C8) 313 (C13) 309 (C13) 299 (C13) 280 (C20) 279 (C20) 276 (C14) 270 (C14)

177 (C28) 123 (C27)

308

N

N

O

H

H

OO

O O21

2223

2425

26

12

3

4

56 7

8 9 10

11 12

1314

151617

18

1920

4131














1362 1351 1324 1278 1272 1270 1268 1237 1222 1176 1148 1107 839

662 469 446 402 384 291 283 279 272 231 IR (neat) 2953 1731 1701

309

1455 1423 1368 1326 1147 1016 747 MS (CI) mz 501 [C30H32N2O5 (M+1)









1488 (C18) 1362 (C23) 1351 (C1) 1324 (C17) 1278 (C25) 1272 (C26) 1270

(C24) 1268 (C26) 1237 (C4) 1222 (C5) 1176 (C3) 1148 (C7) 1107 (C11) 839

(C19) 662 (C22) 469 (C9) 446 (C13) 402 (C16) 384 (C11) 291 (C15) 283 (C10)

279 (C8) 272 (C20) 231 (C14)

NH

HN

OH

H

H

12

3

4

56 7

8 9 10

1112

1314

151617

4133




310













CD3OD) δ 1376 1355 1286 1217 1196 1184 1118 1082 729 497 455 422

394 354 341 323 300 IR (neat) 3394 29241450 1335 742 MS (CI) mz 270








311

1286 (C6) 1217 (C4) 1196 (C5) 1184 (C3) 1118 (C7) 1082 (C2) 729 (C12) 497

(C9) 455 (C16) 422 (C15) 394 (C10) 354 (C13) 341 (C11) 323 (C8) 300 (C14)

N

N

OHO

H

H

OO

O O

20

12

3

4

56 7

8 9 1011 12

1314

151617

18

19

21

2223

2425

26

N

N

OHO

H

H

OO

O O

20

12

3

4

56 7

8 9 1011 12

1314

151617

18

19

21

2223

2425

26

4137a 4137b














312



13C NMR (125 MHz d6-DMSO 100 ˚C) δ 2151 1543 1488 1363 1351 1325

1279 1278 1272 1268 1237 1223 1177 1151 1148 839 729 662 472 451

405 390 307 272 257 232 IR (neat) 3436 2976 1729 1699 1456 1424 1360

1328 1153 754








(C23) 1351 (C1) 1325 (C17) 1279 (C6) 1278 (C25) 1272 (C26) 1268 (C24)

1237 (C4) 1223 (C5) 1177 (C3) 1151 (C7) 1148 (C2) 839 (C19) 729 (C11) 662

(C22) 472 (C16) 451 (C10) 405 (C13) 390 (C9) 307 (C15) 272 (C20) 257 (C8)

232 (C14)

313

19

N

N

OO

OO

4144

12

3

45

6 7

8 9

1718

2021

22

2324

25 26

1011

1314

15

16

H

HO

O12

27

OH
















314

1543 1488 1364 1349 1337 1277 1271 1266 1236 1222 1176 1147 837

659 576 503 463 453 360 336 296 272 262 250 231 IR (neat) 2931 1729

1697 1454 1367 1328 1155 1116 912 747 MS (CI) mz 549 [C31H36N2O7 (M+1)

requires 549] 549 (base) 493 449








DMSO 100 ˚C) δ 1716 (C17) 1543 (C22) 1488 (C19) 1364 (C1) 1349 (C14) 1337

(C6) 1277 (C24) 1271 (C26) 1269 (C27) 1266 (C25) 1236 (C2) 1222 (C5) 1176

(C4) 1153 (C3) 1147 (C7) 837 (C20) 659 (C23) 576 (C15) 503 (C18) 463 (C13)

453 (C9) 360 (C10) 336 (C16) 296 (C8) 272 (C21) 262 (C12) 231 (C11)

315

19

N

N

OO

OO

4145

12

3

45

6 7

8 9

17

18

20

21

2223

2425

26

10

11

1314

1516

H

H

12OO
















316




1352 1324 1278 1272 1269 1259 1222 1176 1149 1107 1064 839 674

662 474 469 368 336 306 299 272 234 IR (neat) 2976 1731 1698 1455


517 (base) 417









1487 (C18) 1362 (C1) 1352 (C17) 1324 (C6) 1278 (C23) 1272 (C25) 1269

(C26) 1259 (C24) 1222 (C2) 1176 (C5) 1149 (C4) 1107 (C3) 1064 (C7) 839

(C11) 674 (C19) 662 (C22) 474 (C16) 469 (C9) 368 (C8) 336 (C13) 306 (C15)

299 (C10) 272 (C20) 234 (C14)

317

19

N

N

OO

OO

4147

12

3

45

6 7

8 9

17

18

20

21

2223

2425

26

10

11

1314

1516

H

H

12O

















318




˚C) δ 1538 1488 1428 1362 1351 1325 1277 1273 1272 1269 1236 1222

1176 1149 1148 1036 838 662 637 475 465 379 320 272 260 233 IR

(neat) 2976 1729 1699 1455 1422 1330 1142 747 MS (CI) mz 500 [C30H32N2O5

(M) requires 500] 500 401 387 (base) 267 229








(125 MHz d6-DMSO 100 ˚C) δ 1538 (C21) 1488 (C18) 1428 (C12) 1362 (C1)

1351 (C17) 1325 (C6) 1277 (C23) 1273 (C25) 1272 (C26) 1269 (C24) 1236

(C2) 1222 (C5) 1176 (C4) 1149 (C3) 1148 (C7) 1036 (C13) 838 (C19) 662

(C22) 637 (C11) 475 (C16) 465 (C9) 379 (C8) 320 (C15) 272 (C20) 260 (C10)

233 (C14)

319

NH

NH

H O

12

3

4

56 7

8 9 10

11

12

1314

151617

18

4148













1 H) 13C NMR (100 MHz C6D6) δ 1441 1362 1320 1285 1216 1197 1185

1111 1072 1050 668 555 549 417 408 358 242 228 IR (neat) 3394 2927

2360 1646 1457 1244 1070 741 668 MS (CI) mz 2811657 [C18H21N2O (M+1)

requires 2811654]

320








(C6) 1216 (C4) 1197 (C5) 1185 (C3) 1111 (C7) 1072 (C2) 1050 (C13) 668

(C11) 555 (C9) 549 (C16) 417 (C10) 408 (C15) 358 (C18) 242 (C8) 228 (C14)

N

NH

H O

19

12

3

45

6 7

8 9 10

11

12

1314

151617

18

4149









321








1188 1179 1097 1087 1063 1048 666 552 536 418 405 379 347 237

229 IR (neat) 2925 2360 2340 1644 1467 1379 1070 895 738 668 MS (CI) mz

2931659 [C19H21N2O (M-1) requires 2931654]








(C1) 1265 (C17) 1208 (C6) 1188 (C4) 1179 (C5) 1097 (C3) 1087 (C7) 1063

(C2) 1048 (C13) 666 (C11) 552 (C8) 536 (C16) 418 (C10) 405 (C15) 379 (C19)

347 (C18) 237 (C8) 229 (C14)

322

19

N

N

OO

OO

4152

12

3

45

6 7

8 9

17

18

20

21

2223

2425

26

10

11

1314

1516

H

H

12O

O27

28














100 ˚C) δ 815 (d J = 80 Hz 1 H) 771 (s 1 H) 747 (d J = 80 Hz 1 H) 733-723



323



1488 1362 1351 1327 1277 1274 1273 1269 1237 1223 1193 1176 1148

1107 838 662 647 477 460 359 299 272 257 242 223 IR (neat) 2913

1721 1691 1612 1427 1318 1090 740 MS (CI) mz 543 [C32H35N2O6 (M+1)

requires 543] 544 543 488 444 (base) 400








MHz d6-DMSO 100 ˚C) δ 1939 (C27) 1568 (C21) 1539 (C18) 1488 (C12) 1362

(C1) 1351 (C17) 1327 (C6) 1277 (C23) 1274 (C25) 1273 (C26) 1269 (C24)

1237 (C2) 1223 (C5) 1193 (C4) 1176 (C3) 1148 (C7) 1107 (C13) 838 (C19)

662 (C22) 647 (C11) 477 (C16) 460 (C9) 359 (C8) 299 (C15) 272 (C20) 257

(C10) 242 (C28) 223 (C14)

324

NH

NH

4154

12

3

45

6 7

8 9

17

10

11

14

1516

H

H

12O

O13

1819
















MHz) δ 1955 1575 1356 1355 1272 1215 1213 1193 1177 1112 1079 674

325

483 477 374 323 288 250 237 IR (neat) 2921 1614 1453 1321 1195 738 MS









1355 (C1) 1272 (C6) 1215 (C2) 1213 (C5) 1193 (C4) 1177 (C3) 1112 (C13)

1079 (C7) 674 (C11) 483 (C16) 477 (C9) 374 (C8) 323 (C15) 288 (C10) 250

(C19) 237 (C14)

N

N

41

12

3

45

6 7

8 9

17

10

11

14

1516

H

H

12O

O13

1819

20

21





326










211 (ddd J = 112 46 40 Hz 1 H) 207 (s 3 H) 189 (m 1 H) 180 (dd J = 120 36

Hz 1 H) 13C NMR (75 MHz) δ 1955 1574 1372 1332 1265 1211 1208 1187

1178 1090 1059 678 547 538 418 385 324 291 250 229 228 IR (neat)

2895 2359 1617 1468 1320 1276 1192 911 741 MS (CI) mz 337 [C21H25N2O2










327

(C17) 1265 (C6) 1211 (C4) 1208 (C5) 1187 (C3) 1178 (C2) 1090 (C13) 1059

(C7) 678 (C11) 547 (C9) 538 (C16) 418 (C21) 385 (C20) 324 (C8) 291 (C10)

250 (C19) 229 (C15) 228 (C14)

328

References












329















330















331














332

















333

















334













335

















336














337













338

















339














340
















341



342

Vita










Dedication

To Stephanie Hall

v

Acknowledgements











work was based

vi




















vii
















viii

Table of Contents

List of Tables xii


List of Schemes xiv




121 Introduction2












141 Introduction33




ix













16 Conclusions51













x

24 Conclusions95


31 Introduction97

311 Alstonerine98





















36 Conclusions141


41 Introduction144


421 Introduction148

xi















45 Conclusions209


51 General 211

52 Compounds 212

References328

Vitahellip342

xii

List of Tables


xiii

List of Figures


xiv

List of Schemes


xv


xvi


xvii


1





















2











121 Introduction













3










Scheme 11

M

X-Nuc-

11

X

12

X

M

13

M

14

Nuc

M

15

Nuc

4













Scheme 12

Br

OAcPd(PPh3)4

THF

DMF

OAc

MeO2C

SO2Ph

Br

+CO2Me

SO2Ph

SO2Ph

CO2Me16 17

18

19





5



Scheme 13

R1 R2

X M

R1 R2

M

110 111

Nuc-Nuc-

a b

R1 R2

Nuc

112

R1 R2

113

Nuc

path a

path b

-X-









used as a substrate

6

Scheme 14

LG Nuc

LG Nuc

Pd

Pd

Ru Mo Rh Ir W

Ru Mo Rh Ir W

+ Nuc

115114

116 117










7

Scheme 15

NaHCH2(CO2Me)

OAc

118NaH

CH2(CO2Me)

Pd(PPh3)4

W(CO)3(MeCN)383

or

119 E = CO2Me

E

E

E E

120 E = CO2Me

+

119 E = CO2Me

E

E

E E

120 E = CO2Me

+

119120 = 8614

119120 = 496









8

Scheme 16

OAc

OAc

NaHCH2(CO2Me)

Mo(CO)6

NaHHCMe(CO2Me)

orE

E

E

EMe

121 122

123 E = CO2Me

124 E = CO2Me

89

84















9


sections

Scheme 17

nPr OAc

THF reflux 19 h66

THF rt 1 h94



[Ir(COD)Cl]2 (2)

nPr

nPr

CO2Me

CO2Me

MeO2C CO2Me

126

125

127

126127 = 8812

+

nPr

nPr

CO2Me

CO2Me

MeO2C CO2Me

126 127

126127 = 397

+








documented1316


Alkylations



10








membered) rings

Scheme 18

LG

Nuc Nuc

M

M

127 128











11



favored (Eq 12)

O

O

OAcH

H

CO2Me

SO2Ph

NaH THF

Pd(PPh3)4 dppe60

O

O

SO2PhCO2Me

H

H

129 130

SO2Ph

OAc

SO2Ph

131

SO2Ph

SO2PhBSA THF

Pd(dppe)244

132

(11)

(12)







12

O

SO2Ph

OO

SO2Ph

O134 135

O

SO2Ph

O

133

OAc

+

NaH Pd(PPh3)4Diphos

THF reflux73

134135 = 928

OPh

CO2Me

O

Pd(OAc)2 PPh3

62

CO2Me

O

136 137

(13)

(14)














13
















14

Scheme 19

soft Nuc-

hard Nuc-

H

Nuc

M

140

M

NucM

142

oxidativeaddition

H

Nuc

141

Nuc

H

M

143


Nuc

H

144

M

139

H

LG

138

M

M












minimize A13-strain

15

Scheme 110

R OAc OAc

R

145 146

R OAc OAc

R

147 148


MLn MLn

syn anti

R Nuc Nuc

R

149 150

Nuc- Nuc-








16

Me

PhOAc


151

Me Ph

CO2MeMeO2C

152THF rt

99

Me

OAc


154

THF rt96

Ph

Me Ph

153

CO2MeMeO2C

Me Ph

CO2MeMeO2C

152

Me Ph

153

CO2MeMeO2C

+

+

152153 = 9010

152153 = 928

(15)

(16)










palladium catalysis

Me

PhOAc

155

TfaN

Zn OOtBu

PPh3 [Pd(allyl)Cl]2

THF -78 degC - rt69

Ph157

tBuO2C

NHTfa

156

(17)

17















Scheme 111

nPr OAcTHF reflux

85

NaCH(CO2Et)2


158

nPr

159

CO2Et

CO2EtnPr

nPr

CO2Me

CO2Me

MeO2C CO2Me

160

161

+

+

159160161 = 9073

18















OCO2Me

OMe

O O

RhH(PPh3)4 (5)PBu3 (10)

CO2Me

O162

163

164

THF rt93

(18)




19











OCO2Me

OMe

O O


O

CO2Me

O

+

165

163

166 167

168

OCO2Me

dioxane 100 degC97

OMe

O O

RhH(PPh3)4 (5)PBu3 (10)

163

dioxane 100 degC81

CO2Me

O

CO2Me

O

+

166 167

166167 = 7228

166167 = 1486

(19)

(110)

20























21




991 91

982 89

OCO2Me

169

R1 R2

170

R1 R2CO2Me

CO2MeR1

171

R2

MeO2C

CO2Me



+


1

2

3

4

5

6

phosphite

H

H

H

Me

Me

Me

Me

nPr

Ph

Me

nPr

Ph

P(OMe)3

P(OMe)3

P(OMe)3

P(OPh)3

P(OPh)3

P(OPh)3

982

gt991

964

gt991

95

89

73

32









22



nucleophilic attack

Scheme 112

OCO2Me

165

168

OCO2Me


P(OMe)3 (20) THF

173172

+

From 168 172173 = 421 99From 165 172173 = 21 83

or

MeO2C CO2Me

CO2Me

CO2Me














23



Me

OCO2Me

MeD

Me MeD

CO2MeMeO2C

Me Me

D

CO2MeMeO2C

+

P(OPh)3 (20) THF92


174 175 176

175176 = gt191

R1

OCO2Me

R2 Me iPr

CO2MeMeO2C

+

P(OPh)3 (20) THF92


179 180

From 177 179180 = 973From 178 179180 = 397

iPrMe

MeO2C CO2Me


(111)

(112)










24

Scheme 113

R

Rh(I)

R

Rh(III)

Nuc

R

LG

R

Rh(III)

NucRh(I)

Path A

Path B

R

LG

R

R

R

k1k-1

k2

k3

R

Nuc

R

RNuc

R

181 182 183

184185

186
















25

Scheme 114

R


P(OMe)3 THF R

OR


R

OAr

R

TsNBnor or

187 188 189 190







Group












26











27


OCO2MeR1


NaCH(CO2Me)2 R1

R2R3 R4

CO2Me

CO2Me

+ MeO2CR4

R3R1 R2

CO2Me191 192

193

THF rt


majorminor

1

2

3

OCO2Me CO2Me

CO2Me

OCO2MeCO2Me

CO2Me

OCO2Me

CO2Me

CO2Me

75

80

86

928

946

991(973 ZE)

OCO2MeCO2Me

CO2Me

4 84 973

Ph OCO2Me PhCO2Me

CO2Me

593 9010

194

196

198

1100

1102

195

197

199

1101

1103






28











29


OCO2MeR1

R2R3 R4

R1

R2R3 R4

CO2Me

CO2Me

+ MeO2CR4

R3R1 R2

MeO2C

191

11051106

THF


majorminor

1

2

3

OCO2Me

OCO2Me

OCO2Me

85

98

98

991

8812

1000(8812 ZE)

OCO2Me4 98 gt955

194

196

198

1110

CO2MeMeO2C

Me

+

NaH[Rh(CO)2Cl]2

1104

Me

CO2Me

CO2Me

Me

CO2Me

CO2Me

Me

CO2Me

CO2Me

Me

CO2Me

CO2Me

1111

1109

1108

1107

Me Me

30











OCO2Me

1102

[Rh(CO)2Cl]2 PhLi

ZnBr2 THF rt99


Ph

1112

99 ee 92 ee

(113)










31










regioselectively

32


OCO2MeR1


NucR1

R2R3 R4

+Nuc R4

R3R1 R2

191 1113 1114


majorminor

1OCO2Me

84 928

1100

NucTHFrt

nucleophile

OCu(I)

Ph Ph

O

2OCO2Me

75 gt955

1117

OCu(I)

PhPh

O

1115

1115

1116

1118

3OCO2Me

78 9010

1100

11191120

4OCO2Me

42 8812

1100

11211122

NTsLiTsN Ph

LiTsN TsN





33










Scheme 115

R

Rh(I)

R

Rh(III)

Nuc

R

LG

R

Rh(III)

NucRh(I)

Path A

Path B

R

LG

R

R

R

k1k-1

k2

k3

R

Nuc

R

RNuc

R

181 182 183

184185

186


141 Introduction





34












MeO

H

H+

Co2(CO)8 ∆

Me1123 1124

1125

(114)









35







Scheme 116

Co2(CO)8

Co(CO)3(CO)3Co

R-CO

Co(CO)2

Co(CO)3

R

Co

Co(CO)3

R

COCO

Co

Co(CO)3

R

CO

O

(CO)3CoCo(CO)

O

R

O-Co2(CO)4

R

1126 1127 1128 1129

1132 1131 1130

R








36







MOMO

PhCo2(CO)8

toluene 100 degC41

11351136 = 32

O

Ph

MOMO

O

Ph

MOMO

+

11341133

+

1135 1136

MeS

PhCo2(CO)8

toluene 100 degC61

11371138 = 181

O

Ph

MeS

O

Ph

MeS

+

11381137

+

1139 1140

(115)

(116)








37
















OEtO2C

EtO2C



EtO2C

EtO2C

1141 1142

(117)





38



catalysts






fashion64


toluene 90 degC92

O

Ph

O

1143 1144

OPh

(118)







Me

O

1145 1146

MeEtO2C

EtO2CEtO2C

EtO2C

CO (10-15 atm)Ru(CO)12 (2)


86-76

(119)



39







Scheme 117

Ph

O

11471148

PhEtO2C

EtO2C

EtO2C

EtO2C



toluene 110 degC 99









40

Scheme 118

TBSOMe Co2(CO)8


50

Me

O

TBSO

H

1148 1149

6 steps HO

H

1150

O

OH

H

HO

H

1151

O

OH

H

O

O

H











41

Scheme 119

OOAc

N NO

H H

H


51

1152 1153

N

H H

H

1154

O

9 steps

OAc






Scheme 120


THF 65 degC67

11561157 = 611155

MeO MeO1156

N

O

MeO1158

N

7 steps

MeO1157

N

O+

H

42







Scheme 121

O O

1159 n = 1 or 2

PKR

n

1160 1161

or










43

O

Me

MeO

O

Me

Me

O

Co2(CO)8 CH2Cl2

1164 1165

then NMO48

O

O

O

OO

1162 1163

Co2(CO)8 CH2Cl2

then NMO31

(120)

(121)







cedrene (1170)

Scheme 122

O O

OO

O

DCE 83 degC95

11671166

Co2(CO)8nBuSMe

1170

H

1169

H

1168

O

H

5 steps

44











Scheme 123

O O

O

H


then Me3NO2H2O60-70

OO

OO

11731174

K2CO3MeOH

55O

CO2Me

O

H

1175

O

H

1176

HO HOHO

HO

H

H

O O

O

H

1171

H

TMS

Br


1172

45
























46






Cl

CO2Me+

MesN NMes

RuPh

PCy3ClCl

1178

1176 1177

then H2 (100 psi)69

CO2Me

Cl

1179

OOHi) 1178


11801181

56

(122)

(123)









47







reported

EtO2C

EtO2C

CO (441 psi)Co2(CO)8 (5 )

CH2Cl2 130 degC68

OEtO2C

EtO2C

PhPh

1182 1183

MeO2C

MeO2C

1184

Co nanoparticles


98

OMeO2C

MeO2CH

H

1185

(124)

(125)









48




dodecylsulfate)

MeO2C

MeO2C

1186

OMeO2C

MeO2C

1187


SDS H2O 100 degC

PhPh

O

HH+ (126)















49


back bonding81

Scheme 124

∆

Me


NaH

CO CH3CN 30 degC

CO2MeMeO2C

168

1188

Me

MeO2C

MeO2C

CO2Me

CO2Me

Me+

1189 1190

OMeO2C

MeO2C

Me H

OMeO2C

MeO2C

Me H

+

1191 1192

11891190 = 371 88

11911192 = 71 87









50








Scheme 125

X

+ LG

R

[Rh(CO)2Cl]2X

R

X

R

X O

R

XR

PKR

X = C(CO2Me)2 NTs O

[5+2]

cycloisom

CO

11931194

1195

1196

1197

1198








51











fashion

Scheme 126

OCOCF3


72

MeO2C

MeO2CCO2MeMeO2C

Me


89

OCOCF3 MeO2C

MeO2C

1200

1202

1104

1199

1201

16 Conclusions



52












palladium catalysis












53






















54











R

R

OCO2Me

Nuc[Rh(CO)2Cl]2

R

R

Nuc

R

OCO2Me

R

Nuc[Rh(CO)2Cl]2

R

Nuc

R

21 22

23 24

(21)

(22)








55









Scheme 21

O

NBn

Rh(I)

RO

NBn

R

XX

MeO2CO

Rh(I)

X O

R

Rh(I)X

R

MeO2CO R

OCu(I)

NBn

[Rh(CO)2Cl]2

[Rh(CO)2Cl]2

[Rh(CO)2Cl]2

25

26


2728




-CO


X


X

56
















R R R R215 216


OCO2Me Nuc






57




Scheme 22

OCO2Me

OCO2Me


THF rtor

218

217

219 220

+

From 217 72 7624 219220From 218 76 5545 219220











58

Scheme 23

OCO2Me

OCO2Me


THF rtor

222

221

223 224

+

From 221 56 955 223224From 222 58 8614 223224










Scheme 24


THF rt227 228

+

From 225 29 946 227228From 226 21 919 227228


OCO2Me

OCO2Me

or

226

225



59











[Rh(CO)2Cl]2 +

220 219

CH2(CO2Me)2 NaH

218


1

2

3

4

DMSO

CH3CN

THF

DMF

62

62

76

73

2575

3664

4555

6931






60


DMF -20 degC88

[Rh(CO)2Cl]2 +

219 220

CH2(CO2Me)2 NaH

217

219220 = 964

(24)









this chapter

OCO2Me

217

CO2MeMeO2C

+

229

MeO2C

MeO2C

MeO2C

MeO2C 231

230

+

NaH[Rh(CO)2Cl]2

DMF -20 degC88

230231 = 937

(25)






61


Scheme 25

OCO2Me


DMF -20 degC

222

OCO2Me

226

orno reaction












112)37




62














21)






OCO2Me

HN



232

233

(26)

63









OCO2Me

HN


96234235 = 11

232

233

234

N

235

N

+(27)





OCOCF3

HN


233

N

CF3O

OH

238

+

237

(28)




64




O

HN



with TBAI 98 5 h

OH

N

233

239

240

(29)













65

Scheme 26

RhCl

OC

OC

ClRh

CO

CO

HN

RhClOC

NHOC


233

240

I-

RhI

OC

OC

IRh

CO

CO

HN

RhIOC

NHOC

RhI

OC

OC

I

slower

Bu4N+I-

Bu4N+

233

242

243

244-I-










66




R2

R1 OCO2Me


NHR1R2 (2 eq)DCE rt

R2

R1 NR2

R3R4 R3

R4R2N

R2R1

+

TBAI (20 mol)



HN

HN

NHBn

Me

OCO2Me

OCO2Me

Me

OCO2Me NMe

Bn

N

Me

N 96

99

89

gt955

gt955

gt955

233

233

250

232

248

251

234

249

252

245 246 247

NHBn

MeN

Me

Bn

85 gt955

250 253 252

OCO2Me






67















PKR

68

Scheme 27

BnNH2

Br

64 BnHN

PhI CuIPd(PPh3)4

Et3N82

BnHNPh

254255 256

OCO2Me

257


DCE rt-reflux86

BnNPh

258

not BnN

Ph

O

259















69








structures like 264

Scheme 28

OH

R1260


O

R1

R2

R5

R4R3

261


O

O

O

O

R2

R3

R4

R5

R2

R3

R4R5

R2

R3

264

262

263

HeckR1 = halide

RCMR1 = alkene

or alkyne

PKRR1 = alkyne

[Rh(CO)2Cl]2





70













71


R2

R1 OCO2Me

R3R4 R2

R1 Nuc

R3R4 R3

R4Nuc

R2R1

+



245 265 266


THF rt

OH

OH

Br

OH

Ph

+

267

270

272

OCO2Me

268

OCO2Me

268

217

OCO2Me

OH

Ph

272

OCO2Me

251

O

269

O

Br271

O

Ph273

O

Ph274

77 gt955

87 7129

lt10 NA

73 gt955

Nuc







72























73


Scheme 29

O

OO

OCO2Me

O

O O

O

OO

catalyst

base

Pd

Rh 275

276

277

278

O

OO

M






Scheme 210

OH OTHP

On-BuLi

HMPA Et2OTHF65

OTHP

HO


OODMAP

O

O O

279

TsOHH2O

O

280 281

282 283

CH2Cl293

EtOAc78

Et2O84 THPO


74







Scheme 211

O

O O

283THPO

conditionsO

O O

284HO

+ HO

282

THPO

HO

285

HO

+










75

Scheme 212

OH

TBSCl imid

OTBS

On-BuLi

BF3Et2O THF

71OTBS

HO


OO

DMAP

O

O O

OTBS

TBAF THFO

O O

OH

O

O O

OCO2Me

pyr CH2Cl291

279 286 287

288 289

290 275

91

ClCO2Me

DMF99

EtOAc99

Et2O84









76


O

O O

OCO2Me275

O

OO

Conditions


1

2

3

4

5

NaH

NaH

KOtBu

KOtBu

KOtBu

THF

DMF

THF

DMF

DMF

rt

rt

rt

rt

0

20

34

51

54

68

278







O

O O

+O

OO

O

O O

OCO2Me275

278 277

278277 = 5545

55(210)



77






Scheme 213

HOOTBS

288

CBr4 PPh3

Et3N CH2Cl278

BrOTBS

291

OMe

OO

NaH n-BuLi

MeO

O O

OTBS

TBAF

MeO

O O

OH

pyr CH2Cl283

MeO

O O

OCO2Me

292 293

294

ClCO2Me

THF69

THF63








78


MeO

O O OO

OMe

+

O

OMe

OKOtBu[Rh(CO)2Cl]2

(10 mol)

DMF -20 degC52

294295 296

295296 = 4357

(211)

MeO2CO




212)21

OPh

CO2Me

O

Pd(OAc)2 PPh3

62

CO2Me

O

297 296

(212)


Reactions





(Eq 213)84

79

NBn

O


ii) 1 N HCl (aq) 71

O

O

298 299

(213)





Scheme 214

NBn

O

i) [Rh(CO)2Cl]2 ∆

ii) 1 N HCl (aq)

O

O

2101 2102

NBn

OH

2100

[Rh(CO)2Cl]2

OCO2Me

R2

R1

R3 R4

245

R2

R1

R4 R3

R2

R1

R4R3







80

NBn

O

298

then HCl53 O

O

299


(214)










O

OH

2103

+ OCO2Me

257

O

O

2104


THFwithout CuI 33

with CuI 64

(215)




moderate yield

81

NBn

OH

2100

+ OCO2Me

257

NBn

O

298


THF55

(216)









Scheme 215

NBn

OH

2100

OCO2Me257

NBn

O

298


THF or toluenert

rt-150 degCX

then HClO

O

299





reaction sequences

82








CO2MeMeO2C

MeO2CO

MeO2C CO2Me

2106

2105

CH3CN 80 degC75


(217)





83

Scheme 216

CO2MeMeO2C+

OCO2Me

OCO2Me2107

2108

CO2MeMeO2C

MeO2CO

[Rh(CO)2Cl]2


2106

2105









84


CO2MeMeO2C+

OCO2Me

OCO2Me


solvent rt-reflux

MeO2C CO2Me

equiv 2107

21072108

2106

MeO2CCO2Me

CO2MeMeO2C

+

2109


1

2

3

4

5

6

25

25

25

25

15

15

1

1

1

1

1

1

2

2

2

2

1

1

THF

dioxane

toluene

DMF

THF

dioxane

15

23

20

0

20

32

--

24

7

32

17

16







85

CO2MeMeO2C+

OAc

OCO2Me


(10 mol)

dioxane rt-reflux45

21062109 = 21

MeO2C CO2Me

21072110

2106 MeO2CCO2Me

CO2MeMeO2C

+

2109

15equiv

1equiv

(218)


















86

MeO2C CO2Me+

R


MeO2C

MeO2C

R

1

23

4

5

67

8

2111 2112

2113

(219)







Scheme 217

+

R

LG

R LG

or

or

[Rh(CO)2Cl]2

OMeO2C

R

4

2115

2114

2119R LG2116

R

R

MeO2C CO2Me

2111

2

MeO2C

OMeO2C

2117

R

2

MeO2C

OMeO2C

R

42118

MeO2C

[Rh(CO)2Cl]2

[Rh(CO)2Cl]2






87




Scheme 218

CO2MeMeO2C

Ph

OCO2Me


91

PhMeO2C

MeO2C


THF reflux99

MeO2C

MeO2C

Ph

O

CO (1 atm)

21212120

2122

257




2121

CO2MeMeO2C

PhNaH CO (1 atm)


THF rt - reflux

PhMeO2C

MeO2C

2120

OCO2Me

257

not 2122 (220)






88









inhibited the PKR

O

Ph

MeO2C

MeO2C

2122


NaOMe or NaOAcX

MeO2C

MeO2C

2121

(221)











89











promote the PKR

CO2MeMeO2C

Ph

+ OCO2Me


O

Ph

MeO2C

MeO2C

2120

257

2122



(222)








90



223)

CO2MeMeO2C

Ph

+ LGCO NaH

[Rh(CO)2Cl]2O

Ph

MeO2C

MeO2C2120

2123

2122



rt - reflux(223)











Scheme 219

91

MeO2CCO2Me

OCOCF3 OMeO2C

MeO2C+

R

CO [Rh(CO)2Cl]2

(10 mol )

R

azeotroped wtoluene

2126

2127 R=H = 732122 R=Ph = 682128 R=Me = 67

2124 R = H2120 R = Ph2125 R = Me










Scheme 220

CO2MeMeO2C

PhCO (1-40 atm)


Ph

OMeO2C

MeO2C

Et

X


2120 2130

OCOCF3

2129





92



reagent

Scheme 221

2120

+OCOCF3

2129

CO NaH [Rh(CO)2Cl]2

(10 mol)THF

MeO2C

MeO2C

2131

MeO2C CO2Me

Ph

2 eq 1 eq

1 eq 2 eq

Ph

Isolated Yield96

24












93

O

Ph

MeO2C

MeO2C2122

MeO2C

MeO2C

2121

Ph

CO [Rh(CO)2Cl]2


O

Ph

MeO2C

MeO2C

2122

MeO2C

MeO2C

2121

Ph

+51 24 h

2126

(224)

(225)

CO [Rh(CO)2Cl]2

(10 mol) THF reflux

2120

MeO2C CO2Me

Ph








[Rh(CO)2Cl]2 +O O

BaCO3O

ORh

CO

CO

[Rh(CO)2Cl]2 +

O

O O

O

Base OMeO

MeOO

RhCO

CO

R R

2132 2133

21342135

(226)

(227)




94











Scheme 222

O

OO

O

2138

THF rt-reflux

PhOH


2) BH3Me2NH


2136

O O

O O

Ph2137

O

OO

O Ph

O

2139

Ph

not observed


OCOCF3

2129




95





Scheme 223

CO2MeMeO2C

Ph

OCOCF3 Ph

OMeO2C

MeO2C

EtH

21202130


2129

Ph

OEtO2C

EtO2C

MeH

2140

24 Conclusions










96











97


31 Introduction













linkage


N

NMe

Me

OH

O

H

H

H

H

macroline (31)

NH

NHO

H

H H

HOH

sarpagine (32)

421

16

4 21

98

311 Alstonerine







ring


N

MeN

Me

O

O

H

H

H

H

33

A BC D

E










99



Scheme 31

NH

N

H

H H

HOH

37

NH

NH

34 Strictosidine

O

MeO2C

OGlu

HNH

N

35

OH

MeO2CH

H H

NH

N

H

H H

CHO

CO2Me

36








100

Scheme 32

NH

NH

34 Strictosidine

O

MeO2C

OGlu

HH N

H

NH

38

OHCHO

MeO2CH

H

NH

NH CHO

H

H H

CHOCO2Me

39

NH

NH CHO

H

H H

CHOCO2Me

310

NH

N

H

H H

CHO

CO2Me

36










Tamelen

101

Scheme 33

NH

N

311

OHC

H

CO2H

NH

N

312

OHC

H

DCC PTSA

dioxane

NH

N

H

H H

313

CHO

NMe

N

H H

ajmaline (314)

OHHO

H

H

NMe

N

CN

315

H

TBSO

BF3Et2O

NMe

N

316

H

TBSO

NMe

N

H

H H

317

HCHO

NMe

N

H

H H


HCHO

KOHMeOH

56






102






Scheme 34

N

MeN

Me

OH

O

H

H

H

H

31

N

MeN

Me

O

O

H

H

H

H

33

NH

N

H

H H

HOH

37

NH

N

H

H H

HOTBS

319

TBS-Cl imid

DMF

NH

N

H

H H

HOTBS

320

Oi) Me2SO4 K2CO3

ii) TBAF






103






norsuaveoline (322)

Scheme 35

H

NMe

BnN

O

Dieckmann

Pictet-SpenglerH

323

NH

NH2

CO2H

324

NMe

MeN

OH

H

H

H

alstonerine (33)

O

NMe

MeN

talcarpine (321)

H

H

H

H

OMe

CHO

NH

HN

H

H

N

Et

norsuaveoline (322)







104















105

Scheme 36

NH

NH2

CO2H

324

1) NaNH3 MeI


Me

NH2

CO2Me

325

PhCHO MeOH

NaBH4 -5 degC88 N

Me

NHBn

CO2Me

326

1) C6H6dioxane ∆

HO2C

O

CO2H

2) HClMeOH ∆

80NMe

NBn

CO2Me

CO2Me

327

NaH MeOH

PhMe ∆

92

NMe

BnN

328

O

CO2Me

H

H

AcOHHClH2O

∆ 91NMe

BnN

323

OH

H

3

5







106

Scheme 37

N NNMe

H

CO2Me

CO2Me

MeNPh

H

CO2Me

CO2Me

Ph

HNNMe

H

CO2Me

CO2MePh

HNNMe

H

CO2Me

Ph

CO2Me

NMe

NBn

CO2Me

CO2Me

trans-327

cis-327

329 330

HCl

trans-327









107





reaction vessels

Scheme 38


NH

NH2

CO2Me

324


CH2Cl2 rt 48h

83 NH

NBn

CO2Me

CO2Me

331

NMe

N

323 gt98 ee

OH

H Ph85NMe

NBn

CO2Me

CO2Me

327

NaH MeI

DMF95









108










as the acid source

Scheme 39

NH

NHBn

CO2Me

332

TFA CH2Cl2 92

MeO CO2Me

OMe 336

NH

NBn

CO2Me

CO2Me

331

HO2C CO2H

O 333

PhHdioxane

pTsOH ∆ 86N

NBn

CO2Me

334 O

+

N

NBn

CO2Me

335 O

41 transcis

109




ketone 338

Scheme 310

NH

NBn

CO2Me

CO2Me

331

N

NBn

CO2Me

334 O

NaOMe

NH

BnN

337

O

CO2Me

H

H NH

BnN

338

OH

H

AcOHHClH2O

∆ 91









110



Scheme 311

H

NMe

BnN

O

H

323

NMe

MeN

321

H

H

H

H

OMe

CHO

NMe

BnN

339

H

H

H

H

OOMe

conjugate addn

NMe

BnN

340

H

H

H

H Et

NMe

BnN

341

H

H

CHO

HO R


acetal formation

oxy-cope









111

Scheme 312

NMe

BnN

323

OH

H


2) LiClO4 dioxane

∆ 90 NMe

BnN

341

H

H

CHO

Et Et

Br 342

Mg 90

NMe

BnN

343

H

H

HO

Et

Et

+

NMe

BnN

344

H

H

Et

O Et

H

H

NMe

BnN

345

H

H

Et

O Et

H

H+




313)115116

Scheme 313

NMe

BnN

343

H

H

HO

Et

Et

NMe

BnN

344

H

H

Et

O Et

H

H

NMe

BnN

345

H

H

Et

O Et

H

H+

KH18-crown-6

cumene150 degC 88





112











Scheme 314

NMe

BnN

341

H

H

CHO

NMe

BnN

347

H

H

HO

Et

Li-biphenylBaI2 THF

Et Br

346

90

NMe

BnN

348

H

H

Et

OH

H

NMe

BnN

349

H

H

Et

OH

H+

KH18-crown-6

dioxane100 degC 85

MeOK

15 20

1615 20

16



113




Scheme 315

NMe

BnN

349

H

H

Et

OH

H

NaBH4 MeOH

96NMe

BnN

350

H

H

Et

HOH

H


2) NaIO4 MeOH 78

NMe

BnN

351

H

H

H

H

OOH

Et

pTsOH PhH

95

NMe

BnN

352

H

H

H

H

O

Et

N

O

O

SePh

pTsOH MeOH

NMe

BnN

353

H

H

H

H

O

EtSePh

OMe

NaIO4

H2OTHFMeOH90

NMe

BnN

339

H

H

H

H

OOMe

NMe

BnN

354

H

H

H

H

OOMe

+




114




understood117

Scheme 316

NMe

BnN

339

H

H

H

H

OOMe

90NMe

BnN

355

H

H

H

H

OMe

CHO

NMe

BnN

356

H

H

H

H

OMe

CHO+

K2CO3 EtOH 85

01 torr 100 degC 75

H2SO4







115

Scheme 317

NMe

BnN

355

H

H

H

H

OMe

CHO

NMe

BnN

356

H

H

H

H

OMe

CHO

PdC (10 mol)

H2 EtOH92

NMe

MeN

talcarpine (321)

H

H

H

H

OMe

CHO

H2PdC (xs)

MeOH (15 eq)

90

NMe

N

talpinine (357)

H

OMe

H

HO H

H







syntheses







116




(322)

Scheme 318

NH

BnN

358

H

H

Et

OH

H

NH

BnN

338

H

H

O

NH

BnN

359

H

H

Et

CHOH

H

O O

pTsOHacetone

95NH

BnN

360

H

H

CHO

Et

CHOH

H

NH2OHHCl

EtOH ∆

88NH

RN

H

H

N

Et

361 R = Bn322 R = H

H2 PdC92

1) HO(CH2)2OH pTsOH

PhH ∆ 90







117















118

Scheme 319

NH

BnN

338

OH

H

5 PdC H2HCl EtOH

rt 5 H94 N

H

NH

362

OH

H

BrI

K2CO3 THF ∆

87

NH

N

363

OH

HI


DMF-H2O 65 degC80

NH

N

H

H H

364

O

NH

N

H

H H

vellosimine (365)

HCHO






macroline alkaloids







119











31)105

Scheme 320

NMe

N

CN

367

H

NMe

N

H

H H


HCHO

Mannich reaction

NH

NHCl

CO2H

368OTBS

vinylogous Mannich






120



374

Scheme 321

NH

NHCl

CO2H

368

OMe

TBSO 369

1)


H

NH

CO2tBu

370

CO2Mediketene

DMAP PhMe

KOtBu 86

NH

N

CO2tBu

371

H

OO

MeO2C

1) NaBH4 95


H

N

CO2tBu

372

H

O

MeO2C


then NaBH490

NMe

N

CO2tBu

373

H

MeO2C

TFA

PhSMe90

NMe

N

CO2H

374

H

MeO2C






121



Scheme 322

NMe

N

CO2H

374

H

MeO2C

1) EDCI NH4OH 86

2) TFAA py 90NMe

N

CN

375

H

MeO2C

1) LiBH4 THF 98

2) DMP 83

NMe

N

CN

376

H

OHC

NaH TBS-Cl

NMe

N

CN

367

H

TBSO

BF3Et2O

NMe

N

377

H

TBSO

NMe

N

H

H H

378

HCHO

NMe

N

H

H H


HCHO

KOHMeOH

56







122











Scheme 323

NH

NHCl

CO2H

i)Et3N CbzCl

CH2Cl2

ii) MeOH Et3N87 N

H

NCbz

CO2Me

OMe

TMS

BF3Et2O

CH2Cl281

51 cistrans

NH

NCbz

CO2MeDIBAL-H

toluene -78 degC


60NH

NCbz

368 379

380 381




123



Scheme 324

NH

NCbz

381

RuPh

Cy3P

PCy3Cl

Cl

CH2Cl2 rt97

NH

CbzN

383


2) NaIO4 aq THF 54

NH

CbzN

384

CHO

382

H

H H

H
















124







enantiocontrol

Scheme 325

NMe

OH1) BuLi

2) I2 NMe

OH

I DMP

57 (3 steps) NMe

CHO

I

TMSO

OMe

388

385 386 387

Zn(OTf)2 BnNH270 N

Me

I

389

N

O

Bn


P(tBu)3 CH3CN ∆

85NMe

N

390

H

H Ph

O








125













126

Scheme 326

NH

NH2

CO2H

324

1) LAH 98

2) TsCl py 78 NH

NHTs

391

OTs

1) KCN 86

2) NaNH3(l) THF 88

NH

NH2

392

CN

OHCOTBS

393


then CH2Cl2 TFA80

NH

394

NH

CN



NMe

395

NBn

CN

CHO

NMe

397

NBn

CN

(EtO)2PO

Et

O

OEt

396

NaH 65

Et

CO2Et

LiNEt2 THF

-78 degC 99 NMe

N

398

H

H Ph

CO2EtCN

Et

HH

NMe

NH

399

H

H

OHO

Et

H

H

1) LiBH42) pTSA 88

3) DIBAL-H 504) H2Pd-C 100





(3104)

127

Scheme 327

NMe

395

NBn

CN

CHO

(EtO)2PO

Et

CN

3100

NaH 83 NMe

3102

NBn

CN

Et

CN

KOtBu THF

67

NMe

N

3103

H

H Ph

CNCN

Et

HH

NMe

NH

H

H

N

Et

3104

















128











129

Scheme 328

NH

NHBoc

CO2Me

3105

MeNC nBuLi

82NH

NHBoc

3106

O

N

1) TFA 98


NH

NH

3107

O

N

EtO2C

O 1) POCl3

2) Na2CO3 50

NH

3108

NH

CO2Et

O

N

1) H2Pd(OH)2-C 84

2) Boc2O 87

NH

3109

NBoc

CO2Et

O

N

NMe

NH

H

H

N

Et

3104



4) MeI NaH

5) TFA 80









130










alkaloids111

131

Scheme 329

O

O OBnNH2

H2O

NBn

OH

HO

31103111

+

BnN

HO OH

3112

1) TFAA

2) NaOH 95

BnN

HO OH

3112


50

BnN

HO OTBS

3113

1) H2 PdC

2) K2CO3 PhCOCl 85

BzN

HO OTBS

3114


2) HF CH3CN 95

BzN

OH

3115

1) H2NN(Me)Ph

MeOH HCl ∆

2) LiAlH4 THF 95

NMe

BnN

3116

OHH

H


73NMe

BnN

(plusmn)-323

OH

H








132










Scheme 330

H

NMe

BnN

O

H

H

HNMe

MeN

O

O

H

33



323









133




Scheme 331

NMe

BnN

323

OH

H

1) MeOTf

2) H2PdC80 N

Me

MeN

3118

OH

H



NMe

MeN

3119

H

H

CHO

NMe

MeN

3120

H

H

OH

LiAlH4

Et2O -20 degC90

Me

O

Et3N dioxane90

NMe

MeN

3122

H

H

O

PhH 145 degC

sealed tube65 N

Me

MeN

3123

H

H

CHO

O OH

3121







134

Scheme 332

NMe

MeN

3123

H

H

CHO

OH

NaBH4

EtOH86 N

Me

MeN

3124

H

H

OHH

HO

i) 9-BBNTHF rt 20 h


NMe

MeN

3125

H

H

OHH

HOHO

TsCl pyr rt


NMe

MeN

3126

H

H

H

O

OH

H

H

(COCl)2 DMSO CH2Cl2


MeN

33 51

H

H

H

O

O

H

NMe

MeN

3127 30

H

H

H

O

O

H

+









135

Scheme 333

MeN O

MeN

H HH

H

OH

MeH

N

MeN

Me

O

OH

H

H

H

H

3126

H

3126

excess DMSO(COCl)2

MeN O

MeN

H HH

H

O

MeH

3128

SH MeN O

MeN

H HH

H

OH

MeH

3129

tautomerization

MeN O

MeN

H HH

H

OH

Me

3130

DMSO(COCl)2

MeN O

MeN

H HH

H

O

Me

33








136






Scheme 334

NMe

BnN

323

OH

H NMe

N

H

H H


HCHO

4 steps








137

Scheme 335

NMe

N

H

H H

366

HCHO

NaBH4

MeOH 0 degC90 N

Me

N

H

H H

3131

H


90

NMe

N

H

H H

3132

H


NaOH H2O2 rt


85

NMe

N

H

H H

3133

H

OTIPS

H

OH

DMP CH2Cl2

82NMe

N

H

H H

3134

H

OTIPS

H

O

MeI THF

KOtBu EtOH THF ∆

90

NMe

MeN

3135

H

H

H

OTIPS

O

H

NMe

MeN

33

H

H

H

O

O

H


60




323

138










Scheme 336

NMe

CHO


79

NMe

NNs

Ph3POEt

OCO2EtBr

CHCl3 ∆

Ph3POEt

O

EtO2C

Br

AcCl Et3NCH2Cl2

73

CO2Et

CO2Et

3138

3140

3136

3137

3139

+

PBu3 (30)

CH2Cl2 rt73 31 drN

Me3141

NCO2Et

CO2EtNs

H




139





Scheme 337

NMe

3141

NCO2Et

CO2EtNs

H

HCl EtOAc

90 NMe

NsN

3142

H

H

CO2EtO

PhSH K2CO3

DMF99

NMe

HN

3143

H

H

CO2EtO

HCHO HCO2H ∆

99NMe

MeN

3144

H

H

CO2EtO

NaBH3CN ZnI2

DCE ∆74

NMe

MeN

3145

H

H

CO2Et

BH2CN

EtOH ∆

98

NMe

MeN

3146

H

H

CO2Et

NMe

MeN

(plusmn)-3120

H

H

OH

DIBAL-H

tol -78 degC92






140












Scheme 338

NMe

TsN

3152

H

H

SO2Ph

CHO

PhO2S SO2Ph

NMe

NTs


55-64NMe

NHTs

PhO2S

KMnO4Bu4NBr

CH2Cl261 N

Me

NHTs

PhO2SOH

OH



315031493147

NMe

3151

NTs

PhO2S

CHO

3148

141






Scheme 339

NMe

TsN

3152

H

H

SO2Ph

CHO


95 NMe

TsN

3153

H

H

OTBDPS


-78 degC - rt36 N

Me

TsN

3154

H

H

OOTBDPS

H




optimized

36 Conclusions





142


















143


H

NMe

BnN

Pictet-SpenglerH

H

NMe

BnN

HeckH

O

H

NMe

BnN

H

FischerIndole

O

NMe

NsN

H

H



R

390Kuethe

323Rassat

3142Kwon

144



Alstonerine

41 Introduction

















145

Scheme 41

H

NMe

BnN

O

Diekmann

Pictet-SpenglerH

H

HNMe

MeN

O

O

H

41



H

HNMe

MeN

O

O

H

41

Wacker


42

E

E

A B

A B

C D

C D

11 steps

10 steps













146



Scheme 42

H

HNMe

MeN

O

O

H

41

H

H

HNMe

RN

OH

43

H

O

H

HNMe

RN

44

H

O

NMe

NR

45

Acylation

Baeyer-Villiger

PKR








A (49)134

147

Scheme 43

MeN

H2N

O

O

46

RN

47

PGO

O

RN

PGO

48

410

N

N

OH

O

O

Me

MeO

O

O

MeO

Me

Me

HH

H

O Me

O

Me

N

N

R411

N

NR

R

R

O

49










148


421 Introduction













derivative 415136

149

Scheme 44

MeN

H2N

O

O

46

MeN

H2N

412

HO

O

HO

BocN

413

TBSO

O

BocN

TBSO

414

BocN

TBSO

CO2Me

415

O









150

Scheme 45

HN

HO

CO2H SO2Cl

MeOH99

H2+Cl-

N

HO

CO2Me N

HO

CO2Me

Boc

dioxane70

TBS-Climidazole

N

TBSO

CO2Me

Boc RuO2H2O (20)

NaIO4N

TBSO

CO2Me

Boc

O

416 417 418

419 415

Boc2OiPr2NEtDMAP

DMF96

EtOAc96












151

Scheme 46

N

TBSO

CO2Me

Boc

O N

TBSO

CO2Me

Boc

415

R



Et2O toluene

N

TBSO

Boc1 DIBAL-H CH2Cl2


R







152

Scheme 47

N

TBSO

Boc

414

TBAF THF N

HO

Boc

N

HO

Boc

+

Ac2O Et3NCH2Cl2 97

92

N

AcO

Boc

422 423

424





153








complex 425

154

Scheme 48

N

TBSO

Boc

BocN

TBSO

O

426414

Co2(CO)8 N

TBSO

Boc

425

Co2(CO)6

conditions


THFX






Scheme 49

N

TBSO

Boc

BocN

TBSO

O

429422

Co2(CO)8 N

TBSO

Boc

428

Co2(CO)6

conditions


THF






155







N

TBSO

Boc

HCl or ZnBr2 N

TBSO

O O

414 430

(41)





156

Scheme 410

N

TBSO

Boc HN

TBSO

HN

TBSO

+


414 431 432

N

TBSO

K2CO3 MeIacetone

55

Me

433

88431432 = 13






attempted

Scheme 411

N

TBSO

Me

MeN

TBSO

O

435433

Co2(CO)8 N

TBSO

Me

434

Co2(CO)6

conditions


THF

157










Scheme 412

N OBn

O

H

H

Co

Co(CO)3

(CO)2

N OBn

O

H

Co Co

(CO)3 (CO)3

436 437

TBSO TBSO

N

TBSO

Boc

422

Co2(CO)8

N

TBSO

Boc

428

Co2(CO)6

158










Scheme 413

HNMe

RN

O

H

NMe

NR

44 45

PKR

H

PKR

N

R

439

m nRN

O

438

m n




159





Scheme 414

N

X

R

O

A13-Strain N

X

R

O

m

m

n

n

PKR N R

O

X n

m

440 X = H2 O 441 442

O

431 Initial Studies









160

Scheme 415

N

OMe

R1

MgBrn



CbzN

O

R1

n

MgBr

R2

MeLi CuCN (111)

THF -78 degC73-81

CbzN

O

R1

R2

443 444 445

n












Scheme 416

N

OMe

TMSTHF

then Cbz-Cl 95

N

O

Cbz

N

O

CbzTMS


TMS R

443 446447 R=TMS

448 R=H

K2CO3MeOH75

EtMgBr

161










N

O

Cbz

N

O

Cbz

SnBu3


96

TMS

446 448 gt191 dr

(42)








piperidine 448

162

Scheme 417

NO

TMS

O

O

N

H

TMS

OO

O

Nuc

Nuc

449 450










Scheme 418

N

O

Cbz

448

Co2(CO)8

DMSO

THF 65 degC89

NCbz

OH

O

451

H

H

N

O

Cbz HH

451

H

O

3



163
















164




Scheme 419

Co(CO)2

(CO)3Co

H

Co(CO)2

Co(CO)3

H(CO)3Co Co(CO)3

+

452

cis-453

trans-454













165

Scheme 420

N OBn

O

H

H

NCbz

Co2(CO)8

Co

Co

N OBn

O

H

H

Co

N OBn

O

H

H

Co Co

(CO)3 (CO)3

N OBn

O

H

H

O

O

O

O

O

CbzNO

H

H

448

455 456

457 458

451 459

O

HCbzNO

H

HO

H

CoCo

Co

(CO)3(CO)2

(CO)3(CO)2

(CO)3(CO)3




166













Scheme 421

N

OMe

443

TMSBr


77

N

O

Cbz

460

TMS

CuCN MeLi (111)

MgBr

TBAFH2OTHF 69

N

O

Cbz

R


461 R = TMS

462 R = H

6





167













Scheme 422

N

O

Cbz

462

Co2(CO)8

DMSO

THF 65 degC91

N

O

O

CbzH HH

463

N OBn

O

HO

463

H

O

1

2






168






467

169

Scheme 423

NCbz

Co2(CO)8

N OBn

O

H

O

O

CbzNO

H

H

CbzNO

H

H

462

465

468 463

H

Co

N OBn

O

HO

464

Co

(CO)3(CO)3

HCo Co

(CO)3 (CO)3

H HO O

H

N OBn

O

HO

466

Co(CO)2(Co)3Co

N OBn

O

HO

467

H

(CO)2Co Co(CO)3





170












171

Scheme 424

N

O

CbzTMS

446

CuCN MeLi (111)

MgBr

TBAFH2O THF 53

N

O

Cbz

Co2(CO)8

DMSO

THF 65 degC33 31 dr


R

469 R = TMS

470 R = H

N

O

CbzH H

471

N OBn

O

HO

471

H1

2

O

H

O

6












172



Scheme 425

Cbz

N

O

448

H2 PdCor

TMSIX

HN

O

472









173

Scheme 426

Alloc

Ts Ts

N

OMe

MgBrTMS

THF then Alloc-Cl77

N

O443

TMS HN

O

TMS

dimethyl malonate

Pd(PPh3)4 THF93

nBuLi THF -78 degC

then TsCl50

N

O

R

475 R = TMS

476 R = H

K2CO3MeOH48

TMS


N

O

473 474

477






Scheme 427

Bz BzHN

O

TMS

474

nBuLi THF -78 degC

then BzCl98

N

O

TMSSnBu3


91 gt191 dr

N

O

478 479




174















advantageous145

Scheme 428

N

O

R Co2(CO)8

DMSO

THF 65 degCN

O

R HH

H

O

477 R = Ts479 R = Bz

480 R = Ts (61)481 R = Bz (94)

7

175














Scheme 429

CbzN

O

448

L-Selectride

THF -78 degC99

CbzN

OH

482

TBS-Climidazole

DMF81

CbzN

OTBS

483

4 4






176







Scheme 430

N

Cbz

448

O


BF3Et2O

HSCH2CH2SH

CH2Cl284

N

Cbz

485

S S

N

Cbz

486

Raney NiX

X

N

Cbz

484

O

S


XAIBN Bu3SnH








177



Scheme 431

HNO O NaBH4 HCl

EtOH

HNO OEt

HNO SO2Ph

PhSO2ClHCO2H

CH2Cl260

nBuLi

TMS

THF71

487 488 489

HNO

TMSnBuLi

then Cbz-ClTHF81

NO

TMSCbz

490 491

1 DIBAL-H THF

2 Allyl-TMS BF3

Et2O 57

N

RCbz

492 R = TMS

486 R = H

TBAF THF86











178

Scheme 432

N

R

Cbz Co2(CO)8

DMSO

THF 65 degCN

R

Cbz HH

H

O

483 R = OTBS486 R = H

493 R = OTBS (69)494 R = H (74 41 dr)

117
















179


diastereomer

180

Scheme 433

N OBn

O

H

H

CbzN

H

HO

HCbzN

H

HO

H

H

R

(CO)2Co(CO)3Co

N OBn

O

H

H

R

H

(CO)2Co

Co(CO)3

R R

NCbz

Co2(CO)8

N OBn

O

HH

Co Co

(CO)3 (CO)3

N OBn

O

H

H

CoCo

(CO)3 (CO)3

H

R R

H

R

483 R = OTBS486 R = H

4

495 R = OTBS496 R = H

497 R = OTBS498 R = H

499 R = OTBS4100 R = H

4101 R = OTBS4102 R = H

493 R = OTBS494 R = H

4103 R = OTBS4104 R = H

181
















441 Retrosynthesis








182





Scheme 434

H

H

H

HNMe

MeN

O

O

H

H

NH

CbzN

O

H

NMe

CbzN

O

H

O

NH

NCbz

NH

NH2

CO2H

Baeyer-Villiger

414105

4106 4107 4108

PKR

H

H










183




Scheme 435

NH

NH2

CO2H


60 NH

NHCl

CO2H

i)Et3N CbzCl

CH2Cl2

ii) MeOH Et3N87 N

H

NCbz

CO2Me

OMe

TMS

BF3Et2O

CH2Cl281

51 cistrans

NH

NCbz

CO2MeDIBAL-H

toluene -78 degC


60NH

NCbz

4108 4109 4110

4111 4107










184

Scheme 436

N

NCbz

CO2Me

N

NCbz

R R

4111 R = H4112 R = Ts4114 R = Boc

4107 R = H4113 R = Ts4115 R = Boc




20-60







N

NCbz

CO2Me

Boc

N

NCbz

CHO

Boc


rapid decomp at rt

4114 4116

(43)







185




NH

NCbz

CO2MeDIBAL-H

toluene -78 degC


-78 degC -rt60

NH

NCbz

3111 3107

(44)






Scheme 437

NH

NCbz

NH

CbzN

O

H

Co2(CO)8DMSO (6 eq)

THF 65 degC92 H

H

NBoc

CbzN

O

H

H

HBoc2ODMAP

CH3CN 99

4117

4107 4106

186








NBoc

CbzN

O

H

H

H

4117

15







187

Scheme 438

NH

CbzN

O

H

NH

NCbz

Co2(CO)8

4107

4118

4106 4122

H

H

NH

CbzN

O

H

H

H

CoCbzN

BocN

H

H

H

Co

(CO)3

(CO)3

CbzN

BocN

H

H

H

Co

Co (CO)3

(CO)3

CoCbzN

BocN

H

H

H

Co

(CO)3

(CO)3

CbzN

BocN

H

H

HCo

Co(CO)3

(CO)3

4119

41204121




188






Scheme 439

NH

CbzN

O

4106

H

H

H

NMe

CbzN

O

4123

H

H

H

NaH MeI DMF91

Baeyer-Villiger

X

NMe

CbzN

4105

H

H

H

OO









189



Scheme 440

NBoc

CbzN

O

4117

NBoc

CbzN

O

4125

O

MCPBACH2Cl2 60

orCF3COOOH

Na2HPO4CH2Cl2 99

H2O2NaOH

THFMeOH

H

H

H

H

H

H

NBoc

CbzN

4124

H

H

H

OO

O

78








190

NBoc

CbzN

4124

H

H

H

OO

O

deoxygenationX

NBoc

CbzN

4105

H

H

H

OO

(45)








Scheme 441

HNR

CbzN

O

H

OH

4127

H

HNR

CbzN

CO2RCHO

H

H

4128

H

HNH

CbzN

O

H

4106

H

HNR

CbzN

OSiR3

H

4129

H H




191









4130156

192


NBoc

CbzN

OH

H

Hconditions

NBoc

CbzN

OSiEt3H

H

H





25

41304117



Entry

-------

-------1

2

3

5

4

NBoc

CbzN

OH

H

H

4131

+

H H









193




Scheme 442

Me2Si

O

Me2Si

2

Pt


NBoc

CbzN

OH

H

H

NBoc

CbzN

OTIPSH

H

H

4132

4117

H

NBoc

CbzN

OH

H

H

4131

H

NBoc

CbzN

OTESH

H

H

4130

HMe2Si

O

Me2Si

2

Pt

Et3SiH Toluenert 99

41304131 = 41

+







nitrogen atom

194

Scheme 443

NBoc

CbzN

OTIPSH

H

TBAF3H2O

THF 66

NBoc

CbzN

OH

H

NH

HN

OHH

H



H

H

H

H

H

H

4133

4132 4131










195

NBoc

CbzN

OTIPSH

H

H

H

ozonolysis

NBoc

CbzN

CHOH

H

CO2TIPS

4132 4134

X (46)






Scheme 444

HNR

CbzN

OSiR3

H

4136

H H

HNR

CbzN

CO2RCHO

H

H

4128

H

HNR

CbzN

O

H

4135

H HHO






196

HNBoc

CbzN

OTIPS

H

4132

H H

HNBoc

CbzN

O

H

4137

H HHO

mCPBA

CH2Cl20-20

(47)








Scheme 445

O

O

OOCOR

OTIPS mCPBAOTIPS

O

OTIPS

OH

H+

4138 4139 4140

OTIPS

OH

4141

RCO2-

OTIPS

4142

O

ROCOR

4143





197















198


NBoc

CbzN conditions

OTIPSH

H

NBoc

CbzN

OH

H

HO

Conditions

4132 4137

Entry Yield 4137

1 OsO4 (10) NMO (22 eq) THFH2O 23






H

H

H

H







199

Scheme 446

NBoc

CbzN

OH

H

HO

4137

H

H



4144

NBoc

CbzN

OH

CO2Me

H

H

HNBoc

CbzN

O

H

OH

4145

H

pTsOH CH2Cl2

99












200

Scheme 447

H

H

4145

NBoc

CbzN

OTIPS

H


THFH2O 51

NBoc

CbzN

CHO

CO2H

NBoc

CbzNH

H OO

NaBH4 MeOH


H

H

H

H

4132 4146









201

Scheme 448

LiAlH4

THF reflux 99

NaHthen MeI

DMF 88

NBoc

CbzNH

H OO

H

H

4145

NBoc

CbzNH

H OH

H

4147


2 MsCl Et3N THF 67

NH

MeNH

H OH

H

4148

NMe

MeNH

H OH

H

4149






obtained

202

Scheme 449

NMe

MeNH

H O


NMe

MeNH

H O

O

+

NMe

MeNH

H O

O

O



H

H

H

H

H

H

4149

41

4150







recovered

NMe

MeNH

H OH

H

4149

NMe

MeNH

H O

O

H

H

41

NMe2

O

POCl3 or Tf2OX (48)



203




Scheme 450

NBoc

CbzNH

H O


NBoc

CbzNH

H O

O



H

H H

H

4147 4152







204

Scheme 451

NMe

MeNH

H OH

H

4149

NMe

MeNH

H O

Cl3CO

H

H

4151

X

[H]

NMe

MeNH

H O

O

H

H

41

Cl3C

O

Cl














natural products169

205

Scheme 452

NBoc

CbzNH

H OH

H

4147

NBoc

CbzNH

H O

Cl3CO

H

H

4153

NBoc

CbzNH

H O

O

H

H

4152

ClCO2CCl3

pyridine 65 degC

Zn AcOH

75 2 steps










NBoc

CbzNH

H O

O

H

H

4152

NH

HNH

H O

O

H

H

4154

TMS-I

CH3CN78

(49)

206






Scheme 453

NMe

MeNH

H O

O

H

H

41

NMe

HNH

H O

O

H

H

4155

NH

MeNH

H O

O

H

H

4156

NMe

MeNH

H O

O

H

H

4157

NaH then MeI

DMF

side products

NH

HNH

H O

O

H

H

4154







EtOH))128

207

NMe

MeNH

H O

O

H

H

41

NH

HNH

H O

O

H

H

4154

MeI (2 eq)THF


72

(410)












208

Scheme 454

NH

CbzN

O

H

Co2(CO)8DMSO

THF 65 degC92 H

H

4106

NBoc

CbzN

O

H

H

HBoc2ODMAP

CH3CN99

4117

Me2Si

O

Me2Si

2

Pt


NBoc

CbzN

OTIPSH

H

H

4132

H H

H

4145

1 OsO4 (10) NaIO4 (4 eq)

THFH2O 51

NBoc

CbzNH

H OO

2 NaBH4 MeOH


NBoc

CbzNH

H OH

H

4147


2 MsCl Et3N THF 67

TMS-I

CH3CN78

NBoc

CbzNH

H O

O

H

H

4152



NH

HNH

H O

O

H

H

4154

NMe

MeNH

H O

O

H

H

41

MeI THF

then NaH MeI72

NH

NH2

CO2H


60 NH

NHCl

CO2H

i)Et3N CbzCl

CH2Cl2

ii) MeOH Et3N87 N

H

NCbz

CO2Me

OMe

TMS

BF3Et2O

CH2Cl281

51 cistrans

NH

NCbz

CO2Me

NH

NCbz

4108 4109 4110

4111 4107



-78 degC -rt60

209

45 Conclusions























210














211


51 General



















212






52 Compounds

6

51 23

4

78

O

O

O

217












213

NMR (75 MHz) δ 1549 1354 1277 752 541 249 201 128 IR (neat) 2964 2876


requires 1570865] 157 (base) 113





(C2) 541 (C8) 249 (C5) 201 (C1) 128 (C6)

O O

O

1

2

34

56

78

218









214





[C8H13O3 (M+1) requires 1570865]





(C8) 273 (C5) 175 (C1) 93 (C6)

6

6

5 61 2

3

4

78

O

O

O

225







215






NMR (75 MHz) δ 1550 1446 1237 757 543 327 291 205




1446 (C4) 1237 (C3) 757 (C2) 543 (C8) 327 (C5) 291 (C6) 205 (C1)

6

5

6

O O

O

1

2

34 6

78

226







216






1313 1260 865 543 342 256 177




(C7) 1313 (C2) 1260 (C3) 865 (C4) 543 (C8) 342 (C5) 256 (C6) 177 (C1)

6

89

12

34

5

7

O O

OO

219







217







75 3 H) 13C NMR (100 MHz) δ 1688 1687 1334 1301 581 523 521 374 254

186 137





1688 (C8) 1687 (C8) 1334 (C4) 1301 (C3) 581 (C7) 523 (C9) 521 (C9) 374

(C2) 254 (C5) 186 (C1) 137 (C6)

89

12

3 4 5

7

O O

OO

220

6



218









548 (m 1 H) 518 (dd J = 150 93 Hz 1 H) 369 (s 3H) 365 (s 3H) 331 (d J = 90


H)




082 (t J = 72 Hz 3 H C1-H)

O

O

O

O

12

34

5

78

9

6227



219











284 (m 1 H) 104 (d J = 69 3 H) 093 (s 9 H)




H)

220

1

23

45

6

7

8 9 10 1112

13

230

O

O

O

O















= 76 Hz 3 H) 13C NMR (100 MHz) δ 1704 1342 1289 784 741 609 521 402

256 241 169 138 35 IR (neat) 2959 2875 1732 1455 1434 1276 1218 1057

221


235 206 185






784 (C9) 741 (C10) 609 (C5) 521 (C13) 402 (C2) 256 (C7) 241 (C8) 169 (C11)

138 (C6) 35 (C1)

N

249

12

3

4

5

6

7

89

10

3

4

89








222




1372 1340 1296 1285 1272 1262 631 522 233 210 IR (neat) 2967 2780

1494 1446 1310 1167 965 748 692 MS (CI) mz 2021586 [C14H20N1 (M+1)

requires 2021596]





1285 (C8) 1272 (C5) 1262 (C9) 631 (C2) 522 (C3) 233 (C4) 210 (C1)

N

252

3

8

9

3

4

8

9

1

2

5

6

7

10





223






352 (s 2 H) 214 (s 3 H) 125 (s 6H) 13C NMR (75 MHz) δ 1470 1413 1285

1281 1265 1120 586 557 345 228 IR (neat) 2973 2842 2794 1494 1453 1411


1901596]





1265 (C10) 1120 (C1) 586 (C4) 557 (C6) 345 (C5) 228 (C3)








224





O

269

12

3

45

6 78

9

10

11

12

13








13C NMR (100 MHz) δ 1559 1366 1317 1287 1270 1264 1239 1206 1142

1124 692 253 132 IR (CHCl3) 3033 2967 2934 2874 1625 1597 1485 1452


1891279] 189 (base) 122 107



225





(C12) 1317 (C8) 1287 (C9) 1270 (C4) 1264 (C2) 1239 (C1) 1206 (C3) 1142

(C5) 1124 (C13) 692 (C7) 253 (C10) 132 (C11)

Br

O

271

12

3

45

6 78

9

10

11







J = 75 Hz 3 H) 13C NMR (75 MHz) δ 1551 1370 1332 1283 1232 1218 1137

1123 698 253 131 IR (neat) 2967 2934 2875 1586 1478 1276 1243 1031 970


241 137

226






1283 (C3) 1232 (C8) 1218 (C9) 1137 (C5) 1123 (C1) 698 (C7) 253 (C10) 131

(C11)

O

273

12

3

45

6

7 89

1011

12

1314

15

16







1308 1300 1296 1281 1278 1266 1210 1160 759 251 216 133 IR (CHCl3)



227





13C NMR (100 MHz) δ 1550 (C6) 1389 (C13) 1339 (C15) 1320 (C9) 1308 (C10)

1300 (C2) 1296 (C4) 1281 (C14) 1278 (C16) 1266 (C1) 1210 (C3) 1160 (C5)

759 (C8) 251 (C11) 216 (C7) 133 (C12)

HOO

1

2

3 4

5

67

8

Si

288










228


(100 MHz) δ 1322 1275 616 590 310 259 183 -52 IR (neat) 3355 2954 2857


requires 2171624] 217 (base) 199 133





(C5) 590(C1) 310 (C2) 259 (C8) 183(C7) -52 (C6)

O

O O

O9

1011

128

612

34

5 7

Si

289








229




MHz) δ 2004 1670 1326 1251 645 593 500 301 270 259 183 -52 IR







(C2) 1670 (C4) 1326 (C8) 1251 (C7) 645 (C9) 593 (C5) 500 (C3) 301 (C6) 270

(C1) 259 (C12) 183 (C11) -52 (C10)

O

O O

OH

8

612

34

5 7

9

290






230





NMR (100 MHz) δ 2009 1669 1317 1270 643 583 499 303 268 MS (CI) mz

1870970 [C9H15O4 (M+1) requires 1870970]




(C2) 1669 (C4) 1317 (C8) 1270 (C7) 643 (C9) 583 (C5) 499 (C3) 303 (C6) 268

(C1)

O

O O

O

861

23

4

5 7

910

11O

O

275







231






1301 1256 637 630 545 496 298 267 IR (neat) 2955 1802 1747 1714 1442


2451025] 245 186 169 (base) 154




NMR (100 MHz) δ 2002 (C2) 1668 (C4) 1553 (C10) 1301 (C8) 1256 (C7) 637

(C11) 630 (C9) 545 (C5) 496 (C3) 298 (C6) 267 (C1)

O

OO

8

6

7 1 2

3

45

9

278




232







585-576 (comp 2 H) 431-420 (m 2 H) 365 (dd J = 85 55 Hz 1 H) 284-278 (m 1


1738 1311 1292 678 632 292 286 269 IR (neat) 2958 1713 1650 1359 1261





NMR (100 MHz) δ 2016 (C8) 1738 (C7) 1311 (C4) 1292 (C3) 678 (C6) 632 (C1)

292 (C2) 286 (C5) 269 (C9)

233

8

6 7Br

O1

2

3 4

5Si

291











H) 088 (s 9 H) 005 (s 6 H) 13C NMR (100 MHz) δ 1325 1269 594 322 310

259 183 -52 IR (neat) 3021 2955 2856 1471 1360 1254 1095 837 776 MS (CI)





234


(C2) 259 (C8) 183 (C7) -52 (C6)

1386

7

12

34

59

10

1211O

O O

OSi

292















235





O

O O

OH

86

7

12

34

59

10

293










(app p J = 72 Hz 2 H)



236


72 Hz 2 H C6-H)

O

O O

O

86

7

12

34

59

1011 12O

O

294












[C12H19O6 (M+1) requires 2591182]



237


167 (app p J = 72 Hz 2 H C6-H)

10

1 23

9

4

5 67

8

2106

O

O

O

O












238

O CF3

O

12

34

5 67

2129








74 Hz 2 H) 100 (t J = 74 3 H) 13C NMR (100 MHz) δ 1572 1412 1204 1160

688 255 128 IR (neat) 1779 1634 1174 706 cm-1 MS (CI) mz 1830640

[C7H10O2F3 (M+1) requires 1830633]




1412 (C4) 1204 (C3) 1160 (C7) 688 (C5) 255 (C2) 128 (C1)

239

O O

O O

1

3

12

3

4

56

78

910

112137










H) 13C NMR (100 MHz) δ 1642 1317 1281 1227 1053 846 824 461 284

269 175 IR (neat) 3001 1788 1750 1309 1202 1070 941 758 MS (CI) mz

2580889 [C15H14O4 (M+1) requires 2580892]




1227 (C8) 1053 (C2) 846 (C6) 824 (C7) 461 (C4) 284 (C1) 269 (C1) 175 (C5)

240

12 3 4

567

8

9

10

1112

1314

2130

O

H

O

O

OO

15

16













230-210 (m 1 H) 210-190 (m 1 H) 181 (app t J = 153 Hz 1 H) 160-140 (m 1


[C20H23O5 (M+1) requires 3431545]

241





H C16-H) 100 (t J = 75 Hz 3 H C14-H)

N

O O

O

Si

O

O

420

12

3

4

56

7

8

9

10

1112

13

14

15









242









4002519]




185 Hz 9 H C13-H) 066 (dd J = 105 35 Hz 6 H C11-H)

243

N

O O

O

Si

O

O

1

11

2

3

4

56

7

8910

12

14

13

15

16

421
















244







H) 085 (s 9 H) 003 (s 6 H) IR (neat) 2955 2858 1754 1698 1392 1254 1177 MS





002 (s 6 H C12-H)

14 15N

O O

O

Si

422

12

3

4

56

7

8

9

10

1112

13



245














C15-H) 145 (s 9 H C1-H) 088 (s 9 H C13-H) 007 (s 6 H C11-H)

246

16N

O O

O

Si

1

11

2

3

4

56

7

89

10

12

14

13

15

414















H) 240-200 (comp 5 H) 174 (s 3 H) 142 (s 9 H) 089 (s 9 H) 009 (s 3 H) 008

247

(s 3 H) IR (neat) 3312 2955 2858 1704 1649 1385 1254 1123 873 776 MS (CI)






008 (s 3 H C12-H)

N

O O

O

O

1

12

15

2

3

4

56

7

8910

11

13

14

424








248







HN

O

Si

432

1

23

4

567

8

910

11

12 13










249

(100 MHz) δ 1439 1117 876 738 701 608 464 439 383 260 229 182 -46 -

49 IR (neat) 3311 2954 2930 2856 1648 1471 1255 1104 889 836 775 MS (CI)







738 (C2) 701 (C13) 608 (C1) 464 (C4) 439 (C5) 383 (C3) 260 (C8) 229 (C11)

182 (C10) -46 (C9) -49 (C9)

N

Me

O

Si

433

1

2

34

5

678

9

1011

12

13 14






250





006 (s 3 H) 005 (s 3 H) 13C NMR (75 MHz) δ 1443 1108 825 736 723 643

543 420 374 360 260 238 182 -44 -50 MS (CI) mz 2942246







13C NMR (75 MHz) δ 1443 (C7) 1108 (C8) 825 (C13) 736 (C14) 723 (C2) 643

(C5) 543 (C1) 420(C3) 374 (C6) 360 (C4) 260 (C12) 238 (C9) 182 (C11) -44

(C10) -50 (C10)

251

N

O

O OSi

1

2 3 4

5

6

78

910

11

1213

14

446














164 Hz 1 H) 009 (s 9 H) 13C NMR (100 MHz) δ 1911 1348 1288 1287 1286

1281 1077 1003 895 691 456 412 -039 IR (neat) 2960 1732 1677 1609 1329

252


(base) 312 284




13C NMR (100 MHz) δ 1911 (C3) 1348 (C8) 1288 (C1) 1287 (C10) 1286 (C9)

1281 (C11) 1077 (C2) 1003 (C12) 895 (C7) 691 (C13) 456 (C4) 412 (C5) -039

(C14)

N

O

OO

1

2 34

5

67

910

11

12

448

8

13

1415

16








253




NMR (75 MHz) δ 2054 1548 1359 1339 1285 1282 1280 1183 825 679 532

451 429 427 395 IR (neat) 3285 3067 3033 2977 1693 1642 1404 1322 1112






(C13) 1285 (C2) 1282 (C1) 1280 (C3) 1183 (C14) 825 (C15) 737 (C5) 679

(C16) 532 (C8) 451 (C10) 429 (C7) 427 (C11) 395 (C12)

254

N

O

O

O

O

451

17

1

2

3

4

567

8

9 10

11

1213

14

1516

H















2058 2055 1755 1531 1361 1279 1274 1270 1265 665 502 480 440 437


255







MHz) δ 2058 (C6) 2055 (C1) 1755 (C3) 1531 (C12) 1361 (C14) 1279 (C16)

1274 (C17) 1270 (C15) 1265 (C2) 665 (C13) 502 (C4) 480 (C8) 440 (C11) 437

(C7) 411 (C5) 384 (C9) 328 (C10)

N

O

Si

O O

1

2 3 4

5

6 78 9

10

1112

1314

15

460







256







NMR (100 MHz) δ 1917 1410 1346 1285 1281 1271 1266 1009 882 689

647 516 384 219 -04 IR (neat) 2959 2900 1731 1672 1604 1328 1296 1198


342 197 181 (base)





1281 (C15) 1271 (C13) 1266 (C14) 1009 (C2) 882 (C7) 689 (C11) 647 (C8)

516 (C5) 384 (C4 219 (C6) -04 (C9)

257

N

O O

Si

O

12 3 4

567 8

910

11

1213

1415

16

461

17
















MHz d6-DMSO 100 ˚C) δ 2052 1545 1390 1361 1278 1272 1269 1150 1034

258

868 664 526 510 418 417 259 -07 IR (neat) 3089 3034 2959 2900 1698


3701838]






(C3) 1545 (C17) 1390 (C13) 1361 (C7) 1278 (C15) 1272 (C16) 1269 (C14)

1150 (C6) 1034 (C12) 868 (C9) 664 (C10) 526 (C1) 510 (C2) 418 (C4) 417

(C5) 259 (C8) -07 (C11)

N

O O

O

1

2 3 4

567 8

910

1112

1314

15

462

18





259




100 ˚C) δ 740-729 (comp 5 H) 599 (ddd J = 160 105 45 Hz 1 H) 519-512




1361 1278 1272 1270 1152 803 724 664 527 512 417 416 247 IR (neat)

3307 3035 2959 1694 1407 1320 1271 1114 1057 MS (CI) mz 2981443

[C18H20NO3 (M+1) requires 2981443]







1388 (C12) 1361 (C7) 1278 (C14) 1272 (C13) 1270 (C15) 1152 (C6) 803 (C9)

724 (C11) 664 (C10) 527 (C1) 512 (C2) 417 (C4) 416 (C5) 247 (C8)

260

16

17

N

O

H

O

OO

1

2 34

5

6

7

89

10 11

12

13 14

15

463










2050 2043 1735 1533 1361 1317 1279 1273 1270 665 507 474 448 436

387 367 348 IR (neat) 3035 2963 2902 1706 1626 1416 1335 1264 1220 1100






261




(C12) 1361 (C8) 1317 (C14) 1279 (C16) 1273 (C17) 1270 (C15) 665 (C13) 507

(C1) 474 (C5) 448 (C11) 436 (C6) 387 (C10) 367 (C2) 348 (C4)

N

O

O O

469

1

2 34

5

6

78

910

11

1213

14

15

Si

16










262







MHz) δ 2054 1547 1376 1360 1285 1282 1280 1163 1077 1040 907 679

547 453 432 -049 IR (neat) 2959 1704 1403 1309 1250 1224 1054 844 MS






MHz) δ 2054 (C3) 1547 (C11) 1376 (C13) 1360 (C6) 1285 (C15) 1282 (C16)

1280 (C14) 1163 (C7) 1077 (C5) 1040 (C1) 907 (C8) 679 (C12) 547 (C9) 453

(C2) 432 (C4) -049 (C10)

263

N

O

O O

470

1

2 34

5

67

89

10

1112

1314

15










13C NMR (75 MHz) δ 2050 1548 1373 1358 1285 1282 1280 1167 824 738

680 548 449 432 425 IR (neat) 3285 2957 1698 1403 1310 1264 1310 1264


284 (base) 266 240




264




1548 (C10) 1373 (C6) 1358 (C12) 1285 (C14) 1282 (C15) 1280 (C13) 1167

(C7) 824 (C8) 738 (C11) 680 (C9) 548 (C1) 449 (C5) 432 (C2) 425 (C4)

11

10

1

23

45

6

7

89

12 1314

15

16

N

O

O

O

O

471

H










265






N

O O

O

Si

1

2 3 4

5

6

78

9

1011

12

473











266






007 (s 9 H) 13C NMR (100 MHz) δ 1912 1519 1410 1312 1190 1078 1003

895 679 456 413 -04 IR (neat) 3088 2960 2900 1732 1678 1608 1418 1372


2781212]






(C3) 1519 (C6) 1410 (C8) 1312 (C1) 1190 (C9) 1078 (C2) 1003 (C7) 895 (C10)

679 (C11) 456 (C4) 413 (C5) -04 (C12)

267

HN

O

Si

1

2 3 4

56

7

8

474








(100 MHz) δ 1912 1508 1020 992 895 451 418 -03 IR (neat) 3233 3022 2960


1941001]




(C3) 1508 (C1) 1020 (C2) 992 (C6) 895 (C7) 451 (C5) 418 (C4) -03 (C8)

268

NSiSO O

O

1

2 3 4

5

67

89

10

1112

13

475













13C NMR (75 MHz) δ 1899 1451 1408 1345 1300 1278 1078 981 912 469

422 215 -075 IR (neat) 3081 2963 1681 1597 1403 1362 1272 1168 846 MS


269





1899 (C3) 1451 (C6) 1408 (C1) 1345 (C9) 1299 (C7) 1278 (C8) 1078 (C2) 981

(C11) 912 (C12) 469 (C5) 422 (C4) 215 (C10) -075 (C13)

N

SO O

O

1

2 3 4

5

67

89

10

1112

476









270


H) 13C NMR (100 MHz) δ 1897 1454 1409 1344 1299 1278 1079 741 463

419 384 216 IR (neat) 3280 1676 1596 1363 1275 1167 1052 MS (CI) mz

2760693 [C14H14NO3S (M+1) requires 2760694]





(100 MHz) δ 1897 (C3) 1454 (C6) 1409 (C1) 1344 (C9) 1299 (C7) 1278 (C8)

1079 (C2) 741 (C12) 463 (C11) 419 (C5) 384 (C4) 216 (C10)

N

SO O

O

1

2 3 4

5

67

89

10

11

12

13

1415

477





271








NMR (75 MHz) δ 2044 1441 1369 1338 1299 1273 1187 815 748 554 457

446 434 388 216 IR (neat) 3305 1723 1356 1162 1094 MS (CI) mz 3181163







MHz) δ 2044 (C3) 1441 (C6) 1369 (C9) 1338 (C12) 1299 (C7) 1273 (C8) 1187

(C13) 815 (C14) 748 (C15) 554 (C5) 457 (C11) 446 (C4) 434 (C2) 388 (C5)

216 (C10)

272

N

O

SiO

1

2 34

5

67

8

9

10

11

1213

478













1323 1318 1286 1284 1081 1005 895 456 418 -04 IR (neat) 2962 1668


2981263] 298 (base)

273




C8-H) 13C NMR (75 MHz) δ 1914 (C3) 1691 (C9) 1420 (C1) 1323 (C10) 1318

(C13) 1286 (C12) 1284 (C11) 1081 (C2) 1005 (C6) 895 (C7) 456 (C5) 418 (C4)

-04 (C8)

N

O

O

1

2 34

5

67

910

1112

13

479

8

1415










274




1339 1293 1279 1260 1172 827 754 525 447 435 423 379 IR (neat) 3256


268 (base) 250






100 ˚C) δ 2043 (C3) 1697 (C11) 1354 (C12) 1339 (C9) 1293 (C15) 1279 (C14)

1260 (C13) 1172 (C10) 827 (C6) 754 (C7) 525 (C5) 447 (C8) 435 (C1) 423

(C4) 379 (C2)

275

N

O

O

H

SO

O

1

2 3 4

5

67

89

101112

1314

15

16

480








13C NMR (75 MHz) δ 2059 2056 1736 1445 1367 1300 1280 1271 521 501

459 453 416 385 332 216 IR (neat) 3689 2925 1715 1633 1353 1163 1098







(C8) 1736 (C6) 1445 (C12) 1367 (C15) 1300 (C13) 1280 (C7) 1271 (C14) 521

(C5) 501 (C1) 459 (C10) 453 (C9) 416 (C4) 385 (C2) 332 (C11) 216 (C16)

276

N

O

1

2 34

5

6

9

10

11

481

OH

7

8

12 13

O

14

15

16









2058 2056 1754 1685 1348 1294 1280 1266 1260 500 488 441 438 410

384 332 IR (neat) 2917 1713 1633 1410 1338 1217 914 MS (CI) mz 296







277


1754 (C11) 1685 (C12) 1348 (C10) 1294 (C13) 1280 (C15) 1266 (C16) 1260

(C14) 500 (C1) 488 (C5) 441 (C8) 438 (C2) 410 (C4) 384 (C7) 332 (C6)

N

OH

O O

1

2 3 4

5

6

78 9

10

11

1213

1415

16

482











278

3297 2953 1684 1409 1324 1087 1063 990 914 MS (CI) mz 300 [C18H22NO3

(M+1) requires 300] 300 (base) 258 256 238 214





Hz 1 H C4-H)

N

O O

12 3 4

5

6

78

11

1213

14

1516

1718

283

OSi

9

10

19







279






9 H) 007 (s 3 H) 005 (s 3 H) 13C NMR (100 MHz) δ 1555 1366 1365 1284

1279 1278 1168 854 706 673 642 507 391 386 366 336 258 181 -49 -

50 IR (neat) 3307 2953 2856 1694 1640 1407 1335 1312 1255 1093 774 MS (CI)








1366 (C7) 1365 (C16) 1284 (C18) 1279 (C19) 1278 (C17) 1168 (C8) 854 (C12)

706 (C15) 673 (C3) 642 (C13) 507 (C1) 391 (C5) 386 (C6) 366 (C2) 336 (C4)

258 (C11) 181 (C10) -49 (C9) -50 (C9)

280

N

O O

O

S

S

484

1

23

4

5

6

78

9

10

1112

13

1415

16

1718











168 125 68 Hz 1 H) 522 (m 1 H) 518 (s 2 H) 512 (d J = 168 Hz 1 H) 502 (d



H) 13C NMR (100 MHz) δ 2150 1552 1363 1355 1284 1280 1279 1178 843

751 712 676 496 386 383 328 292 191 IR (neat) 3290 2953 1697 1406

281


(base) 346 282







2150 (C9) 1552 (C13) 1363 (C15) 1355 (C7) 1284 (C17) 1280 (C18) 1279

(C16) 1178 (C8) 843 (C11) 751 (C14) 712 (C3) 676 (C12) 496 (C5) 386 (C1)

383 (C6) 328 (C4) 292 (C2) 191 (C10)

N

S S

O O

1

2 3 4

5

6

78

9 10

1112

13

1415

1617

18

485




282









NMR (75 MHz) 1552 1364 1351 1284 1280 1277 1177 841 725 675 619

523 448 418 412 396 385 384 IR (neat) 3288 2923 1698 1406 1318 1262







(C7) 1284 (C17) 1280 (C18) 1277 (C16) 1177 (C8) 841 (C11) 725 (C14) 675

(C12) 619 (C5) 523 (C1) 448 (C3) 418 (C2) 412 (C4) 396 (C6) 385 (C10) 384

(C9)

283

HNO

Si

1

23

4

5 67 8

490












188 -03 IR (neat) 3190 3077 2956 1687 1649 1405 1309 1252 841 756 MS





288 (C3) 188 (C4) -03 (C8)

284

NO

Si9

1011

1213

14

491

O O

1

23

4

5 67 8












1283 1280 1277 1031 888 684 483 340 285 175 -04 IR (neat) 3065 2959

2899 1778 1738 1714 1498 1455 1373 1250 1134 1062 843 MS (CI) mz 330




285


1351 (C11) 1283 (C13) 1280 (C14) 1277 (C12) 1031 (C6) 888 (C10) 684 (C7)

483 (C5) 340 (C2) 285 (C3) 175 (C4) -04 (C8)

N9

10

11

1213

14

486

O O

1

23

4

5

6

78

1516













286










= 100 ˚C) δ 1542 1363 1355 1277 1272 1269 1160 845 724 660 506 409

360 298 260 140 IR (neat) 3294 3248 2944 1697 1406 1318 1267 1098 MS







100 ˚C) δ 1542 (C11) 1363 (C13) 1355 (C7) 1277 (C15) 1272 (C16) 1269 (C14)

1160 (C8) 845 (C9) 724 (C12) 660 (C10) 506 (C6) 409 (C5) 360 (C1) 298 (C5)

260 (C2) 140 (C3)

287

N

O

1

23

4

5

6

9

10

11

494

O

OH

7

8

12 13

14 15

16

17







(dd J = 180 60 Hz 1 H) 249 (m 1 H) 215 (dd J = 135 75 Hz 1 H) 208-152


1278 1272 1268 1258 659 495 466 432 372 355 276 184 141 IR (neat)


312] 334 (base) 312






288

1364 (C10) 1278 (C14) 1272 (C16) 1268 (C17) 1258 (C15) 659 (C13) 495 (C1)

466 (C5) 432 (C7) 372 (C8) 355 (C6) 276 (C2) 184 (C4) 141 (C3)

N

O

O

OH

OSi

1

2 34

5

67

89

10

11 12

13

14 15

16

1718

1920

493










MHz d6-DMSO 100 ˚C) δ 2059 1790 1532 1363 1278 1272 1268 1256 660

622 480 454 418 371 353 350 326 250 169 -56 -57 IR (neat) 2928 2855

1713 1623 1416 1322 1278 1088 839 MS (CI) mz 442 [C25H36NO4Si (M+1)


289








(C11) 1532 (C12) 1363 (C14) 1278 (C16) 1272 (C17) 1268 (C15) 1256 (C10)

660 (C13) 622 (C3) 480 (C1) 454 (C5) 418 (C8) 371 (C6) 353 (C2) 350 (C4)

326 (C7) 250 (C20) 169 (C19) -56 (C18) -57 (C18)

N

N

SO O

O

O

OO

12

345

6

78

910

11

1213

1415

1617

18

1920

21

2223

24 25

26

27

4112





290









H) 313 (m 1 H) 302 (m 1 H) 272 (m 1 H) 240 (dt J = 155 95 Hz 1 H) 225 (s


1339 1336 1294 1293 1285 1278 1273 1270 1254 1246 1236 1184 1164

1159 1144 669 514 510 508 387 204 203 MS (CI) mz 5591909

[C31H31N2O6S (M+1) requires 5591903]








˚C) δ 1715 (C12) 1548 (C22) 1448 (C17) 1360 (C24) 1345 (C30) 1339 (C9)

1336 (C10) 1294 (C16) 1293 (C14) 1285 (C4) 1278 (C26) 1273 (C25) 1270

291

(C27) 1254 (C15) 1246 (C6) 1236 (C5) 1184 (C7) 1164 (C21) 1159 (C3) 1144

(C8) 669 (C23) 514 (C1) 510 (C13) 508 (C11) 387 (C19) 204 (C2) 203 (C18)

10

11

12

3

45

6 7

8 912

1314 15

16

1718

1920

21

22

23

24

25

N

N

O

O

OO

OO

4114











100 Hz 1 H) 365 (s 3 H) 318 (dq J = 80 160 Hz) 252 (m 1 H) 238 (m 1 H)

159 (s 9 H) 13C NMR (125 MHz) δ 1717 1548 1489 1359 1354 1340 1338

292

1278 1274 1273 1239 1223 1178 1162 1148 1122 841 668 513 512 509


requires 5052339]







1717 (C10) 1548 (C23) 1489 (C12) 1359 (C14) 1354 (C1) 1340 (C20) 1338

(C22) 1278 (C16) 1274 (C17) 1273 (C6) 1272 (C15) 1239 (C4) 1223 (C5) 1178

(C3) 1162 (C21) 1148 (C7) 1122 (C2) 841 (13) 668 (C24) 513 (C9) 512 (C11)

509 (C18) 385 (C19) 273 (C25) 204 (C8)

293

N

N

SO O

O

O

12

345

6

78

910

11

1213

1415

1617

18

1920

21

2223

24 25

26

27

4113
















294



1340 1334 1293 1292 1278 1274 1272 1254 1247 1238 1184 1168 1158

1147 838 736 668 518 384 383 266 203 MS (CI) mz 5251849

[C31H29N2O4S (M+1) requires 5251848]









(C24) 1359 (C10) 1343 (C14) 1340 (C15) 1334 (C4) 1293 (C16) 1292 (C26)

1278 (C25) 1274 (C15) 1272 (C27) 1254 (C6) 1247 (C6) 1238 (C5) 1184 (C7)

1168 (C21) 1158 (C8) 1147 (C4) 838 (C12) 736 (C13) 668 (C23) 518 (C1) 384

(C11) 383 (C19) 266 (C2) 203 (C18)

295

12

3

45

6 7

8 910

11

12

1314 15

16

1718

1920

21

22

23

24

25

N

N

O

O

OO

4115
















1489 1358 1356 1343 1330 1279 1278 1274 1272 1240 1224 1176 1165

296

1148 1119 841 733 668 664 514 386 377 272 265 IR (neat) 3293 3068








(C14) 1356 (C20) 1343 (C1) 1330 (C22) 1279 (C6) 1278 (C17) 1274 (C16)

1272 (C15) 1240 (C4) 1224 (C5) 1176 (C3) 1165 (C21) 1148 (C7) 1119 (C2)

841 (C10) 733 (C24) 668 (C13) 664 (C11) 514 (C9) 386 (C18) 377 (C19) 272

(C25) 265 (C8)

297

12

1314

151617

18

12

3

45

6 78

9 1011

NH

N

OO

O19

20

21

2223

4106

H















1774 1534 1361 1356 1323 1278 1273 1270 1265 1258 1206 1182 1172

298

1108 1055 663 493 476 402 371 344 250 IR (neat) 3464 3052 2985 1702









(C12) 1774 (C10) 1534 (C18) 1361 (C20) 1356 (C1) 1323 (C17) 1278 (C22)

1273 (C23) 1270 (C21) 1265 (C11) 1258 (C6) 1206 (C4) 1182 (C5) 1172 (C3)

1108 (C2) 1055 (C7) 663 (C19) 493 (C9) 476 (C16) 402 (C13) 371 (C14) 344

(C15) 250 (C8)

299

12

1314

151617

18

12

3

45

6 78

9 1011

N

N

O

OO

O

O19

20

21

2223

2425

26

4117













= 127 41 Hz 1 H) 162 (s 9 H) 13C NMR (125 MHz) δ 2059 1768 1533 1488

1360 1351 1323 1278 1275 1274 1271 1265 1239 1224 1178 1149 1141

300

841 665 541 481 403 362 339 272 246 IR (neat) 3400 2977 2929 1771








C26-H) 13C NMR (125 MHz) δ 2059 (C12) 1768 (C10) 1533 (C24) 1488 (C18)

1360 (C20) 1351 (C1) 1323 (C17) 1278 (C22) 1275 (C23) 1274 (C24) 1271

(C11) 1265 (C6) 1239 (C4) 1224 (C5) 1178 (C3) 1149 (C2) 1141 (C7) 841

(C25) 665 (C19) 541 (C9) 481 (C16) 403 (C13) 362 (C14) 339 (C15) 272 (C26)

246

301

19

N

N

O

OO

OO

H

OO

4124

12

3

45

6 7

8 9 10

11

12

1314

151617

18

20

21

2223

24 25

26














1710 1632 1421 1307 1252 1150 739 MS (CI) mz 531 [C30H31N2O7 (M+1)

requires 531] 531 463 319 243 (base)

302







35 Hz 1 H C15-H) 170 (m 1 H C15-H) 157 (s 9 H C20-H)

N

N

OO

H

OO

OO

4125

12

3

4

56 7

8 910

11

12

1314

151617

18

19

20

21

22

2324 25

26









303







100 ˚C) δ 2071 1534 1487 1359 1352 1321 1278 1275 1272 1270 1240

1224 1178 1148 1142 841 696 666 613 477 473 376 351 290 272 228

IR (neat) 2977 2928 1750 1730 1703 1455 1417 1360 1326 1156 1012 755 MS








(C18) 1487 (C21) 1359 (C23) 1352 (C1) 1321 (C17) 1278 (C25) 1275 (C6)

1272 (C26) 1270 (C24) 1240 (C4) 1224 (C5) 1178 (C3) 1148 (C7) 1142 (C2)

841 (C11) 696 (C22) 666 (C19) 613 (C10) 477 (C9) 473 (C16) 376 (C13) 351

(C15) 290 (C14) 272 (C20) 228 (C8)

304

N

N

O

H

H

OO

O O

Si

21

2223

2425

26

27

28

12

3

45

6 7

8 9 10

11 12

1314

151617

18

19

20

4130














NMR (125 MHz d6-DMSO 100 ˚C) δ 1648 1544 1538 1488 1364 1352 1328

1279 1278 1272 1268 1236 1222 1176 1148 1040 838 781 659 466 362

305

304 293 272 262 231 57 40 IR (neat) 2954 1729 1699 1636 1455 1421 1327









(C18) 1538 (C12) 1488 (C23) 1364 (C1) 1352 (C17) 1328 (C6) 1279 (C25)

1278 (C24) 1272 (C26) 1268 (C3) 1236 (C5) 1222 (C4) 1176 (C2) 1148 (C7)

1040 (C11) 838 (C9) 781 (C16) 659 (C22) 466 (C10) 362 (C13) 304 (C19) 293

(C15) 272 (C20) 262 (C8) 231 (C14) 57 (C28) 40 (C27)

306

19

N

N

OO

OO

4132

12

3

45

6 7

8 9

151617

18

20

21

2223

24 25

26

27

28

OSi10

11 12

1314

H

H













1547 1497 1367 1365 1359 1335 1332 1287 1286 1283 1282 1278 1277

1274 1240 1239 1226 1225 1177 1176 1156 1153 1147 1042 1038 838

836 671 668 480 478 476 474 473 471 407 406 313 309 299 280 279

307

276 270 177 123 IR (neat) 2943 2865 1731 1698 1634 1455 1424 1366 1325


405








1497 (C12) 1367 (C1) 1365 (C1) 1359 (C17) 1335 (C6) 1332 (C6) 1287 (C23)

1286 (C23) 1283 (C25) 1282 (C25) 1278 (C26) 1277 (C26) 1274 (C24) 1240

(C2) 1239 (C2) 1226 (C5) 1225 (C5) 1177 (C3) 1176 (C3) 1156 (C4) 1153 (C7)

1147 (C7) 1042 (C11) 1038 (C11) 838 (C19) 836 (C19) 671 (C22) 668 (C22)

480 (C16) 478 (C16) 476 (C9) 474 (C9) 473 (C10) 471 (C10) 407 (C8) 406

(C8) 313 (C13) 309 (C13) 299 (C13) 280 (C20) 279 (C20) 276 (C14) 270 (C14)

177 (C28) 123 (C27)

308

N

N

O

H

H

OO

O O21

2223

2425

26

12

3

4

56 7

8 9 10

11 12

1314

151617

18

1920

4131














1362 1351 1324 1278 1272 1270 1268 1237 1222 1176 1148 1107 839

662 469 446 402 384 291 283 279 272 231 IR (neat) 2953 1731 1701

309

1455 1423 1368 1326 1147 1016 747 MS (CI) mz 501 [C30H32N2O5 (M+1)









1488 (C18) 1362 (C23) 1351 (C1) 1324 (C17) 1278 (C25) 1272 (C26) 1270

(C24) 1268 (C26) 1237 (C4) 1222 (C5) 1176 (C3) 1148 (C7) 1107 (C11) 839

(C19) 662 (C22) 469 (C9) 446 (C13) 402 (C16) 384 (C11) 291 (C15) 283 (C10)

279 (C8) 272 (C20) 231 (C14)

NH

HN

OH

H

H

12

3

4

56 7

8 9 10

1112

1314

151617

4133




310













CD3OD) δ 1376 1355 1286 1217 1196 1184 1118 1082 729 497 455 422

394 354 341 323 300 IR (neat) 3394 29241450 1335 742 MS (CI) mz 270








311

1286 (C6) 1217 (C4) 1196 (C5) 1184 (C3) 1118 (C7) 1082 (C2) 729 (C12) 497

(C9) 455 (C16) 422 (C15) 394 (C10) 354 (C13) 341 (C11) 323 (C8) 300 (C14)

N

N

OHO

H

H

OO

O O

20

12

3

4

56 7

8 9 1011 12

1314

151617

18

19

21

2223

2425

26

N

N

OHO

H

H

OO

O O

20

12

3

4

56 7

8 9 1011 12

1314

151617

18

19

21

2223

2425

26

4137a 4137b














312



13C NMR (125 MHz d6-DMSO 100 ˚C) δ 2151 1543 1488 1363 1351 1325

1279 1278 1272 1268 1237 1223 1177 1151 1148 839 729 662 472 451

405 390 307 272 257 232 IR (neat) 3436 2976 1729 1699 1456 1424 1360

1328 1153 754








(C23) 1351 (C1) 1325 (C17) 1279 (C6) 1278 (C25) 1272 (C26) 1268 (C24)

1237 (C4) 1223 (C5) 1177 (C3) 1151 (C7) 1148 (C2) 839 (C19) 729 (C11) 662

(C22) 472 (C16) 451 (C10) 405 (C13) 390 (C9) 307 (C15) 272 (C20) 257 (C8)

232 (C14)

313

19

N

N

OO

OO

4144

12

3

45

6 7

8 9

1718

2021

22

2324

25 26

1011

1314

15

16

H

HO

O12

27

OH
















314

1543 1488 1364 1349 1337 1277 1271 1266 1236 1222 1176 1147 837

659 576 503 463 453 360 336 296 272 262 250 231 IR (neat) 2931 1729

1697 1454 1367 1328 1155 1116 912 747 MS (CI) mz 549 [C31H36N2O7 (M+1)

requires 549] 549 (base) 493 449








DMSO 100 ˚C) δ 1716 (C17) 1543 (C22) 1488 (C19) 1364 (C1) 1349 (C14) 1337

(C6) 1277 (C24) 1271 (C26) 1269 (C27) 1266 (C25) 1236 (C2) 1222 (C5) 1176

(C4) 1153 (C3) 1147 (C7) 837 (C20) 659 (C23) 576 (C15) 503 (C18) 463 (C13)

453 (C9) 360 (C10) 336 (C16) 296 (C8) 272 (C21) 262 (C12) 231 (C11)

315

19

N

N

OO

OO

4145

12

3

45

6 7

8 9

17

18

20

21

2223

2425

26

10

11

1314

1516

H

H

12OO
















316




1352 1324 1278 1272 1269 1259 1222 1176 1149 1107 1064 839 674

662 474 469 368 336 306 299 272 234 IR (neat) 2976 1731 1698 1455


517 (base) 417









1487 (C18) 1362 (C1) 1352 (C17) 1324 (C6) 1278 (C23) 1272 (C25) 1269

(C26) 1259 (C24) 1222 (C2) 1176 (C5) 1149 (C4) 1107 (C3) 1064 (C7) 839

(C11) 674 (C19) 662 (C22) 474 (C16) 469 (C9) 368 (C8) 336 (C13) 306 (C15)

299 (C10) 272 (C20) 234 (C14)

317

19

N

N

OO

OO

4147

12

3

45

6 7

8 9

17

18

20

21

2223

2425

26

10

11

1314

1516

H

H

12O

















318




˚C) δ 1538 1488 1428 1362 1351 1325 1277 1273 1272 1269 1236 1222

1176 1149 1148 1036 838 662 637 475 465 379 320 272 260 233 IR

(neat) 2976 1729 1699 1455 1422 1330 1142 747 MS (CI) mz 500 [C30H32N2O5

(M) requires 500] 500 401 387 (base) 267 229








(125 MHz d6-DMSO 100 ˚C) δ 1538 (C21) 1488 (C18) 1428 (C12) 1362 (C1)

1351 (C17) 1325 (C6) 1277 (C23) 1273 (C25) 1272 (C26) 1269 (C24) 1236

(C2) 1222 (C5) 1176 (C4) 1149 (C3) 1148 (C7) 1036 (C13) 838 (C19) 662

(C22) 637 (C11) 475 (C16) 465 (C9) 379 (C8) 320 (C15) 272 (C20) 260 (C10)

233 (C14)

319

NH

NH

H O

12

3

4

56 7

8 9 10

11

12

1314

151617

18

4148













1 H) 13C NMR (100 MHz C6D6) δ 1441 1362 1320 1285 1216 1197 1185

1111 1072 1050 668 555 549 417 408 358 242 228 IR (neat) 3394 2927

2360 1646 1457 1244 1070 741 668 MS (CI) mz 2811657 [C18H21N2O (M+1)

requires 2811654]

320








(C6) 1216 (C4) 1197 (C5) 1185 (C3) 1111 (C7) 1072 (C2) 1050 (C13) 668

(C11) 555 (C9) 549 (C16) 417 (C10) 408 (C15) 358 (C18) 242 (C8) 228 (C14)

N

NH

H O

19

12

3

45

6 7

8 9 10

11

12

1314

151617

18

4149









321








1188 1179 1097 1087 1063 1048 666 552 536 418 405 379 347 237

229 IR (neat) 2925 2360 2340 1644 1467 1379 1070 895 738 668 MS (CI) mz

2931659 [C19H21N2O (M-1) requires 2931654]








(C1) 1265 (C17) 1208 (C6) 1188 (C4) 1179 (C5) 1097 (C3) 1087 (C7) 1063

(C2) 1048 (C13) 666 (C11) 552 (C8) 536 (C16) 418 (C10) 405 (C15) 379 (C19)

347 (C18) 237 (C8) 229 (C14)

322

19

N

N

OO

OO

4152

12

3

45

6 7

8 9

17

18

20

21

2223

2425

26

10

11

1314

1516

H

H

12O

O27

28














100 ˚C) δ 815 (d J = 80 Hz 1 H) 771 (s 1 H) 747 (d J = 80 Hz 1 H) 733-723



323



1488 1362 1351 1327 1277 1274 1273 1269 1237 1223 1193 1176 1148

1107 838 662 647 477 460 359 299 272 257 242 223 IR (neat) 2913

1721 1691 1612 1427 1318 1090 740 MS (CI) mz 543 [C32H35N2O6 (M+1)

requires 543] 544 543 488 444 (base) 400








MHz d6-DMSO 100 ˚C) δ 1939 (C27) 1568 (C21) 1539 (C18) 1488 (C12) 1362

(C1) 1351 (C17) 1327 (C6) 1277 (C23) 1274 (C25) 1273 (C26) 1269 (C24)

1237 (C2) 1223 (C5) 1193 (C4) 1176 (C3) 1148 (C7) 1107 (C13) 838 (C19)

662 (C22) 647 (C11) 477 (C16) 460 (C9) 359 (C8) 299 (C15) 272 (C20) 257

(C10) 242 (C28) 223 (C14)

324

NH

NH

4154

12

3

45

6 7

8 9

17

10

11

14

1516

H

H

12O

O13

1819
















MHz) δ 1955 1575 1356 1355 1272 1215 1213 1193 1177 1112 1079 674

325

483 477 374 323 288 250 237 IR (neat) 2921 1614 1453 1321 1195 738 MS









1355 (C1) 1272 (C6) 1215 (C2) 1213 (C5) 1193 (C4) 1177 (C3) 1112 (C13)

1079 (C7) 674 (C11) 483 (C16) 477 (C9) 374 (C8) 323 (C15) 288 (C10) 250

(C19) 237 (C14)

N

N

41

12

3

45

6 7

8 9

17

10

11

14

1516

H

H

12O

O13

1819

20

21





326










211 (ddd J = 112 46 40 Hz 1 H) 207 (s 3 H) 189 (m 1 H) 180 (dd J = 120 36

Hz 1 H) 13C NMR (75 MHz) δ 1955 1574 1372 1332 1265 1211 1208 1187

1178 1090 1059 678 547 538 418 385 324 291 250 229 228 IR (neat)

2895 2359 1617 1468 1320 1276 1192 911 741 MS (CI) mz 337 [C21H25N2O2










327

(C17) 1265 (C6) 1211 (C4) 1208 (C5) 1187 (C3) 1178 (C2) 1090 (C13) 1059

(C7) 678 (C11) 547 (C9) 538 (C16) 418 (C21) 385 (C20) 324 (C8) 291 (C10)

250 (C19) 229 (C15) 228 (C14)

328

References












329















330















331














332

















333

















334













335

















336














337













338

















339














340
















341



342

Vita










v

Acknowledgements











work was based

vi




















vii
















viii

Table of Contents

List of Tables xii


List of Schemes xiv




121 Introduction2












141 Introduction33




ix













16 Conclusions51













x

24 Conclusions95


31 Introduction97

311 Alstonerine98





















36 Conclusions141


41 Introduction144


421 Introduction148

xi















45 Conclusions209


51 General 211

52 Compounds 212

References328

Vitahellip342

xii

List of Tables


xiii

List of Figures


xiv

List of Schemes


xv


xvi


xvii


1





















2











121 Introduction













3










Scheme 11

M

X-Nuc-

11

X

12

X

M

13

M

14

Nuc

M

15

Nuc

4













Scheme 12

Br

OAcPd(PPh3)4

THF

DMF

OAc

MeO2C

SO2Ph

Br

+CO2Me

SO2Ph

SO2Ph

CO2Me16 17

18

19





5



Scheme 13

R1 R2

X M

R1 R2

M

110 111

Nuc-Nuc-

a b

R1 R2

Nuc

112

R1 R2

113

Nuc

path a

path b

-X-









used as a substrate

6

Scheme 14

LG Nuc

LG Nuc

Pd

Pd

Ru Mo Rh Ir W

Ru Mo Rh Ir W

+ Nuc

115114

116 117










7

Scheme 15

NaHCH2(CO2Me)

OAc

118NaH

CH2(CO2Me)

Pd(PPh3)4

W(CO)3(MeCN)383

or

119 E = CO2Me

E

E

E E

120 E = CO2Me

+

119 E = CO2Me

E

E

E E

120 E = CO2Me

+

119120 = 8614

119120 = 496









8

Scheme 16

OAc

OAc

NaHCH2(CO2Me)

Mo(CO)6

NaHHCMe(CO2Me)

orE

E

E

EMe

121 122

123 E = CO2Me

124 E = CO2Me

89

84















9


sections

Scheme 17

nPr OAc

THF reflux 19 h66

THF rt 1 h94



[Ir(COD)Cl]2 (2)

nPr

nPr

CO2Me

CO2Me

MeO2C CO2Me

126

125

127

126127 = 8812

+

nPr

nPr

CO2Me

CO2Me

MeO2C CO2Me

126 127

126127 = 397

+








documented1316


Alkylations



10








membered) rings

Scheme 18

LG

Nuc Nuc

M

M

127 128











11



favored (Eq 12)

O

O

OAcH

H

CO2Me

SO2Ph

NaH THF

Pd(PPh3)4 dppe60

O

O

SO2PhCO2Me

H

H

129 130

SO2Ph

OAc

SO2Ph

131

SO2Ph

SO2PhBSA THF

Pd(dppe)244

132

(11)

(12)







12

O

SO2Ph

OO

SO2Ph

O134 135

O

SO2Ph

O

133

OAc

+

NaH Pd(PPh3)4Diphos

THF reflux73

134135 = 928

OPh

CO2Me

O

Pd(OAc)2 PPh3

62

CO2Me

O

136 137

(13)

(14)














13
















14

Scheme 19

soft Nuc-

hard Nuc-

H

Nuc

M

140

M

NucM

142

oxidativeaddition

H

Nuc

141

Nuc

H

M

143


Nuc

H

144

M

139

H

LG

138

M

M












minimize A13-strain

15

Scheme 110

R OAc OAc

R

145 146

R OAc OAc

R

147 148


MLn MLn

syn anti

R Nuc Nuc

R

149 150

Nuc- Nuc-








16

Me

PhOAc


151

Me Ph

CO2MeMeO2C

152THF rt

99

Me

OAc


154

THF rt96

Ph

Me Ph

153

CO2MeMeO2C

Me Ph

CO2MeMeO2C

152

Me Ph

153

CO2MeMeO2C

+

+

152153 = 9010

152153 = 928

(15)

(16)










palladium catalysis

Me

PhOAc

155

TfaN

Zn OOtBu

PPh3 [Pd(allyl)Cl]2

THF -78 degC - rt69

Ph157

tBuO2C

NHTfa

156

(17)

17















Scheme 111

nPr OAcTHF reflux

85

NaCH(CO2Et)2


158

nPr

159

CO2Et

CO2EtnPr

nPr

CO2Me

CO2Me

MeO2C CO2Me

160

161

+

+

159160161 = 9073

18















OCO2Me

OMe

O O

RhH(PPh3)4 (5)PBu3 (10)

CO2Me

O162

163

164

THF rt93

(18)




19











OCO2Me

OMe

O O


O

CO2Me

O

+

165

163

166 167

168

OCO2Me

dioxane 100 degC97

OMe

O O

RhH(PPh3)4 (5)PBu3 (10)

163

dioxane 100 degC81

CO2Me

O

CO2Me

O

+

166 167

166167 = 7228

166167 = 1486

(19)

(110)

20























21




991 91

982 89

OCO2Me

169

R1 R2

170

R1 R2CO2Me

CO2MeR1

171

R2

MeO2C

CO2Me



+


1

2

3

4

5

6

phosphite

H

H

H

Me

Me

Me

Me

nPr

Ph

Me

nPr

Ph

P(OMe)3

P(OMe)3

P(OMe)3

P(OPh)3

P(OPh)3

P(OPh)3

982

gt991

964

gt991

95

89

73

32









22



nucleophilic attack

Scheme 112

OCO2Me

165

168

OCO2Me


P(OMe)3 (20) THF

173172

+

From 168 172173 = 421 99From 165 172173 = 21 83

or

MeO2C CO2Me

CO2Me

CO2Me














23



Me

OCO2Me

MeD

Me MeD

CO2MeMeO2C

Me Me

D

CO2MeMeO2C

+

P(OPh)3 (20) THF92


174 175 176

175176 = gt191

R1

OCO2Me

R2 Me iPr

CO2MeMeO2C

+

P(OPh)3 (20) THF92


179 180

From 177 179180 = 973From 178 179180 = 397

iPrMe

MeO2C CO2Me


(111)

(112)










24

Scheme 113

R

Rh(I)

R

Rh(III)

Nuc

R

LG

R

Rh(III)

NucRh(I)

Path A

Path B

R

LG

R

R

R

k1k-1

k2

k3

R

Nuc

R

RNuc

R

181 182 183

184185

186
















25

Scheme 114

R


P(OMe)3 THF R

OR


R

OAr

R

TsNBnor or

187 188 189 190







Group












26











27


OCO2MeR1


NaCH(CO2Me)2 R1

R2R3 R4

CO2Me

CO2Me

+ MeO2CR4

R3R1 R2

CO2Me191 192

193

THF rt


majorminor

1

2

3

OCO2Me CO2Me

CO2Me

OCO2MeCO2Me

CO2Me

OCO2Me

CO2Me

CO2Me

75

80

86

928

946

991(973 ZE)

OCO2MeCO2Me

CO2Me

4 84 973

Ph OCO2Me PhCO2Me

CO2Me

593 9010

194

196

198

1100

1102

195

197

199

1101

1103






28











29


OCO2MeR1

R2R3 R4

R1

R2R3 R4

CO2Me

CO2Me

+ MeO2CR4

R3R1 R2

MeO2C

191

11051106

THF


majorminor

1

2

3

OCO2Me

OCO2Me

OCO2Me

85

98

98

991

8812

1000(8812 ZE)

OCO2Me4 98 gt955

194

196

198

1110

CO2MeMeO2C

Me

+

NaH[Rh(CO)2Cl]2

1104

Me

CO2Me

CO2Me

Me

CO2Me

CO2Me

Me

CO2Me

CO2Me

Me

CO2Me

CO2Me

1111

1109

1108

1107

Me Me

30











OCO2Me

1102

[Rh(CO)2Cl]2 PhLi

ZnBr2 THF rt99


Ph

1112

99 ee 92 ee

(113)










31










regioselectively

32


OCO2MeR1


NucR1

R2R3 R4

+Nuc R4

R3R1 R2

191 1113 1114


majorminor

1OCO2Me

84 928

1100

NucTHFrt

nucleophile

OCu(I)

Ph Ph

O

2OCO2Me

75 gt955

1117

OCu(I)

PhPh

O

1115

1115

1116

1118

3OCO2Me

78 9010

1100

11191120

4OCO2Me

42 8812

1100

11211122

NTsLiTsN Ph

LiTsN TsN





33










Scheme 115

R

Rh(I)

R

Rh(III)

Nuc

R

LG

R

Rh(III)

NucRh(I)

Path A

Path B

R

LG

R

R

R

k1k-1

k2

k3

R

Nuc

R

RNuc

R

181 182 183

184185

186


141 Introduction





34












MeO

H

H+

Co2(CO)8 ∆

Me1123 1124

1125

(114)









35







Scheme 116

Co2(CO)8

Co(CO)3(CO)3Co

R-CO

Co(CO)2

Co(CO)3

R

Co

Co(CO)3

R

COCO

Co

Co(CO)3

R

CO

O

(CO)3CoCo(CO)

O

R

O-Co2(CO)4

R

1126 1127 1128 1129

1132 1131 1130

R








36







MOMO

PhCo2(CO)8

toluene 100 degC41

11351136 = 32

O

Ph

MOMO

O

Ph

MOMO

+

11341133

+

1135 1136

MeS

PhCo2(CO)8

toluene 100 degC61

11371138 = 181

O

Ph

MeS

O

Ph

MeS

+

11381137

+

1139 1140

(115)

(116)








37
















OEtO2C

EtO2C



EtO2C

EtO2C

1141 1142

(117)





38



catalysts






fashion64


toluene 90 degC92

O

Ph

O

1143 1144

OPh

(118)







Me

O

1145 1146

MeEtO2C

EtO2CEtO2C

EtO2C

CO (10-15 atm)Ru(CO)12 (2)


86-76

(119)



39







Scheme 117

Ph

O

11471148

PhEtO2C

EtO2C

EtO2C

EtO2C



toluene 110 degC 99









40

Scheme 118

TBSOMe Co2(CO)8


50

Me

O

TBSO

H

1148 1149

6 steps HO

H

1150

O

OH

H

HO

H

1151

O

OH

H

O

O

H











41

Scheme 119

OOAc

N NO

H H

H


51

1152 1153

N

H H

H

1154

O

9 steps

OAc






Scheme 120


THF 65 degC67

11561157 = 611155

MeO MeO1156

N

O

MeO1158

N

7 steps

MeO1157

N

O+

H

42







Scheme 121

O O

1159 n = 1 or 2

PKR

n

1160 1161

or










43

O

Me

MeO

O

Me

Me

O

Co2(CO)8 CH2Cl2

1164 1165

then NMO48

O

O

O

OO

1162 1163

Co2(CO)8 CH2Cl2

then NMO31

(120)

(121)







cedrene (1170)

Scheme 122

O O

OO

O

DCE 83 degC95

11671166

Co2(CO)8nBuSMe

1170

H

1169

H

1168

O

H

5 steps

44











Scheme 123

O O

O

H


then Me3NO2H2O60-70

OO

OO

11731174

K2CO3MeOH

55O

CO2Me

O

H

1175

O

H

1176

HO HOHO

HO

H

H

O O

O

H

1171

H

TMS

Br


1172

45
























46






Cl

CO2Me+

MesN NMes

RuPh

PCy3ClCl

1178

1176 1177

then H2 (100 psi)69

CO2Me

Cl

1179

OOHi) 1178


11801181

56

(122)

(123)









47







reported

EtO2C

EtO2C

CO (441 psi)Co2(CO)8 (5 )

CH2Cl2 130 degC68

OEtO2C

EtO2C

PhPh

1182 1183

MeO2C

MeO2C

1184

Co nanoparticles


98

OMeO2C

MeO2CH

H

1185

(124)

(125)









48




dodecylsulfate)

MeO2C

MeO2C

1186

OMeO2C

MeO2C

1187


SDS H2O 100 degC

PhPh

O

HH+ (126)















49


back bonding81

Scheme 124

∆

Me


NaH

CO CH3CN 30 degC

CO2MeMeO2C

168

1188

Me

MeO2C

MeO2C

CO2Me

CO2Me

Me+

1189 1190

OMeO2C

MeO2C

Me H

OMeO2C

MeO2C

Me H

+

1191 1192

11891190 = 371 88

11911192 = 71 87









50








Scheme 125

X

+ LG

R

[Rh(CO)2Cl]2X

R

X

R

X O

R

XR

PKR

X = C(CO2Me)2 NTs O

[5+2]

cycloisom

CO

11931194

1195

1196

1197

1198








51











fashion

Scheme 126

OCOCF3


72

MeO2C

MeO2CCO2MeMeO2C

Me


89

OCOCF3 MeO2C

MeO2C

1200

1202

1104

1199

1201

16 Conclusions



52












palladium catalysis












53






















54











R

R

OCO2Me

Nuc[Rh(CO)2Cl]2

R

R

Nuc

R

OCO2Me

R

Nuc[Rh(CO)2Cl]2

R

Nuc

R

21 22

23 24

(21)

(22)








55









Scheme 21

O

NBn

Rh(I)

RO

NBn

R

XX

MeO2CO

Rh(I)

X O

R

Rh(I)X

R

MeO2CO R

OCu(I)

NBn

[Rh(CO)2Cl]2

[Rh(CO)2Cl]2

[Rh(CO)2Cl]2

25

26


2728




-CO


X


X

56
















R R R R215 216


OCO2Me Nuc






57




Scheme 22

OCO2Me

OCO2Me


THF rtor

218

217

219 220

+

From 217 72 7624 219220From 218 76 5545 219220











58

Scheme 23

OCO2Me

OCO2Me


THF rtor

222

221

223 224

+

From 221 56 955 223224From 222 58 8614 223224










Scheme 24


THF rt227 228

+

From 225 29 946 227228From 226 21 919 227228


OCO2Me

OCO2Me

or

226

225



59











[Rh(CO)2Cl]2 +

220 219

CH2(CO2Me)2 NaH

218


1

2

3

4

DMSO

CH3CN

THF

DMF

62

62

76

73

2575

3664

4555

6931






60


DMF -20 degC88

[Rh(CO)2Cl]2 +

219 220

CH2(CO2Me)2 NaH

217

219220 = 964

(24)









this chapter

OCO2Me

217

CO2MeMeO2C

+

229

MeO2C

MeO2C

MeO2C

MeO2C 231

230

+

NaH[Rh(CO)2Cl]2

DMF -20 degC88

230231 = 937

(25)






61


Scheme 25

OCO2Me


DMF -20 degC

222

OCO2Me

226

orno reaction












112)37




62














21)






OCO2Me

HN



232

233

(26)

63









OCO2Me

HN


96234235 = 11

232

233

234

N

235

N

+(27)





OCOCF3

HN


233

N

CF3O

OH

238

+

237

(28)




64




O

HN



with TBAI 98 5 h

OH

N

233

239

240

(29)













65

Scheme 26

RhCl

OC

OC

ClRh

CO

CO

HN

RhClOC

NHOC


233

240

I-

RhI

OC

OC

IRh

CO

CO

HN

RhIOC

NHOC

RhI

OC

OC

I

slower

Bu4N+I-

Bu4N+

233

242

243

244-I-










66




R2

R1 OCO2Me


NHR1R2 (2 eq)DCE rt

R2

R1 NR2

R3R4 R3

R4R2N

R2R1

+

TBAI (20 mol)



HN

HN

NHBn

Me

OCO2Me

OCO2Me

Me

OCO2Me NMe

Bn

N

Me

N 96

99

89

gt955

gt955

gt955

233

233

250

232

248

251

234

249

252

245 246 247

NHBn

MeN

Me

Bn

85 gt955

250 253 252

OCO2Me






67















PKR

68

Scheme 27

BnNH2

Br

64 BnHN

PhI CuIPd(PPh3)4

Et3N82

BnHNPh

254255 256

OCO2Me

257


DCE rt-reflux86

BnNPh

258

not BnN

Ph

O

259















69








structures like 264

Scheme 28

OH

R1260


O

R1

R2

R5

R4R3

261


O

O

O

O

R2

R3

R4

R5

R2

R3

R4R5

R2

R3

264

262

263

HeckR1 = halide

RCMR1 = alkene

or alkyne

PKRR1 = alkyne

[Rh(CO)2Cl]2





70













71


R2

R1 OCO2Me

R3R4 R2

R1 Nuc

R3R4 R3

R4Nuc

R2R1

+



245 265 266


THF rt

OH

OH

Br

OH

Ph

+

267

270

272

OCO2Me

268

OCO2Me

268

217

OCO2Me

OH

Ph

272

OCO2Me

251

O

269

O

Br271

O

Ph273

O

Ph274

77 gt955

87 7129

lt10 NA

73 gt955

Nuc







72























73


Scheme 29

O

OO

OCO2Me

O

O O

O

OO

catalyst

base

Pd

Rh 275

276

277

278

O

OO

M






Scheme 210

OH OTHP

On-BuLi

HMPA Et2OTHF65

OTHP

HO


OODMAP

O

O O

279

TsOHH2O

O

280 281

282 283

CH2Cl293

EtOAc78

Et2O84 THPO


74







Scheme 211

O

O O

283THPO

conditionsO

O O

284HO

+ HO

282

THPO

HO

285

HO

+










75

Scheme 212

OH

TBSCl imid

OTBS

On-BuLi

BF3Et2O THF

71OTBS

HO


OO

DMAP

O

O O

OTBS

TBAF THFO

O O

OH

O

O O

OCO2Me

pyr CH2Cl291

279 286 287

288 289

290 275

91

ClCO2Me

DMF99

EtOAc99

Et2O84









76


O

O O

OCO2Me275

O

OO

Conditions


1

2

3

4

5

NaH

NaH

KOtBu

KOtBu

KOtBu

THF

DMF

THF

DMF

DMF

rt

rt

rt

rt

0

20

34

51

54

68

278







O

O O

+O

OO

O

O O

OCO2Me275

278 277

278277 = 5545

55(210)



77






Scheme 213

HOOTBS

288

CBr4 PPh3

Et3N CH2Cl278

BrOTBS

291

OMe

OO

NaH n-BuLi

MeO

O O

OTBS

TBAF

MeO

O O

OH

pyr CH2Cl283

MeO

O O

OCO2Me

292 293

294

ClCO2Me

THF69

THF63








78


MeO

O O OO

OMe

+

O

OMe

OKOtBu[Rh(CO)2Cl]2

(10 mol)

DMF -20 degC52

294295 296

295296 = 4357

(211)

MeO2CO




212)21

OPh

CO2Me

O

Pd(OAc)2 PPh3

62

CO2Me

O

297 296

(212)


Reactions





(Eq 213)84

79

NBn

O


ii) 1 N HCl (aq) 71

O

O

298 299

(213)





Scheme 214

NBn

O

i) [Rh(CO)2Cl]2 ∆

ii) 1 N HCl (aq)

O

O

2101 2102

NBn

OH

2100

[Rh(CO)2Cl]2

OCO2Me

R2

R1

R3 R4

245

R2

R1

R4 R3

R2

R1

R4R3







80

NBn

O

298

then HCl53 O

O

299


(214)










O

OH

2103

+ OCO2Me

257

O

O

2104


THFwithout CuI 33

with CuI 64

(215)




moderate yield

81

NBn

OH

2100

+ OCO2Me

257

NBn

O

298


THF55

(216)









Scheme 215

NBn

OH

2100

OCO2Me257

NBn

O

298


THF or toluenert

rt-150 degCX

then HClO

O

299





reaction sequences

82








CO2MeMeO2C

MeO2CO

MeO2C CO2Me

2106

2105

CH3CN 80 degC75


(217)





83

Scheme 216

CO2MeMeO2C+

OCO2Me

OCO2Me2107

2108

CO2MeMeO2C

MeO2CO

[Rh(CO)2Cl]2


2106

2105









84


CO2MeMeO2C+

OCO2Me

OCO2Me


solvent rt-reflux

MeO2C CO2Me

equiv 2107

21072108

2106

MeO2CCO2Me

CO2MeMeO2C

+

2109


1

2

3

4

5

6

25

25

25

25

15

15

1

1

1

1

1

1

2

2

2

2

1

1

THF

dioxane

toluene

DMF

THF

dioxane

15

23

20

0

20

32

--

24

7

32

17

16







85

CO2MeMeO2C+

OAc

OCO2Me


(10 mol)

dioxane rt-reflux45

21062109 = 21

MeO2C CO2Me

21072110

2106 MeO2CCO2Me

CO2MeMeO2C

+

2109

15equiv

1equiv

(218)


















86

MeO2C CO2Me+

R


MeO2C

MeO2C

R

1

23

4

5

67

8

2111 2112

2113

(219)







Scheme 217

+

R

LG

R LG

or

or

[Rh(CO)2Cl]2

OMeO2C

R

4

2115

2114

2119R LG2116

R

R

MeO2C CO2Me

2111

2

MeO2C

OMeO2C

2117

R

2

MeO2C

OMeO2C

R

42118

MeO2C

[Rh(CO)2Cl]2

[Rh(CO)2Cl]2






87




Scheme 218

CO2MeMeO2C

Ph

OCO2Me


91

PhMeO2C

MeO2C


THF reflux99

MeO2C

MeO2C

Ph

O

CO (1 atm)

21212120

2122

257




2121

CO2MeMeO2C

PhNaH CO (1 atm)


THF rt - reflux

PhMeO2C

MeO2C

2120

OCO2Me

257

not 2122 (220)






88









inhibited the PKR

O

Ph

MeO2C

MeO2C

2122


NaOMe or NaOAcX

MeO2C

MeO2C

2121

(221)











89











promote the PKR

CO2MeMeO2C

Ph

+ OCO2Me


O

Ph

MeO2C

MeO2C

2120

257

2122



(222)








90



223)

CO2MeMeO2C

Ph

+ LGCO NaH

[Rh(CO)2Cl]2O

Ph

MeO2C

MeO2C2120

2123

2122



rt - reflux(223)











Scheme 219

91

MeO2CCO2Me

OCOCF3 OMeO2C

MeO2C+

R

CO [Rh(CO)2Cl]2

(10 mol )

R

azeotroped wtoluene

2126

2127 R=H = 732122 R=Ph = 682128 R=Me = 67

2124 R = H2120 R = Ph2125 R = Me










Scheme 220

CO2MeMeO2C

PhCO (1-40 atm)


Ph

OMeO2C

MeO2C

Et

X


2120 2130

OCOCF3

2129





92



reagent

Scheme 221

2120

+OCOCF3

2129

CO NaH [Rh(CO)2Cl]2

(10 mol)THF

MeO2C

MeO2C

2131

MeO2C CO2Me

Ph

2 eq 1 eq

1 eq 2 eq

Ph

Isolated Yield96

24












93

O

Ph

MeO2C

MeO2C2122

MeO2C

MeO2C

2121

Ph

CO [Rh(CO)2Cl]2


O

Ph

MeO2C

MeO2C

2122

MeO2C

MeO2C

2121

Ph

+51 24 h

2126

(224)

(225)

CO [Rh(CO)2Cl]2

(10 mol) THF reflux

2120

MeO2C CO2Me

Ph








[Rh(CO)2Cl]2 +O O

BaCO3O

ORh

CO

CO

[Rh(CO)2Cl]2 +

O

O O

O

Base OMeO

MeOO

RhCO

CO

R R

2132 2133

21342135

(226)

(227)




94











Scheme 222

O

OO

O

2138

THF rt-reflux

PhOH


2) BH3Me2NH


2136

O O

O O

Ph2137

O

OO

O Ph

O

2139

Ph

not observed


OCOCF3

2129




95





Scheme 223

CO2MeMeO2C

Ph

OCOCF3 Ph

OMeO2C

MeO2C

EtH

21202130


2129

Ph

OEtO2C

EtO2C

MeH

2140

24 Conclusions










96











97


31 Introduction













linkage


N

NMe

Me

OH

O

H

H

H

H

macroline (31)

NH

NHO

H

H H

HOH

sarpagine (32)

421

16

4 21

98

311 Alstonerine







ring


N

MeN

Me

O

O

H

H

H

H

33

A BC D

E










99



Scheme 31

NH

N

H

H H

HOH

37

NH

NH

34 Strictosidine

O

MeO2C

OGlu

HNH

N

35

OH

MeO2CH

H H

NH

N

H

H H

CHO

CO2Me

36








100

Scheme 32

NH

NH

34 Strictosidine

O

MeO2C

OGlu

HH N

H

NH

38

OHCHO

MeO2CH

H

NH

NH CHO

H

H H

CHOCO2Me

39

NH

NH CHO

H

H H

CHOCO2Me

310

NH

N

H

H H

CHO

CO2Me

36










Tamelen

101

Scheme 33

NH

N

311

OHC

H

CO2H

NH

N

312

OHC

H

DCC PTSA

dioxane

NH

N

H

H H

313

CHO

NMe

N

H H

ajmaline (314)

OHHO

H

H

NMe

N

CN

315

H

TBSO

BF3Et2O

NMe

N

316

H

TBSO

NMe

N

H

H H

317

HCHO

NMe

N

H

H H


HCHO

KOHMeOH

56






102






Scheme 34

N

MeN

Me

OH

O

H

H

H

H

31

N

MeN

Me

O

O

H

H

H

H

33

NH

N

H

H H

HOH

37

NH

N

H

H H

HOTBS

319

TBS-Cl imid

DMF

NH

N

H

H H

HOTBS

320

Oi) Me2SO4 K2CO3

ii) TBAF






103






norsuaveoline (322)

Scheme 35

H

NMe

BnN

O

Dieckmann

Pictet-SpenglerH

323

NH

NH2

CO2H

324

NMe

MeN

OH

H

H

H

alstonerine (33)

O

NMe

MeN

talcarpine (321)

H

H

H

H

OMe

CHO

NH

HN

H

H

N

Et

norsuaveoline (322)







104















105

Scheme 36

NH

NH2

CO2H

324

1) NaNH3 MeI


Me

NH2

CO2Me

325

PhCHO MeOH

NaBH4 -5 degC88 N

Me

NHBn

CO2Me

326

1) C6H6dioxane ∆

HO2C

O

CO2H

2) HClMeOH ∆

80NMe

NBn

CO2Me

CO2Me

327

NaH MeOH

PhMe ∆

92

NMe

BnN

328

O

CO2Me

H

H

AcOHHClH2O

∆ 91NMe

BnN

323

OH

H

3

5







106

Scheme 37

N NNMe

H

CO2Me

CO2Me

MeNPh

H

CO2Me

CO2Me

Ph

HNNMe

H

CO2Me

CO2MePh

HNNMe

H

CO2Me

Ph

CO2Me

NMe

NBn

CO2Me

CO2Me

trans-327

cis-327

329 330

HCl

trans-327









107





reaction vessels

Scheme 38


NH

NH2

CO2Me

324


CH2Cl2 rt 48h

83 NH

NBn

CO2Me

CO2Me

331

NMe

N

323 gt98 ee

OH

H Ph85NMe

NBn

CO2Me

CO2Me

327

NaH MeI

DMF95









108










as the acid source

Scheme 39

NH

NHBn

CO2Me

332

TFA CH2Cl2 92

MeO CO2Me

OMe 336

NH

NBn

CO2Me

CO2Me

331

HO2C CO2H

O 333

PhHdioxane

pTsOH ∆ 86N

NBn

CO2Me

334 O

+

N

NBn

CO2Me

335 O

41 transcis

109




ketone 338

Scheme 310

NH

NBn

CO2Me

CO2Me

331

N

NBn

CO2Me

334 O

NaOMe

NH

BnN

337

O

CO2Me

H

H NH

BnN

338

OH

H

AcOHHClH2O

∆ 91









110



Scheme 311

H

NMe

BnN

O

H

323

NMe

MeN

321

H

H

H

H

OMe

CHO

NMe

BnN

339

H

H

H

H

OOMe

conjugate addn

NMe

BnN

340

H

H

H

H Et

NMe

BnN

341

H

H

CHO

HO R


acetal formation

oxy-cope









111

Scheme 312

NMe

BnN

323

OH

H


2) LiClO4 dioxane

∆ 90 NMe

BnN

341

H

H

CHO

Et Et

Br 342

Mg 90

NMe

BnN

343

H

H

HO

Et

Et

+

NMe

BnN

344

H

H

Et

O Et

H

H

NMe

BnN

345

H

H

Et

O Et

H

H+




313)115116

Scheme 313

NMe

BnN

343

H

H

HO

Et

Et

NMe

BnN

344

H

H

Et

O Et

H

H

NMe

BnN

345

H

H

Et

O Et

H

H+

KH18-crown-6

cumene150 degC 88





112











Scheme 314

NMe

BnN

341

H

H

CHO

NMe

BnN

347

H

H

HO

Et

Li-biphenylBaI2 THF

Et Br

346

90

NMe

BnN

348

H

H

Et

OH

H

NMe

BnN

349

H

H

Et

OH

H+

KH18-crown-6

dioxane100 degC 85

MeOK

15 20

1615 20

16



113




Scheme 315

NMe

BnN

349

H

H

Et

OH

H

NaBH4 MeOH

96NMe

BnN

350

H

H

Et

HOH

H


2) NaIO4 MeOH 78

NMe

BnN

351

H

H

H

H

OOH

Et

pTsOH PhH

95

NMe

BnN

352

H

H

H

H

O

Et

N

O

O

SePh

pTsOH MeOH

NMe

BnN

353

H

H

H

H

O

EtSePh

OMe

NaIO4

H2OTHFMeOH90

NMe

BnN

339

H

H

H

H

OOMe

NMe

BnN

354

H

H

H

H

OOMe

+




114




understood117

Scheme 316

NMe

BnN

339

H

H

H

H

OOMe

90NMe

BnN

355

H

H

H

H

OMe

CHO

NMe

BnN

356

H

H

H

H

OMe

CHO+

K2CO3 EtOH 85

01 torr 100 degC 75

H2SO4







115

Scheme 317

NMe

BnN

355

H

H

H

H

OMe

CHO

NMe

BnN

356

H

H

H

H

OMe

CHO

PdC (10 mol)

H2 EtOH92

NMe

MeN

talcarpine (321)

H

H

H

H

OMe

CHO

H2PdC (xs)

MeOH (15 eq)

90

NMe

N

talpinine (357)

H

OMe

H

HO H

H







syntheses







116




(322)

Scheme 318

NH

BnN

358

H

H

Et

OH

H

NH

BnN

338

H

H

O

NH

BnN

359

H

H

Et

CHOH

H

O O

pTsOHacetone

95NH

BnN

360

H

H

CHO

Et

CHOH

H

NH2OHHCl

EtOH ∆

88NH

RN

H

H

N

Et

361 R = Bn322 R = H

H2 PdC92

1) HO(CH2)2OH pTsOH

PhH ∆ 90







117















118

Scheme 319

NH

BnN

338

OH

H

5 PdC H2HCl EtOH

rt 5 H94 N

H

NH

362

OH

H

BrI

K2CO3 THF ∆

87

NH

N

363

OH

HI


DMF-H2O 65 degC80

NH

N

H

H H

364

O

NH

N

H

H H

vellosimine (365)

HCHO






macroline alkaloids







119











31)105

Scheme 320

NMe

N

CN

367

H

NMe

N

H

H H


HCHO

Mannich reaction

NH

NHCl

CO2H

368OTBS

vinylogous Mannich






120



374

Scheme 321

NH

NHCl

CO2H

368

OMe

TBSO 369

1)


H

NH

CO2tBu

370

CO2Mediketene

DMAP PhMe

KOtBu 86

NH

N

CO2tBu

371

H

OO

MeO2C

1) NaBH4 95


H

N

CO2tBu

372

H

O

MeO2C


then NaBH490

NMe

N

CO2tBu

373

H

MeO2C

TFA

PhSMe90

NMe

N

CO2H

374

H

MeO2C






121



Scheme 322

NMe

N

CO2H

374

H

MeO2C

1) EDCI NH4OH 86

2) TFAA py 90NMe

N

CN

375

H

MeO2C

1) LiBH4 THF 98

2) DMP 83

NMe

N

CN

376

H

OHC

NaH TBS-Cl

NMe

N

CN

367

H

TBSO

BF3Et2O

NMe

N

377

H

TBSO

NMe

N

H

H H

378

HCHO

NMe

N

H

H H


HCHO

KOHMeOH

56







122











Scheme 323

NH

NHCl

CO2H

i)Et3N CbzCl

CH2Cl2

ii) MeOH Et3N87 N

H

NCbz

CO2Me

OMe

TMS

BF3Et2O

CH2Cl281

51 cistrans

NH

NCbz

CO2MeDIBAL-H

toluene -78 degC


60NH

NCbz

368 379

380 381




123



Scheme 324

NH

NCbz

381

RuPh

Cy3P

PCy3Cl

Cl

CH2Cl2 rt97

NH

CbzN

383


2) NaIO4 aq THF 54

NH

CbzN

384

CHO

382

H

H H

H
















124







enantiocontrol

Scheme 325

NMe

OH1) BuLi

2) I2 NMe

OH

I DMP

57 (3 steps) NMe

CHO

I

TMSO

OMe

388

385 386 387

Zn(OTf)2 BnNH270 N

Me

I

389

N

O

Bn


P(tBu)3 CH3CN ∆

85NMe

N

390

H

H Ph

O








125













126

Scheme 326

NH

NH2

CO2H

324

1) LAH 98

2) TsCl py 78 NH

NHTs

391

OTs

1) KCN 86

2) NaNH3(l) THF 88

NH

NH2

392

CN

OHCOTBS

393


then CH2Cl2 TFA80

NH

394

NH

CN



NMe

395

NBn

CN

CHO

NMe

397

NBn

CN

(EtO)2PO

Et

O

OEt

396

NaH 65

Et

CO2Et

LiNEt2 THF

-78 degC 99 NMe

N

398

H

H Ph

CO2EtCN

Et

HH

NMe

NH

399

H

H

OHO

Et

H

H

1) LiBH42) pTSA 88

3) DIBAL-H 504) H2Pd-C 100





(3104)

127

Scheme 327

NMe

395

NBn

CN

CHO

(EtO)2PO

Et

CN

3100

NaH 83 NMe

3102

NBn

CN

Et

CN

KOtBu THF

67

NMe

N

3103

H

H Ph

CNCN

Et

HH

NMe

NH

H

H

N

Et

3104

















128











129

Scheme 328

NH

NHBoc

CO2Me

3105

MeNC nBuLi

82NH

NHBoc

3106

O

N

1) TFA 98


NH

NH

3107

O

N

EtO2C

O 1) POCl3

2) Na2CO3 50

NH

3108

NH

CO2Et

O

N

1) H2Pd(OH)2-C 84

2) Boc2O 87

NH

3109

NBoc

CO2Et

O

N

NMe

NH

H

H

N

Et

3104



4) MeI NaH

5) TFA 80









130










alkaloids111

131

Scheme 329

O

O OBnNH2

H2O

NBn

OH

HO

31103111

+

BnN

HO OH

3112

1) TFAA

2) NaOH 95

BnN

HO OH

3112


50

BnN

HO OTBS

3113

1) H2 PdC

2) K2CO3 PhCOCl 85

BzN

HO OTBS

3114


2) HF CH3CN 95

BzN

OH

3115

1) H2NN(Me)Ph

MeOH HCl ∆

2) LiAlH4 THF 95

NMe

BnN

3116

OHH

H


73NMe

BnN

(plusmn)-323

OH

H








132










Scheme 330

H

NMe

BnN

O

H

H

HNMe

MeN

O

O

H

33



323









133




Scheme 331

NMe

BnN

323

OH

H

1) MeOTf

2) H2PdC80 N

Me

MeN

3118

OH

H



NMe

MeN

3119

H

H

CHO

NMe

MeN

3120

H

H

OH

LiAlH4

Et2O -20 degC90

Me

O

Et3N dioxane90

NMe

MeN

3122

H

H

O

PhH 145 degC

sealed tube65 N

Me

MeN

3123

H

H

CHO

O OH

3121







134

Scheme 332

NMe

MeN

3123

H

H

CHO

OH

NaBH4

EtOH86 N

Me

MeN

3124

H

H

OHH

HO

i) 9-BBNTHF rt 20 h


NMe

MeN

3125

H

H

OHH

HOHO

TsCl pyr rt


NMe

MeN

3126

H

H

H

O

OH

H

H

(COCl)2 DMSO CH2Cl2


MeN

33 51

H

H

H

O

O

H

NMe

MeN

3127 30

H

H

H

O

O

H

+









135

Scheme 333

MeN O

MeN

H HH

H

OH

MeH

N

MeN

Me

O

OH

H

H

H

H

3126

H

3126

excess DMSO(COCl)2

MeN O

MeN

H HH

H

O

MeH

3128

SH MeN O

MeN

H HH

H

OH

MeH

3129

tautomerization

MeN O

MeN

H HH

H

OH

Me

3130

DMSO(COCl)2

MeN O

MeN

H HH

H

O

Me

33








136






Scheme 334

NMe

BnN

323

OH

H NMe

N

H

H H


HCHO

4 steps








137

Scheme 335

NMe

N

H

H H

366

HCHO

NaBH4

MeOH 0 degC90 N

Me

N

H

H H

3131

H


90

NMe

N

H

H H

3132

H


NaOH H2O2 rt


85

NMe

N

H

H H

3133

H

OTIPS

H

OH

DMP CH2Cl2

82NMe

N

H

H H

3134

H

OTIPS

H

O

MeI THF

KOtBu EtOH THF ∆

90

NMe

MeN

3135

H

H

H

OTIPS

O

H

NMe

MeN

33

H

H

H

O

O

H


60




323

138










Scheme 336

NMe

CHO


79

NMe

NNs

Ph3POEt

OCO2EtBr

CHCl3 ∆

Ph3POEt

O

EtO2C

Br

AcCl Et3NCH2Cl2

73

CO2Et

CO2Et

3138

3140

3136

3137

3139

+

PBu3 (30)

CH2Cl2 rt73 31 drN

Me3141

NCO2Et

CO2EtNs

H




139





Scheme 337

NMe

3141

NCO2Et

CO2EtNs

H

HCl EtOAc

90 NMe

NsN

3142

H

H

CO2EtO

PhSH K2CO3

DMF99

NMe

HN

3143

H

H

CO2EtO

HCHO HCO2H ∆

99NMe

MeN

3144

H

H

CO2EtO

NaBH3CN ZnI2

DCE ∆74

NMe

MeN

3145

H

H

CO2Et

BH2CN

EtOH ∆

98

NMe

MeN

3146

H

H

CO2Et

NMe

MeN

(plusmn)-3120

H

H

OH

DIBAL-H

tol -78 degC92






140












Scheme 338

NMe

TsN

3152

H

H

SO2Ph

CHO

PhO2S SO2Ph

NMe

NTs


55-64NMe

NHTs

PhO2S

KMnO4Bu4NBr

CH2Cl261 N

Me

NHTs

PhO2SOH

OH



315031493147

NMe

3151

NTs

PhO2S

CHO

3148

141






Scheme 339

NMe

TsN

3152

H

H

SO2Ph

CHO


95 NMe

TsN

3153

H

H

OTBDPS


-78 degC - rt36 N

Me

TsN

3154

H

H

OOTBDPS

H




optimized

36 Conclusions





142


















143


H

NMe

BnN

Pictet-SpenglerH

H

NMe

BnN

HeckH

O

H

NMe

BnN

H

FischerIndole

O

NMe

NsN

H

H



R

390Kuethe

323Rassat

3142Kwon

144



Alstonerine

41 Introduction

















145

Scheme 41

H

NMe

BnN

O

Diekmann

Pictet-SpenglerH

H

HNMe

MeN

O

O

H

41



H

HNMe

MeN

O

O

H

41

Wacker


42

E

E

A B

A B

C D

C D

11 steps

10 steps













146



Scheme 42

H

HNMe

MeN

O

O

H

41

H

H

HNMe

RN

OH

43

H

O

H

HNMe

RN

44

H

O

NMe

NR

45

Acylation

Baeyer-Villiger

PKR








A (49)134

147

Scheme 43

MeN

H2N

O

O

46

RN

47

PGO

O

RN

PGO

48

410

N

N

OH

O

O

Me

MeO

O

O

MeO

Me

Me

HH

H

O Me

O

Me

N

N

R411

N

NR

R

R

O

49










148


421 Introduction













derivative 415136

149

Scheme 44

MeN

H2N

O

O

46

MeN

H2N

412

HO

O

HO

BocN

413

TBSO

O

BocN

TBSO

414

BocN

TBSO

CO2Me

415

O









150

Scheme 45

HN

HO

CO2H SO2Cl

MeOH99

H2+Cl-

N

HO

CO2Me N

HO

CO2Me

Boc

dioxane70

TBS-Climidazole

N

TBSO

CO2Me

Boc RuO2H2O (20)

NaIO4N

TBSO

CO2Me

Boc

O

416 417 418

419 415

Boc2OiPr2NEtDMAP

DMF96

EtOAc96












151

Scheme 46

N

TBSO

CO2Me

Boc

O N

TBSO

CO2Me

Boc

415

R



Et2O toluene

N

TBSO

Boc1 DIBAL-H CH2Cl2


R







152

Scheme 47

N

TBSO

Boc

414

TBAF THF N

HO

Boc

N

HO

Boc

+

Ac2O Et3NCH2Cl2 97

92

N

AcO

Boc

422 423

424





153








complex 425

154

Scheme 48

N

TBSO

Boc

BocN

TBSO

O

426414

Co2(CO)8 N

TBSO

Boc

425

Co2(CO)6

conditions


THFX






Scheme 49

N

TBSO

Boc

BocN

TBSO

O

429422

Co2(CO)8 N

TBSO

Boc

428

Co2(CO)6

conditions


THF






155







N

TBSO

Boc

HCl or ZnBr2 N

TBSO

O O

414 430

(41)





156

Scheme 410

N

TBSO

Boc HN

TBSO

HN

TBSO

+


414 431 432

N

TBSO

K2CO3 MeIacetone

55

Me

433

88431432 = 13






attempted

Scheme 411

N

TBSO

Me

MeN

TBSO

O

435433

Co2(CO)8 N

TBSO

Me

434

Co2(CO)6

conditions


THF

157










Scheme 412

N OBn

O

H

H

Co

Co(CO)3

(CO)2

N OBn

O

H

Co Co

(CO)3 (CO)3

436 437

TBSO TBSO

N

TBSO

Boc

422

Co2(CO)8

N

TBSO

Boc

428

Co2(CO)6

158










Scheme 413

HNMe

RN

O

H

NMe

NR

44 45

PKR

H

PKR

N

R

439

m nRN

O

438

m n




159





Scheme 414

N

X

R

O

A13-Strain N

X

R

O

m

m

n

n

PKR N R

O

X n

m

440 X = H2 O 441 442

O

431 Initial Studies









160

Scheme 415

N

OMe

R1

MgBrn



CbzN

O

R1

n

MgBr

R2

MeLi CuCN (111)

THF -78 degC73-81

CbzN

O

R1

R2

443 444 445

n












Scheme 416

N

OMe

TMSTHF

then Cbz-Cl 95

N

O

Cbz

N

O

CbzTMS


TMS R

443 446447 R=TMS

448 R=H

K2CO3MeOH75

EtMgBr

161










N

O

Cbz

N

O

Cbz

SnBu3


96

TMS

446 448 gt191 dr

(42)








piperidine 448

162

Scheme 417

NO

TMS

O

O

N

H

TMS

OO

O

Nuc

Nuc

449 450










Scheme 418

N

O

Cbz

448

Co2(CO)8

DMSO

THF 65 degC89

NCbz

OH

O

451

H

H

N

O

Cbz HH

451

H

O

3



163
















164




Scheme 419

Co(CO)2

(CO)3Co

H

Co(CO)2

Co(CO)3

H(CO)3Co Co(CO)3

+

452

cis-453

trans-454













165

Scheme 420

N OBn

O

H

H

NCbz

Co2(CO)8

Co

Co

N OBn

O

H

H

Co

N OBn

O

H

H

Co Co

(CO)3 (CO)3

N OBn

O

H

H

O

O

O

O

O

CbzNO

H

H

448

455 456

457 458

451 459

O

HCbzNO

H

HO

H

CoCo

Co

(CO)3(CO)2

(CO)3(CO)2

(CO)3(CO)3




166













Scheme 421

N

OMe

443

TMSBr


77

N

O

Cbz

460

TMS

CuCN MeLi (111)

MgBr

TBAFH2OTHF 69

N

O

Cbz

R


461 R = TMS

462 R = H

6





167













Scheme 422

N

O

Cbz

462

Co2(CO)8

DMSO

THF 65 degC91

N

O

O

CbzH HH

463

N OBn

O

HO

463

H

O

1

2






168






467

169

Scheme 423

NCbz

Co2(CO)8

N OBn

O

H

O

O

CbzNO

H

H

CbzNO

H

H

462

465

468 463

H

Co

N OBn

O

HO

464

Co

(CO)3(CO)3

HCo Co

(CO)3 (CO)3

H HO O

H

N OBn

O

HO

466

Co(CO)2(Co)3Co

N OBn

O

HO

467

H

(CO)2Co Co(CO)3





170












171

Scheme 424

N

O

CbzTMS

446

CuCN MeLi (111)

MgBr

TBAFH2O THF 53

N

O

Cbz

Co2(CO)8

DMSO

THF 65 degC33 31 dr


R

469 R = TMS

470 R = H

N

O

CbzH H

471

N OBn

O

HO

471

H1

2

O

H

O

6












172



Scheme 425

Cbz

N

O

448

H2 PdCor

TMSIX

HN

O

472









173

Scheme 426

Alloc

Ts Ts

N

OMe

MgBrTMS

THF then Alloc-Cl77

N

O443

TMS HN

O

TMS

dimethyl malonate

Pd(PPh3)4 THF93

nBuLi THF -78 degC

then TsCl50

N

O

R

475 R = TMS

476 R = H

K2CO3MeOH48

TMS


N

O

473 474

477






Scheme 427

Bz BzHN

O

TMS

474

nBuLi THF -78 degC

then BzCl98

N

O

TMSSnBu3


91 gt191 dr

N

O

478 479




174















advantageous145

Scheme 428

N

O

R Co2(CO)8

DMSO

THF 65 degCN

O

R HH

H

O

477 R = Ts479 R = Bz

480 R = Ts (61)481 R = Bz (94)

7

175














Scheme 429

CbzN

O

448

L-Selectride

THF -78 degC99

CbzN

OH

482

TBS-Climidazole

DMF81

CbzN

OTBS

483

4 4






176







Scheme 430

N

Cbz

448

O


BF3Et2O

HSCH2CH2SH

CH2Cl284

N

Cbz

485

S S

N

Cbz

486

Raney NiX

X

N

Cbz

484

O

S


XAIBN Bu3SnH








177



Scheme 431

HNO O NaBH4 HCl

EtOH

HNO OEt

HNO SO2Ph

PhSO2ClHCO2H

CH2Cl260

nBuLi

TMS

THF71

487 488 489

HNO

TMSnBuLi

then Cbz-ClTHF81

NO

TMSCbz

490 491

1 DIBAL-H THF

2 Allyl-TMS BF3

Et2O 57

N

RCbz

492 R = TMS

486 R = H

TBAF THF86











178

Scheme 432

N

R

Cbz Co2(CO)8

DMSO

THF 65 degCN

R

Cbz HH

H

O

483 R = OTBS486 R = H

493 R = OTBS (69)494 R = H (74 41 dr)

117
















179


diastereomer

180

Scheme 433

N OBn

O

H

H

CbzN

H

HO

HCbzN

H

HO

H

H

R

(CO)2Co(CO)3Co

N OBn

O

H

H

R

H

(CO)2Co

Co(CO)3

R R

NCbz

Co2(CO)8

N OBn

O

HH

Co Co

(CO)3 (CO)3

N OBn

O

H

H

CoCo

(CO)3 (CO)3

H

R R

H

R

483 R = OTBS486 R = H

4

495 R = OTBS496 R = H

497 R = OTBS498 R = H

499 R = OTBS4100 R = H

4101 R = OTBS4102 R = H

493 R = OTBS494 R = H

4103 R = OTBS4104 R = H

181
















441 Retrosynthesis








182





Scheme 434

H

H

H

HNMe

MeN

O

O

H

H

NH

CbzN

O

H

NMe

CbzN

O

H

O

NH

NCbz

NH

NH2

CO2H

Baeyer-Villiger

414105

4106 4107 4108

PKR

H

H










183




Scheme 435

NH

NH2

CO2H


60 NH

NHCl

CO2H

i)Et3N CbzCl

CH2Cl2

ii) MeOH Et3N87 N

H

NCbz

CO2Me

OMe

TMS

BF3Et2O

CH2Cl281

51 cistrans

NH

NCbz

CO2MeDIBAL-H

toluene -78 degC


60NH

NCbz

4108 4109 4110

4111 4107










184

Scheme 436

N

NCbz

CO2Me

N

NCbz

R R

4111 R = H4112 R = Ts4114 R = Boc

4107 R = H4113 R = Ts4115 R = Boc




20-60







N

NCbz

CO2Me

Boc

N

NCbz

CHO

Boc


rapid decomp at rt

4114 4116

(43)







185




NH

NCbz

CO2MeDIBAL-H

toluene -78 degC


-78 degC -rt60

NH

NCbz

3111 3107

(44)






Scheme 437

NH

NCbz

NH

CbzN

O

H

Co2(CO)8DMSO (6 eq)

THF 65 degC92 H

H

NBoc

CbzN

O

H

H

HBoc2ODMAP

CH3CN 99

4117

4107 4106

186








NBoc

CbzN

O

H

H

H

4117

15







187

Scheme 438

NH

CbzN

O

H

NH

NCbz

Co2(CO)8

4107

4118

4106 4122

H

H

NH

CbzN

O

H

H

H

CoCbzN

BocN

H

H

H

Co

(CO)3

(CO)3

CbzN

BocN

H

H

H

Co

Co (CO)3

(CO)3

CoCbzN

BocN

H

H

H

Co

(CO)3

(CO)3

CbzN

BocN

H

H

HCo

Co(CO)3

(CO)3

4119

41204121




188






Scheme 439

NH

CbzN

O

4106

H

H

H

NMe

CbzN

O

4123

H

H

H

NaH MeI DMF91

Baeyer-Villiger

X

NMe

CbzN

4105

H

H

H

OO









189



Scheme 440

NBoc

CbzN

O

4117

NBoc

CbzN

O

4125

O

MCPBACH2Cl2 60

orCF3COOOH

Na2HPO4CH2Cl2 99

H2O2NaOH

THFMeOH

H

H

H

H

H

H

NBoc

CbzN

4124

H

H

H

OO

O

78








190

NBoc

CbzN

4124

H

H

H

OO

O

deoxygenationX

NBoc

CbzN

4105

H

H

H

OO

(45)








Scheme 441

HNR

CbzN

O

H

OH

4127

H

HNR

CbzN

CO2RCHO

H

H

4128

H

HNH

CbzN

O

H

4106

H

HNR

CbzN

OSiR3

H

4129

H H




191









4130156

192


NBoc

CbzN

OH

H

Hconditions

NBoc

CbzN

OSiEt3H

H

H





25

41304117



Entry

-------

-------1

2

3

5

4

NBoc

CbzN

OH

H

H

4131

+

H H









193




Scheme 442

Me2Si

O

Me2Si

2

Pt


NBoc

CbzN

OH

H

H

NBoc

CbzN

OTIPSH

H

H

4132

4117

H

NBoc

CbzN

OH

H

H

4131

H

NBoc

CbzN

OTESH

H

H

4130

HMe2Si

O

Me2Si

2

Pt

Et3SiH Toluenert 99

41304131 = 41

+







nitrogen atom

194

Scheme 443

NBoc

CbzN

OTIPSH

H

TBAF3H2O

THF 66

NBoc

CbzN

OH

H

NH

HN

OHH

H



H

H

H

H

H

H

4133

4132 4131










195

NBoc

CbzN

OTIPSH

H

H

H

ozonolysis

NBoc

CbzN

CHOH

H

CO2TIPS

4132 4134

X (46)






Scheme 444

HNR

CbzN

OSiR3

H

4136

H H

HNR

CbzN

CO2RCHO

H

H

4128

H

HNR

CbzN

O

H

4135

H HHO






196

HNBoc

CbzN

OTIPS

H

4132

H H

HNBoc

CbzN

O

H

4137

H HHO

mCPBA

CH2Cl20-20

(47)








Scheme 445

O

O

OOCOR

OTIPS mCPBAOTIPS

O

OTIPS

OH

H+

4138 4139 4140

OTIPS

OH

4141

RCO2-

OTIPS

4142

O

ROCOR

4143





197















198


NBoc

CbzN conditions

OTIPSH

H

NBoc

CbzN

OH

H

HO

Conditions

4132 4137

Entry Yield 4137

1 OsO4 (10) NMO (22 eq) THFH2O 23






H

H

H

H







199

Scheme 446

NBoc

CbzN

OH

H

HO

4137

H

H



4144

NBoc

CbzN

OH

CO2Me

H

H

HNBoc

CbzN

O

H

OH

4145

H

pTsOH CH2Cl2

99












200

Scheme 447

H

H

4145

NBoc

CbzN

OTIPS

H


THFH2O 51

NBoc

CbzN

CHO

CO2H

NBoc

CbzNH

H OO

NaBH4 MeOH


H

H

H

H

4132 4146









201

Scheme 448

LiAlH4

THF reflux 99

NaHthen MeI

DMF 88

NBoc

CbzNH

H OO

H

H

4145

NBoc

CbzNH

H OH

H

4147


2 MsCl Et3N THF 67

NH

MeNH

H OH

H

4148

NMe

MeNH

H OH

H

4149






obtained

202

Scheme 449

NMe

MeNH

H O


NMe

MeNH

H O

O

+

NMe

MeNH

H O

O

O



H

H

H

H

H

H

4149

41

4150







recovered

NMe

MeNH

H OH

H

4149

NMe

MeNH

H O

O

H

H

41

NMe2

O

POCl3 or Tf2OX (48)



203




Scheme 450

NBoc

CbzNH

H O


NBoc

CbzNH

H O

O



H

H H

H

4147 4152







204

Scheme 451

NMe

MeNH

H OH

H

4149

NMe

MeNH

H O

Cl3CO

H

H

4151

X

[H]

NMe

MeNH

H O

O

H

H

41

Cl3C

O

Cl














natural products169

205

Scheme 452

NBoc

CbzNH

H OH

H

4147

NBoc

CbzNH

H O

Cl3CO

H

H

4153

NBoc

CbzNH

H O

O

H

H

4152

ClCO2CCl3

pyridine 65 degC

Zn AcOH

75 2 steps










NBoc

CbzNH

H O

O

H

H

4152

NH

HNH

H O

O

H

H

4154

TMS-I

CH3CN78

(49)

206






Scheme 453

NMe

MeNH

H O

O

H

H

41

NMe

HNH

H O

O

H

H

4155

NH

MeNH

H O

O

H

H

4156

NMe

MeNH

H O

O

H

H

4157

NaH then MeI

DMF

side products

NH

HNH

H O

O

H

H

4154







EtOH))128

207

NMe

MeNH

H O

O

H

H

41

NH

HNH

H O

O

H

H

4154

MeI (2 eq)THF


72

(410)












208

Scheme 454

NH

CbzN

O

H

Co2(CO)8DMSO

THF 65 degC92 H

H

4106

NBoc

CbzN

O

H

H

HBoc2ODMAP

CH3CN99

4117

Me2Si

O

Me2Si

2

Pt


NBoc

CbzN

OTIPSH

H

H

4132

H H

H

4145

1 OsO4 (10) NaIO4 (4 eq)

THFH2O 51

NBoc

CbzNH

H OO

2 NaBH4 MeOH


NBoc

CbzNH

H OH

H

4147


2 MsCl Et3N THF 67

TMS-I

CH3CN78

NBoc

CbzNH

H O

O

H

H

4152



NH

HNH

H O

O

H

H

4154

NMe

MeNH

H O

O

H

H

41

MeI THF

then NaH MeI72

NH

NH2

CO2H


60 NH

NHCl

CO2H

i)Et3N CbzCl

CH2Cl2

ii) MeOH Et3N87 N

H

NCbz

CO2Me

OMe

TMS

BF3Et2O

CH2Cl281

51 cistrans

NH

NCbz

CO2Me

NH

NCbz

4108 4109 4110

4111 4107



-78 degC -rt60

209

45 Conclusions























210














211


51 General



















212






52 Compounds

6

51 23

4

78

O

O

O

217












213

NMR (75 MHz) δ 1549 1354 1277 752 541 249 201 128 IR (neat) 2964 2876


requires 1570865] 157 (base) 113





(C2) 541 (C8) 249 (C5) 201 (C1) 128 (C6)

O O

O

1

2

34

56

78

218









214





[C8H13O3 (M+1) requires 1570865]





(C8) 273 (C5) 175 (C1) 93 (C6)

6

6

5 61 2

3

4

78

O

O

O

225







215






NMR (75 MHz) δ 1550 1446 1237 757 543 327 291 205




1446 (C4) 1237 (C3) 757 (C2) 543 (C8) 327 (C5) 291 (C6) 205 (C1)

6

5

6

O O

O

1

2

34 6

78

226







216






1313 1260 865 543 342 256 177




(C7) 1313 (C2) 1260 (C3) 865 (C4) 543 (C8) 342 (C5) 256 (C6) 177 (C1)

6

89

12

34

5

7

O O

OO

219







217







75 3 H) 13C NMR (100 MHz) δ 1688 1687 1334 1301 581 523 521 374 254

186 137





1688 (C8) 1687 (C8) 1334 (C4) 1301 (C3) 581 (C7) 523 (C9) 521 (C9) 374

(C2) 254 (C5) 186 (C1) 137 (C6)

89

12

3 4 5

7

O O

OO

220

6



218









548 (m 1 H) 518 (dd J = 150 93 Hz 1 H) 369 (s 3H) 365 (s 3H) 331 (d J = 90


H)




082 (t J = 72 Hz 3 H C1-H)

O

O

O

O

12

34

5

78

9

6227



219











284 (m 1 H) 104 (d J = 69 3 H) 093 (s 9 H)




H)

220

1

23

45

6

7

8 9 10 1112

13

230

O

O

O

O















= 76 Hz 3 H) 13C NMR (100 MHz) δ 1704 1342 1289 784 741 609 521 402

256 241 169 138 35 IR (neat) 2959 2875 1732 1455 1434 1276 1218 1057

221


235 206 185






784 (C9) 741 (C10) 609 (C5) 521 (C13) 402 (C2) 256 (C7) 241 (C8) 169 (C11)

138 (C6) 35 (C1)

N

249

12

3

4

5

6

7

89

10

3

4

89








222




1372 1340 1296 1285 1272 1262 631 522 233 210 IR (neat) 2967 2780

1494 1446 1310 1167 965 748 692 MS (CI) mz 2021586 [C14H20N1 (M+1)

requires 2021596]





1285 (C8) 1272 (C5) 1262 (C9) 631 (C2) 522 (C3) 233 (C4) 210 (C1)

N

252

3

8

9

3

4

8

9

1

2

5

6

7

10





223






352 (s 2 H) 214 (s 3 H) 125 (s 6H) 13C NMR (75 MHz) δ 1470 1413 1285

1281 1265 1120 586 557 345 228 IR (neat) 2973 2842 2794 1494 1453 1411


1901596]





1265 (C10) 1120 (C1) 586 (C4) 557 (C6) 345 (C5) 228 (C3)








224





O

269

12

3

45

6 78

9

10

11

12

13








13C NMR (100 MHz) δ 1559 1366 1317 1287 1270 1264 1239 1206 1142

1124 692 253 132 IR (CHCl3) 3033 2967 2934 2874 1625 1597 1485 1452


1891279] 189 (base) 122 107



225





(C12) 1317 (C8) 1287 (C9) 1270 (C4) 1264 (C2) 1239 (C1) 1206 (C3) 1142

(C5) 1124 (C13) 692 (C7) 253 (C10) 132 (C11)

Br

O

271

12

3

45

6 78

9

10

11







J = 75 Hz 3 H) 13C NMR (75 MHz) δ 1551 1370 1332 1283 1232 1218 1137

1123 698 253 131 IR (neat) 2967 2934 2875 1586 1478 1276 1243 1031 970


241 137

226






1283 (C3) 1232 (C8) 1218 (C9) 1137 (C5) 1123 (C1) 698 (C7) 253 (C10) 131

(C11)

O

273

12

3

45

6

7 89

1011

12

1314

15

16







1308 1300 1296 1281 1278 1266 1210 1160 759 251 216 133 IR (CHCl3)



227





13C NMR (100 MHz) δ 1550 (C6) 1389 (C13) 1339 (C15) 1320 (C9) 1308 (C10)

1300 (C2) 1296 (C4) 1281 (C14) 1278 (C16) 1266 (C1) 1210 (C3) 1160 (C5)

759 (C8) 251 (C11) 216 (C7) 133 (C12)

HOO

1

2

3 4

5

67

8

Si

288










228


(100 MHz) δ 1322 1275 616 590 310 259 183 -52 IR (neat) 3355 2954 2857


requires 2171624] 217 (base) 199 133





(C5) 590(C1) 310 (C2) 259 (C8) 183(C7) -52 (C6)

O

O O

O9

1011

128

612

34

5 7

Si

289








229




MHz) δ 2004 1670 1326 1251 645 593 500 301 270 259 183 -52 IR







(C2) 1670 (C4) 1326 (C8) 1251 (C7) 645 (C9) 593 (C5) 500 (C3) 301 (C6) 270

(C1) 259 (C12) 183 (C11) -52 (C10)

O

O O

OH

8

612

34

5 7

9

290






230





NMR (100 MHz) δ 2009 1669 1317 1270 643 583 499 303 268 MS (CI) mz

1870970 [C9H15O4 (M+1) requires 1870970]




(C2) 1669 (C4) 1317 (C8) 1270 (C7) 643 (C9) 583 (C5) 499 (C3) 303 (C6) 268

(C1)

O

O O

O

861

23

4

5 7

910

11O

O

275







231






1301 1256 637 630 545 496 298 267 IR (neat) 2955 1802 1747 1714 1442


2451025] 245 186 169 (base) 154




NMR (100 MHz) δ 2002 (C2) 1668 (C4) 1553 (C10) 1301 (C8) 1256 (C7) 637

(C11) 630 (C9) 545 (C5) 496 (C3) 298 (C6) 267 (C1)

O

OO

8

6

7 1 2

3

45

9

278




232







585-576 (comp 2 H) 431-420 (m 2 H) 365 (dd J = 85 55 Hz 1 H) 284-278 (m 1


1738 1311 1292 678 632 292 286 269 IR (neat) 2958 1713 1650 1359 1261





NMR (100 MHz) δ 2016 (C8) 1738 (C7) 1311 (C4) 1292 (C3) 678 (C6) 632 (C1)

292 (C2) 286 (C5) 269 (C9)

233

8

6 7Br

O1

2

3 4

5Si

291











H) 088 (s 9 H) 005 (s 6 H) 13C NMR (100 MHz) δ 1325 1269 594 322 310

259 183 -52 IR (neat) 3021 2955 2856 1471 1360 1254 1095 837 776 MS (CI)





234


(C2) 259 (C8) 183 (C7) -52 (C6)

1386

7

12

34

59

10

1211O

O O

OSi

292















235





O

O O

OH

86

7

12

34

59

10

293










(app p J = 72 Hz 2 H)



236


72 Hz 2 H C6-H)

O

O O

O

86

7

12

34

59

1011 12O

O

294












[C12H19O6 (M+1) requires 2591182]



237


167 (app p J = 72 Hz 2 H C6-H)

10

1 23

9

4

5 67

8

2106

O

O

O

O












238

O CF3

O

12

34

5 67

2129








74 Hz 2 H) 100 (t J = 74 3 H) 13C NMR (100 MHz) δ 1572 1412 1204 1160

688 255 128 IR (neat) 1779 1634 1174 706 cm-1 MS (CI) mz 1830640

[C7H10O2F3 (M+1) requires 1830633]




1412 (C4) 1204 (C3) 1160 (C7) 688 (C5) 255 (C2) 128 (C1)

239

O O

O O

1

3

12

3

4

56

78

910

112137










H) 13C NMR (100 MHz) δ 1642 1317 1281 1227 1053 846 824 461 284

269 175 IR (neat) 3001 1788 1750 1309 1202 1070 941 758 MS (CI) mz

2580889 [C15H14O4 (M+1) requires 2580892]




1227 (C8) 1053 (C2) 846 (C6) 824 (C7) 461 (C4) 284 (C1) 269 (C1) 175 (C5)

240

12 3 4

567

8

9

10

1112

1314

2130

O

H

O

O

OO

15

16













230-210 (m 1 H) 210-190 (m 1 H) 181 (app t J = 153 Hz 1 H) 160-140 (m 1


[C20H23O5 (M+1) requires 3431545]

241





H C16-H) 100 (t J = 75 Hz 3 H C14-H)

N

O O

O

Si

O

O

420

12

3

4

56

7

8

9

10

1112

13

14

15









242









4002519]




185 Hz 9 H C13-H) 066 (dd J = 105 35 Hz 6 H C11-H)

243

N

O O

O

Si

O

O

1

11

2

3

4

56

7

8910

12

14

13

15

16

421
















244







H) 085 (s 9 H) 003 (s 6 H) IR (neat) 2955 2858 1754 1698 1392 1254 1177 MS





002 (s 6 H C12-H)

14 15N

O O

O

Si

422

12

3

4

56

7

8

9

10

1112

13



245














C15-H) 145 (s 9 H C1-H) 088 (s 9 H C13-H) 007 (s 6 H C11-H)

246

16N

O O

O

Si

1

11

2

3

4

56

7

89

10

12

14

13

15

414















H) 240-200 (comp 5 H) 174 (s 3 H) 142 (s 9 H) 089 (s 9 H) 009 (s 3 H) 008

247

(s 3 H) IR (neat) 3312 2955 2858 1704 1649 1385 1254 1123 873 776 MS (CI)






008 (s 3 H C12-H)

N

O O

O

O

1

12

15

2

3

4

56

7

8910

11

13

14

424








248







HN

O

Si

432

1

23

4

567

8

910

11

12 13










249

(100 MHz) δ 1439 1117 876 738 701 608 464 439 383 260 229 182 -46 -

49 IR (neat) 3311 2954 2930 2856 1648 1471 1255 1104 889 836 775 MS (CI)







738 (C2) 701 (C13) 608 (C1) 464 (C4) 439 (C5) 383 (C3) 260 (C8) 229 (C11)

182 (C10) -46 (C9) -49 (C9)

N

Me

O

Si

433

1

2

34

5

678

9

1011

12

13 14






250





006 (s 3 H) 005 (s 3 H) 13C NMR (75 MHz) δ 1443 1108 825 736 723 643

543 420 374 360 260 238 182 -44 -50 MS (CI) mz 2942246







13C NMR (75 MHz) δ 1443 (C7) 1108 (C8) 825 (C13) 736 (C14) 723 (C2) 643

(C5) 543 (C1) 420(C3) 374 (C6) 360 (C4) 260 (C12) 238 (C9) 182 (C11) -44

(C10) -50 (C10)

251

N

O

O OSi

1

2 3 4

5

6

78

910

11

1213

14

446














164 Hz 1 H) 009 (s 9 H) 13C NMR (100 MHz) δ 1911 1348 1288 1287 1286

1281 1077 1003 895 691 456 412 -039 IR (neat) 2960 1732 1677 1609 1329

252


(base) 312 284




13C NMR (100 MHz) δ 1911 (C3) 1348 (C8) 1288 (C1) 1287 (C10) 1286 (C9)

1281 (C11) 1077 (C2) 1003 (C12) 895 (C7) 691 (C13) 456 (C4) 412 (C5) -039

(C14)

N

O

OO

1

2 34

5

67

910

11

12

448

8

13

1415

16








253




NMR (75 MHz) δ 2054 1548 1359 1339 1285 1282 1280 1183 825 679 532

451 429 427 395 IR (neat) 3285 3067 3033 2977 1693 1642 1404 1322 1112






(C13) 1285 (C2) 1282 (C1) 1280 (C3) 1183 (C14) 825 (C15) 737 (C5) 679

(C16) 532 (C8) 451 (C10) 429 (C7) 427 (C11) 395 (C12)

254

N

O

O

O

O

451

17

1

2

3

4

567

8

9 10

11

1213

14

1516

H















2058 2055 1755 1531 1361 1279 1274 1270 1265 665 502 480 440 437


255







MHz) δ 2058 (C6) 2055 (C1) 1755 (C3) 1531 (C12) 1361 (C14) 1279 (C16)

1274 (C17) 1270 (C15) 1265 (C2) 665 (C13) 502 (C4) 480 (C8) 440 (C11) 437

(C7) 411 (C5) 384 (C9) 328 (C10)

N

O

Si

O O

1

2 3 4

5

6 78 9

10

1112

1314

15

460







256







NMR (100 MHz) δ 1917 1410 1346 1285 1281 1271 1266 1009 882 689

647 516 384 219 -04 IR (neat) 2959 2900 1731 1672 1604 1328 1296 1198


342 197 181 (base)





1281 (C15) 1271 (C13) 1266 (C14) 1009 (C2) 882 (C7) 689 (C11) 647 (C8)

516 (C5) 384 (C4 219 (C6) -04 (C9)

257

N

O O

Si

O

12 3 4

567 8

910

11

1213

1415

16

461

17
















MHz d6-DMSO 100 ˚C) δ 2052 1545 1390 1361 1278 1272 1269 1150 1034

258

868 664 526 510 418 417 259 -07 IR (neat) 3089 3034 2959 2900 1698


3701838]






(C3) 1545 (C17) 1390 (C13) 1361 (C7) 1278 (C15) 1272 (C16) 1269 (C14)

1150 (C6) 1034 (C12) 868 (C9) 664 (C10) 526 (C1) 510 (C2) 418 (C4) 417

(C5) 259 (C8) -07 (C11)

N

O O

O

1

2 3 4

567 8

910

1112

1314

15

462

18





259




100 ˚C) δ 740-729 (comp 5 H) 599 (ddd J = 160 105 45 Hz 1 H) 519-512




1361 1278 1272 1270 1152 803 724 664 527 512 417 416 247 IR (neat)

3307 3035 2959 1694 1407 1320 1271 1114 1057 MS (CI) mz 2981443

[C18H20NO3 (M+1) requires 2981443]







1388 (C12) 1361 (C7) 1278 (C14) 1272 (C13) 1270 (C15) 1152 (C6) 803 (C9)

724 (C11) 664 (C10) 527 (C1) 512 (C2) 417 (C4) 416 (C5) 247 (C8)

260

16

17

N

O

H

O

OO

1

2 34

5

6

7

89

10 11

12

13 14

15

463










2050 2043 1735 1533 1361 1317 1279 1273 1270 665 507 474 448 436

387 367 348 IR (neat) 3035 2963 2902 1706 1626 1416 1335 1264 1220 1100






261




(C12) 1361 (C8) 1317 (C14) 1279 (C16) 1273 (C17) 1270 (C15) 665 (C13) 507

(C1) 474 (C5) 448 (C11) 436 (C6) 387 (C10) 367 (C2) 348 (C4)

N

O

O O

469

1

2 34

5

6

78

910

11

1213

14

15

Si

16










262







MHz) δ 2054 1547 1376 1360 1285 1282 1280 1163 1077 1040 907 679

547 453 432 -049 IR (neat) 2959 1704 1403 1309 1250 1224 1054 844 MS






MHz) δ 2054 (C3) 1547 (C11) 1376 (C13) 1360 (C6) 1285 (C15) 1282 (C16)

1280 (C14) 1163 (C7) 1077 (C5) 1040 (C1) 907 (C8) 679 (C12) 547 (C9) 453

(C2) 432 (C4) -049 (C10)

263

N

O

O O

470

1

2 34

5

67

89

10

1112

1314

15










13C NMR (75 MHz) δ 2050 1548 1373 1358 1285 1282 1280 1167 824 738

680 548 449 432 425 IR (neat) 3285 2957 1698 1403 1310 1264 1310 1264


284 (base) 266 240




264




1548 (C10) 1373 (C6) 1358 (C12) 1285 (C14) 1282 (C15) 1280 (C13) 1167

(C7) 824 (C8) 738 (C11) 680 (C9) 548 (C1) 449 (C5) 432 (C2) 425 (C4)

11

10

1

23

45

6

7

89

12 1314

15

16

N

O

O

O

O

471

H










265






N

O O

O

Si

1

2 3 4

5

6

78

9

1011

12

473











266






007 (s 9 H) 13C NMR (100 MHz) δ 1912 1519 1410 1312 1190 1078 1003

895 679 456 413 -04 IR (neat) 3088 2960 2900 1732 1678 1608 1418 1372


2781212]






(C3) 1519 (C6) 1410 (C8) 1312 (C1) 1190 (C9) 1078 (C2) 1003 (C7) 895 (C10)

679 (C11) 456 (C4) 413 (C5) -04 (C12)

267

HN

O

Si

1

2 3 4

56

7

8

474








(100 MHz) δ 1912 1508 1020 992 895 451 418 -03 IR (neat) 3233 3022 2960


1941001]




(C3) 1508 (C1) 1020 (C2) 992 (C6) 895 (C7) 451 (C5) 418 (C4) -03 (C8)

268

NSiSO O

O

1

2 3 4

5

67

89

10

1112

13

475













13C NMR (75 MHz) δ 1899 1451 1408 1345 1300 1278 1078 981 912 469

422 215 -075 IR (neat) 3081 2963 1681 1597 1403 1362 1272 1168 846 MS


269





1899 (C3) 1451 (C6) 1408 (C1) 1345 (C9) 1299 (C7) 1278 (C8) 1078 (C2) 981

(C11) 912 (C12) 469 (C5) 422 (C4) 215 (C10) -075 (C13)

N

SO O

O

1

2 3 4

5

67

89

10

1112

476









270


H) 13C NMR (100 MHz) δ 1897 1454 1409 1344 1299 1278 1079 741 463

419 384 216 IR (neat) 3280 1676 1596 1363 1275 1167 1052 MS (CI) mz

2760693 [C14H14NO3S (M+1) requires 2760694]





(100 MHz) δ 1897 (C3) 1454 (C6) 1409 (C1) 1344 (C9) 1299 (C7) 1278 (C8)

1079 (C2) 741 (C12) 463 (C11) 419 (C5) 384 (C4) 216 (C10)

N

SO O

O

1

2 3 4

5

67

89

10

11

12

13

1415

477





271








NMR (75 MHz) δ 2044 1441 1369 1338 1299 1273 1187 815 748 554 457

446 434 388 216 IR (neat) 3305 1723 1356 1162 1094 MS (CI) mz 3181163







MHz) δ 2044 (C3) 1441 (C6) 1369 (C9) 1338 (C12) 1299 (C7) 1273 (C8) 1187

(C13) 815 (C14) 748 (C15) 554 (C5) 457 (C11) 446 (C4) 434 (C2) 388 (C5)

216 (C10)

272

N

O

SiO

1

2 34

5

67

8

9

10

11

1213

478













1323 1318 1286 1284 1081 1005 895 456 418 -04 IR (neat) 2962 1668


2981263] 298 (base)

273




C8-H) 13C NMR (75 MHz) δ 1914 (C3) 1691 (C9) 1420 (C1) 1323 (C10) 1318

(C13) 1286 (C12) 1284 (C11) 1081 (C2) 1005 (C6) 895 (C7) 456 (C5) 418 (C4)

-04 (C8)

N

O

O

1

2 34

5

67

910

1112

13

479

8

1415










274




1339 1293 1279 1260 1172 827 754 525 447 435 423 379 IR (neat) 3256


268 (base) 250






100 ˚C) δ 2043 (C3) 1697 (C11) 1354 (C12) 1339 (C9) 1293 (C15) 1279 (C14)

1260 (C13) 1172 (C10) 827 (C6) 754 (C7) 525 (C5) 447 (C8) 435 (C1) 423

(C4) 379 (C2)

275

N

O

O

H

SO

O

1

2 3 4

5

67

89

101112

1314

15

16

480








13C NMR (75 MHz) δ 2059 2056 1736 1445 1367 1300 1280 1271 521 501

459 453 416 385 332 216 IR (neat) 3689 2925 1715 1633 1353 1163 1098







(C8) 1736 (C6) 1445 (C12) 1367 (C15) 1300 (C13) 1280 (C7) 1271 (C14) 521

(C5) 501 (C1) 459 (C10) 453 (C9) 416 (C4) 385 (C2) 332 (C11) 216 (C16)

276

N

O

1

2 34

5

6

9

10

11

481

OH

7

8

12 13

O

14

15

16









2058 2056 1754 1685 1348 1294 1280 1266 1260 500 488 441 438 410

384 332 IR (neat) 2917 1713 1633 1410 1338 1217 914 MS (CI) mz 296







277


1754 (C11) 1685 (C12) 1348 (C10) 1294 (C13) 1280 (C15) 1266 (C16) 1260

(C14) 500 (C1) 488 (C5) 441 (C8) 438 (C2) 410 (C4) 384 (C7) 332 (C6)

N

OH

O O

1

2 3 4

5

6

78 9

10

11

1213

1415

16

482











278

3297 2953 1684 1409 1324 1087 1063 990 914 MS (CI) mz 300 [C18H22NO3

(M+1) requires 300] 300 (base) 258 256 238 214





Hz 1 H C4-H)

N

O O

12 3 4

5

6

78

11

1213

14

1516

1718

283

OSi

9

10

19







279






9 H) 007 (s 3 H) 005 (s 3 H) 13C NMR (100 MHz) δ 1555 1366 1365 1284

1279 1278 1168 854 706 673 642 507 391 386 366 336 258 181 -49 -

50 IR (neat) 3307 2953 2856 1694 1640 1407 1335 1312 1255 1093 774 MS (CI)








1366 (C7) 1365 (C16) 1284 (C18) 1279 (C19) 1278 (C17) 1168 (C8) 854 (C12)

706 (C15) 673 (C3) 642 (C13) 507 (C1) 391 (C5) 386 (C6) 366 (C2) 336 (C4)

258 (C11) 181 (C10) -49 (C9) -50 (C9)

280

N

O O

O

S

S

484

1

23

4

5

6

78

9

10

1112

13

1415

16

1718











168 125 68 Hz 1 H) 522 (m 1 H) 518 (s 2 H) 512 (d J = 168 Hz 1 H) 502 (d



H) 13C NMR (100 MHz) δ 2150 1552 1363 1355 1284 1280 1279 1178 843

751 712 676 496 386 383 328 292 191 IR (neat) 3290 2953 1697 1406

281


(base) 346 282







2150 (C9) 1552 (C13) 1363 (C15) 1355 (C7) 1284 (C17) 1280 (C18) 1279

(C16) 1178 (C8) 843 (C11) 751 (C14) 712 (C3) 676 (C12) 496 (C5) 386 (C1)

383 (C6) 328 (C4) 292 (C2) 191 (C10)

N

S S

O O

1

2 3 4

5

6

78

9 10

1112

13

1415

1617

18

485




282









NMR (75 MHz) 1552 1364 1351 1284 1280 1277 1177 841 725 675 619

523 448 418 412 396 385 384 IR (neat) 3288 2923 1698 1406 1318 1262







(C7) 1284 (C17) 1280 (C18) 1277 (C16) 1177 (C8) 841 (C11) 725 (C14) 675

(C12) 619 (C5) 523 (C1) 448 (C3) 418 (C2) 412 (C4) 396 (C6) 385 (C10) 384

(C9)

283

HNO

Si

1

23

4

5 67 8

490












188 -03 IR (neat) 3190 3077 2956 1687 1649 1405 1309 1252 841 756 MS





288 (C3) 188 (C4) -03 (C8)

284

NO

Si9

1011

1213

14

491

O O

1

23

4

5 67 8












1283 1280 1277 1031 888 684 483 340 285 175 -04 IR (neat) 3065 2959

2899 1778 1738 1714 1498 1455 1373 1250 1134 1062 843 MS (CI) mz 330




285


1351 (C11) 1283 (C13) 1280 (C14) 1277 (C12) 1031 (C6) 888 (C10) 684 (C7)

483 (C5) 340 (C2) 285 (C3) 175 (C4) -04 (C8)

N9

10

11

1213

14

486

O O

1

23

4

5

6

78

1516













286










= 100 ˚C) δ 1542 1363 1355 1277 1272 1269 1160 845 724 660 506 409

360 298 260 140 IR (neat) 3294 3248 2944 1697 1406 1318 1267 1098 MS







100 ˚C) δ 1542 (C11) 1363 (C13) 1355 (C7) 1277 (C15) 1272 (C16) 1269 (C14)

1160 (C8) 845 (C9) 724 (C12) 660 (C10) 506 (C6) 409 (C5) 360 (C1) 298 (C5)

260 (C2) 140 (C3)

287

N

O

1

23

4

5

6

9

10

11

494

O

OH

7

8

12 13

14 15

16

17







(dd J = 180 60 Hz 1 H) 249 (m 1 H) 215 (dd J = 135 75 Hz 1 H) 208-152


1278 1272 1268 1258 659 495 466 432 372 355 276 184 141 IR (neat)


312] 334 (base) 312






288

1364 (C10) 1278 (C14) 1272 (C16) 1268 (C17) 1258 (C15) 659 (C13) 495 (C1)

466 (C5) 432 (C7) 372 (C8) 355 (C6) 276 (C2) 184 (C4) 141 (C3)

N

O

O

OH

OSi

1

2 34

5

67

89

10

11 12

13

14 15

16

1718

1920

493










MHz d6-DMSO 100 ˚C) δ 2059 1790 1532 1363 1278 1272 1268 1256 660

622 480 454 418 371 353 350 326 250 169 -56 -57 IR (neat) 2928 2855

1713 1623 1416 1322 1278 1088 839 MS (CI) mz 442 [C25H36NO4Si (M+1)


289








(C11) 1532 (C12) 1363 (C14) 1278 (C16) 1272 (C17) 1268 (C15) 1256 (C10)

660 (C13) 622 (C3) 480 (C1) 454 (C5) 418 (C8) 371 (C6) 353 (C2) 350 (C4)

326 (C7) 250 (C20) 169 (C19) -56 (C18) -57 (C18)

N

N

SO O

O

O

OO

12

345

6

78

910

11

1213

1415

1617

18

1920

21

2223

24 25

26

27

4112





290









H) 313 (m 1 H) 302 (m 1 H) 272 (m 1 H) 240 (dt J = 155 95 Hz 1 H) 225 (s


1339 1336 1294 1293 1285 1278 1273 1270 1254 1246 1236 1184 1164

1159 1144 669 514 510 508 387 204 203 MS (CI) mz 5591909

[C31H31N2O6S (M+1) requires 5591903]








˚C) δ 1715 (C12) 1548 (C22) 1448 (C17) 1360 (C24) 1345 (C30) 1339 (C9)

1336 (C10) 1294 (C16) 1293 (C14) 1285 (C4) 1278 (C26) 1273 (C25) 1270

291

(C27) 1254 (C15) 1246 (C6) 1236 (C5) 1184 (C7) 1164 (C21) 1159 (C3) 1144

(C8) 669 (C23) 514 (C1) 510 (C13) 508 (C11) 387 (C19) 204 (C2) 203 (C18)

10

11

12

3

45

6 7

8 912

1314 15

16

1718

1920

21

22

23

24

25

N

N

O

O

OO

OO

4114











100 Hz 1 H) 365 (s 3 H) 318 (dq J = 80 160 Hz) 252 (m 1 H) 238 (m 1 H)

159 (s 9 H) 13C NMR (125 MHz) δ 1717 1548 1489 1359 1354 1340 1338

292

1278 1274 1273 1239 1223 1178 1162 1148 1122 841 668 513 512 509


requires 5052339]







1717 (C10) 1548 (C23) 1489 (C12) 1359 (C14) 1354 (C1) 1340 (C20) 1338

(C22) 1278 (C16) 1274 (C17) 1273 (C6) 1272 (C15) 1239 (C4) 1223 (C5) 1178

(C3) 1162 (C21) 1148 (C7) 1122 (C2) 841 (13) 668 (C24) 513 (C9) 512 (C11)

509 (C18) 385 (C19) 273 (C25) 204 (C8)

293

N

N

SO O

O

O

12

345

6

78

910

11

1213

1415

1617

18

1920

21

2223

24 25

26

27

4113
















294



1340 1334 1293 1292 1278 1274 1272 1254 1247 1238 1184 1168 1158

1147 838 736 668 518 384 383 266 203 MS (CI) mz 5251849

[C31H29N2O4S (M+1) requires 5251848]









(C24) 1359 (C10) 1343 (C14) 1340 (C15) 1334 (C4) 1293 (C16) 1292 (C26)

1278 (C25) 1274 (C15) 1272 (C27) 1254 (C6) 1247 (C6) 1238 (C5) 1184 (C7)

1168 (C21) 1158 (C8) 1147 (C4) 838 (C12) 736 (C13) 668 (C23) 518 (C1) 384

(C11) 383 (C19) 266 (C2) 203 (C18)

295

12

3

45

6 7

8 910

11

12

1314 15

16

1718

1920

21

22

23

24

25

N

N

O

O

OO

4115
















1489 1358 1356 1343 1330 1279 1278 1274 1272 1240 1224 1176 1165

296

1148 1119 841 733 668 664 514 386 377 272 265 IR (neat) 3293 3068








(C14) 1356 (C20) 1343 (C1) 1330 (C22) 1279 (C6) 1278 (C17) 1274 (C16)

1272 (C15) 1240 (C4) 1224 (C5) 1176 (C3) 1165 (C21) 1148 (C7) 1119 (C2)

841 (C10) 733 (C24) 668 (C13) 664 (C11) 514 (C9) 386 (C18) 377 (C19) 272

(C25) 265 (C8)

297

12

1314

151617

18

12

3

45

6 78

9 1011

NH

N

OO

O19

20

21

2223

4106

H















1774 1534 1361 1356 1323 1278 1273 1270 1265 1258 1206 1182 1172

298

1108 1055 663 493 476 402 371 344 250 IR (neat) 3464 3052 2985 1702









(C12) 1774 (C10) 1534 (C18) 1361 (C20) 1356 (C1) 1323 (C17) 1278 (C22)

1273 (C23) 1270 (C21) 1265 (C11) 1258 (C6) 1206 (C4) 1182 (C5) 1172 (C3)

1108 (C2) 1055 (C7) 663 (C19) 493 (C9) 476 (C16) 402 (C13) 371 (C14) 344

(C15) 250 (C8)

299

12

1314

151617

18

12

3

45

6 78

9 1011

N

N

O

OO

O

O19

20

21

2223

2425

26

4117













= 127 41 Hz 1 H) 162 (s 9 H) 13C NMR (125 MHz) δ 2059 1768 1533 1488

1360 1351 1323 1278 1275 1274 1271 1265 1239 1224 1178 1149 1141

300

841 665 541 481 403 362 339 272 246 IR (neat) 3400 2977 2929 1771








C26-H) 13C NMR (125 MHz) δ 2059 (C12) 1768 (C10) 1533 (C24) 1488 (C18)

1360 (C20) 1351 (C1) 1323 (C17) 1278 (C22) 1275 (C23) 1274 (C24) 1271

(C11) 1265 (C6) 1239 (C4) 1224 (C5) 1178 (C3) 1149 (C2) 1141 (C7) 841

(C25) 665 (C19) 541 (C9) 481 (C16) 403 (C13) 362 (C14) 339 (C15) 272 (C26)

246

301

19

N

N

O

OO

OO

H

OO

4124

12

3

45

6 7

8 9 10

11

12

1314

151617

18

20

21

2223

24 25

26














1710 1632 1421 1307 1252 1150 739 MS (CI) mz 531 [C30H31N2O7 (M+1)

requires 531] 531 463 319 243 (base)

302







35 Hz 1 H C15-H) 170 (m 1 H C15-H) 157 (s 9 H C20-H)

N

N

OO

H

OO

OO

4125

12

3

4

56 7

8 910

11

12

1314

151617

18

19

20

21

22

2324 25

26









303







100 ˚C) δ 2071 1534 1487 1359 1352 1321 1278 1275 1272 1270 1240

1224 1178 1148 1142 841 696 666 613 477 473 376 351 290 272 228

IR (neat) 2977 2928 1750 1730 1703 1455 1417 1360 1326 1156 1012 755 MS








(C18) 1487 (C21) 1359 (C23) 1352 (C1) 1321 (C17) 1278 (C25) 1275 (C6)

1272 (C26) 1270 (C24) 1240 (C4) 1224 (C5) 1178 (C3) 1148 (C7) 1142 (C2)

841 (C11) 696 (C22) 666 (C19) 613 (C10) 477 (C9) 473 (C16) 376 (C13) 351

(C15) 290 (C14) 272 (C20) 228 (C8)

304

N

N

O

H

H

OO

O O

Si

21

2223

2425

26

27

28

12

3

45

6 7

8 9 10

11 12

1314

151617

18

19

20

4130














NMR (125 MHz d6-DMSO 100 ˚C) δ 1648 1544 1538 1488 1364 1352 1328

1279 1278 1272 1268 1236 1222 1176 1148 1040 838 781 659 466 362

305

304 293 272 262 231 57 40 IR (neat) 2954 1729 1699 1636 1455 1421 1327









(C18) 1538 (C12) 1488 (C23) 1364 (C1) 1352 (C17) 1328 (C6) 1279 (C25)

1278 (C24) 1272 (C26) 1268 (C3) 1236 (C5) 1222 (C4) 1176 (C2) 1148 (C7)

1040 (C11) 838 (C9) 781 (C16) 659 (C22) 466 (C10) 362 (C13) 304 (C19) 293

(C15) 272 (C20) 262 (C8) 231 (C14) 57 (C28) 40 (C27)

306

19

N

N

OO

OO

4132

12

3

45

6 7

8 9

151617

18

20

21

2223

24 25

26

27

28

OSi10

11 12

1314

H

H













1547 1497 1367 1365 1359 1335 1332 1287 1286 1283 1282 1278 1277

1274 1240 1239 1226 1225 1177 1176 1156 1153 1147 1042 1038 838

836 671 668 480 478 476 474 473 471 407 406 313 309 299 280 279

307

276 270 177 123 IR (neat) 2943 2865 1731 1698 1634 1455 1424 1366 1325


405








1497 (C12) 1367 (C1) 1365 (C1) 1359 (C17) 1335 (C6) 1332 (C6) 1287 (C23)

1286 (C23) 1283 (C25) 1282 (C25) 1278 (C26) 1277 (C26) 1274 (C24) 1240

(C2) 1239 (C2) 1226 (C5) 1225 (C5) 1177 (C3) 1176 (C3) 1156 (C4) 1153 (C7)

1147 (C7) 1042 (C11) 1038 (C11) 838 (C19) 836 (C19) 671 (C22) 668 (C22)

480 (C16) 478 (C16) 476 (C9) 474 (C9) 473 (C10) 471 (C10) 407 (C8) 406

(C8) 313 (C13) 309 (C13) 299 (C13) 280 (C20) 279 (C20) 276 (C14) 270 (C14)

177 (C28) 123 (C27)

308

N

N

O

H

H

OO

O O21

2223

2425

26

12

3

4

56 7

8 9 10

11 12

1314

151617

18

1920

4131














1362 1351 1324 1278 1272 1270 1268 1237 1222 1176 1148 1107 839

662 469 446 402 384 291 283 279 272 231 IR (neat) 2953 1731 1701

309

1455 1423 1368 1326 1147 1016 747 MS (CI) mz 501 [C30H32N2O5 (M+1)









1488 (C18) 1362 (C23) 1351 (C1) 1324 (C17) 1278 (C25) 1272 (C26) 1270

(C24) 1268 (C26) 1237 (C4) 1222 (C5) 1176 (C3) 1148 (C7) 1107 (C11) 839

(C19) 662 (C22) 469 (C9) 446 (C13) 402 (C16) 384 (C11) 291 (C15) 283 (C10)

279 (C8) 272 (C20) 231 (C14)

NH

HN

OH

H

H

12

3

4

56 7

8 9 10

1112

1314

151617

4133




310













CD3OD) δ 1376 1355 1286 1217 1196 1184 1118 1082 729 497 455 422

394 354 341 323 300 IR (neat) 3394 29241450 1335 742 MS (CI) mz 270








311

1286 (C6) 1217 (C4) 1196 (C5) 1184 (C3) 1118 (C7) 1082 (C2) 729 (C12) 497

(C9) 455 (C16) 422 (C15) 394 (C10) 354 (C13) 341 (C11) 323 (C8) 300 (C14)

N

N

OHO

H

H

OO

O O

20

12

3

4

56 7

8 9 1011 12

1314

151617

18

19

21

2223

2425

26

N

N

OHO

H

H

OO

O O

20

12

3

4

56 7

8 9 1011 12

1314

151617

18

19

21

2223

2425

26

4137a 4137b














312



13C NMR (125 MHz d6-DMSO 100 ˚C) δ 2151 1543 1488 1363 1351 1325

1279 1278 1272 1268 1237 1223 1177 1151 1148 839 729 662 472 451

405 390 307 272 257 232 IR (neat) 3436 2976 1729 1699 1456 1424 1360

1328 1153 754








(C23) 1351 (C1) 1325 (C17) 1279 (C6) 1278 (C25) 1272 (C26) 1268 (C24)

1237 (C4) 1223 (C5) 1177 (C3) 1151 (C7) 1148 (C2) 839 (C19) 729 (C11) 662

(C22) 472 (C16) 451 (C10) 405 (C13) 390 (C9) 307 (C15) 272 (C20) 257 (C8)

232 (C14)

313

19

N

N

OO

OO

4144

12

3

45

6 7

8 9

1718

2021

22

2324

25 26

1011

1314

15

16

H

HO

O12

27

OH
















314

1543 1488 1364 1349 1337 1277 1271 1266 1236 1222 1176 1147 837

659 576 503 463 453 360 336 296 272 262 250 231 IR (neat) 2931 1729

1697 1454 1367 1328 1155 1116 912 747 MS (CI) mz 549 [C31H36N2O7 (M+1)

requires 549] 549 (base) 493 449








DMSO 100 ˚C) δ 1716 (C17) 1543 (C22) 1488 (C19) 1364 (C1) 1349 (C14) 1337

(C6) 1277 (C24) 1271 (C26) 1269 (C27) 1266 (C25) 1236 (C2) 1222 (C5) 1176

(C4) 1153 (C3) 1147 (C7) 837 (C20) 659 (C23) 576 (C15) 503 (C18) 463 (C13)

453 (C9) 360 (C10) 336 (C16) 296 (C8) 272 (C21) 262 (C12) 231 (C11)

315

19

N

N

OO

OO

4145

12

3

45

6 7

8 9

17

18

20

21

2223

2425

26

10

11

1314

1516

H

H

12OO
















316




1352 1324 1278 1272 1269 1259 1222 1176 1149 1107 1064 839 674

662 474 469 368 336 306 299 272 234 IR (neat) 2976 1731 1698 1455


517 (base) 417









1487 (C18) 1362 (C1) 1352 (C17) 1324 (C6) 1278 (C23) 1272 (C25) 1269

(C26) 1259 (C24) 1222 (C2) 1176 (C5) 1149 (C4) 1107 (C3) 1064 (C7) 839

(C11) 674 (C19) 662 (C22) 474 (C16) 469 (C9) 368 (C8) 336 (C13) 306 (C15)

299 (C10) 272 (C20) 234 (C14)

317

19

N

N

OO

OO

4147

12

3

45

6 7

8 9

17

18

20

21

2223

2425

26

10

11

1314

1516

H

H

12O

















318




˚C) δ 1538 1488 1428 1362 1351 1325 1277 1273 1272 1269 1236 1222

1176 1149 1148 1036 838 662 637 475 465 379 320 272 260 233 IR

(neat) 2976 1729 1699 1455 1422 1330 1142 747 MS (CI) mz 500 [C30H32N2O5

(M) requires 500] 500 401 387 (base) 267 229








(125 MHz d6-DMSO 100 ˚C) δ 1538 (C21) 1488 (C18) 1428 (C12) 1362 (C1)

1351 (C17) 1325 (C6) 1277 (C23) 1273 (C25) 1272 (C26) 1269 (C24) 1236

(C2) 1222 (C5) 1176 (C4) 1149 (C3) 1148 (C7) 1036 (C13) 838 (C19) 662

(C22) 637 (C11) 475 (C16) 465 (C9) 379 (C8) 320 (C15) 272 (C20) 260 (C10)

233 (C14)

319

NH

NH

H O

12

3

4

56 7

8 9 10

11

12

1314

151617

18

4148













1 H) 13C NMR (100 MHz C6D6) δ 1441 1362 1320 1285 1216 1197 1185

1111 1072 1050 668 555 549 417 408 358 242 228 IR (neat) 3394 2927

2360 1646 1457 1244 1070 741 668 MS (CI) mz 2811657 [C18H21N2O (M+1)

requires 2811654]

320








(C6) 1216 (C4) 1197 (C5) 1185 (C3) 1111 (C7) 1072 (C2) 1050 (C13) 668

(C11) 555 (C9) 549 (C16) 417 (C10) 408 (C15) 358 (C18) 242 (C8) 228 (C14)

N

NH

H O

19

12

3

45

6 7

8 9 10

11

12

1314

151617

18

4149









321








1188 1179 1097 1087 1063 1048 666 552 536 418 405 379 347 237

229 IR (neat) 2925 2360 2340 1644 1467 1379 1070 895 738 668 MS (CI) mz

2931659 [C19H21N2O (M-1) requires 2931654]








(C1) 1265 (C17) 1208 (C6) 1188 (C4) 1179 (C5) 1097 (C3) 1087 (C7) 1063

(C2) 1048 (C13) 666 (C11) 552 (C8) 536 (C16) 418 (C10) 405 (C15) 379 (C19)

347 (C18) 237 (C8) 229 (C14)

322

19

N

N

OO

OO

4152

12

3

45

6 7

8 9

17

18

20

21

2223

2425

26

10

11

1314

1516

H

H

12O

O27

28














100 ˚C) δ 815 (d J = 80 Hz 1 H) 771 (s 1 H) 747 (d J = 80 Hz 1 H) 733-723



323



1488 1362 1351 1327 1277 1274 1273 1269 1237 1223 1193 1176 1148

1107 838 662 647 477 460 359 299 272 257 242 223 IR (neat) 2913

1721 1691 1612 1427 1318 1090 740 MS (CI) mz 543 [C32H35N2O6 (M+1)

requires 543] 544 543 488 444 (base) 400








MHz d6-DMSO 100 ˚C) δ 1939 (C27) 1568 (C21) 1539 (C18) 1488 (C12) 1362

(C1) 1351 (C17) 1327 (C6) 1277 (C23) 1274 (C25) 1273 (C26) 1269 (C24)

1237 (C2) 1223 (C5) 1193 (C4) 1176 (C3) 1148 (C7) 1107 (C13) 838 (C19)

662 (C22) 647 (C11) 477 (C16) 460 (C9) 359 (C8) 299 (C15) 272 (C20) 257

(C10) 242 (C28) 223 (C14)

324

NH

NH

4154

12

3

45

6 7

8 9

17

10

11

14

1516

H

H

12O

O13

1819
















MHz) δ 1955 1575 1356 1355 1272 1215 1213 1193 1177 1112 1079 674

325

483 477 374 323 288 250 237 IR (neat) 2921 1614 1453 1321 1195 738 MS









1355 (C1) 1272 (C6) 1215 (C2) 1213 (C5) 1193 (C4) 1177 (C3) 1112 (C13)

1079 (C7) 674 (C11) 483 (C16) 477 (C9) 374 (C8) 323 (C15) 288 (C10) 250

(C19) 237 (C14)

N

N

41

12

3

45

6 7

8 9

17

10

11

14

1516

H

H

12O

O13

1819

20

21





326










211 (ddd J = 112 46 40 Hz 1 H) 207 (s 3 H) 189 (m 1 H) 180 (dd J = 120 36

Hz 1 H) 13C NMR (75 MHz) δ 1955 1574 1372 1332 1265 1211 1208 1187

1178 1090 1059 678 547 538 418 385 324 291 250 229 228 IR (neat)

2895 2359 1617 1468 1320 1276 1192 911 741 MS (CI) mz 337 [C21H25N2O2










327

(C17) 1265 (C6) 1211 (C4) 1208 (C5) 1187 (C3) 1178 (C2) 1090 (C13) 1059

(C7) 678 (C11) 547 (C9) 538 (C16) 418 (C21) 385 (C20) 324 (C8) 291 (C10)

250 (C19) 229 (C15) 228 (C14)

328

References












329















330















331














332

















333

















334













335

















336














337













338

















339














340
















341



342

Vita










copyright by kenneth aaron miller 2007

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