Toward the Asymmetric Synthesis of the

AB-ring System of Phorbol

Amita Chaudhari

A thesis submitted in conformity with the requirements

for the degree of Master of Science

Graduate Department of Chemistry

University of Toronto

O Copyright by Amita Chaudhari 2000

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'Toward the Asymmetric Synthesis of the AB-ring Systern of Phorbol"

Master of Science 2000

Amita Chaudhari

Department of Chemistry

University of Toronto

Abstract

A second-generation asymmetric synthesis of the AB-ring system of

phorbol was investigated. This study has alleviated the problems associated with

the first generation racemic synthesis of the AB-ring system. The key step in the

approach is an intramolecular anionic cyclization reaction, which effectively forrns

the trans-5,7-fused AB-ring. Chiral auxiliaries and the asymmetric aldol reaction

were utilized to furnish the appropriate stereochemistry. The formation of the

[3.2.1] oxabicycle 63 was achieved using the Rh-catalyzed [4+3] cycloaddition

reaction, which imparts high diastereoselectivity . A selective zinc reduction was

performed to give 64 with the hydroxyl and methyl groups restored in a syn

orientation to each other. Cleavage of the chiral auxiliaries proved troublesome,

however, under the Krapcho conditions, selective removal of R-pantolactone was

achieved. Further manipulations involving protections, reductions and cleavage

reactions were investigated. The precursors en route to the AB-ring have been

made and the conditions have been optimized.

Acknowledgements

1 would like to acknowledge and thank my supervisor Dr. Mark Lautens for

his guidance and support throughout the duration of my research. Expression of

my gratitude is also directed toward members of the Lautens group. Sheldon

Hiebert, thanks for the numerouç discussions pertaining to our projects.

This research was supported by funds from BioChem Pharma, the Natural

Sciences and Engineering Research Council of Canada (NSERC), and the

University of Toronto. Thank you for financial support of the research.

Finally, I would like to thank my family and close friends for their

continuous and relentless love and support.

iii

Table of Contents

Title Page

Abst ract

Acknowledgernents

Table of Contents

List of Abbreviations

List of Schemes

CHAPTER 1

Introduction

1.1 Phorbol and Daphnane

1.2 Strategies for a Total Synthesis of Phorbol

1 -3 lntramolecular Anionic Cyclizations

1.4 [3.2.1] Oxabicyclic Cyclization Precursors

1.5 Anionic Cyclization of Non-Stabilized Anions

1.6 Modification of Protecting Groups and Conversion to One Isomer

1.7 Functionalization of B-ring

1.8 Problems Associated with Current Approach to AB-ring System

CHAPTER 2

Toward the Asymmetric Synthesis of the AB-ring System

2.1 Synthesis of Furan Precursor Using Aldol Condensation

2.2 Davies' [4+3] Cycloaddition and [3.2.1] Oxabicycles

2.3 Cleavage of Both Chiral Auxiliaries

2.4 Selective Removal of One Chiral Auxiliary

2.5 Diastereoselective Synthesis of lodide Precursor

viii

CHAPTER 3

Discussion and Conclusions

3.1 Discussion

3.2 Conclusions

CHAPTER 4

Experirnental

References

Appendix: Selected Spectra

List of Abbreviations

[al0 Ac

acac

Su

DBU

de

Dess-Martin

DIBAL

DMF

DMSO

equ iv.

Et

EtOAc

FT

HPLC

HRMS

IR

LDA

LRMS

L-Seiectride

Me

MOM

mP k 6 ~

NMR

ooct OP

~xone@

specific rotation measured at 589 nm and room temperature

acetyl

acety laceto nate

butyl

1,8-diazabicyclo[5.4.0]undec-7-ene

diastereomeric excess

1 ,l ,l 4riacetoxy-l,1 -di hydro-l,2-benziodoxol-3(l H)-one

diisobutylaluminum hydride

dimethylformamide

dimethylsulfoxide

equivalent

ethy l

ethyl acetate

fourier transform

high performance liquid chromatography

high resolution mass spectrum

infrared

lithium diisopropylamide

low resolution mass spectrum

lithium tri-seobutylborohydnde

methyl

rnethoxyrnethy l

melting point

rrbutyl

nuclear magnetic resonance

octanoate

generic protecting group

potassium peroxyrnonosulfate

PPTS

R

rt

TBAF

TBDMS

TBDPS

TBHP

TBS

t-BU

TES

T f

TFA

THF

TLC

TMEDA

TMS

Ts

phenyl

pyridinium ptoluenesulfonate

generic alkyl group

room temperature

tetra-n-butylammonium fluoride

tert-butyldimethylsilyl

tert-butyldiphenylsil yl

tert-butyl hydroperoxide

tert-butyldimethylsilyl

tert-butyl

triethylsilyl

trifluorornethanesulfonyl

trifluoroacetic acid

tetrah ydrofuran

thin layer chromatography

tetramethylethylene diamine

trimethylsil yl

tosyl, ptoluenesulfonyl

vii

List of Schemes

Chapter 1

Scheme 1 : Wender's asymmetric synthesis of phorbol.

Scheme 2: Our retrosynthetic approach to phorbol.

Scheme 3: lntramolecular anionic cyclization.

Scheme 4: Anionic cyclization using stannanes.

Scheme 5: Anionic cyclization reaction using iodides.

Scheme 6: lntramolecular anionic cyclization using t2.2.11 oxabicycles.

Scheme 7: Use of stabilized anions in anionic cyclization of [3.2.1]

oxabicycles.

Scheme 8: Davies' approach to optically enriched [3.2.l] oxabicycles.

Scheme 9: Synthesis of sulfone-containing [3.2.1] oxabicycle.

Scherne 10: Synthesis of iodide cyclization precursor.

Scheme 11 : lntramolecular anionic cyclization of a non-stabilized anion.

Scheme 12: Effect of side chain stereochemistry on the anionic cyclization.

Scheme 13: Use of non-chelating groups in the anionic cyclization.

Scheme 14: TES-protecting group and the anionic cyclization.

Scheme 15: Marko oxidation and epimerization.

Scheme 16: Selective reduction of C3 ketone to forrn syndiol.

Scheme 17: Functionalization of B-ring.

Scheme 18: Strategy for diastereoselective synthesis of AB-ring of phorbol.

viii

Chapter 2

Scheme 19: Synthesis of chiral oxazolidinone.

Scheme 20: Aldol condensation via boron enolate.

Scheme 21 : Titanium mediated aldol reaction.

Scheme 22: Dess-Martin oxidation.

Scheme 23: Selective reduction using zinc borohydride.

Scheme 24: TES protection of oxabicycle 64.

Scheme 25: Krapcho decarboxylation of oxabicycle 64.

Scheme 26: Preparation of oxabicycle for cleavage conditions.

Scheme 27: Cieavage of chiral auxiliary.

Scheme 28: Synthetic approach for remaining steps.

Chapter 3

Scheme 29: Another synthetic approach to iodide precursor.

Chapter 1

Introduction

1.1 Phorbol and Daphnane

Human diseases and disorders have been the focus of intense research

in the medical and biochemical communities for many years. From its early

beginnings, this research focussed on the benefits provided by substances found

in nature. With chernical extraction of biologically active compounds frorn the

natural substances, the treatment of diseases and disorders is made possible.

Problems arise in attaining adequate supplies of these substances due to

geographic isolation and diminishing supplies of natural resources. Therefore,

for effective drug development t hese naturally occurring biolog ically active

compounds must be synthesized. Many biologists and synthetic chemists have

targeted their research toward the discovery of processes to create known

biologically active compounds in the laboratory in order to find a novel lead

compound for medicinal purposes.

One group of plant substances promoting tumour growth, the phorbol

esters, depends for its effects on a molecular resemblance to diacylglycerol

(DAG).' DAG activates a crucial serineAhreonine protein kinase that

phosphorylates selected proteins in the target cell. The activated enzyme is

called protein kinase C (PKC) because it is calcium ion dependent. The initial

rise in cytosolic calcium ion is thought to alter PKC so that it translocates from

the cytosol to the cytoplasmic face of the plasma membrane. There it is

activated by DAG. Through cascades of highly regulated protein

phosphorylations, elaborate sets of interacting proteins relay most sig nals from

the ce11 surface to the nucleus, thereby altering the cell's pattern of gene

expression and, as a consequence, its behaviour.

Phorbol Daphnane

Figure 1 : Phorbol and daphnane.

The phorbol esters, 12,13-diesters of phorbol (Figure l), provide an

interesting example of a group of chernicals that promotes the growth of cancer

cells rather than inducing mutation^.'^ These molecules resemble the DAG

second messenger, which allows them to stimulate the segment of the pathway

activating protein kinase C. Of medical significance is the ability of phorbol ester

tumour promoters to activate protein kinase C directly. This leads to elevated

and unregulated activation of PKC and the consequent disruption in normal

cellular growth and proliferation control leading ultimately to neoplasia. The

phorbol esters are especially effective in activating PKC because they are

rnetabolized very slowly inside cells. Thus their effects last much longer than

DAG, which is typically degraded very quickly after its formation.

The structurally analogous daphnane compounds exhibit different

biological activities, and dernonstrate no binding affinity for PKC.* Their most

noticeable properties are as skin irritants and analgesics. Consequently, phorbol

and related compounds may lead to new chemotherapeutic agents that combat

diseases such as cancer and HIV~.

1.2 Strategies for a Total Synthesis of Phorbol

The generation of the 5,7,6-fused carbocyclic framework of phorbol has

been the focus of most synthetic studies reporteda4 Despite numerous studies

and several synthetic approaches, only Wender's group has developed a total

asymmetric synthesis of phorbol? The key step in Wender's approach is an

intramolecular [5+2] cycloaddition utilizing oxidopyrylium-olefin 3 to achieve the

7,6-tram-fused BC-ring in compound 4 (Scheme 1). Annelation of the A ring

was accomplished through zirconocene-mediated enyne cyclization (5 to 6).

Scheme 1 : Wender's asymmetric synthesis of phorbol.

We envisaged a different route, which involves the initial construction of

the trans-fused AB-ring systern (Scheme 2). The biological activity of phorbol

esters appears to be related to the hydroxyl groups attached to this AB-ring

system? Construction of the AB-ring system would, therefore, be advantageous

in the quest for biologically active analogs of phorbol.

Scheme 2: Our retrosynthetic approach to phorbol.

1.3 lntramolecular Anionic Cyclizations

The trans-5,7-fused ring systern can be obtained via an anionic

intramolecular cyclization of oxabicycl ic su bstrate 1 2, a strategy developed by

Lautens and Kurnanovic (Scheme 3).6 Halogen-metal exchange occurs

generating carbanion 13, which attacks the double bond, and subsequent

opening of the bridging ether ring provides trans-fused bicyclic compound 14 in a

stereoselective rnanner.

Scheme 3: lntramolecular anionic cyclization.

The intermolecular addition of nucleophiles to [3.2.1] oxabicyclic

substrates, resulting in nucleophilic addition followed by ring opening, is well

documented? Lautens' group has also studied intramolecular anionic

cyclizations of [3.2.1] oxabicyclic c~ rn~ounds .~ This reaction provided a trans-

fusedd,7-bicyclic system, as required for a total synthesis of phorbol, in al1 cases

studied. Some examples of this cyclization, leading to trans-fused [5.3.0] bicyclic

compounds are shown in Scheme 4. MeLi was chosen as the transmetalation

agent since they had previously established that it did not result in intermolecular

coupling.

15

X = CH2, O, S, NMe

MeLi (5 eq.)

Scheme 4: Anionic cyclization using stannanes.

Use of this approach in a synthesis of phorbols requires that an all-carbon

chah must cyclize efficientiy (Scheme 5). Cyclized substrate 18 was prepared in

iodide precursor 17.6 The cyclized product

17 containing a free hydroxyl group was

good yield from the corresponding

was not obtained when substrate !

employed. In addition, when the all-carbon side chain contained substituents,

cyclization was achieved to give product 20 in reasonable yield.8 However, the

presence of methyl substituents in 20 at Cs and C7 are not required in a total

synthesis of phorbol. They are present due to the ease with which iodide

precursor 19 containing these methyl groups could be prepared. Consequently,

a different çynthetic route to the precursor was desirable.

17 OMe

Scheme 5: Anionic cyclization reaction using iodides.

[2.2.1] Oxabicyclic substrates have also been utilized in intramolecular

anionic cyclizations. For [2.2.1] systems, stabilized anions next to a nitrile or

sulfone group could be employed (Scheme 6).' These anions were found to give

the desired cyclized productç (22) in good yields, although they are less reactive

than the corresponding non-stabilized alkyllithium species.

EWG &ze 21

EWG = CN, PhS02

Scherne 6: lntramolecular anlonic cyclization using 12.2.11 oxabicycles.

However, [3.2.1] oxabicycles with nitrile or sulfone groups did not undergo

the anionic cyclization reaction (Scheme 7).1° Only starting material was

recovered. Due to the absence of any sign of cyclization of these stabilized

anions, it was decided to focus attention on the cyclization of non-stabilized

alkyllithium substrates. The required alkyllithium compounds are accessible from

the corresponding alkyl iodides or alkyltin compounds.

O?) EWG OTBS OTBS

LDA + TBSO

a)EWG=CN,R=H b) EWG = S02Ph, R = Me

Scheme 7: Use of stabilized anions in anionic cyclization of [3.2.1] oxabicycles.

1.4 [3.2.1] Oxabicyclic Cyclizatlon Precursors

A useful synthetic approach to optically active [3.2.1] oxabicyclic

substrates is a tandem cyclopropanationlCope rearrangement reaction between

a furan and a vinyl carbene, as developed by ~avies." Initialiy, the rhodium

carbene reacts with the furan to give the cyclopropane intermediate (Scheme 8).

This cyclopropanation is a highly stereoselective process resulting from a

preferred Si-face attack when R-pantolactone is employed as a chiral auxiliary

on vinyldiazomethane 25. The carbonyl group of the chiral auxiliary is believed

to provide stabilization by interacting with the rhodium carbene. Since the

reaction is performed in refluxing hexanes, the cyclopropane diene undergoes a

3,3-sigmatropic rearrangement to give [3.2.1] oxabicyclic compound 26. This

method allows for the diastereoselective synthesis of [3.2.1] oxabicycles in

excellent yields and diastereoselectivities of 97:3 to 84: 1 6 depending on the

substituent R on the furan. van Oeveren has shown that the diastereoselectivity

for the formation of the [3.2.1] oxabicycle is greater for a keto-substituted side-

chain on the furan (88% de) than the corresponding alkoxy-substituted furan

(68% de)." Additional stereocenters on the furan side-chah had no influence on

the stereoselectivity of the cyclopropanation step.

- Si-face attack

Scheme 8: Davies' approach to optically enriched [3.2.1] oxabicycles.

The synthesis of the [3.2.1] oxabicyclic cornpound possessing the

electron-withdrawing sulfone group (23b) was carried out by van Oeveren

utilizing Davies' rhodium-catalyzed [4+3] cycloaddition reaction (Scheme 9) .'O

HCI

EtOH, reflux 16 h, 96%

TB&JL~*O

N2 O (slow addition)

Rh2(Wct)4 hexanes, reflux 91% Yield 88% d.e.

PhS O

YX3 MeOH : H20 (1 :1), r.t. 97%

*:.*

PhO2S O OTBS

1) HCI, MeOH, THF

MeOH, 0% 96%

2) NaCl, H20 DMSO, 160°C

TBDMSCI, im idazole

DMF 3296

23b

Scheme 9: Synthesis of sulfone-containing [3.2.1] oxabicycle.

The synthesis of the iodide cyclization precursor seemed to be the easiest

goal, especially since the iodide could be accessed from sulfone 31 (Scheme

IO), a precursor to 23b that can be synthesized on large scale without column

chromatography. Sulfone 31 was reduced with LselectrideB to give the

monoreduced endo alcohol 33, which was then protected as its TBDPS ether 34

in good yield. Elimination of the p-sulfone group with basic alumina afforded

enone 35 in quantitative yield. Successful 1,4-addition of TMSI gave P-

iodoketone 36 in excellent yield. The iodoketone was reduced to the alcohol with

NaBH4 to give two pairs of diastereomers following chromatography, which were

then protected as the MOM ether 37.

TBDPSCI, L-Selectride imidazole THF, -78OC - CH2CI2

Ph02S O 76%

Ph02S O 31 33

0 Basic alumina +,A3 TMS I - CH2CI2, t.t. CH2CI2

'OTBDPS 99% ~ T B D P S 96 %

Ph02S O O 34 35

1) NaBH,

),,A3 MeOH 97 % @

1 OMOM ~ T B D P S ~ T B D P S 2) (Me0)2CH2

1 O TMSI (cat) 36 30% 37

Scheme 10: Synthesis of iodide cyclization precursor.

1.5 Anionic Cyclization of Non-Stabilized Anions

The effects of the stereochemistry of the sida-chah substituents and the

protecting group on the sideçhain alcohol on the efficiency of the anionic

cyclization were then studied. 60th pairs of diastereorners of 37 were subjected

to the anionic ring-closing, ring-opening reaction using tert-butyllithiurn. For one

of the pain of diastereomers, some cyclization was observed at -78OC, and upon

warming to O°C more cyclized product was formed (Scheme 11). The products

observed were cyclized product 38 (70%), along with reduced product 39 (15%)

resulting from protic quenching of the intermediate alkyllithium species, and

product 40 (15%) resulting frorn the addition of tert-butyllithium to the [3.2.1]

oxabicyclic su bstrate.

Scheme 11 : lntramolecular anionic cyclization of a non-stabilized anion.

For the other pair of diastereomers under the same conditions, the main

product was tert-butyl substituted 40 and almost no cyclized product 38 was

observed. It is clear that the cyclization rates differ for each pair of

diastereomers and that the stereochemistry of the substituents on the side chain

has a remarkable influence on this rate. Since the relative configuration of the

two pairs of diastereomers of iodide 37 could not be readily determined, three of

the four diastereomers were prepared separately.

It was found that the reaction of syrrdisubstituted substrate 41 with tert-

butyllithium afforded the cyclized product in high yield, whereas the antk

disu bstituted substrate 42 (plus diastereomer) gave mainly the addition product,

with cyclized products obtained in poor yield (Scheme 12). In order ta determine

if the observed side-chain controlled cyclization was the result of chelation of the

formed alkyllithium species with the MOM protecting group, a substrate with non-

chelating silyl protective groups was synthesized.

t-Bu ti (3.0 eq) C

Et20 / Pentane (1 :1) -78 to -30°C

I OMOM

t-BuLi (3.0 eq)

Scheme 12: Effect of side chah stereoclremistry on the anionic cyclization.

The diastereomeric mixture of alcohols 43 was separated and protected

as their TBDMS ethers 44 and then treated with an excess of tert-butyllithium

(Scheme 13). The crude product was a mixture of the desired cyclized product

45 and the reduced product. No intermolecular addition of the t-butyl group was

observed. The use of the non-chelating protecting group is, therefore, preferred

over the MOM ethers, to give cyclized product 45 in good yield and suppress

side reactions in the intramolecular anionic cyclization. The reaction does not

seem to be controlled by the stereochemistry of the side-chain substituents when

a non-chelating protective group is used.

T BDMSOTf t-8uli (2.2 eq)

~ D P S Et20 / Pentane (1 :1) I OH 1 OTBS -78 to -3pC OH 'OTBDPS

Scheme 13: Use of non-chelating groups in the anionic cyclization.

1.6 Modification of Protecting Groups and Conversion to One lsomer

Albeit van Oeveren's success with the intramolecular anionic cyclization

and its use in the construction of the AB-ring of phorbol, trans-57-fused

compound 45 was obtained as a mixture of diastereomers, which was potential

for difficulties in the remaining part of the synthesis toward phorbol arising from

different reactivities in reactions and/or characterization problems. To alleviate

these anticipated problerns, Takimoto converted the diastereomers to a single

compound in order to avoid mixture in the remaining steps.12 In his studies, it

was noticed that the protecting groups present in 45 would have to be modified.

The TBDMS group was too stable in al1 diastereomers such that it could not be

deprotected selectively over the TBDPS group at Cs. Thus, the search for a new

combination of protecting groups was sought. Alteration of the Cg protecting

group would be the easiest goal since this protecting group is introduced

irnmediately prior to the anionic cyclization. Takimoto examined different

protecting groups at both Cg and Cg, and the best combination of groups was

found to be TES-protected Cs-hydroxyl and TBDPS-protected Cs-hydroxyl. The

approach used to incorporate the TES group is shown in Scheme 14. Treatment

of compound 43 with TESOTf and 2,6-lutidine afforded the TES-protected

compound (46) in excellent yield. The intramolecular anionic cyclization was

performed on 46 to give cyclized product 47 in high yield following

chromatography . The acid-labile TES group waç then selectively deprotected

using TFA in aqueous THF to give desired di0148 in outstanding yield.

02) TESOTf 2,6-lutidine - 0 t-Bu Li (2.2 eq)

4

~ T B D P S CH2C12, rt BTBDPS Et20 / Pentane (1 :1) I OH 95% I OTES -78 to OOC

H =a TFA / THF / HP0

I Eau - . V I UUI u

Scheme 14: TES-protecting graup and the anionic cyclization.

With diol 48 in hand, Takimoto pursued converting it to a single

diastereomer. Diol 48 was effectively oxidized under Marko's conditions,13 using

oxygen in the presence of a catalytic amount of copper (1) chloride and electron

acceptor di-tert-butyl azodicarboxylate to give desired hydroxy ketones 49

(Scheme 15). Takimoto reported that this was the first exarnple in which Marko's

conditions were applied to the oxidation of a complex molecule. Given that both

possible diastereomers from the oxidation were obtained, 49a and 49b,

epimerization of the methyl group was still required. Epimerization was

performed three times using DBU to convert 49a to 49b in 86% yield.

0, (1 atm), CuCl(40 rnol9/0) 1 ,l0-phenanthroline (41 mol%) - Ill*..

di-tert-buty l azodicarboxy late (41 mo ffi)

HO K2C@ (2 eq). loluene. 75%. 13 hr 82%

3 times 86%

Scheme 15: Mark6 oxidation and epimerization.

Consistent with the initial strategy

reduction of 49b waç required (Scheme

depicted in Scheme 2, a stereoselective

16). The hydroxy ketone was protected

as the TMS ether (50) to prevent attack of the hydride from the 13-face. Effective

reduction of the ketone was carried out using the bulky reducing agent LiBH(sec

BU)^ and subsequent removal of the TMS group was done under mildly acidic

conditions to give P-sym3,4-diol 51 in excellent yield as a single isomer.

TMSOTf 1) L ~ B H ( s ~ ~ B u ) ~ 2,6-lutidine THF, -78 to O C, 3 h

2) TFA I THF I H20 - (0.2 1 5 1 1). r L 15 min HO OH ~ T B D P S

49b 50 96 % (over 2 steps) 51

Scheme 16: Selective reduction of & ketone to form symdiol.

1.7 Functionalization of B-ring

Takimoto was able to synthesize an optically pure AB-ring systern

intermediate (51) by building upon the work done by van Oeveren. With this

intermediate, he continued the approach toward phorbol by functionalising the 6-

ring (Scheme 17). Acetonization of diol 51 followed by deprotection of the

TBDPS group were carried out, in preparation for a hydroxy-directed epoxidation,

to yield allylic alcohol 53 in good yield. Vanadium-catal yzed h ydroxy-directed

epoxidation with TBHP followed by oxidation with Dess-Martin reagent gave 54

as a single diastereomer. Treatment of 54 with base afforded enone 8 after

elimination of the epoxide. Enone 8 serves as the building block for the C-ring of

phorbol. Studies toward the synthesis of the C-ring are in progress.

(Me0)2CH2, PPTS TBAF - --'

CHCI3, r.t., 2 days THF, 40 OC, 14 h

51 52

VQ(acac)2, TBHP CH2C12, r.t., 3 h 86 %

Dess-M@!n CH2C12, r.t., 30 min. 88 %

DBU

CH2CI2, r.t., 20 min 99 %

53 54

Scheme 17: Functionalization of B-ring.

1.8 Problems Associated with Current Approach to AB-ring System

In the current approach, the intramolecular anionic cyclization is very

effective for the formation of the AB-ring of phorbol. However, since the

synthesis of the precursors is not stereoselective, inefficiencies in this route can

be found. The precursor to the anionic cyclization (46) was obtained as a

mixture of four diastereomers and hence, conversion to diastereomerically pure

interrnediate 51 was required. The conversion involved five extra steps -

oxidation, epimerization, protection, reduction, and deprotection (Schemes 15

and 16) - which could be eliminated if a diastereomerically pure intermediate

such as 10 can be prepared. An efficient preparation of a compound resernbling

55 is, therefore, desired to circurnvent this problem. The cyclized product 56 can

then be converted to a syn-di01 (57) in a single step (Scheme 18). It should be

noted that the absolute stereochernistry of the methyl group at C2 is net

important in the cyclized product as C2 is destined to becorne sp2-hybn'dized in

phorbol.

QTES

1

55 56 57

Scheme 18: Strategy for diastereoselective synthesis of AB-ring of phorbol.

As a result of the aforementioned advances en route to phorbol and its

inefficiencies, studies directed toward the asymmetric synthesis of the AB-ring

system were implernented.

Chapter 2

Toward the Asymmetric Synthesis of the AB-ring System

2.1 Synthesis of Furan Precursor Using Aldol Condensation

The initial strategy was shown in Section 1.2. It was envisioned that

setting the stereochemistry of the side chain of the furan before subjecting the

furan to the [4+3] cycloaddition was the desired route to obtaining the iodide as a

single isomer. This was accomplished by performing an asymmetric aldol

condensation between furfural and propionyl oxazolidinone.

Since a rather substantial arnount of indanol 58 was readily accessible, it

was decided to use this amino alcohol as the chiral auxiliary for the synthesis.

Chiral oxazolidinone 59 was prepared from indanol 58 and diethyl carbarnate in

good yield. Lithiation of 59 with n-butyllithiurn followed by reaction with propionyl

choride formed propionyl oxazolidinone 60 (Scheme 19).14 It was found that

elevated temperatures were required after the addition of propionyl chloride at

-78°C in order to prepare compound 60 in good yield.

59 78% 60

Scheme 19: Synthesis of chiral oxazolidinone.

The conformational rigidity of the tricyclic ring system of the oxazolidinone

should impart complete diastereofacial selectivity in an aldol reaction. The

Evans dialkylboron triflate mediated aldol reaction is a well-accepted and useful

method for the preparation of the Evans syn aldol products.'5 Boronates

generally givs higher aldo! diastereoselectivity than other enolates. Prooionyl

oxazolidinone 60 was treated with dibutylboron triflate and triethylamine to form

the 2-(O)-enolate, followed by addition of Pfurfural to yield the Evans syn

product 61 (Scheme 20). The yield of the reaction is highly dependent on the

quality of the dibutylboron triflate. Yields from 34-770h were obtained with

consistent diastereoselective excess of 70%.

Scheme 20: Aldol condensation via boron enolate.

Titanium metal centers have also been shown to be effective in aldol

additions? ~ecently, Crimmins reported the use of titaniurn (IV) enolates of

acyloxazolidinethiones and acyloxazolidinones in asymmetric aldol additions.l7

He reported that syn aldol products could be obtained in high diastereomeric

purity by changing the stoichiornetry of the Lewis acid and the nature of the

amine base. Therefore, an aldol reaction was conducted on propionyl

oxazolidinone 60 in the presence of titanium (IV) chloride (1.05 equiv.) and

TMEDA (2.5 equiv.) followed by the addition of 2-furfural (1.1 equiv.) to give syn

aldol adduct 61 in 74% yield and >99% de after recrystallization (Scheme 21).

No other diastereomers were detected by 'H NMR spectroscopy or HPLC

analysis. The reaction could be carried out on large scale, which is necessary

for reactions at an early stage in the synthesis. Given these results, the

Crimmins chemistry was used to prepare material for the subsequent studies.

1. Ti&, TMEDA, CH2CI2, O°C

b

60 74% >99% de

61

Scheme 21 : Titanium rnediated aldol reaction.

2.2 Davies' [4+3] Cycloaddition and [3.2.1] Oxabicycles

As mentioned earlier, the preferred substrate for the [4+3] cycloaddition is

one that contains a keto-substituted furan as opposed to an alkoxy-substituted

furan. Therefore, furan 61 had to be oxidized. The oxidation was achieved

using the Dess-Martin periodinane. The reaction was complete in 40 minutes at

room temperature, as observed by TLC, and the crude 'H NMR spectrum was

clean. No purification was necessary, and the desired furan (62) was obtained in

99'' yield as an off-white solid (Scheme 22). Epimerization of the methyl group

between the 1,Sdicarbonyl did not occur during the reaction due to the sp2

planarity inhibited by the chiral a ~ x i l i a r ~ . ' ~ By not allowing it to become planar,

the proton at the carbon atom bearing the methyl group is less acidic.

Swern oxidation of furan 61 was also attempted, however, the TLC was

not clean and the product was isolated in poor yield. This reaction was not

investigated further since the Dess-Martin oxidation worked well on large scale.

Dess-Martin

CH Cl2 rt 46 min.

Scheme 22: ûess-Martin oxidation.

Rhodium(l1)-catalyzed decornposition of vinyldiazomethane 25 in the

presence of f u ran 62 was performed. Various conditions, which are surnmarized

in Table 1, were investigated to obtain optimal results for the [4+3] cycloaddition.

The reaction did not proceed to completion for entry 1 under the original

conditions. It was found that the furan did not fully dissolve in hexanes, even at

reflux, therefore the reaction was carried out at high dilution (entri 2). The yield

increased, however, the use of dilute solute concentrations is not desirable for

large scale. When n-hexane was employed as the solvent, the furan was found

to be slightly more soluble (entry 3). However, the reaction still did not proceed

to cornpletion, which gave rise to tremendous difficulties during the separation of

starting material 62 and product 63. The use of 10% dichloromethane proved

helpful to dissolve the starting material and the reaction proceeded to cornpletion

and in high yield (entries 4, 5, 7).

Table 1 : [4+3] Cycloaddition of 62 under various conditions.

Entry Catalyst Solvent [Furan 621 No. of equiv. Yield of (moi %) (M) of diazo 25 63 (%)

1 5 Hexanes 0.005 1 .O5 25 2 5 Hexanes 0.002 1 .O5 63 3 5 n-hexane 0.005 1 .O5 71 4 5 n-hexane/ 0.005 1 .O5 73

10% CH2C12 5 5 n-hexane/ 0.005 1.20 85

IO0' CH2CI2 6 5 n-hexane/ 0.005 1.15 51

20% CH2C12 7 1 n-hexane/ 0.01 5 1.20 90

10% CH2C12

The diastereoselectivity of the reaction was determined by 'H NMR of the

crude product and found to be constant at 86% de for al1 conditions tested. The

additional stereocenters on the furan side chah did not appear to have any

influence on the stereoselectivity of the cyclopropanation step. The

diastereoselectivity is governed by the chiral auxiliary on diazoester 25 as

evidenced by the lack of induction of the added stereocenters. These results

highlight the remarkable stability of P-ketoimides and should be generally useful

for other cycloaddition reactions.

Selective reduction of the ketone group in oxabicycle 63 was attempted

using zinc borohydride. This reduction restores the alcohol functionality in a syn

orientation to the methyl group. At elevated tempeiatures, non-selective

reduction occurred as indicated by the presence of a proton in the chemical shift

region of aldehydes of the 'H NMR spectra. Lowering the temperature to -40°C

in ether resuited in selective reduction of the ketone (63) to the alcohol (64) in

870h yield, >9990 de (Scheme 23).

Scheme 23: Selective reduction using zinc borohydride.

The oxidation prior to the cycloaddition reaction as well as the zinc

borohydride reduction are high yielding steps, and as such, it was worthwhile to

perform these reactions in order to achieve the high diastereoselectivity obtained

in the [4+3] cycloaddition.

2.3 Cleavage of 80th Chiral Auxiliaries

The chiral auxiiiaries of oxabicycle 64 are no longer needed and must be

cleaved from the molecule. Before cieavage was attempted, protection of the

hydroxyl group of 64 was achieved using TESOTf in 2,blutidine at -20°C to

provide compound 65 in 91% yield (Scheme 24).

TESOTf

Scheme 24: TES protection of oxabicycle 64.

Cleavage was first attempted by hydrolysis of the oxazolidinone with

lithium hydroperoxide. The use of lithium hydroperoxide to cleave both

auxiliaries would furnish a diacid (66). Oxabicyclic compound 65 was treated

with varying amounts of LiOH, H202, and 12-crown-4 (Table 2). In most cases,

cleavage of the chiral auxiliaries was observed. However, for entry 1, analysis of

the isolated product from extraction of the acidic phase revealed there was no

TES group by 'H NMR, and IR showed three carbonyl stretches and a hydroxyl

group stretch. This product still contained some R-pantolactone. 12-Crown-4

was added to increase nucleophilicity and trap the lithium cation (entries 2-5).

This resulted in the disappearance of a triplet at 4.3 ppm in cornparison to the

product obtained from entry 1. By TLC, it was observed that pantolactone was

cleaved before oxazolidinone and the cleavage of the oxazolidinone occurred

after the addition of the crown ether (entry 5).

Table 2: Cleavage of chiral auxiiiaries with LiOOH.

1. LiOH, H202, 12-C4, THFIH20 (3:1), OTBDMS

0% to 10%

2. Na$03 OH

Entry LiOH H202 12çrown-4 [65] Time (h) Cleavage equiv. equiv. equiv. (Ml of chiral

auxiliaries

1 2 8 - 0.05 7 Yes

2 2 8 2 0.05 7 Yes

3 4 8 4 0.1 overnight Yes

4 4 8 4 0.2 overnight No

5 4 8 4= 0.1 5 yesb

a) added after 3 hours b) During the first two hourç, TLC showed the presence of R-

pantolactone. There was no cleavage of the oxazolidinone until after the addition of 12-crown4.

In order to determine if diacid 66 had indeed been formed and isolated, it

was decided to prepare the corresponding diester using sodium methoxide, and

then convert the diester to the diacid. However, only cleavage of the chiral

oxazolidinone (59) was observed by TLC. There were no methoxy signals

observed on the 'H NMR spectrum and further analysis of the spectrum revealed

that the oxabicyclic moiety had been destroyed.

2.4 Selective Removal of One Chiral Auxiliary

To overcome the problems of producing and

26

handling a diacid, selective

removal of one chiral auxiliary was attempted. Acidic hydrolysis of the silyl enol

ether of 64 provided the P-ketoester, which could be decarboxylated under

standard Krapcho conditions (DMSO, NaCI, H20, 160°C) to give the oxabicycle

containing the oxazolidinone rnoiety, 67 (Scheme 25).

1.10% HCI Me0H:TH F (53)

2. NaCl DMSO:H20

64 67

Scheme 25: Krapcho decarboxylation of oxabicycle 64.

2.5 Diastereoselective Synthesis of lodide Precursor

In order to synthesize the desired iodide precursor 55 for the anionic

cyclization reaction from oxabicycle 67, the chiral oxazolidinone must be cleaved.

To achieve this cleavage reductively , the free hydroxyl must be protected, and

the ketone needs to be selectively reduced. TES protection of compound 67

was accomplished using TESOTf and 2,6-lutidine at -20°C in 58% yield (Scheme

26). L-selectrideB, a bulky reducing agent, was used to selectively reduce

compound 68 to the alcohol (69) in 46% yield.

THF, -78OC 46%

Scheme 26: Preparation of oxabicycle for cleavage conditions.

Subsequent TBDPS protection of 69 proved to be unsuccessful.

Molecular modelling showed that steric interactions between the phenyl groups

of TBDPS and the oxazolidinone are a factor. Lithium borohydride reductive

cleavage of the oxazolidinone was attempted on oxabicycle 69 (Scheme 27).j9

The reaction was performed on srnall scale and preliminary results indicated

cleavage by TLC. However, we could not isolate acid 70 and it appeared that

the oxabicyclic ring system was destroyed in the reaction. The addition of water

proved helpful in keeping the oxabicycle intact during the cleavage and desired

product 70 was obtained in poor yield.

HaO, ether O C to rt

'OH

Scheme 27: Cleavage of chiral auxiliary.

The preliminary results relating to the reductive cleavage reaction are

promising. On larger scale, the reaction should be clean and high yielding. With

diol 70, the rernaining manipulations en route to the iodide precursor entail

selective protections of the alcohols, followed by conversion of the tosylated

alcohol to the iodide (Scheme 28).

OTES -

OTES A 1

TBDPSO TBDPSO

72 55

Scheme 28: Synthetic approach for remaining steps.

Chapter 3

Discussion and Conclusions

3.1 Discussion

This approach to the diastereoseiective synthesis of iodide precursor 55 has

advantages over the previous route, but also some unresolved problems. The

cleavage of the chiral auxiliaries seemed to pose the most challenge. Since both

auxiliaries could not be cleaved at the same time, selective removal was

required. However, the R-pantolactone auxiliary was cleaved in low yield (61 Oh)

under conditions tried to date, and the initial results of the oxazolidinone

cleavage indicated potential for high yield, although, the possibility that the

oxabicycle could be destroyed still exists. It would be advantageous to cleave

the oxazolidinone before the [4+3] cycloaddition. This auxiliary does not have

any stereoelectronic effect in the reaction and thus is not required. Removal of

oxazolidinone from furan 62 should be smooth since there is no oxabicyclic

rnoiety that can be destroyed and the molecule does not contain many functional

groups that could be affected by cleavage reaction conditions. The [4+3]

cycloaddition rnay proceed in higher yield without this auxil iary.

Alternatively, different reaction conditions could be employed for the

cleavage of the oxazolidinone. Only basic conditions have been attempted for

this reaction, however, the use of DlBAL or other reagents in acidic media may

prove to be fruitful.

Nevertheless, to avoid the use of a chiral auxiliary such as 59, another route

to the iodide precursor, which employs the Weinreb amide, can be envisioned

(Scheme 29). In fact, recent unpublished results from the Lautens lab have

indicated that this route is efficient and effective in obtaining iodide precursor 55

and the cyclized product of the anionic cyclization reaction was produced in high

yield.

OTBDMS

OP

TBD

76 55

Scheme 29: Another synthetic approach to iodide precursor.

Therefore, studies along the path utilizing the ch ira1 auxiliary were halted.

This third-generation route was the desired synthetic pathway for the formation

of the tram-5,7-fused AB-ring of phorbol.

31

Conclusions

The second-generation asyrnrnetric synthesis studied has alleviated the

problems associated with the first generation racemic synthesis of the AB-ring

of phorbol. The reactions employed were stereoselective so intermediates

prepared were diastereomerically pure and thus, there were no mixtures to

separate or cornplex spectra. Progress was made toward the large-scale

asymrnetric synthesis of iodide 55. However, some problems were

encountered du ring the synthesis of diastereomerically pure iodide

intermediate 55. Searching for optimal reaction conditions solved many of

these problems. These reactions are applicable to the third-generation

synthesis described above. Accordingly, the optimized conditions studied will

contribute to the efficiency of that route, and ultimately to the synthesis of the

AB-ring of phorbol.

Chapter 4

Experimental

General Procedures

1 H NMR spectra were recorded in CDCI3, unless otherwise stated, on a

Varian VXR4OO spectrometer and are reported as follows: chernical shift, S

(pprn), (rnultiplicity, number of protons, coupling constant, J in Hz). Residual

protic solvent CHC13 (& = 7.26 pprn) and tetrarnethylsilane were vsed as the

interna! references. 13c NMR spectra were recorded in CD&, unless otherwise

stated, at 100 MHz on a Varian VXR400 spectrometer, using CDCI3 (6c = 77.23

ppm) as the internai reference. lnfrared spectra were recorded in a solution of

CC14 on a Perkin-Elmer spectrum 1000 FT-IR spectrorneter and are reported in

cm-'. Mass spectra were obtained at the Department of Chemistry, University of

Toronto. Optical rotations were measured with a Perkin-Elmer 2438

spectrometer. Melting points were determined on a Fisher-Johns rnelting point

apparatus and are uncorrected.

Flash column chromatography was carried out using silica gel provided by

Toronto Research Chemicals Ltd. or Silicycle, Inc. (230-400 mesh). Analytical

TLC was performed using pre-coated aluminum sheets (Merck Kieselgel60 F~s)

and visualized by UV, anisaldehyde, or potassium permanganate solutions.

All reactions were carried out under an argon or nitrogen atmosphere in

flame-dried glassware. Diethyl ether and tetrahydrofuran were distilled from

sodium benzophenone ketyl; dichloromethane, triethylamine, and

tetramethylethylenediamine were distilled from calcium hydride. Other reagents

were used as purchased or purified using standard techniques. Aqueous

solutions are saturated unless otherwise specified.

Propionyl oxazolidinone 6 0 ' ~ and diazo ester 25" were prepared following

literature procedures, as was the Dess-Martin reagent.*'

To a solution of oxazolidinone 60 (4.07 g, 17.6 rnmol) in CH2C12 (1 00 ml ) at 0°C

was added TiCI4 (2.03 mL, 18.5 mmol) dropwise by syringe. The yellow slurry

was stirred for 5 min. at this temperature and then TMEDA (6.65 mL, 44.0 mmol)

was added. The dark red titanium enolate was stirred for 20 min. at 0°C.

Freshly distilled furfural (1.61 mL, 19.4 mmol) was added dropwise and the

reaction mixture was stirred at 0°C for 5 hours. The reaction was quenched with

half-saturated NH&l and the layers were separated. The aqueous layer was

extracted with CH&. The combined organic layers were washed with saturated

aq. NaHC03 and brine, dried over Na2S04, filtered and concentrated under

reduced pressure to give an oil. Recrystallized frorn dichloromethane, adding

hexanes to the hot solution until precipitation, to give 4.26 g (74%) of off-white

crystals of 61 (mp = 150.5 - 151.5 OC). Rf = 0.25 (25% EtOAc in hexanes).

1 H NMR: S 7.55 (d, 1 H, J=7.2), 7.28-7.37 (m, 4H), 6.34 (s, 2H), 5.92 (dd, 1 H,

J=6.8,2) 5.26 (m, 1H) 5.15 (m, IH), 4.19-4.23 (m, IH), 3.39 (s, 2H), 3.10 (s, IH),

1.26 (dd, 3H, J=7,2.8).

13c NMR: 6 177.01, 154.30, 152.40, 142.17, 139.62, 139.1 1, 130.1 9, 128.59,

127.05, 125.50,110.49, 107.01, 78.49,66.92,63.19,42.44, 38.08, 12.05.

IR (CC14): 3550, 3076, 3046, 3032, 2972, 2942, 2879, 2839, 1794, 1700, 1550,

1362, 1247, 1 190, 1002,977 cm-'. [alo = +l96" (c=0.0161, CHC13).

LRMS m/z (intensity): 327 (M*, 26), 231 (1 OO), 187 (20). 176 (56), 131 (31), 124

(58), 11 6 (91), 97 (41).

HRMS: Calculated Wz for CiaH1705N 327.1 1 07, found 327.1 1 00.

1 -Furan-2-yl-2Smethyl-3-(2=0xo-û,8adi h y d r a ndeno[l ,2-d]oxazol-3-YI)-

propane-1,34ione (62)

To a solution of alcohol 61 (4.5 g, 13.7 mmol) in CH2C12 (450 mL) at 0°C was

cannulated a solution of the Dess-Martin reagent (8.74 g, 20.6 mmol) in CH2C12

(40 mL) at room temperature. The cloudy white mixture was stined at room

temperature for 40 min. (rxn followed by TLC, 30:70 Et0Ac:hexanes). The

reaction was quenched with a saturated aqueous 1 :1 solution of Na2S203 and

NaHC03 (450 mL) and stirred for 15 minutes. The mixture was extracted with

ether. The combined organic layers were washed with saturated aq. NaHC03

and brine, dried over Na2S04, filtered and concentrated in vacuo to give 4.40 g

(99%) of off-white solid 62 (mp = 151 - 152 OC). No purification was necessary.

Rt = 0.35 (25% EtOAc in hexaneç).

'H NMR: 6 7.66 (d, IH, J=7.6), 7.59 (s, IH), 7.26-7.28 (m, 4H), 6.55 (m, IH),

6.02 (d, 1 H, J=6.8), 5.30-5.34 (m, 1 H), 5.20 q, 1 H, J=7.2), 3.39 (s, 2H), 1 -53 (d,

3H, J=7.2).

13c NMR: 6 186.34, 170.56, 153.8, 151.63, 146.75, 139.74, 139.19, 130.14,

128.39, 127.50, 125.43, 118.22, 112.77, 78.70,63.52,49.25, 38.18, 13.74.

IR (CC14): 3071, 3043, 3034,2988, 2970, 2944, 2922, 2878, 2841, 1784, 171 2,

1681,1568,1541,1466,1363,1250,1192,101 1,904 cm".

[alD = +215" (c=0.0148, CHCb).

LRMS m/z (intensity): 325 (M*, Z ) , 297 (1 6), 176 (1 7), 130 (1 g), 1 22 (28), 1 1 5

(24). 95 (1 00).

HRMS: Calculated Wz for Cl8HI5O5N 325.0950, found 325.0945.

3 - ( M - B u t y l d i m e t h y I s i l a n y l o x y ) - 5 - [ 2 m 9 8 a - d i hydro-

3aHindeno[l ,2-djoxazol-3-YI)-propionyll-(1 S, 5R)-û-oxa-bicyclo[3.2.1]octa-

2,6-diene-2-carboxylic acid 4,4-dimethyl-2-oxo-tetrahydro-furan5Ryl ester

(63)

A suspension of furan 62 (3.73 g, 1 1.5 mmol) and Rh2(OOct)* (89 mg, 1 mol%)

in n-hexane (100 mL) and CH2C12 (1 1 mL) was brought to reflux (-68OC). A

solution of diazo ester 25 (4.87 g, 13.8 mrnol) in n-hexane (40 mL) was added

via syringe pump over a 2-hour period to the refluxing mixture. After completion

of the addition, the reaction was stirred for an additional 1.5 hours at reflux. TLC

showed that the reaction proceeded to completion (60:40 hexanes:EtOAc). The

mixture was diluted with ethyl acetate and then concentrated under reduced

pressure. The crude product was purified by flash chromatography, eluting with

70:30 hexanes:EtOAc, to afford 6.75 g (90% yield, 86% de) of foarny white

oxabicyclic compound 63 (mp = 88.5 - 90 OC). Rf = 0.40 (25% EtOAc in

hexanes).

'H NMR: 6 7.60 (d, 1H, J=7.2), 7.28-7.37 (m, 3H), 6.64 (dd, 1H, J=5.6,1.6), 6.0

(d, 1H, J=5.6), 5.96 (d, 1H, J=6.8), 5.46 (s, IH), 5.48 (s, IH), 5.34-5.36 (m, IH),

5.00 (q, IH, J=7.2), 4.03-4.13 (m, 2H), 3.41 (d, 2H, J=7.2), 2.57 d, IH, J=18),

2.28 (dl 1H, J=18), 1.44 (d, 3H, J=6.8), 1.26 (s, 3H), 1.17 (s, 3H), 0.96 (s, 9H),

0.22 (d, 6H, J=4.8).

13c NMR: 6 205.14, 172.90, 170.83, 161.42, 161.20, 152.69, 139.63, 139.03,

137.78, 130.19, 128.75, 128.46, 127.38, 125.45, 112.05, 89.77, 78.57, 77.63,

76.43, 74.24, 63.41 , 48.76, 40.54, 38.24, 36.57,25.85 (3C), 23.33, 20.39, 1 8.61 ,

12.45, -3.33, -3.36.

IR (CC14): 3076, 3030, 2961, 2931, 2893,2854, 1805, 1733, 1714, 1596, 1565,

1462,1375,1245,1184,979,895,872,811 cm'.

LRMS m/z (intensity): 594 ((M - c4ti9)', 100), 522 (1 9), 492 (23), 307 (60), 289

(23), 258 (40), 187 (61 ), 143 (%), 1 15 (49), 73 (47).

HRMS: Calculated d z for C30H32010NSi (M-C4Hg) 594.1 796, found 594.1 790.

3-(tert-ButyldimethyIsilanyloxy)-5-[1 Shydroxy-2Smethyl-3-oxo-3-(2-oxo-

8,8a-di hydro-3aKindeno[l,2-djoxazol-3-yl)-propyI]-(f SY5R)-8-oxa-

bicycIo[3.2.1]octa-2s6diene-2-carboxylic acid 4,4-dimethyl-2-0x0-

tetrahydro-furan-3RyI ester (64)

A solution of oxabicycle 63 (0.30 g, 0.46 mmol) in diethyl ether (16 ml) was

cooled to -40°C in a dry ice/acetone bath. ZII(BH*)~ (0.91 mL, 0.25M in €120,

0.23 mmol) was added to this solution dropwise by syringe. The reaction was

complete after 30 min, as observed by TLC (4:1 hexanes:EtOAc). Saturated

aqueous NH&l (10 mL) was added CAREFULLY to the reaction mixture

followed H20 (1 0 mL). The mixture was extracted with ether. The ethereal

layers were combined and washed with water and brine, dried over Na2S04,

filtered and concentrated in vacuo. Purification of the crude product by column

chromatography, eluting with 4 1 hexanesEtOAc, gave 0.26 g (87%, >99% de)

of oxabicyclic compound 64 as a foamy white product (mp = 79 - 82 "C).

Crystallization in ether produced 64 as a white solid; however, there was a

lengthy crystallization period. Rf = 0.21 (25% EtOAc in hexanes).

1 H NMR: 6 7.57 (d, 1 H, J=7.6), 7.34 (d, 1 H, J=8), 7.28 (d, 2H, J=9.2), 6.59 (d, 1 H

J=5.6), 5.93 (d, 1 Hl J=7.2), 5.86 (d, 1 H, J=5.6), 5.45 (s, 1 H), 5.20 (s, IH), 5.27

(dt, 1H, J=6.8,3.2), 4.17 (m, IH), 4.0-4.1 (m, 3H), 3.39 (d, 2H, J=2.8), 3.07 (d,

IH, J=17.6), 2.56 (dl IH, J=7.6), 1.82 (d, 1H, J=18), 1.30 (d, 3H, J=6.8), 1.22 (s,

3H), 1.14 (s, 3H), 0.95 (s, 9H), 0.23 (d, 6H, J=7.2).

NMR: 6 176.44, 173.08, 162.91, 161.41, 152.69, 139.62, 139.12, 138.89,

130.10, 128.46, 127.10, 127.00, 125.42, 111.49, 88.31, 78.35, 76.36, 73.92,

72.82, 63.39, 40.45, 39.38, 38.08, 35.79,25.82 (3C), 23.1 8, 20.29, 1 8.55, 1 2.80,

-3.40, -3.44.

IR (CCI4): 3575, 3481, 3076, 2968, 2932, 2903, 2852, 1787, 1729, 1693, 1602,

1545,1465,1361,1249,1198,1094,986,895,872 cm".

[alD = +161 O (~~0.021, CHC13).

LRMS m/z (intensity): 596 ((M-c~H~)+, 95), 494 (67), 476 (99), 291 (89), 187

(1 OO), 73 (71 ).

HRMS: Calculated mh for C30H34010NSi (M-C4H9) 596.1 952, found 596.1 964.

3-(tert-ButyldirnethyIsilanyloxy)-5-[Z-ro-

3aKindeno[l ,2-djoxazol-3-YI)-1 Çtriethylsilanyloxy-propyll- (1 S, 5R)-8-oxa-

bicyclo[3.2.l]octa-2,6-diene-2-carboxylic acid 4,4-dimethyl-290x0-

tetrahydro-f uran-3 RyI ester (65)

Alcohol 64 (0.61 g, 0.93 mmol) was dissolved in CH2C12 (18 mL) and cooled to

-20°C. 26-lutidine (0.44 mL, 3.74 mmol) followed by TESOTf (0.37 mL, 1.40

mmol) was then added dropwise by syringe. The reaction mixture was stirred at

-20°C for 3 hours (reaction followed by TLC 4:1 hexanes:EtOAc). The reaction

was quenched with NaHC03 (sat. aq.). The mixture was extracted with ether.

The ethereal layers were washed with saturated aq. NHGI, NaHC03 and brine,

dried over Na2S04, filtered and concentrated under reduced pressure to give an

oil. The crude product was purified by chromatography, eluting with 5 1

hexanes:ethyl acetate (ended 1 A), to give the pure desired product 65 (0.65 g,

91 Oh) as an oil. R1 = 0.45 (25% EtOAc in hexanes).

IR &Cl4): 3686, 3080,2954, 2933,2885, 1799, 1757, 1716, 1601, 1546, 1466,

1366,1321,1297,1234,1186,1124,990,897,875 cm*'.

[alD = +66" (~=0.028, CHC13).

LRMS m/I (intensity): 71 1 (M-C4~9)+, 52), 624 (64), 608 (34), 476 (IOO), 374

(Q), 291 (42), 235 (66), 1 99 (83), 1 1 5 (86).

HRMS: Calculated m/z for C3sH48010NSi2 (M-C4H9) 71 0.281 7, found 71 0.281 2.

3-(ter?-ButyldirnethyIsilanyloxy)-5-(2-1 Striethylsilanyloxy-propy1)-

(1 S, 5R)-&oxa-bicyclo[3.2.1]octa-2,6-diene-2carboxylic acid (66)

To a 0.05 M solution of substrate $5 (0.18 g, 0.24 mmol) in 3:1 THF/H20 at O°C

was added 30% H202 (0.058 mL, 1.88 mmol, 8 eq.) followed by LiOH (1 9.7 mg,

0.47 mmol, 2 eq.). 12-crown-4 (0.08 mL, 0.47 mmol, 2 eq.) was added in other

atternpts. The resulting mixture was stirred at 0-10°C until the starting material

was consumed (-7 hours). Excess peroxide was quenched at 0°C with a 10%

excess of 1.5 N aq. Na2S03. After buffering to pH = 9-1 0 with NaHC03 (aq.) and

evaporation of TH F, the chiral oxazolidinone was recovered by CHzC12

extraction. The carboxylic acid (desired product 66) was possi bly isolated by

EtOAc extraction of the acidified (pH=I-2) aqueous phase. In this phase, R-

pantolactone was present by 'H NMR analysis.

Substrate 64 (0.43 g, 0.65 mmol) was dissolved in MeOH (1.63 mL) and THF

(0.33 ml). A 10% HCI solution (0.68 mL) was added dropwise by syringe. A

white precipitate was observed upon addition of the acid. The reaction mixture

was stirred at room temperature for 24 hours. Water (70 mL) was added to the

reaction mixture and a white precipitate was observed. The mixture was

extracted with 1 :1 EtOAc:Et20 (4 x 60 mL). The cornbined organic layers were

washed with H20 and brine. The organic layer was then dried over Na2S04,

filtered and concentrated under reduced pressure to give white foamy product

64a of mass 0.36 g (lOOoh). This was used directly in the Krapcho

decarboxylation.

Ar bubbling for 1 h 30 min degassed DMSO. The oil bath was preheated

to 160°C. NaCl (0.39 g, 6.60 mrnol) was added to a solution of ketone 64a (0.36

g, 0.66 mmol) in DMSO (2.64 mL) through the condenser head. The system was

flushed for 5 min. with Ar. Distilled water (0.08 mL) was added. The reaction

was warmed to 160°C for exactly 30 min. The reaction turned from yellow to

red-brown. After 30 min., the flask was removed from the oil bath and DMSO

was removed under high vacuum pump (-45°C bath). The residual oil was

purified by flash chromatography, eluting with 25% ethyl acetate in hexanes, to

give 0.1 5 g (61%) of white solid 67 (mp = 172 - 173 OC). Rt = 0.24 (1 :1

Et0Ac:hexanes).

'H NMR: 6 7.56 (d, 1 H, J=7.7), 7.36 (d, 1 H, J=6.4), 7.27-7.30 (m, 2H), 6.24 (dd,

IH, J=6.1,1.7), 6.15 (d, 1H, J=6.1), 5.94 (dl IH, P6.8), 5.27-5.29 (ml IH), 5.10

(d, IH, J=5.3), 4.17-4.20 (m, IH), 4.08-4.11 (m, IH), 3.4 (d, 2H, J=3.5), 3.04 (d,

IH, J=16.5), 2.71 (dd, IH+OH, J=16.7,5), 2.34 (d, IH, J=10.8), 2.30 (d, IH,

J=10.8), 1.31 (d, 3H, J=7).

l3c NMR: 6 205.94, 176.85, 152.70, 139.60, 139.10, 134.49, 133.32, 130.21,

128.57, 127.09, 125.50, 89.16, 78.39, 77.46, 72.67, 63.30, 48.37, 45.38, 39.57,

38.1 1, 12.66.

IR (CC&): 3400,3077, 3044,2964,2926, 2857, 1785, 171 6, 1553, 1255, 121 5,

1002,976 cm*'. [alD = +197" (c-0.007, CHC13).

LRMS m/z (intensity): 383 (M', 13), 326 (21), 260 (30), 231 (29), 208 (64), 176

(IOO), 151 (35), 115 (52), 81 (29).

HRMS: Calculated Wz for CZ1 H21 06N 383.1 369, found 383.1 369.

Oxabicycle 67 (0.1 g, 0.27 mmol) was dissolved in CH2CI2 (5.43 mL) and cooled

to -20°C. 2,6-lutidine (0.13 mL, 1 .O9 mmol) followed by TESOTf (0.1 2 mL, 0.54

mmol) was then added dropwise by syringe. The reaction mixture was stirred at

-20°C for 30 min. (reaction followed by TLC 4:l hexanes:EtOAc). The reaction

was quenched with NaHC03 (sat. aq.). The mixture was extracted with ether.

The ethereal layers were washed with saturated aq. NH4Cl, NaHC03 and brine,

dried over Na2S04, filtered and concentrated under reduced pressure to give an

oil. The crude product was purified by chromatography, eluting with 4:l

hexanes:ethyt acetate (ended 1:1), to give the pure desired product 68 (85 mg,

58%) as a white foam. Rf = 0.27 (25% EtOAc in hexanes).

1 H NMR: S 7.58 (d, 1 H, J=7.6), 7.34 (d, 1 H, J=7.2), 7.26-7.29 (m, 2H), 6.20 (d,

IH, J=5.6), 6.17 (d, IH, J=6), 5.91 (d, IH, J=6.4), 5.24 (m, IH), 5.00 (d, 1H,

J=4.8), 4.20 (d, 1 H, J=6), 4.10 (m, 1 H), 3.39 (d, 2H, J=3.2), 2.80 (d, 1 H, J=6),

2.67 (dd, IH, J=16.4,5.2), 2.34 (d, IH, J=16), 2.28 (d, IH, J=16), 1.24 (d, 3H,

J=8.4), 0.99 (t, 9H, J=8), 0.67 (q, 6H, J=8).

NMR: 6 206.22, 175.91, 152.93, 139.61, 139.33, 134.46, 133.58, 130.09,

1 28.47, 1 27.26, 1 25.43, 89.82, 78.23, 77.00, 74.79, 63.57, 47.49, 45.57, 39.71 ,

38.1 5, 1 3.65, 7.22 (3C), 5.52 (3C).

IR (CCIù: 3079, 3044, 2958,2909, 2873, 1780, 1 71 6, 1699, 1543, 1462, 1362,

1334,1239,1192,1178,1125, IOSI , lOO8,98O,SlO cm".

[alo = +140° (~=0.009, CHC13).

LRMS m/z (intensity): 468 (1 OO), 31 6 (57), 293 (40), 275 (28), 21 6 (31 ), 199

(43), 115 (55), 87 (37).

HRMS: Calculated mh for C27H3506NSi 497.2233, found 497.221 9.

A solution of ketone 68 (24 mg, 0.05 mmol) in THF (0.32 mL) was cooled to

-78°C and L-Selectride (0.07 mL, 1 .O M in THF, 0.07 mmol) was added by

syringe. After 1 hour at -78OC, the reaction mixture was put in an ice bath (O°C)

and 5 M NaOH (0.05 rnL) was added. The mixture was stirred in an ice bath for

15 min. 30% H202 (0.1 1 mL) was added and the mixture was stirred for 5 min.

more. The mixture was extracted with ether (2 x 5 mL). The combined ethereal

layers were washed with water and brine, and dried over Na2SOc Concentration

in vacuo yielded an oit, which was punfied by chromatography (4:l

hexanes:EtOAc to 2:l hexanes:EtOAc) to afford a white foam of 69 (1 1 mg,

46%).

'H NMR: 6 7.60 (d, 1 H, J=7.3), 7.26-7.34 (ml 3H), 6.38 (s, ZH), 5.89 (d, 1H,

J=6.8), 5.21-5.23 (m, IH), 4.74 (dl IH, J=3.5), 4.25 (d, 1H, J=6.1), 4.05-4.10 (ml

ZH), 3.38 (dl 2H, J=3), 2.1-2.3 (m, 2H), 1.76 (d, 1H, J=14.5), 1.68 (d, IH,

J=14.7), 1.59 (s, IH), 1.23 (d, 3H, J=6.8), 0.98 (t, 9H, J=7.9), 0.66 (q, 6H, J=8.2).

13c NMR: 6 175.82, 152.93, 139.38, 139.21, 136.74, 136.02, 129.77, 128.20,

127.15, 125.15, 88.96, 78.03, 78.01, 75.50, 65.59, 63.50, 39.36, 37.88, 36.31,

35.47, 13.14, 7.02 (SC), 5.31 (3C).

LRMS m/z (intensity): 499 (M', 28), 470 (1 OO), 31 6 (34), 295 (35), 199 (34), 11 5

(45), 87 (33).

HRMS: Calculated m/z for C27H3706NSi 499.2390, found 499.2396.

Alcohol 69 (1 5 mg, 0.03 mmol) was stirred in diethyl ether (0.6 mL) under Ar.

Distilled water (0.6 pl ) was added. The mixture was cooled to O°C in an ice

bath. LiBH4 (17 PL, 2.0 M in THF, 0.033 mmol) was added dropwise by syringe.

The reaction mixture was stirred in the ice bath for 3 hours (allowing the ice to

melt and the water to warm to room temperature). The reaction was quenched

with 1 M NaOH (aq.) and the mixture was stirred until both layers were clear.

The mixture was poured into ether and water, and the ether layer was washed

with brine, dried over Na2SQ and concentrated under reduced pressure.

Purification was accomplished by flash chromatography (30:70 hexanes:EtOAc)

to give 1 mg (1 0%) of diol70.

1 H NMR: 6 6.33 (dd, IH, J=6,1.6), 6.21 (d, IH, J=6), 5.38 (dd, IH, J=8.4,4.8),

4.89 (ml IH), 4.67 (m, IH), 4.10-4.13 (m, IH), 4.0 (m, IH), 3.91 (s, IH), 3.1 (dd,

IH, J=16.8,5.2), 2.96 (d, IH, J=16.8), 2.77-2.80 (m, IH), 2.55 (m, IH), 2.35 (dd,

IH, J=14.8,6), 2.13-2.18 (m, IH), 1.25 (m, 3H), 0.93 (t, QH, J=8), 0.66 (q, 6H,

J=8).

References

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Appendix:

Selected Spectra