catalytic enantioselective aldol addition reactions
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CHAPTER 1
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS
ERICK M. CARREIRA, ALEC FETTES, AND CHRISTIANE MARTI
Laboratory of Organic Chemistry, Swiss Federal Institute of Technology (ETH-Z),HCI H337 ETH-Hönggerberg, CH 8093 Zürich, Switzerland
CONTENTS
PAGE
INTRODUCTION . . . . . . . . . . . . . . . 2Background . . . . . . . . . . . . . . . 6
MECHANISM AND STEREOCHEMISTRY . . . . . . . . . . . . 8General Aspects . . . . . . . . . . . . . . 8Catalyst Turnover . . . . . . . . . . . . . . 11
SCOPE AND LIMITATIONS . . . . . . . . . . . . . . 15Acetate, Methyl Ketone, and Unsubstituted Dienolates . . . . . . . . 15
Enoxysilanes and Stannanes . . . . . . . . . . . . 15Direct Aldol Addition Reactions of Unsubstituted Systems . . . . . . 28
Propionates and Substituted Enolates . . . . . . . . . . . 30Enoxysilanes and Stannanes . . . . . . . . . . . . 30Direct Aldol Addition Reactions of Substituted Systems . . . . . . . 48Enoxysilanes of Acetoacetate and Furan . . . . . . . . . . 52Domino Reactions Involving Aldol Additions . . . . . . . . . 58
COMPARISON WITH OTHER METHODS . . . . . . . . . . . . 61EXPERIMENTAL CONDITIONS . . . . . . . . . . . . . 70EXPERIMENTAL PROCEDURES . . . . . . . . . . . . . 71
Phenyl (2R,3S)-2-(Benzyloxy)-5-(tert-butyldimethylsiloxy)-3-hydroxypentanoate . . . 71Phenyl (2S,3S)-3-Hydroxy-2-methyl-3-(4-methoxyphenyl)propanoate . . . . . 72(R)-1-Hydroxy-1-phenyl-3-heptanone . . . . . . . . . . . 73Methyl (R)-3-Hydroxy-8-phenyloct-4-ynoate . . . . . . . . . 73(R)-S-tert-Butyl 4-Benzyloxy-3-hydroxybutanethioate . . . . . . . . 74(S)-4-Hydroxy-4-phenyl-2-butanone . . . . . . . . . . . 75(R)-4,4-Dimethyl-1-hydroxy-1-phenyl-3-pentanone . . . . . . . . 75(S)-3-Hydroxy-4-methyl-1-(3-nitrophenyl)-1-pentanone . . . . . . . 76(R)-3-Cyclohexyl-3-hydroxy-1-phenylpropan-1-one . . . . . . . . 77(R)-4-Hydroxy-5-methylhexan-2-one . . . . . . . . . . . 77S-tert-Butyl (3S)-3-Hydroxy-3-methoxycarbonylbutanethioate . . . . . . 77
1
carreira@org.chem.ethz.chOrganic Reactions, Vol. 67, Edited by Larry E. Overman et al.ISBN 0-470-04145-5 © 2006 Organic Reactions, Inc. Published by John Wiley & Sons, Inc.
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(2S,1�R)-2-(Hydroxyphenylmethyl)cyclohexanone . . . . . . . . 78(4S,5R)-4-(Methoxycarbonyl)-5-phenyl-2-oxazoline . . . . . . . . 79(2R,3S)-2,3-Dihydroxy-2,3-O-isopropylidene-1-(2-methoxyphenyl)-5-phenyl-1-pentanone . 80(3S,4S)-4-Cyclohexyl-3,4-dihydroxybutan-2-one . . . . . . . . . 80(R)-6-(2-Hydroxy-4-phenylbut-3-enyl)-2,2-dimethyl-[1,3]-dioxin-4-one . . . . 81(2S,3S)-Methyl 4-Benzyloxy-3-hydroxy-2-methylbutanoate . . . . . . . 82
TABULAR SURVEY . . . . . . . . . . . . . . . 82Table 1A. Silver-Catalyzed Mukaiyama-Type Aldol Additions . . . . . . 84Table 1B. Boron-Catalyzed Mukaiyama-Type Aldol Additions . . . . . . 88Table 1C. Copper-Catalyzed Mukaiyama-Type Aldol Additions . . . . . . 106Table 1D. Tin-Catalyzed Mukaiyama-Type Aldol Additions . . . . . . . 117Table 1E. Titanium-Catalyzed Mukaiyama-Type Aldol Additions . . . . . . 124Table 1F. Other Metal-Catalyzed Mukaiyama-Type Aldol Additions . . . . . 139Table 1G. Non-Metal-Catalyzed Mukaiyama-Type Aldol Additions . . . . . 150Table 2A. Gold-Catalyzed Aldol Additions of Unmodified Nucleophiles . . . . 164Table 2B. Non-Gold Metal-Catalyzed Aldol Additions of Unmodified Nucleophiles . . 175Table 2C. Non-Metal-Catalyzed Aldol Additions of Unmodified Nucleophiles . . . 189Table 3. Aldol Tandem Reactions . . . . . . . . . . . 204
REFERENCES . . . . . . . . . . . . . . . . 208
INTRODUCTION
The aldol addition reaction has become a strategically important, reliable trans-formation that is widely employed in the asymmetric synthesis of complex mole-cules (Eq. 1).1 – 17 It can be counted upon not only to provide access to polyketidefragments with their characteristic 1,3-oxygenation pattern,18 but also to numerousother classes of compounds, such as oxo-heterocycles,19 �- and �-amino acids,20 – 22
and nucleosides.23 Indeed, its numerous applications in synthesis attest to the versa-tile role of this reaction in the pantheon of organic transformations.12
Two general approaches have emerged for the asymmetric aldol reaction: (1) di-astereoselective additions, wherein stoichiometric quantities of a covalently bound,chiral controlling element shepherds the stereochemical course of the reac-tion,3 – 8,11,14 and, alternatively, (2) enantioselective methods, wherein a chiral catalystfunctions as the stereochemical controlling element, preferably in substoichiometricamounts.15,24 – 29
Given the intensive research activities in this area by numerous groups over thelast three decades, diastereoselective methods remain dominant in practice to datewith respect to the frequency of use. This is hardly surprising as such methods haveenjoyed a long period of intense scrutiny and possess a high degree of predictabilityand reliability. By comparison, useful catalytic, enantioselective methods are fairly
(Eq. 1)R H
O O
XR1 R
OH O
XR1+ R2
R2
R2 = H Acetate AldolR2 = Me Propionate Aldol
2 ORGANIC REACTIONS
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recent arrivals on the scene. Nonetheless, explosive developments in the field are be-ginning to provide the practitioner with additional useful tools for complex moleculeassembly via catalytic asymmetric aldol transformations.30 – 40 In this respect, it isimportant to note that enantioselective asymmetric, catalytic aldol addition methodscan furnish ketide fragments such as polyacetate or unsubstituted skipped polyolfragments that have not otherwise been conveniently accessible through more tradi-tional diastereoselective approaches.
Enantioselective aldol methods use small-molecule (often termed chemical cata-lysts) as well as macromolecule catalysis (commonly referred to as biological cata-lysts, such as enzymes or antibodies).41 – 48 The origins of the differentiation betweenchemical or biological is likely historical. It is debatable whether such a categoriza-tion is at all reasonable, because the only obvious differentiation between catalystsof either group is molecular weight or, correspondingly, size, properties that varycontinually. Moreover, the advances in mutagenesis techniques, library synthesis,and high-throughput screening methods49 – 54 for the generation of non-natural cata-lysts in both classes serve to further blur the distinction between bio- and abiologi-cal catalysis. It is certainly the case that members of either group share many morefeatures in common than an artificial designation would suggest. Thus examples of catalytic processes in both types can be found that are metal-mediated as well as metal-free, operate in organic or aqueous media, and exhibit both high and low efficiencies.
The early work with isocyanoacetates and ferrocenyl bis-phosphine 1 establishedthat catalytic enantioselective aldol additions could be carried out with in-situgeneration of an enolate (Eq. 2),55 – 64 and the commonly held distinction that only
Eq. (2)
biocatalytic aldol additions would be tolerant of nucleophilic substrate partners possessing polar unprotected groups (e.g., hydroxyls) is no longer tenable (Eq. 3).65
The two approaches (biological and chemical) are complementary in scope. Certainclasses of reactions are at present best effected with macromolecular catalysts,whereas others are best effected with small-molecule catalysts such as 2-9(Eqs. 3–13).22,39,66 – 75 Given the immense breadth of the field, a compilation of cat-alytic methods for asymmetric aldol reactions is best when it is focused. Conse-quently, the coverage in this chapter is limited to catalytic enantioselective aldoladdition methods using small-molecule catalysts, wherein the products in general
[Au(C6H11CN)2]BF4 (1 mol%),CH2Cl2, 0°, 20-100 h
OMe
OCNPhCHO
O N
PhO
OMe
O N
PhO
OMe
Fe PPh2
PPh2
MeN N
I:II 94:6, 95% ee
+ +
I II
1 (1.1 mol%)
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 3
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(Eq. 6)
OTMS
O O
Cu(OTf)2 (2 mol%), n-Bu4NPh3SiF (4 mol%),
THF, –78°Ar = 4-MeC6H4
RCHO O
O
O
R
TMSO
(98%) 95% ee
+
P(Ar)2P(Ar)2
3 (2.1 mol%)
R = 2-thienyl
(Eq. 5)O
CO2Et
CO2Et
Ph
OH
(10 mol%)
THF, rt, 72 h; then PhCHO2. PCC
(82%) 89% ee
O
OO
AlOO
Li1.
CO2Et
CO2Et
(Eq. 4)
1. (R)-BINOL/TiCl2(OPr-i)2, (20 mol%), PhMe, 0°OTMS
SBu-tSBu-t
OH O
(47%) 96% ee
OH
OEt+F
F
F
F2. H+
(Eq. 3)Ph(CH2)3CHO
KHMDS (9 mol%), H2O (20 mol%), THF, –40°
Ph(CH2)3 Ar
O
OH
OH
Ph(CH2)3 Ar
O
OH
OH
+
Ar
O
OH
+
(50%) I:II = 81:19, I 98% ee, II 79% ee
III
Ar = 4-MeOC6H4
OO O
OOOLi Li
Li
La
2 (S)-LLB (10 mol%)
4 ORGANIC REACTIONS
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retain �-hydroxycarbonyl functionality. For historical reasons there are three excep-tions to such boundary conditions on the topical discussion, namely the aldol addi-tion reactions leading to oxazoline products (Eq. 2),55 – 64,76 aldehyde ene additionreactions of enol silanes,77 and domino processes (cf Eq. 5).65 In the aldol reactionsthat form the basis of this compilation, catalytic turnover is a necessary requirement,with reactions in which the turnover number is unity excluded, as these are consid-ered best classified with processes that rely on the use of chiral auxiliaries or stoi-chiometric controlling groups or additives.
(Eq. 9)
(Eq. 10)OTMS
Ph
O
Ph
OH
i-PrO
OPr-i
O
CO2HOCO2H
OH
1.
2-PhOC6H4B(OH)2 (20 mol%), EtCN, –78°2. HCl
(93%) 94% ee
+Ph H
O
Ph
6
NClH
O
MOMOOMe
OTMS NClTMSO
MOMO
OMe
O
(90%) 94% ee
+
N
Bu-t
BrO O
O
t-Bu
Bu-t
OO
Ti
Et2O, –10°
5 (1.1 mol%)
(Eq. 8)O O
t-Bu
OHL-proline (30 mol%)
DMSO, rt
(81%) 99% ee
t-Bu H
O+
(Eq. 7)
O
O
SBu-t
OTMS
OSBu-t
OOH
(85%) dr = 93:7, 97% ee
O
N N
O
t-Bu Bu-tCu 2 OTf–
2+
1.
CH2Cl2, –78° 2. aq. HCl
+4 (10 mol%)
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 5
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(Eq. 13)
BackgroundThe use of catalysts to channel the stereochemical outcome of the aldol addition
reaction process is feasible because the aldol addition reaction is overall an atom-transfer reaction (Fig. 1).78 In the reactions involving enolate additions to aldehydes,
Figure 1. Aldol addition reactions as atom transfer reactions.
R H
O
O
XR1
R
OH O
XR1
H
O
XR1
R3Si
R1
R2
R
O O
XR1
+O
XR1R3Sn
R1 R2
R1 R2
R1 R2
R1 R2
R3Si or R3Sn
C5H11
OSiCl3Ph
OHCHO
C5H11
Ph
OHCHO
C5H11
+ CHCl3/CH2Cl2 (4:1), –78°, 6 h2. MeOH
(92%) dr = 99:1, 90% ee
+Ph
O
H
NN
P
Me
MeO
NMe
(CH2)5
2
1.
9 (5 mol%),
(Eq. 12)
O
OTMS
O
OOHBnO
(95%) dr = 96:4, 95% ee
CHOBnO +
NNN Cu
OO
Ph Ph
2 SbF6–
CH2Cl2, –78°2. aq. HCl, THF
1.
8 (10 mol%)
2+
(Eq. 11)
O
EtOSPh
OTMS
O
EtOSPh
OOH
O
N N
O
Bn BnSn 2 OTf–
2+
1.
CH2Cl2, –78°2. aq. HCl
(90%) 98% ee
7 (10 mol%)H
O
+
6 ORGANIC REACTIONS
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an O–Si or C–Sn bond in the starting material is exchanged for another O–Si or O–Sn bond in the product with concomitant trade of the C=O bond in the elec-trophile and C=C in the enolate component for a C–C bond and a new C=O in theadduct.79 In aldol additions involving direct addition of enolizable carbonyls, theC–H and C=O bonds in the educts are exchanged for C–C and O–H bonds in the adduct.
Although the larger number of catalytic enantioselective aldol processes involvethe use of enoxysilanes, the direct addition of enolizable ketones and esters to alde-hydes and ketones in aldol additions have been documented as well. The classic inthis respect is rooted in the proline-catalyzed Robinson annulation reaction (Eq. 14)
for the preparation of the Wieland-Miescher ketone80 – 82 and the direct addition ofisocyanoacetates to aldehydes to give isoxazolines catalyzed by gold complexes pre-pared from 1 (Eq. 2).55 – 64 More recently, impressive advances have been made incatalytic, enantioselective aldol reactions involving the direct addition of enolizablecarbonyls to aldehydes (Eqs. 15–18), mediated by chiral metal phenoxides such as 10 or alkoxides (11) as well as by amines, such as proline or derivatives like11.15,55 – 65,82 – 87
(Eq. 17)O O
i-Pr
OHL-proline (30 mol%)
DMSO, rt+
i-Pr H
O
(97%) 96% ee
(Eq. 16)
O
c-C6H11
OOH
NNPhPh OH HO
PhPh
OH
Et2Zn (20 mol%), 4 Å MS,THF, 5° (85%) 93% ee
c-C6H11 H
O 11 (10 mol%)+
(Eq. 15)
O
OO
OO
Zn
Zn
i-Pr
O
OH
OH10 (1 mol%)
THF, –30°, 16-24 hi-Pr H
OO
OH
OMe
+
OMe
(83%) dr = 97:3, 98% ee
(Eq. 14)O+
(S)-proline (3 mol%)
MeCNO
(97%) 93% eeOH
OO
O
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 7
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MECHANISM AND STEREOCHEMISTRY
General Aspects. The diastereoselective aldol addition reactions that are bestunderstood and provide adducts with a high degree of stereochemical control andpredictability are those proceeding from a metal enolate through closed, Zimmerman-Traxler-like transition states, such as those derived from alkali or alkaline earth metals or boron.1 – 8,12,88 – 91 By contrast, catalytic enantioselective counterparts lackthorough mechanistic understanding. Earlier analyses suggesting open transitionstates (Fig. 2, A-C),92 – 96 despite their historical importance and utility, are likelyoversimplifications, because at the very least they tend to ignore the fate of the silylgroup in the course of C=O addition and C–C bond formation. Given the inherenthigh energy of a trialkylsilyl cation, its formation in the course of the aldol processis unlikely. In this respect, it is interesting to note that more recent models (D-H) takeinto account the silicon in the transition state.97 – 101 Indeed, focusing on the fate ofthe silyl group can lead to useful new catalytic processes.102 – 110
Figure 2. Proposed transition states for aldol addition reactions.
Under typical conditions, most enoxysilanes are unreactive toward aldehydes,notable exceptions being silyl enolates derived from amides, enoxy-silacyclobu-tanes,105 – 109 and trihalosilyl enolates.102 The typical lack of reactivity for the parenttrialkylsilyl enolates is critical, as it ensures that the uncatalyzed background aldoladditions are precluded. The enoxytrihalosilanes represent an interesting exception.Thus, although their reactions with aldehydes are fast even at low temperature, theLewis base catalyzed processes are even faster.75
In the simplest analysis, the enoxysilanes and aldehydes can be induced to reactby either of two fundamentally different mechanisms: electrophilic activation of theC=O component25 or nucleophilic activation of the enolate15,57,69,111 – 114 or enol sur-rogate (Fig. 3).71 In reality, it is likely that mechanistic pathways form a continuum
O
M
R2
R1
Ln
X
H
R OXR4
SiR3
OR2
R1
R4XO
RMLn
R3Si X
OSiR3
MXLn
R2
R1
H
R OXR4
H
O
R
R1
R2
MXLn
XR4
OSiR3
H
O
RR1
MXLn
R2R4X
R3SiO
O
SiR2
R1
R
RR4X
OH R
R MXLn
H
O
SiR2
R1
R
R
R4XO
H R
R
YY
A B C D
E F G H
H
O
R
MXLn
R1
R4X OSiR3
R2
(Eq. 18)CHO
i-Pr
OHL-proline (10 mol%)
DMF, 4°
(82%) dr = 24:1, >99% ee
i-Pr H
O+ H
O
8 ORGANIC REACTIONS
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of possibilities and possess some component of both activation modes.115 – 117 Recentreports involving the use of enolizable carbonyl substrates that undergo in situ con-version to the corresponding enolate or enamine provide new mechanistic optionsfor this transformation. Moreover, these add to the class of traditional closed cyclictransition-state arrangements found in the aldol addition reactions such as those ofalkali, alkaline earth, and boron enolates.
Figure 3. Electrophilic vs. nucleophilic activation of an enolate intermediate.
Close inspection of the few cases that have been studied in some detail revealsthat the mechanistic possibilities are as numerous as the catalysts and conditions thathave been described for this venerable reaction. Given the complexity of the reac-tion, there are a number of important issues that can be examined in the process: sub-strate binding and activation (C=O electrophile, enolate nucleophile, or both), C=Oface differentiation, as well as catalyst turnover.
With respect to the activation and facial differentiation of the electrophilic C=Ocomponent, little detailed structural information is available at the kind of resolutionthat would permit generalization and/or understanding at a fundamental level.118
However, a number of binding modes of aldehydes to Lewis acidic centers have beenproposed and are worth examining because of their great value in formulating thebinding event (Fig. 4).119 – 124 In the most general mode of C=O activation, a Lewisacidic center (or Brønsted acid) binds to an aldehyde (A in Fig. 4), for example,through the lone pair of the oxygen syn to the formyl proton (Fig. 4). Although thisarrangement sets the position of the metal in the plane defined by the aldehyde, itleaves ill-defined the dihedral angle X–M–O=C, which is critical to understandingthe facial differentiation event, assuming that C=O addition is the stereochemicallydetermining step. A number of intriguing hypotheses have been proffered dealingwith factors that may be operating in constraining the critical dihedral angle. Theseinclude secondary contacts between the polarized coordinated aldehyde and aro-matic surfaces on the ligand (A1 in Fig. 4).125,126 Indeed, examination of the crystalstructure of benzyloxyacetaldehyde bound to a bisoxazoline-copper complexstrongly implicates aromatic/aromatic � interactions as an organizational element.39
An additional control element can be stereoelectronic in nature such as a putative interaction between the aldehyde C=O lone pair and an M–X antibonding orbital(A2 in Fig. 4).127 An intriguing model implicates a hydrogen bond between theformyl C–H and a heteroatom ligating group (A3 in Fig. 4).128 – 132
R H
O O
XR1 R
OH O
XR1+ R2
R2
R H
OA
Y
XR1R2
B
O
XR1R2
R H
O
electrophilic activation
nucleophilic activation
+
+
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 9
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Figure 4. Possible binding modes of aldehydes to Lewis acid centers.
Special classes of substrates such as �-alkoxy or �-amino carbonyls and 1,2-dicarbonyls that bind to activating metal centers via chelate formation have been investigated and developed to furnish aldol adducts in high selectivity.133 The detailsof how the chiral metal complex binds and activates substrates have been the subjectof structural studies. It has been suggested that the subtle differences in the variousbinding modes arise from the differences in the Lewis basicity between the carbonyland ether oxygens. The more basic ether oxygen is bound at the site that displays thecomplementary greater electron deficiency, with the less basic carbonyl oxygen coordinating in the corresponding complementary site. The study illustrates that numerous subtle features need to be considered in order to fully understand the details of the coordination complexes formed between substrates and Lewis acidiccatalysts. It is an analysis that goes beyond simple consideration of ligand steric effects, but also must include analysis of stereoelectronic effects at the metal center.
As new types of asymmetric, catalytic aldol addition processes are identified andstudied, such as those proceeding via metalloenolates and those catalyzed by Lewisbases or amines (e.g., proline), the collection of transition states for the aldol addi-tion processes is dramatically augmented (Fig. 5). Reactions proceeding throughmetalloenolate intermediates have numerous options available that require addi-tional study. Thus, for the systems that have been examined, metals are typically employed in which at least three structures are possible: O- (A, C, F), C�- (B, D),or C�- (E) regioisomeric enolates. Additionally, there is the possibility of the in-volvement of multiple metal sites. Much remains to be learned about the new Lewisbase catalyzed processes of trihalosilyl enolates. In this respect, the reactions oftrichloroenoxysilanes are currently believed to proceed through hexavalent siliconintermediates G, wherein the high degree of stereoselectivity results from a closedZimmerman-Traxler-like arrangement with the silicon serving as an organizationallocus.134 Although the amine-catalyzed aldol addition reactions have been known forsome time, it is only recently that computational studies have shed some light on thenature of the transition state in these processes. Thus, it has been suggested that thehydrogen bond formed between the carboxylic acid and the ensuing aldol alcohol instructure H is critical to the organization in the transition state and accounts for thesense of induction.135,136
ML
LM
O
XLL X
X
X
H
R
M
O
XL
LX
H
R
M
O
XL
LX
H
RCHO
M
O
XL
LX
H
R
A
A1 A2 A3
10 ORGANIC REACTIONS
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Figure 5. Transition states for asymmetric, catalytic aldol addition processes.
Catalyst Turnover. The general aspects of turnover in the catalytic, enantiose-lective aldol addition reaction have been discussed (Figs. 6 and 7).25 Depending onthe aldol type, namely electrophile versus nucleophile activation, various possibili-ties for turnover exist. The proline-catalyzed processes provide additional features toconsider in the catalytic turnover. For the aldol additions involving enoxysilanes that undergo additions via Lewis acid coordinated aldehydes, three distinct mechanisticpossibilities may be postulated. In the first of these, silyl transfer takes place from asilylated oxonium species, the first formed adduct, to the newly installed �-alkoxidein a distinct step subsequent to the C–C bond formation. Such silicon transfer maybe imagined to occur via either direct transfer of the silicon moiety from C=O to themetal alkoxide in the product in an intramolecular manner (A, Fig. 6), or alterna-
Figure 6. Catalytic cycle of the Lewis acid catalyzed aldol reaction.
R R2
OX4M
OSiR3
R H
O
R R2
R3SiO O R H
R2
O
OSiR3
MX4
R R2
OX4M
O
R R2
OX3M
O + R3SiX
A
C
B
vs
vs
R3Si + +
+–
––
OO O
OOOM M
M
Ln
O
O
Y
O O
OM
XOR
Y
MXOR
O
SiO
R2
R3
R5
R4R1
Cl
ClO
O
PL1 L3
L2
P
L1
L3
L2
H
metalloenolate:
Lewis base catalysis: amine catalysis:
G
Y
OM
XOR
O
O O
O
MXOR
O O
OM
XOR
E
A B
C D F
H
OH
NO
O
R
HH
+
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 11
c01_tex 4/18/06 12:31 PM Page 11
Figure 7. Intramolecular silyl group transfer in boron- and titanium-catalyzed aldol reactions.
tively, in an intermolecular process (from B or C and R3SiX, Fig. 6). The intramol-ecular transfer of the silyl unit has been suggested to be operating in the reaction involving titanium-BINOL catalysts,137,138 and, more recently, in simple R3SiNTf2-catalyzed additions.104 In a related process (Fig. 7), the intramolecular transfer of thesilyl group is suggested to occur through an intermediate, wherein the ligand asso-ciated with the metal complex serves as a shuttle, undergoing silylation tran-siently.139,140 This option has been hypothesized to occur in the aldol additionreactions involving boron and titanium complexes. The alternative third option,wherein silyl transfer occurs in an intermolecular fashion has been proffered in thecontext of aldol addition reactions catalyzed by chiral copper-bisoxazoline com-plexes (Fig. 8).74,141 The silylating species is presumably R3SiOTf. The Cu-catalyzed
BH O
R OPh
OTMS
TsN
BH O
R OPh
O
TMSO
R OPh
O
+–
OTMS
O
Ar
OTsN
Ar
O
BH O
R OPh
O
– OTsN
Ar
OTMS
TsNB
O
H
OAr
TiOO
OR
R
–
OL
R OMe
OTMS
+X
X
TiOO
OR
R
O
R OMe
OXL
TMSX
TiOO
OR
R
OL
R OMe
OX
X
TMS+–
TiOO
OR
R
TMSO
R OMe
O
XL
X
RCHO +OPh
OTMS
RCHO +
OMe
OTMS
12 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 12
Figure 8. Intermolecular silyl group transfer in copper-catalyzed aldol reactions.
process74 is rather interesting, as it represents a case wherein the metal activation ofthe aldehyde substrate and the subsequent turnover is faster than a potentially com-peting stereorandom silicon-catalyzed process. This situation may be the result oftwo key features of the system. The fact that chelating substrates are employed inthis reaction may considerably favor activation of the substrate by the metal complexover the silyl triflate. Indeed, it is well known that chelation of electrophilic sub-strates leads to significant rate acceleration as compared to the monodentate sub-strates.142 Additionally, the metal aldolate that is first formed in these additionreactions is a copper alkoxide, which may be silylated at considerably faster ratesthan harder metal alkoxides derived from early transition metals such as titanium(IV).The operation of intermolecular silylation in the turnover event is consistent withdouble-labeling experiments.97
When the reactions involve the use of enolsilanes that in turn produce an inter-mediate metalloenolate, the key turnover event is likely the silylation of the aldolateproduct by the starting enoxysilane (Fig. 9).114 Such an event is necessarily inter-molecular; given the metals that are involved in such systems (e.g., soft metals suchas platinum,143 copper,69 and palladium144,145) the process is driven by the exchangeof a weak metal oxygen bond in the first formed adduct for a strong Si–O bond inthe silylated product.
BnOX
OO
X
OTMS
BnOH
O
BnO
H
O
O
N N
O
t-Bu Bu-tCu
2 OTf–
2+
BnO O
O
N N
O
t-Bu Bu-tCu
OTf–
+
X
O
+ TMSOTf
BnO O
O
N N
O
t-Bu Bu-tCu
OTf–
+
X
O
TMS+ 4
X
OTMS+
BnOX
OOTMS
racemic
kcat
kSi-cat
kturnover
kcat and kturnover >> kSi-cat
O
N N
O
t-Bu Bu-tCu
2 OTf–
2+
4
TMSOTf
TMSOTfBnO
H
O
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 13
c01_tex 4/18/06 12:31 PM Page 13
Figure 9. Catalytic cycle of the aldol reaction of enoxysilane.
Commentary on the turnover step in the recently reported systems involving di-rect addition of ketones and aldehydes to aldehyde electrophiles is warranted. Thesegenerally fall into two categories: metal-mediated enolization and addition or, alter-natively, amine-mediated additions via formation of an enamine. Turnover in thefirst of these systems is possible, because the pKa values of the alcohol adducts arewithin range of the starting ketone or aldehyde. Thus, for the lanthanide BINOLcomplexes65 and zinc(II)-mediated aldol additions84 involving the direct addition of ketones to aldehydes, the product metal alkoxide may effect direct deprotonation ofthe ketone subsequent to aldol addition to furnish the aldol product and regenerate aketone enolate. For the amine-catalyzed aldol addition processes (Fig. 10), model-ing suggests that the proton transfer that occurs from the carboxylic acid to the aldoladduct is crucial for selectivity.80 – 82,135,136 Thus, in the course of the enamine addi-tion to aldehyde substrates, a carboxylic acid surrenders its proton to the more basicoxygen acceptor in the adduct. Of greater significance in these processes with re-spect to turnover is the hydrolytic cleavage of the enamine in the adduct to releasethe amine for a subsequent round of C–C bond formation. The precarious balance inthese systems is manifest in the conditions that are used in the amine-catalyzedcrossed aldol addition reactions, where it is worth noting that the experimental pro-cedures prescribe long reaction times and highlight the importance in proper selec-tion of polar solvents, where presumably the requisite enamine forming and cleavage
Figure 10. Amine-catalyzed aldol addition processes.
O HNO
O
R
HH
ON
(S)-proline
N
HO2C
HO2C
R
OHO
R
OH
RCHO
O O
OTMS
initiation
LnMF
O O
OM
RCHO
O O
OR
OMO O
OTMS
O O
OR
OTMS
TMSF
14 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 14
steps are facilitated. The prescription for slow addition of aldehyde substrates insome of the reported processes highlights another aspect of these systems, whereinthe adduct as an enamine could itself participate in aldol addition chemistry, as suchslow addition of substrate is necessary to allow sufficient time for enamine exchangebetween product and reactant. Nonetheless, it is important to note that even in theearliest reports of this process in the 1970’s, aldol addition reactions could be con-ducted with low catalytic loadings of proline.
SCOPE AND LIMITATIONS
Acetate, Methyl Ketone, and Unsubstituted DienolatesReports of catalytic, enantioselective aldol addition reactions involving unsubsti-
tuted enolates (acetate aldol) are far fewer than the corresponding additions involv-ing substituted enolates (e.g., propionates). Some of the more prominent examplesfor both categories are selected in this section for discussion.
Enoxysilanes and Stannanes. The classic examples in the area of catalyticenantioselective aldol addition methodology originate from the work involving theaddition of enol silanes under the influence of tin catalysts.146 – 165 The tin(II) com-plexes are typically assembled from Sn(OTf)2 and optically active diamine ligandssuch as 12, in particular, in the early work those derived from proline. These earlyexamples involve the addition of thioacetate-derived O-silyl ketene acetals to a widerange of aldehydes (Eqs. 19–21).141,153 The additions are typically conducted at low
temperature (�78º) with 20–30 mol% loadings of catalysts 12 or ent-12. Thethioester-derived enoxysilanes are optimal for these systems. Of additional benefit isthe presence of a thioester in the product as it is conveniently converted directly intoan aldehyde.166,167 This catalytic system has been extensively studied, and much in-formation is available concerning the effect of numerous additives and variations ina number of reaction parameters on the reaction selectivity, rates, and catalystturnover. One particular aspect of the process that is worth noting is the fact that thereactions can be carried out under reagent control. Thus, in additions to the enan-tiomers of 2-silyloxypropionaldehyde, both diastereomeric adducts can be obtainedin high selectivities (Eqs. 20 and 21).141
(Eq. 19)OTMS
SEt Sn(OTf)2 (20 mol%), CH2Cl2,–78°, slow addition
O
SEt
TMSO
(79%) 93% ee
+H
O
6 6
NMe
HN
(20 mol%)
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 15
c01_tex 4/18/06 12:31 PM Page 15
(Eq. 20)
(Eq. 21)
Aldol addition reactions employing BINOL/TiClx(OPr-i)4-x complexes as cata-lysts are highly attractive because of the convenient access to the catalyst components(BINOL, Ti(OPr-i)4, and/or TiCl4) along with the simplicity of their prepara-tion.67,77,168 – 174 Two general formulations have been reported to be effective in the acetate aldol addition reaction: a catalyst prepared from BINOL and eitherTiCl2(OPr-i)2
137 or Ti(OPr-i)4171 in the absence or presence of molecular sieves. Both
formulations have been documented to give aldol adducts in excellent yields and enantioselectivities (Eqs. 22 and 23). A particularly attractive feature of the
(Eq. 22)
(Eq. 23)
TiCl2(OPr-i)2 system is the fact that the addition to a wide range of functionalizedaldehydes has been documented, such as trifluoro- (Eq. 24),67 chloro- (Eq. 25),137
and azido acetaldehydes, all of which are rare substrates in catalytic, enantioselec-tive aldol addition reactions. It is worth noting that these titanium catalysts are alsoquite general with respect to the enolate component, thus both silyl ketene andthioketene acetals in addition to ketone-derived enol ethers have been employed
SBu-t
OTMS
SBu-t
OH O(S)-BINOL (20 mol%)
H
OBnO + BnO
(82%) >98% eeTi(OPr-i)4 (20 mol%), 4 Å MS,
Et2O, –20°
SEt
TMSO O (S)-BINOL/TiCl2(OPr-i)2 (5 mol%)
PhMe, 0°
(80%) 96% ee
SEt
OTMS+BnO
H
OBnO
O
SEt
OHR
OTBS
R
OTBS
O
SEt
OHR
OTBSH
OOTMS
SEt++
RMePh
(85%)(86%)
dr94:694:6
ent-12 (20 mol%)
Sn(OTf)2 (20 mol%), EtCN,–78°, slow addition
OTMS
SEt
ent-12 (20 mol%)
Sn(OTf)2 (20 mol%), EtCN,–78°, slow addition
O
SEt
OH
OTBSOTBS
O
SEt
OH
OTBS
(85%) dr = 96:4
+ +H
ONMe
HN
1-naphthyl
16 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 16
(Eq. 26).77,175,176 They have been utilized in the context of a complex natural productsynthesis, namely that of dermostatin A (Fig. 11).177 These reactions are best con-sidered as aldehyde ene additions in which the C=C of the ketone-derived enol etherhas undergone a shift in the product. The ease with which the product silyl enolethers are hydrolyzed to the corresponding hydroxycarbonyl compound rendersthese synthetically equivalent to aldol addition reactions.178 The addition reactionsare reported to give adducts in high selectivity in a procedure that prescribes �20 to0º with 10–20 mol% catalyst loadings. For the processes employing Ti(OPr-i)2/BINOL complexes, certain peculiarities of the process have been noted, with the re-action rate and product selectivity not only being dramatically sensitive to solventand reaction temperature, but also to catalyst concentration and loading.
Figure 11. Application of the titanium-catalyzed aldol to the synthesis of dermostatin A.
There has been an interesting report of chiral Zr(IV) complexes that mediateenantioselective aldol addition reactions of thioester-derived silyl ketene acetals(Eq. 27).179,180 The catalyst is readily assembled from 3,3�-diiodo-2,2�-BINOL derivatives and Zr(OBu-t)4. Using as little as 10 mol% of this convenient catalyst,adducts are isolated in useful yields and high enantioselectivity. It is noteworthy that
OTMS
SBu-t
OH
SBu-t
O(R)-BINOL (20 mol%)
Ti(OPr-i)4 (20 mol%), 4 Å MS,+
(47%) dr = 2:1
H
BnO O BnO
O OH
O OH
OH OH OHOHOHOHOH
dermostatin A
Et2O, –20°, 12 h
313535
3531
(Eq. 26)
OTBS (R)-BINOL/TiCl2(OPr-i)2, (5 mol%)
CH2Cl2, 0° MeO2C
OH OTBS
MeO2C
(71%) 99% ee
O
H+
(Eq. 25)
OTMS
SBu-t SBu-t
TMSO O(R)-BINOL/TiCl2(OPr-i)2 (5 mol%)
PhMe, 0°
(61%) 91% ee
ClO
ClH
+
(Eq. 24)SPh SPhCF3
OH O1. (R)-BINOL/TiCl2(OPr-i)2 (20 mol%) PhMe, 0°
+
(38%) 96% eeCF3 H
O OTMS
2. H+
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 17
c01_tex 4/18/06 12:31 PM Page 17
the reactions are carried out under optimal conditions in aqueous 2-propanol/toluenesolvent mixtures. As such, it is remarkable that the process is tolerant and indeedthrives in the presence of water.
(Eq. 27)
Another popular family of catalysts for the acetate aldol addition reaction of unsubstituted silyl ketene acetals utilizes simple ligands derived from tartaric acid oramino acids as donors for metals, such as boron or zinc, with the former being mostcommon (Eqs. 28–32).72,73,140,181 – 184 The typical boron catalyst is assembled uponmixing diol or amide acid ligands with BH3 � THF (with concomitant release of hydrogen gas), RB(OH)2 (with azeotropic removal of the released water), or RBCl2
(in the presence of base). The use of monosubstituted boronic acids offers the opportunity to vary the nature of the substituents for reaction optimization. Indeed,there can be benefits to the use of 3,5-bis(trifluoromethyl)phenylboron,185 which offers advantages with corresponding reduction of reaction time. The fact that theligands are straightforward and convenient to access permits a number of ligandvariations to be used, allowing an optimal system to be found for a given substrate.These have included ligands derived from tartrate (6, Eq. 28), natural (13, Eq. 29) andnon-natural amino acids, such as C�-substituted � amino acids (14, Eqs. 30–31).140 Ingeneral, the addition reactions are conducted at �78° with 20–30 mol% of catalystto give adducts in useful levels of enantioselectivity. One particularly attractive fea-ture of these catalysts is that they allow considerable flexibility in the types of enol-ates that can be employed, such as enol silanes derived from methyl ketones(Eq. 29), alkyl thioacetates (Eq. 30), and phenyl acetate (Eq. 31).
(Eq. 29)
Ph
OTMS
NH
TsN BBuO
O
1.
c-C6H11
OH
Ph
O
(67%) 93% ee
+c-C6H11 H
O 13 (20 mol%)
EtCN, –78°, 14 h2. 1 M HCl
(Eq. 28)OTMS
Ph
O
Ph
OH
1. 2-PhOC6H4B(OH)2 (20 mol%), EtCN, –78°2. HCl
(93%) 94% ee
+Ph H
O
Ph
i-PrO
OPr-i
O
CO2HOCO2H
OH
6
OTMS
SEt
(R)-3,3'-I2BINOL (12 mol%)
H
O
(76%) 97% eeSEt
OH O+
Zr(OBu-t)4 (10 mol%), n-PrOH (80 mol%), H2O (20 mol%), PhMe, 0°
18 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 18
The related complexes prepared from Et2Zn have also been reported.186 Althoughthese do not have the broad substrate scope displayed by the boron complexes, thereare some remarkable aldol addition reactions that have been described, such as thosewith trihaloacetaldehydes (Eq. 32).
A complex derived from titanium(IV), a tridentate Schiff base ligand, and di-tert-butylsalicylic acid is effective in catalyzing the addition of the trimethylsilyl keteneacetal derived from methyl acetate or other simple alkyl acetates (Eqs. 33 and 34).187,188
(Eq. 33)
OMe
OTMS
R OMe
OOH+
R H
O
N
Bu-t
BrO O
O
t-Bu
Bu-t
OO
Ti
1. Et2O, –10°2. TBAF, THF
ent-5 (2 mol%)
R(E)-PhCH=CH TBSOCH2C≡C
(81)(95)
% ee9899
(Eq. 32)
OTBS
OBn
NHTf
CO2TBS(40 mol%)
O
OBn
OH
R
RCCl3CBr3
(61%)(66%)
% ee8893
+R H
O1.
ZnEt2 (20 mol%), PhMe, –78°2. H3O+
(Eq. 31)OPh
OTMS
Ph
OH
OPh
O
2. 1 N HCl/THF
(77%) 93% ee
+H
O
Ph
1. 14 (20 mol%), BH3MTHF (20 mol%), –78°
(Eq. 30)
SBu-t
OTMS OH
SBu-t
O
BH3MTHF (20 mol%), –78°,2. 1 N HCl/THF
i-Pr
NHTsCO2H
(77%) 91% ee
+Ph H
O
Ph
14 (20 mol%)
1.
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 19
c01_tex 4/18/06 12:31 PM Page 19
The reaction is typically conducted at 0° with 2–5 mol% catalyst loadings to giveacetate aldol adducts in high selectivities for a broad range of aldehydes. There area number of unique features of this catalyst system that are worth noting: (1) the re-action does not require the use of low temperatures, (2) the additions can be conducted
with as little as 0.5 mol% catalyst, and (3) the additions are effected with methyl orethyl ester-derived enoxysilanes and aliphatic, aromatic, and unsaturated aldehydes.The tridentate ligand from which the complex is prepared is readily obtained from()- or (�)-2-amino-2�-hydroxy-1,1�-binaphthyl and 3-bromo-5-tert-butylsalicy-laldehyde. Treatment of the Schiff base with Ti(OPr-i)4 and di-tert-butylsalicylicacid followed by evaporation of the solvent with concomitant azeotropic removal of2-propyl alcohol affords an orange crystalline solid which can be used as a catalystin the reactions. The reaction can be carried out in a variety of solvents such as toluene, benzene, chloroform, or diethyl ether; with solvents such as dichloro-methane and dichloroethane significant reduction in the reaction enantioselectivityis observed. The catalytic aldol addition reaction may be conducted between thetemperature range of �20 to 23° without adversely affecting the reaction rate (2–8hours) or enantioselectivity (90% ee). For the aldol addition reaction of the methylacetate-derived silyl ketene acetal and aldehydes mediated by 5, no diminution in theoptical purity of the aldol products is observed throughout the catalyst range of0.5–10 mol%. The complex 5 has been shown to perform well in the synthesis of avariety of natural products including the antitumor depsipeptide FR-9001,228(Fig. 12),33 the polyene macrolide antibiotic roflamycoin (Fig. 13),32 kedarcidin(Fig. 14),22 phorboxazole A (Fig. 15),189 and the polyol fragment of amphotericin.190
Figure 12. Application of the titanium-catalyzed aldol reaction to the synthesis of FR-9001,228.
1. ent-5 (2 mol%), Et2O, –10°
2. TBAF, THFTrtSCHO
TrtS
OHCO2Bn
(99%) >98% eeOBn
OTMS+
HNO
HN
O
HNi-Pr O
Pr-iO
OH
NH
S
S
FR-9001,228
3
3
O
(Eq. 34)OMe
OTMSOMe
OOH
(88%) 97% ee
H
O
TIPS TIPS
+
1. ent-5 (2 mol%), Et2O, –10°
2. TBAF, THF
20 ORGANIC REACTIONS
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Figure 13. Application of the titanium-catalyzed aldol reaction to the synthesis of roflamycoin.
Figure 14. Application of the titanium-catalyzed aldol reaction to the synthesis of kedarcidin.
Figure 15. Application of the titanium-catalyzed aldol reaction to the synthesis of phorboxaxole A.
OBn
OTMSOH
OBn
O+ ent-5 (2 mol%), Et2O
(84%) 99% ee
O
NPMBO
O
NPMBO
O
H
O
OMeHO
MeO Br
HHO
O
N
O
N
O
O
O
OH
H
H
O
O
H
H H
phorboxazole A
15
15
H
NClH
O
MOMOOMe
OTMS NClTMSO
MOMO
OMe
O
(90%) 94% ee
+ 5 (1.1 mol%), Et2O
kedarcidin
NO
O
O
O
O
Cl
HN
O
OH
OMeMeO
i-PrO
OO
ONMe2
OH
OHHO
BnO TBSO O
H
OMe
OTMS
BnO TBSO OHCO2Me
1. ent-5 (1.1 mol%), Et2O
+
O OH
OH OH OH OH OH O OH
OO
roflamycoin
35 31 29
35
31 29
(84%)
2. TBAF
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 21
c01_tex 4/18/06 12:31 PM Page 21
The protocol most widely employed for the preparation of catalyst 5 prescribesthe co-mixing of the various catalyst components, as described above, followed byevaporation of solvent and released isopropanol. A simplified experimental protocolfor the preparation of the active catalyst has been developed.191 Thus, the addition of20 mol% TMSCl and one equivalent of Et3N to a solution of 2 mol% of catalyst 5(generated from ligand 15) gives a catalyst solution which can be directly utilized inthe aldol addition reaction (Eq. 35). This in situ procedure leads to substantial sim-plification of the overall protocol, because it obviates the need to remove iso-propanol. Importantly, the efficiency of the catalytic process (high ee’s and yieldswith low catalyst loads) is not jeopardized by the presence of the Et3NHCl and TMSOPr-i byproducts. Moreover, the in situ procedure described provides in prin-ciple a useful alternative to the more commonly employed methods for the removalof isopropanol released in the preparation of Ti(IV) complexes with Ti(OPr-i)4
(evaporation and addition of 4 Å sieves). As an application of the catalytic, enan-tioselective aldol addition employing the in situ catalyst preparation procedure, thesynthesis of (R)-(–)-epinephrine has been carried out through a convenient seven-step sequence from commercially available veratraldehyde (Eq. 35).191
Aldehyde and ketone substrates incorporating an oxygenated C� substituent thatcan participate in metal chelation, such as �-alkoxyacetaldehydes, pyruvates, and �-diketones, have been shown to be ideal substrates in a class of highly selective aldoladdition reactions employing bisoxazoline-derived ligands and copper(II),37,67,192 – 197
tin(II),39,194 scandium(III),198,199 and zinc(II) catalytic systems (Eqs. 36 and 37).38 Twogeneral ligand classes have been examined: bidentate bisoxazolines prepared frommalonate esters, and the complementary tridentate bisoxazoline-derived ligands accessed from 2,6-dicarboxypyridine (PYBOX).200 Some general comments can bemade about these ligand classes and their corresponding metal complexes as cata-lysts for the aldol addition reaction.133,201 Interestingly, for the copper-mediated reactions, glyoxylates cannot be used as substrates, despite the fact that, in principle,these meet the structural criteria for this general class of catalysts. Typically, triflates
(Eq. 35)OBn
OTMS
OH
OBn
O
+
(81%) 95% ee
H
OMeO
MeO
NOH
HO Br
Bu-tH
HO2C
HOBu-t
Bu-t
+
Ti(OPr-i)4 (2 mol%), TMSCl (20 mol%),
MeO
MeO
HONHMeHO
HO(R)-(–)-epinephrine
1.
Et3N (1 equiv)2. TFA (work up)
15 (4.4 mol%)
22 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 22
are the counterions accompanying the metal centers, although other non-participatingcounterions such as the corresponding hexafluoroantimonate have been examined.Of additional importance for this process is the fact that the additions are tolerant of a wide range of enolic partners including thioester-, ester-, and ketone-derived enol silanes. The typical protocol for catalyst generation proceeds by addi-tion of ligand to a solution of a metal triflate; after allowing a brief time for com-plexation the subtrates are then added. A highly attractive feature of this system isthe fact that a meticulous study of the process and a range of reaction parametershave been undertaken. In this respect, catalyst preparation time, catalyst hydrationstate, catalyst loading, time, solvent, and temperature, along with the typical scopehas been the subject of in-depth investigations, which are well worth consulting forthe practical and mechanistic insight they provide.133 For a broad range of complexa-tion times, 15 minutes to 4 hours, no difference in catalytic efficiency or selectivitywas observed. Only at extended complexation times (12 hours) were some delete-rious effects in efficiency observed. The fact that catalyst activity and efficiency canbe regained on addition of molecular sieves strongly implies catalyst hydration as theculprit in deactivation; indeed, studies have revealed that the bishydrates are less efficient catalysts than their anhydrous counterparts. The reactions are exceptionalfor the high level of enantioselectivity, and for the fact that in certain cases that havebeen investigated, the additions can be carried out with as little as 0.5 mol% catalystwithout detriment to product selectivities. In a typical reaction, the additions are con-ducted at �78° with 5–10 mol% complex. A careful study of the copper-bisoxazolinecomplexes has revealed that for a range of solvents such as THF, Et2O, CH2Cl2,toluene, hexane, and trifluoromethylbenzene, the enantioselectivity of the adducts ismaintained at 95% ee. For all but hexane, yields of more than 88% have beennoted with reaction times of 1–3 hours. Only in hexane is a slight decrease in prod-uct yield observed as well as a dramatic increase in reaction time (3 days), presum-ably because of partial insolubility of the catalyst in this solvent. Nonetheless, the
(Eq. 37)
BnOX
OTMS
X = SBu-t, SEt, OEt
BnOX
OOH
(95-100%) 98-99% ee
+H
O
NNN Cu
OO
Ph Ph
2 SbF6–
CH2Cl2, –78°
8 (0.5 mol%)
2+
(Eq. 36)
BnOX
OOH
X
OTMS
X = SBu-t, OEt, Me, Ph
CH2Cl2, –78°2. aq. HCl, THF
BnO
(51-91%) 99% ee
+H
O
O
N N
O
t-Bu Bu-tCu2 OTf–
2+
4 (10 mol%)
1.
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 23
c01_tex 4/18/06 12:31 PM Page 23
use of THF is optimal, as it routinely provides high yields and selectivities in theshortest amount of time over a broad temperature range. For example, in the addi-tion of tert-butyl thioacetate O-trimethylsilyl ketene acetal in Et2O the enantioselec-tivity fluctuates between 98 and 85% ee in the temperature range �78 to 20°; bycontrast, in THF over the same range of temperature the enantioselectivities are between 92 and 99% ee. Over a range of electrophile concentration (0.3 M–1.5 M)no change in product selectivity is observed. Studies aimed at gaining mechanisticinsight have revealed the beneficial effects of added TMSOTf, which leads to con-siderable acceleration of the reaction. Thus the addition reaction of pyruvate andtrimethylsilyl tert-butyl thioketene acetal mediated by 2 mol% of copper(bisoxazo-line) affords product in 97% ee over the course of 14 hours; interestingly, when thesame addition is conducted with one equivalent of TMSOTf and Cu catalyst underotherwise identical conditions, reaction is observed to reach completion in 35 min-utes with no diminution in product enantioselectivity. This represents a rare examplewhere the TMSOTf-catalyzed reaction in the absence of Cu complex is considerablyslower than the metal-mediated process, a feature that is intimately related to the ability of the substrates to undergo significant activation by chelate formation.The benefits of chelate formation leading to highly organized transition states withconcomitant high selectivities also result in some limitations.202 Thus, carbonyl substrates forming chelates greater than five-membered rings (e.g., 3-benzyloxypro-pionaldehyde) are not good substrates. The process can display significant match-ing/mismatching with chiral substrates. In particular, when the configuration at Cαinterferes with chelation by the substrate, diminished product diastereoselectivitycan be observed (Fig.16).
(Eq. 39)
O
EtO
O
EtOOH O
SBu-tSBu-t
OTMS
(92%) 90% ee
+H
O
NNN Sc
OO
Ph Ph
CH2Cl2, –78°2. aq. HCl
1.
16 (10 mol%)
+
Cl ClSbF6
–
(Eq. 38)
O
EtO
SPh
OTMS
O
EtOSPh
OOH
(90%) 98% ee
+H
O
CH2Cl2, –78°2. aq. HCl
O
N N
O
Bn BnSn
2 OTf–
2+
7 (10 mol%)
1.
24 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 24
Figure 16. Matching and mismatching in the copper-catalyzed aldol reaction.
The extensive structural and mechanistic studies to which the process has beensubjected has permitted an in-depth understanding of not only the detailed aspects ofthe aldol process, but also the structural and coordination chemistry of the corre-sponding metal complexes. Consequently, of particular significance is the fact that ahigh level of predictability is possible in this process; moreover, the insight affordedby these studies is sure to impact the evolution of metal-based complexes for enan-tioselective catalysis. Key applications of a tin catalyst and copper complex 8 can befound in the synthesis of phorboxazole A and altohyrtin C, respectively (Figs. 17 and18).196,203 – 205
Figure 17. Application of the tin-catalyzed aldol reaction to the synthesis of phorboxaxole A.
CHON
O
Ph
SBu-t
OTMSN
O
Ph
OH
SBu-t
O
(91%) 94% ee
O
N N
O
Ph PhSn
2+
1.
CH2Cl2, –78°2. aq. HCl
+
O
OMeHO
MeO Br
HHO
O
N
O
N
O
O
O
OH
H
H
O
O
H
H H
phorboxazole A
2 OTf–
(10 mol%)
H
CHOBnO
SBu-t
OTMS
BnOSBu-t
OTMSO
dr = 1:1
CHOBnOBnO
SBu-t
OTMSO 8 (5 mol%), CH2Cl2
–78°, 12 h
dr = 98.5:1.5
8
N
NN CuOO
Ph Ph
2 SbF6–
2+
+
SBu-t
OTMS+
8 (5 mol%), CH2Cl2
–78°, 12 h
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 25
c01_tex 4/18/06 12:31 PM Page 25
Figure 18. Application of the copper-catalyzed aldol reaction to the synthesis of altohyrtin C.
The aldol addition reactions of enoxysilanes are not limited to the use of trialkylsubstituted silyl ketene acetals. Indeed, recent studies describe the use of enoxytri-chlorosilanes in enantioselective addition reactions to aldehydes (Eq. 40).102,134,206 – 212
These processes are noteworthy for a number of reasons, not the least of which is the
fact that they are at present rare examples of Lewis base catalyzed asymmetric reac-tions. Interestingly, the background rate of aldol addition between such enolates andaldehydes in the absence of additives has been shown to be rapid, even at low tem-perature. Nonetheless, stereoselective additions are possible since the Lewis basecatalyzed processes are markedly faster. In this respect, the basic oxygen of chiralphosphoramides interacts with silicon leading to the formation of a hypervalent sili-conate species with enhanced Lewis acidity that is subsequently poised to activatean aldehyde. The resulting cyclic arrangement of aldehyde, enoxysilane, and phos-phoramide leads to selective addition processes. A key advance in this exciting areais the use of chiral silicon Lewis acids that are generated from SiCl4 and chiral Lewisbasic phosphoramides. Such processes that rely on chiral Si-Lewis acids employ themore conventional trialkylenoxysilanes as reacting partners (Eqs. 41 and 42). Stud-ies of the mechanism of activation have led to the design of bisphosphoramides forsilicon, resulting in even more highly selective additions.
(Eq. 40)OSiCl3
1.
CH2Cl2, –78° 2. aq. NaHCO3
O
Ph
OH
NPON
NPh
Ph
Me
Me
(98%) 87% eePh H
O+
17 ( 5 mol%),
altohyrtin C
t-BuS HOBn
OTMS O
t-BuSOBn
O OH8 (5 mol%)
CH2Cl2, –78°
(100%) 99% ee
O
O
O
OMeHO
O
AcO
OO
AcO
OH
OH
OH
O
O
O
HO
H
OHHO
H
+41
41
26 ORGANIC REACTIONS
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Despite the numerous documented examples of the catalytic, enantioselectivealdol addition reactions to aldehydes, addition reactions to ketones are rare. The dif-ficulty faced by investigators working in this area are manifold, not only because ketones are less reactive than aldehydes, but also because differentiation of the twoalkyl groups flanking the ketone C=O on the basis of sterics alone presents a moredifficult challenge in comparison to the corresponding differentiation that mustoccur with aldehyde involving alkyl versus proton. Nonetheless, with Lewis basecatalysts such as 18 there are some noteworthy examples (Fig 19). The addition reaction of trichlorosilyl enolates to aryl ketones is impressive in that products are obtained in high yields and useful levels of induction.102 Given the fact that little else can be relied upon to access such compounds, the results are remark-able.75,134,154 – 156,209 – 211,213
Figure 19. N-oxide-catalyzed aldol reaction of aryl ketones.
An additional departure from the traditional aldol addition reaction of enol silanescatalyzed by Lewis acid activation of the electrophilic aldehyde component is theuse of complexes that lead to activation of the enoxysilane component via transientformation of metalloenolates. One of the earliest examples in catalytic asymmetricsynthesis is the report that acetophenone-derived trimethylsilyl enol ethers can be
OMe
OSiCl3Ph
O
N NBu-t
BuOt-Bu
OBu
1. , 18 (10 mol%), CH2Cl2
2. aq. NaHCO3
Ph
OH
OMe
O
O HO OMe
O
(90%) 80% ee
(96%) 83% ee
18
OO
(Eq. 42)
OMe
OTBS OH
OMe
O
SiCl4, CH2Cl2, –78°(95%) 94% ee
O
HPh Ph
NN
P
Me
Me O
NMe
(CH2)5
2
9 (5 mol%)+
(Eq. 41)OMe
OTBS
c-C6H11
OH
OMe
O
2. NaHCO3
(86%) 88% ee
c-C6H11 H
O+
1. 9 (5 mol%), SiCl4, CH2Cl2, –78°
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 27
c01_tex 4/18/06 12:31 PM Page 27
activated by BINAP/palladium(II) complexes to afford putative palladium eno-lates.144,145 These are generated from a mixture of enol silane and a complex formedbetween palladium(II) and p-Tol-BINAP (5 mol%) in the presence of molecularsieves and have been shown to undergo aldol additions in up to 89% ee (Eq. 43).
By comparison to enol silanes, there is a paucity of catalytic, enantioselectivealdol addition reactions involving the corresponding stannanes. Stannyl enolates derived from methyl ketones have been shown to participate in enantioselective addition reactions to a wide range of aldehydes at �20° in THF in the presence of anovel silver(I)/BINAP complex. The adducts can be isolated in up to 95% ee anduseful yields (Eq. 44).94 Control experiments have led to the conclusion that the sys-tems behave in analogy to the typical reaction of enol silanes with electrophilic ac-tivation of the aldehyde component, without proceeding through a silver(I) enolate.
Direct Aldol Addition Reactions of Unsubstituted Systems. In parallel withreactions involving the generation of metal enolates from stannylated or silylatedprecursors, there have been recent developments on the use of ketones that undergoin situ enolization or activation by transient conversion into enamines and participatein aldol addition reactions.214 In the first of these, lanthanum binaphthoxide com-plexes (LLB) are able to effect deprotonation of ketones and activation of aldehydesto afford aldol adducts in high selectivities and yields (Eqs. 45 and 46).65,215,216
This process has been utilized elegantly in the synthesis of epothilones A and B(Fig. 20).40 The reactions proceed at 0°, giving products in high enantioselectivity.Related processes utilizing barium,217 zinc,83,218 and calcium (Eq. 47)219 have beendocumented.
(Eq. 46)
CHO
OTBS
OH
Ph
O
OTBS
O
Ph
(R)-LLB (8 mol%), KHMDS (7.2 mol%)
OH
Ph
O
OTBS
+
I II(85%) I:II = 86:14, I 99% ee, II 93% ee
+H2O (16 mol%),THF, –20°, 48 h
(Eq. 45)
(R)-LLB (20 mol%)
THF, –20°
OOHO
HPh
O+
(71%) 94% ee
Ph
(Eq. 44)Bu-tPh
OOH
Ph H
O+
Bu-t
OSn(Bu-n)3 (R)-BINAPMAgOTf (10 mol%)
THF, –20°
(78%) 95% ee
(Eq. 43)[Pd((R)-Tol-BINAP)(H2O)2](BF4)2 (5 mol%)
4 Å MS, 1,1,3,3-tetramethylurea, 0°Ph
OTMS
PhPh
OOH
(92%) 89% eePh H
O+
28 ORGANIC REACTIONS
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Figure 20. Application of the hetero-bimetallic-catalyzed aldol reaction to the synthesis of epothilone A.
The easily accessible ligand 11 and its bimetallic zinc complex have also beenused in aldol addition reactions of methyl ketones and aldehydes that proceed via in situ enolization (Eq. 48).84,220,213
Another way that ketones can undergo activation and participate in stereo-selective aldol additions is through their in situ conversion to the correspondingenamines. Proline is remarkably effective in this process. Indeed, the enantioselec-tive synthesis of Wieland-Miescher ketone using proline had been established as early as 1973.80 – 82 Recent dramatic advancements in this area have taken the pro-line-catalyzed processes in new directions to include other amine catalysts(Eqs. 49–52).85,66,221,222 The addition can be conducted with acetone223,85 in DMSO,
(Eq. 48)
O
c-C6H11
OOH
Et2Zn (20 mol%), 4 Å MS, THF, 5°
(85%) 93% ee
c-C6H11 H
O+
NNPhPh OH HO
PhPh
OH
11 (10 mol%)
(Eq. 47)OH
Ph
OPh Ph
HO OH
Ph
O
Ca[N(TMS)2]2(thf)2, KSCNBnO H
O
(76%) 91% ee
+BnO
CHOO O
(R)-LLB (20 mol%),KHMDS (18 mol%)
O O OH
Ph
O
O
Ph
(±)O O OH
Ph
O
(59%) I:II = 1:1, I 89% ee, II 88% eeI II
+
O
O
O
HO
OHO
N
S
1
epothilone A
11
H2O (40 mol%),THF, –20°
+
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 29
c01_tex 4/18/06 12:31 PM Page 29
a solvent which appears to be critical, utilizing 30 mol% of proline at ambient tem-peratures giving adducts in up to 99% ee. The proline-catalyzed aldol addition reac-tion of acetaldehyde can be carried out in a domino process proceeding by a doublealdol addition and elimination to give useful building blocks for asymmetric synthe-sis (Eqs. 51 and 52).
Propionates and Substituted EnolatesEnoxysilanes and Stannanes. The addition reactions of propionate-derived
silyl ketene acetals and other substituted enolates or their equivalents can be effectedwith a broader range of catalysts than that of the unsubstituted systems described inthe previous section. In principle, two kinds of stereochemical families of reactionprocesses can be identified: (1) those processes in which each geometrical isomer ofthe enolate gives divergent, complementary diastereomeric products and (2) those inwhich both enolates stereoselectively lead to convergent formation of a preferred diastereomer. Examples of both types have been documented. For the first of thesein which the additions are stereospecific, stereoselective generation of enolates is of great importance to the selectivity of the process. In such cases, the ability to generate a particular enolate from a given carbonyl precursor may be limiting to the process. The convergent process obviates such concerns, but in turn can provide
(Eq. 52)2,4-(O2N)2C6H3SO3HM2H2O (3 mol%),
acetone, rt
O
O2N
OH ONH
N
(72%) 93% ee
O2N
+H
O(3 mol%)
(Eq. 51)L-proline (1.7 mol%)
THF, rt, 14 h
OHCHOH
O
(10%) 90% ee
(Eq. 50)
O
O
O O
O
CHO O L-proline (30 mol%)
DMSO, rt
O
O
O O
O
OOH
dr = 99:1
+
(Eq. 49)i-Pr H
O O
i-Pr
OHL-proline (30 mol%)
DMSO, rt
(97%) 96% ee
O+
30 ORGANIC REACTIONS
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limitations as to the type of stereochemical relationships in the product that can be accessed.
As with the additions of acetates and other unsubstituted enolates, the classics inthis area are the enantioselective aldol additions mediated by tin(II) diamine com-plexes (Eq. 52). These complexes are conveniently prepared from Sn(OTf)2 and proline-derived diamines.31,146 – 165,224 – 231 There are numerous studies of these systemsand careful scrutiny of these can be rewarding because this system represents one inwhich the effect of many different variables on reaction selectivity and rate havebeen carefully examined. Moreover, there is an equally large amount of mechanis-tically relevant data making the careful study of these reports a fruitful venture. Inthe typical procedure the reactions employ thioester-derived silyl ketene acetals andare carried out with 20 mol% catalyst at �78° in propionitrile. The selection of this unusual solvent rests on two key observations: (1) the ability of nitriles to lead to effective turnover in the addition reactions and (2) the fact that, unlike acetonitrile,this solvent permits reactions to be carried out at low temperature where the enan-tioselectivity is maximized. Optimal selectivities are obtained when the aldehyde isadded slowly to the reaction mixture, minimizing stereorandom, background reac-tions while allowing for concomitant catalyst turnover. Both O-trimethylsilyl and O-dimethyl-tert-butylsilyl enol ethers give adducts in equally good selectivities. Thepropionate additions using these complexes have been conducted with the Z-enolates and afford products displaying syn simple diastereoselectivity and highenantiomeric purity (Eq. 53). The use of ester-derived enol silanes has been exam-ined for alkoxyacetate-derived enolates (Eqs. 54 and 55).225,230,232 High anti or synselectivity was shown to be a function of whether the Z- or E-starting enolate wasemployed, respectively.227
(Eq. 54)
OTMS
OPh
O
OPh
TMSO
OBnBnO+
(80%) dr = 98:2, 96% ee
H
O (20 mol%), Sn(OTf)2 (20 mol%)
CH2Cl2, –78°, slow addition
NMe
HN
(Eq. 53)
OTMS
SEt Sn(OTf)2 (20 mol%), CH2Cl2, –78°, slow addition
O
SEt
TMSO
R+
O
R H
ent-12 (22 mol%)
NMe
HN
1-naphthyl
Rn-C7H15
Ph(76%)(86%)
% ee9891
dr99:193:7
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 31
c01_tex 4/18/06 12:31 PM Page 31
Catalysts derived from titanium(IV) or zirconium(IV) and BINOL or its substi-tuted derivatives mediate the addition of propionate enolates to aldehydes(Eqs. 56–60). The use of the complex derived from BINOL and TiCl2(OPr-i)2 hasbeen studied extensively in the addition of substituted ester137,67 as well as ketone-derived77,233 silyl enolates to chelating aldehydes, such as benzyloxyacetaldehydeand ethyl glyoxylates. The addition of the E-enol silanes preferentially affords synadducts in up to 98% ee (Eq. 56).137 By comparison, addition of the Z-enol silanesfurnishes the complementary anti adduct in 90% ee (Eq. 57). A particularly attract-ive feature of these titanium-catalyzed reactions is the fact that trifluoroacetaldehyde
(Eq. 57)
can be utilized, albeit the products exhibit poor diastereoselectivity (Eqs. 58 and59).67 There have been some interesting studies involving the enol silane derivedfrom 3-pentanone (Eq. 60), wherein a highly selective aldehyde addition is ob-served.77 Although the process is best classified as an ene addition, the products iso-lated after exposure to acid are �-hydroxy ketones. In this process the addition ofeither the Z- or E-trimethylsilyl enolate of 3-pentanone to glyoxaldehyde gives synadducts in up to 99% ee.
OTMS
SEt
SEt
TMSO O
I
SEt
TMSO O
II
+
(R)-BINOL/TiCl2(OPr-i)2 (5 mol%)
PhMe, 0°
(72%) dr = 8:92, 90% ee
O
HO
BuO +
O
BuO BuO
O
(Eq. 56)
OTMS
SEt
(R)-BINOL/TiCl2(OPr-i)2 (5 mol%)
PhMe, 0°
(64%) dr = 92:8, 98% ee
O
HO
BuO
SEt
TMSO O
I
SEt
TMSO O
II
+
O
BuO BuO
O
+
(Eq. 55)OTMS
OPr-i
O
OPr-i
OH
PhOBnOBn
(60%) dr = 90:10, 96% ee
HPh
O Sn(OTf)2 (20 mol%)
CH2Cl2, –78°, slow addition+
E:Z = 71:29
NMe
HN
1-naphthyl
12 (20 mol%)
32 ORGANIC REACTIONS
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Catalysts prepared from Zr(OBu-t)4 and 3,3�-diiodo-BINOL in the presence ofpropanol and water are effective at mediating the addition of primarily phenyl pro-pionate-derived E-enolates to aldehydes. Thus 12 mol% of the putative zirconiumcomplex affords products in excellent diastereo- and enantioselectivities (99% ee),favoring the anti product (95�5 dr) (Eq. 61).179,180,234 In addition to propionates,
(Eq. 61)
isobutyrate-derived silyl ketene acetals have been reported to participate in the addi-tion reaction (Eq. 62),179,180 furnishing adducts in equally high enantioselectivity(98% ee). The fact that the catalytic process prescribes the use of water/isopropyl al-cohol mixtures renders the complex unique as a rare example of an early group-(IV)transition-metal catalyst displaying wide tolerance to moisture.
OTMS
OPh
(R)-3,3'-I2BINOL (12 mol%), Zr(OBu-t)4 (10 mol%)
O
OPh
OH
PhPh H
O
(94%) dr = 95.5, 99% ee
+n-PrOH (80 mol%), H2O (20 mol%), PhMe, 0°
(Eq. 60)
TMSO
Et MeO2C
OH OTMS
(54%) Z:E = 96:4, dr = 98:2, 99% ee
MeO
O
(R)-BINOL/TiCl2(OPr-i)2 (5 mol%)
CH2Cl2, 0°H
O
+
(Eq. 59)
OTMS
SEt
SEtCF3
OH O
I
SEtCF3
OH O
II
+
1. (R)-BINOL/TiCl2(OPr-i)2 (20 mol%), PhMe, 0°
(48%) I:II = 44:56, I 89% ee, II 83% ee
+O
CF3 H 2. H+
(Eq. 58)
OTMS
SEt
SEtCF3
OH O
I
SEtCF3
OH O
II(64%) I:II = 48:52, I 55% ee, II 64% ee
+
2. H++
HCF3
O1. (R)-BINOL/TiCl2(OPr-i)2 (20 mol%), PhMe, 0°
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 33
c01_tex 4/18/06 12:31 PM Page 33
(Eq. 62)
Enantioselective aldol addition reactions employing boron catalysts were some ofthe earliest processes reported for propionate aldol addition reactions. A particularlyattractive feature of the reported catalysts is the ease with which the ligands and thecorresponding complexes are generally accessible. The optically active ligand onboron is typically derived from either �-amino acids or tartrates.181 As such, theprocess is notable because of the large library of structurally and functionally relatedboron catalysts that have been described. The aldehyde addition reaction of the E-silyl ketene acetal prepared from phenyl propionate at �78° employing 20 mol%catalyst affords predominantly the syn adduct in up to 92% ee (Eq. 63).73
This versatile catalytic system can also be employed in the aldol addition reactionof ketone-derived silyl enol ethers. Irrespective of the enolate geometry, these sys-tems afford the syn aldol adduct in useful levels of relative and absolute stereocon-trol (Eqs. 64 and 65).72,177,182,32 The addition of enol silanes derived from cyclicketones and aldehydes is also possible, with the formation of the syn aldol adduct
(Eq. 65)
OTMS
Et
O
Et
OH
Ph +
I II
1. 6 (20 mol%), BH3MTHF (20 mol%)
EtCN, –78°2. 1 N HCl
(96%) I:II = 94:6, 96% ee
Ph H
O+
O
Et
OH
Ph
(Eq. 64)
OTMS
Et
O
Et
OH
Ph
O
Et
OH
Ph+
I II
1. 6 (20 mol%), BH3MTHF (20 mol%)
EtCN, –78°2. 1 N HCl
(97%) I:II = 93:7, 94% ee
Ph H
O+
(Eq. 63)OTMS
OPh
O
OPh
OH
Ph
O
OPh
OH
Ph
I II(73%) I:II = 79:21, I 92% ee, II 3% ee
BH3MTHF (20 mol%), EtCN, –78°2. TBAF/THF
Ph H
O
i-PrO
OPr-i
O
CO2HOCO2H
OH
ent-6 (20 mol%)+ +
1.
OTMS
OMe
(R)-3,3'-I2BINOL (12 mol%) O
OMe
OH
PhPh H
O
(95%) 98% ee
+Zr(OBu-t)4 (10 mol%), n-PrOH (80 mol%),
H2O (20 mol%), PhMe, 0°
34 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 34
once again favored in impressive diastereo- and enantioselectivity (Eqs. 66 and67).181,235 The reaction has been employed in the asymmetric synthesis of chei-monophyllal (Fig. 21).235
Figure 21. Application of the boron-catalyzed aldol reaction to the synthesis of cheimonophyllal.
In addition to catalysts derived from natural amino acids, the use of C�-substituted�-amino acids has been examined and yielded notable results (Eqs. 68–70).140
(Eq. 68)
SEt
OTMS
Ph
OH
SEt
O
BH3MTHF (20 mol%), –78°, EtCN2. 1 M n-Bu4NF, THF (84%) I:II = 55:45, I >98% ee
Ph
OH
SEt
O
+
I II
Ph H
O+
i-Pr
NHTsCO2H
14 (20 mol%)
1.
OTMS OOBz
(85%) dr = 10:1, 97% ee
1. 6 (20 mol%), 2-PhOC6H4B(OH)2 (20 mol%), EtCN, –78°
2. BzCl, Py+
H
O
OHO H
H CHOO
HO
cheimonophyllal
(Eq. 67)OTMS OOH
PhH
OOH
PhH
+ EtCN, –78°, 14 h2. 1M HCl
I II
Ph H
O+
(71%) I:II = 94:6, 92% ee
13 (40 mol%)
NH
NTs
BBuO
O
1.
(Eq. 66)+
OTMS OOH
Ph
I II(57%) I:II >95:5, I >95% ee
OOH
Ph
1. 6 (20 mol%), BH3MTHF (20 mol%)
EtCN, –78°2. 1 N HCl
Ph H
O+
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 35
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Additions of the ethyl thiopropionate-derived E-silyl enolate afford products in goodenantioselectivities (98% ee), albeit modest diastereoselection (syn/anti 55�45). Bycontrast, the use of the Z-silyl enolate furnishes a mixture of syn and anti adductswherein the anti is preferred in up to 94�6 ratio and in up to 82% ee (Eq. 69). Whenthe E-silyl enolate prepared from phenyl propionate is utilized, the absolute selec-tivity is improved (87% ee) in comparison to that observed for the same substratewith thioproprionate enoxysilanes. However, for the phenyl ester the simple dia-stereoselectivity of the addition is somewhat diminished (Eq. 70).140
One particularly interesting aspect of the boron Lewis acid catalysts derived fromamino acids like 19 is that dichloro-, difluoro-,236 and dithio-237 substituted enoxysi-lanes have been employed to give adducts that are otherwise not easily accessed inuseful levels of induction (Eqs. 71–73).
(Eq. 72)+ OEt
OTMSF
Fi-Pr
OH
OEt
O
F F
(20 mol%),
EtNO2, –45°
OH
Ot-Bu
NHNsBH3MTHF (22 mol%),
i-Pr
O
H
(90%) 95% ee
(Eq. 71)OMe
OTMS
Cl
Cl
MeO
PhS
O
O
N BH
O
Oi-Pr
CH2Cl2, –78°, 7 hMeO
OHCO2Me
Cl Cl
(88%) 77% ee
H
O
+
(20 mol%)
(Eq. 70)OPh
OTMS
Ph
OH
OPh
O1. 14 (20 mol%), BH3MTHF (20 mol%)
(77%) I:II = 77:23, I 87% ee
Ph
OH
OPh
O
+
I
Ph H
O+
II
–78°, EtCN2. 1 M n-Bu4NF, THF
(Eq. 69)
SBu-t
OTMS
R
OH
SBu-t
O1. 14 (20 mol%), BH3MTHF (20 mol%)
RPh2-C4H3O
(78%)(54%)
% ee I 8279
I:II94:6
88:12
R
OH
SBu-t
O
+
I II
+R H
O
–78°, EtCN2. 1 M n-Bu4NF, THF
36 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 36
(Eq. 73)
The addition of isobutyrate-derived enoxysilanes has also been documented,184,238
with products obtained in high selectivities and useful yields (Eqs. 74 and75).184,195,236 An unusual catalyst derived from optically active �-trimethylsilyl-�-hydroxyacetic acid functions in such additions (Eq. 76), affording adducts in up to90% ee.239
There has been a single report of the use of allenyl enolates in enantioselectivealdol addition reactions. The phenylalanine-derived ligand has been used in the synthesis of a boronate complex which has been shown to mediate aldol additions,giving products in up to 97% ee (Eq. 77).240
(Eq. 76)OEt
OTMS
CO2HTMS
OH(10 mol%),
OEt
O
Ph
OH
1.
BH3MTHF (10 mol%),
EtCN, –78°, 3 h2. pH 7 buffer
Ph H
O+
(92%) 86% ee
(Eq. 75)
OEt
OTMS OH
OEt
O
H
O
(59%) 96% ee
+BnOBnO BH3MTHF (20 mol%), –78°
2. 1 N HCl/THF
i-Pr
NHTsCO2H
14 (20 mol%)
1.
(Eq. 74)
1. 19 (20 mol%), BH3MTHF (20 mol%), EtNO2, –78°, 1-4 h
2. TBAF
OTMS
OPh OPhPh
OOH
Ph H
O
(92%) 90% ee
+
SNH
BH3MTHF (20 mol%), EtNO2
CO2H1.
–78°, 1 h2. Ni2B/H2
19 (20 mol%),OTMS
OEt
O2N
OO
S
SPh Ph CO2Et
OH
(86%) >98% ee
+H
O
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 37
c01_tex 4/18/06 12:31 PM Page 37
(Eq. 77)
As discussed in the section above on acetate-type additions, substrates such asbenzyloxyacetaldehyde and glyoxal have unique structural features that allow themto chelate with Lewis acidic metal centers. This has been elegantly capitalized uponin the development of highly stereoselective propionate-type aldol addition reactionscatalyzed by copper-, tin-, and scandium- bisoxazoline complexes. The two ligandfamilies that have been reported include either bidentate bisoxazolines derived frommalonate or tridentate bis-oxazolines prepared from 2,6-pyridinedicarboxylic acids.For copper(II), for example, the two ligands afford complementary products, givingadducts with opposite face selectivity (Eqs. 78–80).37
This family of catalysts includes a wide selection of complexes that can be used inenantioselective aldol additions, which is the key advantage of these systems. Thisversatility, when coupled to the range of aldehydes that can be employed, such asglyoxylates and benzyloxyacetaldehyde, provides access to a broad range of substi-tuted aldol adducts possessing the various permutations of complementary, diversestereochemical patterns. The typical reaction calls for the use of 5–10 mol% cata-lyst loadings with the reaction conducted at �78°. The strict requirement for thesubstrate to form five-membered chelated adducts with the metal center leads to asystem that is impressive in its high selectivity, reaction rate, and yield for a widerange of enoxysilanes. These silanes include those derived from esters,197
thioesters,70 ketones,37,197,199 and lactones.74
(Eq. 78)
BnO SBu-t
OTMS
CH2Cl2, –50°2. aq. HCl, THF
SBu-t
OOHBnO
(50%) dr = 81:19, 84% ee
+H
O
O
N N
O
t-Bu Bu-tCu
2 OTf–
2+
4 (10 mol%)
1.
OTMSPr
•
I OH O
Pr
I
OH O
Pr
II II
+
NH
O
n-C3F7 CO2H
Bn
(20 mol%),
BH3MTHF (20 mol%)
1.
i-PrH
O+
(63%) I:II = 1:20, II 97% ee
i-Pri-Pr
EtCN, –78°, 7 h2. aq. HCl
38 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 38
In additions mediated by copper complexes, the correlation between enolategeometry and product diastereoselectivity has been studied and found to be ligandand substrate dependent. Thus, for example, for the tridentate bisoxazoline coppercomplexes the E- and Z-silyl thioketene acetals derived from thiopropionate affordsyn adducts (Eqs. 79 and 80). The additions of the latter are, however, considerablymore selective (Eq. 79).37 In a study involving ketone additions mediated by the tridendate copper-bisoxazoline complexes, the Z-silyl enolates afford exceptionallevels of induction, whereas the corresponding E-enol silanes lead to preferentialformation of the anti adduct, albeit in low yield and selectivity (Eq. 80).37
The tin complexes function equally well in the aldol addition reactions of biden-tate aldehydes. In this regard, the addition of the Z-thioketene acetal derived fromthiopropionate gives the anti aldol adduct in high selectivities (Eq. 81).39 Impor-tantly, the adducts can be obtained in equally good selectivites for a wide range ofC� substituents and are thus not limited to the propionate systems. Scandium(III)catalyst 16 affords the complementary products resulting from addition with oppo-site facial selectivity (Eq. 82).198
(Eq. 81)
O
EtOSPh
OTMS
O
EtOSPh
OOH
CH2Cl2, –78°2. aq. HCl
(87%) dr = 90:10, 95% ee
+
O
H
O
N N
O
Bn BnSn
2 OTf–
2+
7 (10 mol%)
1.
(Eq. 80)
+BnOH
O
Pr-i
OTMS
(90%)(10%)
BnOPr-i
OOH
dr95:5
38:62
% ee 9028
Z:E90:1010:90
2. aq. HCl, THF
1. 8 (10 mol%), CH2Cl2, –20°, 2 d
(Eq. 79)SEt
OTMS
(90%) (48%)
BnOSEt
OOH
dr97:3
86:14
% ee 9785
Z:E95:51:99
+BnOH
O
NNN Cu
OO
Ph Ph
2 SbF6–
CH2Cl2, –78°2. aq. HCl, THF
1.
8 (10 mol%)
2+
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 39
c01_tex 4/18/06 12:31 PM Page 39
(Eq. 82)
These addition reactions have been examined with alkoxy-substituted silyl eno-lates as well as cyclic enolates. The former are reported to work particularly well withthe scandium catalysts (Eq. 83).198 The use of copper-bisoxazoline complexes in theaddition of the butyrolactone-derived enoxysilanes provide access to useful adductsin a 93�7 syn/anti mixture and 96% ee (Eq. 84).74 In addition to propionate-derivedenolates, isobutyrate and related silyl enolates have been examined (Eqs. 85–87).199
(Eq. 83)
(Eq. 84)
(Eq. 85)O
EtOAr
R
R
OTMS
ArR
OEtO
O
OH
R
(85%)(85%)(80%)(81%)
% ee 95959798
+H
O
ArPh4-FC6H4
PhPh
RMeMen-C5H11
n-C4H9
NNN Sc
OO
t-Bu Bu-t
TMSCl (2 equiv), CH2Cl2, –78°2. aq. HCl
1.
(10 mol%)
+
Cl ClSbF6
–
OTMSO O
OHBnO
(95%) dr = 96:4, 95% ee
BnO +H
O
O
NNN Cu
OO
Ph Ph
2 SbF6–
CH2Cl2, –78°2. aq. HCl, THF
1.
8 (10 mol%)
2+
O
EtO
O
EtOOH O
SEtSEt
OTMS
OBn OBn(92%) dr = 92:8, 95% ee
+H
O1. 16 (10 mol%), CH2Cl2, –78°
2. aq. HCl
O
EtOOH O
SBu-tSBu-t
OTMS
(93%) dr = 92:8, 95% ee
+
O
EtOO
H
NNN Sc
OO
Ph Ph
CH2Cl2, –78°2. aq. HCl
1.
16 (10 mol%)
+
Cl ClSbF6
–
40 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 40
In addition to the traditional enoxysilanes derived from ketones and esters, thebisoxazoline catalysts have been shown to mediate an aldol-type addition betweenaldehydes and 5-alkoxy-substituted oxazoles to afford substituted oxazolines(Eq. 88).241 In the initial reports on these unusual addition reactions, wherein copper-bisoxazoline complexes are employed, it was necessary to use aldehydes thatcan chelate the metal center (Eq. 88). Interestingly, the use of a new class of alu-minum complexes permits the use of a wider range of aryl-substituted aldehydes forwhich chelation is not a prerequisite (Eq. 89),241 affording adducts not only possess-ing high relative, but also absolute stereocontrol. For the typical reaction, 20 mol%of aluminum catalyst is prescribed and the addition reactions can be carried out atambient temperature.
(Eq. 88)
The bisoxazoline-derived complexes of tin(II) and copper(II) which have provenso successful in additions to aldehydes that display the ability to form a five membered-ring chelate, are also effective in pyruvate and 1,2-diketone additions(Eqs. 90 and 91).70,197 Thus, at 10 mol% loading, additions of enol silanes to suchketones can be effected in 84–96% yield and up to 99% ee. It is worth noting thatthe tin(II)- and copper(I)-catalyzed additions provide access to products possessingcomplementary simple stereochemical patterns.
N
O OMe O
N
CO2Et
CO2Me
EtO
OTHF, –40°
R R
H
O
+
MeOMeO
O
N N
O
t-Bu Bu-tCu
2 OTf–
2+
4 (1 mol%)
RHMe
(99%)(94%)
dr95:594:6
% ee9799
(Eq. 87)O
EtOSEt
OTMSEtO
O
OH
SEt
O16 (10-15 mol%)
CH2Cl2, –78°, 16 hH
O
+
(90%) 95% ee
(Eq. 86)SEt
OTMSEtO
O
OH
SEt
O
EtO
O
1. 8 (10 mol%), CH2Cl2, –78°, 16 h
(61%) 98% ee
+H
O
2. H+
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 41
c01_tex 4/18/06 12:31 PM Page 41
(Eq. 89)
Recent advances in the use of chiral phosphoramides have permitted the use ofchiral silicon Lewis acid catalysts, which are generated in situ from SiCl4. The reac-tion can be effected with as little as 1 mol% of bisphosphoramide as promoter at�78°. In these additions neither the absolute nor the relative stereochemical out-come of the addition reaction is affected by the geometry of the starting enolate(Eq. 92). This is, of course, a highly desirable feature of the process. Thus, as exemplified by the addition of tert-butyl propionate, both E- and Z-enol silanes afford the anti aldol products in 99�1 enantioselectivity and 99�1 diastereoselec-
(Eq. 91)
O
O
SBu-t
OTMS
OSBu-t
OHO
(85%) dr = 99:1, 98% ee
+
NNN Sn
OO
Ph Ph
2 TfO–
CH2Cl2, –78°2. aq. HCl
1.
(10 mol%)
2+
(Eq. 90)X
OTMS
O
R1OO
R2
O
R1OX
OHO R21. 4 (10 mol%), THF, –78°
2. aq. HCl
(84-96%) 36-99% ee
R1, R2 = Me, Me; Bn, Me; t-Bu, Me; Me, Et; Me, t-Bu; Et, i-Pr
X = SEt, OEt, Ph, Me
+
O
NCO2Me
O
N
XFOMeCl
(100%)(90%)(99%)
I:II89:1191:9
74:26
% ee I989892
YClBrNO2
NN
O
O
Bu-t
t-Bu
Bu-t
t-Bu
AlX
(5 mol%)X = SbF6
LiClO4 (20 mol%), 3 Å MS,PhMe, rt, 20 h
+N
O OMeMeO
H
O
CO2Me
MeO MeO
Y
X
Y
X
I II
+
Y
X
42 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 42
tivity, with preference for the anti-substituted product. Accompanying mechanisticstudies are consistent with an open transition state and rule out isomerization of thestarting enolate.
(Eq. 92)
A significant departure from the use of traditional enoxysilanes involves thechemistry of trichlorosilyl enolates prepared from the corresponding silyl or stannylenolates.208 The use of trichlorosilyl enolates in aldol addition reactions results in aprocess that is quite general with respect to aldehyde as well as enolate components.Thus, in addition to enolates from esters, ketone-derived enoxysilanes can be em-ployed (Eq. 93).207 The addition of the Z-trichlorosilyl enolate prepared from pro-piophenone to a wide range of aldehydes yields adducts in high simple induction
(Eq. 93)
(syn/anti up to 18�1) and absolute selectivity (up to 96% ee). Trichlorosilyl enolatesprepared from cyclohexanone have also been examined in additions to aldehydes(Eqs. 94 and 95).134 Both syn and anti aldol products can be produced at will by selection of the chiral phosphoramide, wherein a simple change in the N-substituentfor a given enantiomer of a phosphoramide catalyst can lead to generation of the diastereomeric product.
(Eq. 94)
OSiCl3 O
Ph
OH O
Ph
OH
I II
+Ph
(94%) dr = 1:99, 97% ee
+H
O
2. aq. NaHCO3
1. 17 (10 mol%), CH2Cl2, –78°, 2 h
Ph
O
Ph
OH
Ph
O
Ph
OH
I II
2. aq. NaHCO3Ph
OSiCl3+
(95%) I:II = 18:1, 95% ee
Ph H
O+
1. 17 (15 mol%), CH2Cl2, –78°, 6-8 h
OBu-t
OTBS
OBu-t
OOH
SiCl4 (1 mol%), –78°, CH2Cl2
E:Z95:5
12:88
% ee>99>99
dr99:199:1
H
O+
NN
P
Me
MeO
NMe
(CH2)5
29 (1 mol%)
(93%)(73%)
Ph Ph
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 43
c01_tex 4/18/06 12:31 PM Page 43
(Eq. 95)
The studies of these systems have included an examination of enolates derivedfrom chiral ketones (Eq. 96).210 For the ketone-derived Z-enolate examined, the synaldol is formed preferentially. Further studies employing chiral ketones have re-vealed interesting results.209,210,242 The addition can show excellent catalyst controlbut having the requisite starting enolate geometry is critical (Eqs. 97 and 98).
(Eq. 96)
(Eq. 97)
OTIPSCl3SiOOTIPSO
Ph
OH OTIPSO
Ph
OH
I II
catalyst (10 mol%),
CH2Cl2, –78°, 8 h
OTIPSO
Ph
OH OTIPSO
Ph
OH
III IV
+
+
Ph
O
H+
Z:E16:116:11:15
(84%)(80%)(86%)
I:IV1:1610:11:1
I+IV:II+III30:126:13:1
+
catent-171717
O
Ph
OH
diastereomers
OTMS
OTBS2. ent-17 (5 mol%), CH2Cl2, –78°, 10 h OTBS
(88%) dr = 95:5
Ph H
O+
1. Hg(OAc)2, SiCl4, CH2Cl2, rt
+
OSiCl3 O
Ph
OH O
Ph
OH
I II
CH2Cl2, –78°
(10 mol%)
NPON
NPh
Ph
R
R
Ph H
O++
RPhMe
(94%)(95%)
I:II97:11:61
% ee I5192
44 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 44
(Eq. 98)
A particularly noteworthy feature of these Lewis base catalyzed additions oftrichlorosilyl enolates is the fact that crossed aldol addition reactions can be effected(Eqs. 99 and 100).75 This rather remarkable process utilizes both E- and Z-enolatesfrom an aldehyde, with each showing complementary relative diastereoselectivity.
(Eq. 99)
(Eq. 100)
Catalysts derived from complexes prepared with metals such as lead,243 sil-ver,244,245 platinum,143 and lanthanides246 mediate catalytic, enantioselective propi-onate aldol addition reactions. The addition of propiophenone to benzaldehydemediated by a praseodynium complex prepared with a chiral macrocyclic ether isnoteworthy, as it is a rare example of the use of a lanthanide in such aldol additionreactions and constitutes the successful use of a macrocyclic ligand (Eq. 101). Theaddition of isobutyrate-derived enoxysilanes catalyzed by platinum(II) complexes isalso interesting for a number of reasons (Eq. 102).143 Firstly, the additions afford amixture of both silylated product and free alcohol, with both adducts formed withidentical enantioselectivity. Secondly, the enantioselectivity of the process actually
C5H11
OSiCl3
Ph
OHCHO
C5H11
1. 9 (5 mol%), CHCl3/CH2Cl2 (4:1), –78°, 6 h
+
(91%) dr = 97:3, 82% ee
Ph
O
H 2. MeOH
C5H11
OSiCl3Ph
OHCHO
C5H11
1. 9 (5 mol%), CHCl3/CH2Cl2 (4:1), –78°, 6 h
(92%) dr = 99:1, 90% ee
+Ph
O
H 2. MeOH
Cl3SiO OTIPScatalyst (10 mol%), Bu4NI (20 mol%),
CH2Cl2, –78°, 8 h
O
R
OH
I
OTIPS O
R
OH
II
OTIPS O
R
OH
III
OTIPS O
R
OH
IV
OTIPS+ +
RPhPh1-C10H7
1-C10H7
(84%)(82%)(71%)(79%)
I:IV24:11:889:11:17
I+IV:II+III53:132:114:114:1
R H
O+
+
catent-1717ent-1717
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 45
c01_tex 4/18/06 12:31 PM Page 45
benefits from the inclusion of oxygen and water during catalyst preparation. It is alsointriguing as it represents one of the few processes in which an isobutyrate additionis proposed to proceed by way of a metalloenolate intermediate. The reaction pre-scribes the use of 20 mol% catalyst, furnishing adducts in up to 95% ee.
(Eq. 102)
Simple chiral bisphosphine silver(I) complexes catalyze enantioselective additionreactions of stannyl enolates,244 trimethoxysilyl enolates,245 and diketene247 with alde-hydes. Under typical conditions, the addition reaction is catalyzed by 5–10 mol% ofsilver-BINAP complexes at �20°. The additions involving tin(II) enolates prescribethe use of a complex prepared from AgOTf and BINAP. The requisite tin enolatesfor the aldol addition can be prepared prior to use (Eq. 103) or can be generated insitu from the corresponding enol acetates (Eq. 104) or diketene (Eq. 105) upontreatment with Me3SnOMe. In such addition reactions, adducts are formed in up to
(Eq. 103)
OSnBu3(R)-BINAPMAgOTf (10 mol%)
THF, –20°
O
Ph
OH O
Ph
OH
+
(90%) I:II = 85:15, I 96% ee
+Ph
O
H
I II
O
OOTMS
OMe
OH
OMe
O
P
PPt
Bu-t
Bu-t(5 mol%),
TMSO
OMe
O+
TfOH (5 mol%), 2,6-lutidine (5 mol%)
CH2Cl2, –25°
(94%) I:II = 51:49, 95% ee
+Ph
O
H
Ph Ph
I II
Ph2
Ph2
(Eq. 101)OTMS
Ph
O
Ph
OH
Ph
N
O
O
O
O
N
Pr(OTf)3 (24 mol%),H2O/EtOH (1:9), 0°, 18 h
(85%) dr = 91:9, 82% ee
+Ph
O
H
(20 mol%)
46 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 46
96�4 anti:syn diastereoselectivity and up to 96% ee. Alternatively, ketone-derivedtrimethoxysilyl enol ethers have been employed in MeOH with the complex pre-pared from BINAP and AgF (Eq. 106). This represents a noteworthy example of atransition metal catalyzed process involving aldol addition that can be carried outsuccessfully in a polar, protic solvent.
(Eq. 104)
(Eq. 106)
There have been some recent exciting advances in asymmetric phase-transfercatalysis that make possible the addition of substituted ketone-derived enol silanesto aldehydes with useful levels of relative and absolute induction (Eq. 107).248
(Eq. 107)
OTMS
N
HSO4–
(2 mol%)
KFM2H2O (0.5 equiv), THF, rtAr = 3,5-(CF3)2C6H3
OOH
Ar
Ar
(90%) dr = 94:6, 91% ee
CHO
+
+
OSi(OMe)3
Bu-t
(R)-BINAPMAgF (10 mol%)
MeOH, –78°
O
Ph
OH O
Ph
OH
Bu-t Bu-t+
(77%) I:II = 1:99, I 97% ee
+Ph
O
H
I II
(Eq. 105)(R)-Tol-BINAPMAgOTf (22 mol%)
(59%) 84% ee
OO
OMePh
OOOH
Ph H
O+
Bu2Sn(OMe)2 (20 mol%), MeOH (2 equiv), THF, –20°
OCOCCl3(R)-p-Tol-BINAPMAgOTf (5 mol%)
O
Ph
OH O
Ph
OH
+
(86%) I:II = 94:6, I 96% ee
+Ph
O
H
I II
Me3SnOMe (5 mol%), MeOH (2 equiv), THF, –20°
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 47
c01_tex 4/18/06 12:31 PM Page 47
Direct Aldol Addition Reactions of Substituted Systems. The direct aldol addition reactions of enolizable carbonyl compounds have been of interest for sometime and are known for a wide range of C=O activated C–H acids, including esters,ketones, and aldehydes. One of the earliest examples from this class involves the ad-dition of isocyanoacetates to aldehydes mediated by bis-phosphine gold complexes(Eqs. 2, 108, and 109).55,56,58 – 60 Despite the fact that the process is now well over 25 years old, it remains noteworthy because of the high levels of relative and ab-solute stereocontrol that can be obtained. Additionally, the process can be conductedwith low catalytic loadings. The addition of substituted �-isocyanoacetates is possi-ble, with the phenyl-substituted derivative affording products in the highest levels ofrelative and absolute induction (Eq. 109). Since its original disclosure the enolateprecursor can be widely varied to include amides63,249 and other esters.250,251 Addi-tional developments in ligand innovation and design,252,253 as well as the use of othermetals (e.g. platinum),254 have also yielded improvements.
(Eq. 108)
(Eq. 109)
The first of the more recent advances in the in situ enolization of carbonyl C–Hacids and the subsequent stereocontrolled addition of the derived enolates to alde-hydes was documented with lanthanide binaphthoxide catalysts, a class of bifunc-tional catalysts notable for their convenient synthesis and ready accessibility. These
Fe PPh2
PPh2
MeN N
O
[Au(c-C6H11CN)2]BF4 (1 mol%),
CH2Cl2, rt, 65-200 h
OMe
OCN
O N
PhO
OMeO N
PhO
OMe
I II
Ph
Ph Ph
Ph H
O
(97%) I:II = 93:7, I 94% ee, II 53% ee
+
+
(1.1 mol%)
[Au(c-C6H11CN)2]BF4 (1 mol%)
CH2Cl2, rt, 20-40 hOMe
OCN
ON
O OMe
n-C13H27n-C13H27
(89%) 93% ee
H
O+
Fe PPh2
ent-1 (1.1 mol%)
MeN
NPPh2
48 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 48
catalysts make possible the direct addition of ketones and hydroxy ketones to alde-hydes in useful levels of relative and absolute stereoselectivity (Eqs. 110 and111).65,83,216
(Eq. 110)
(Eq. 111)
There have also been advances in this area involving the use of zinc(II) com-plexed to chiral alkoxy or phenoxy ligands (Eqs. 112 and 113, and Fig. 22).83,213,214
(Eq. 112)
O
OH
OMe
C5H9
O
OH
OH
C5H9
O
OH
OH
I II
THF, –30°, 16-24 h
(88%) I:II = 88:12, I 95% ee, II 91% ee
OMe OMe
+C5H9 H
O
O
OO
OO
ZnZn
10 (1 mol%)
+
(S)-LLB (10 mol%), KHMDS (9 mol%)
H2O (20 mol%), THF, –40°
O
OH
OH O
OH
OH
+
O
OH
(50%) dr = 81:19, I 98% ee, II 79% ee
OMe
PhH
O
3
Ph Ph
I IIOMe OMe
+
PhCHO
O
OH
Ph
O
(R)-LLB (8 mol%), KHMDS (7.2 mol%)
H2O (16 mol%), THF, –20°, 99 h
OH
Ph
O
+
I II(95%) I:II = 93:7, I 76% ee, II 88% ee
+
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 49
c01_tex 4/18/06 12:31 PM Page 49
Figure 22. Application of the zinc-catalyzed aldol reaction to the synthesis of boronolide 1.
The ligands are derived from linked BINOL or bisprolinols anchored around a phe-nol. The typical addition reactions are conducted at reduced temperature and provideadducts in impressive levels of selectivity. For the BINOL-derived systems catalyticloadings as low as 1 mol% have been documented, while for the prolinol-derivedsystems slightly higher loadings are prescribed.65,218,222 A zinc(II) catalyst has beenused in the synthesis of boronolide 1 (Fig. 22).213
There has been an intriguing report of titanium-catalyzed in situ aldol addition reactions involving ketones and non-enolizable aldehydes (Eq. 114). It is particularlynoteworthy that a racemic titanium/BINOL complex is employed, which in the pres-ence of optically active mandelic acid produces the aldol adducts as a 91�9 mixtureof diastereomers with the major syn isomer formed in 91% ee.255
There are reports of in situ enolization and aldol addition reactions mediated bycatalytic phase-transfer catalysts.256 The addition of glycinate Schiff bases to alde-
(Eq. 114)O
Ph
OOHrac-BINOL2-Ti2(OPr-i)3
(R)-mandelic acid (10 mol%), rtPh H
O
(85%) dr = 91:9, 91% ee
+
OH
OO
OH
OO
n-Bu
OH
(5 mol%)
Et2Zn (10 mol%), 4 Å MS
THF, –35°, 24 h
(90%) dr = 6:1, 97% ee
n-Bu H
O+
O
O
OAc
OAc
OAc
boronolide 1
Ar = 4-PhC6H4
NNArAr OH HO
ArAr
OH
(Eq. 113)OH
OO
OH
OO
c-C6H11
OH Et2Zn (10 mol%), 4 Å MS,
THF, –35°, 24 h(90%) dr = 6:1, 96% ee
c-C6H11 H
O+
NNPhPh OH HO
PhPh
OH
11 (5 mol%)
50 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 50
hydes under basic conditions in the presence of a chiral tetraalkylammonium phasetransfer agent furnishes protected amino alcohol products in 2�1 dr and 95% ee(Eq. 115).
(Eq. 115)
Proline has been investigated in the addition reactions of substituted ketones toaldehydes. These proline-mediated reactions, as well as other amine-catalyzed aldoladdition reactions, are remarkable because of the high level of regio- and enantiose-lectivity they display. Thus, in an early example, the addition of cyclohexanone toisopentanal using 20 mol% of proline affords a 7�1 mixture of anti/syn adducts in86 and 89% ee, respectively (Eq. 116).257 Hydroxyacetone has also been demon-strated to undergo facile, regioselective aldol addition reactions.66,258 The addition ofexcess hydroxyacetone to isobutyraldehyde mediated by 20–30 mol% of L-prolinein DMSO at ambient temperature affords the adducts as a 20�1 mixture favoringthe anti diol, itself isolated in 99% ee (Eq. 117). The ability to access 1,2-anti diolproducts complements the more conventional method involving asymmetric dihy-droxylation of unsaturated ketones.259 These reactions have also been carried out inionic liquids71,260,261 and with polymer-bound 4-hydroxyproline.262,263
(Eq. 116)
Recent studies in this area have subsequently shown that it is possible to effectcrossed aldol addition reactions between two aldehydes to give adducts in useful
(Eq. 117)
O
OH
O
i-PrOH
OHL-proline (25 mol%)
DMSO, rt, 60 hi-Pr H
O
(62%) dr = 20:1, >99% ee
+
L-proline (20 mol%)
CHCl3, rt, 60 h
O
I II
OOH OOH
+H
i-PrO
(41%) I:II = 7:1, I 86% ee, II 89% ee
+ i-Pr i-Pr
OBu-t
ON OBu-t
O
c-C6H11
OH
NH2c-C6H11 H
O
(78%) dr = 2:1, 95% ee
+
Ph
Ph
N
HSO4–
(2 mol%)
aq. NaOH (1 mol%), PhMe, 0°Ar = 3,5-(CF3)2C6H3
Ar
Ar
+
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 51
c01_tex 4/18/06 12:31 PM Page 51
levels of simple diastereoselectivity and high enantioselectivity (Eq. 118).86 For theaddition of propionaldehyde to isobutyraldehyde or cyclohexanecarboxaldehyde thesimple induction can be as high as 24�1; however, for additions to aldehydes suchas propionaldehyde and isopentanal the selectivity is 3–4:1, with a preference forthe anti adduct. The key to the success of this process appears to be the selection ofthe appropriate reactive components and the reaction conditions; thus, slow additionof the nucleophilic aldehyde component to the electrophilic aldehyde counterpartand 10 mol% of proline in DMSO at 4° constitute the optimal conditions for thecross-aldol addition reaction. The addition reaction of aldehydes to non-enolizableketones has also been documented, affording adducts in 90% yield and up to 90% ee(Eq. 119)264,265
Enoxysilanes of Acetoacetate and Furan. The addition reactions of dienolatesare gaining increased attention, as they provide access to densely functionalizedbuilding blocks for asymmetric synthesis. These additions offer a unique advantagein molecule assembly as a C4 carbon unit is appended to the aldehyde in the courseof aldol addition. Consequently, they offer enhanced efficiency over an iterativealdol process that would otherwise require two sequential aldol addition reactionswith concomitant protections and oxidation-state adjustments.
One of the earliest examples of the use of a dienolate, namely 1-methoxy-3-trimethylsilyloxy-1,3-butadiene, is the aldol addition reaction mediated by 20 mol%of a tryptophan-derived oxazaborolidine catalyst at �78° in propionitrile(Eq. 120).181 The first-formed aldol adducts are converted upon treatment with mildacid into the corresponding 4H-pyran-4-ones with optical purity of up to 82% ee.
Pioneering examples of the use of acetoacetate-derived dienoxysilanes in alde-hyde additions were reported using both boron- and titanium(IV)-derived catalysts
(Eq. 120)
OMe
OTMS EtCN, –78°, 14 h
2. CF3CO2H
O
OPhPh H
O+
(100%) 82% ee
NH
NTs
BBuO
O
13 (20 mol%)
1.
(Eq. 119)
O OHEtO2C
EtO2C
L-proline (50 mol%)
CH2Cl2, rt, 3 hEtO
O
+
(90%) 90% ee
O
H H
O
O
OEt
(Eq. 118)
OHL-proline (10 mol%)
DMF, 4°
O
H
(80%) dr = 4:1, 99% ee
H
O
52 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 52
(Eqs. 121 and 122).266,267 In these reactions large loadings of catalyst were necessaryalong with slow addition of the aldehyde substrate and the products were isolated in38–69% yield and 67–92% ee.267
Advances in the enantioselective addition of acetoacetate-derived dienolates hasbeen reported with the titanium(IV) complex 5 and its enantiomer. The adducts areformed with as little as 2 mol% catalyst loading (Eq. 123).35,139 The fact that �-stannylpropenal can be used successfully as a substrate permits access to aldoladducts that can be subsequently extensively functionalized, providing convenientbuilding blocks for complex molecule assembly. This ability significantly facilitatesthe assembly of polyacetate-derived natural products, as exemplified in the synthe-sis of macrolactin A (Fig. 23).35
(Eq. 123)
OTMS
O O
O
OO
R
OHRCHO Et2O, 0°
2. TFA, THF+
N
Bu-t
BrO O
O
t-Bu
Bu-t
OO
Ti
ent-5 (2 mol%),
1.
R(E)-PhCH=CHPh
(88%)(83%)
% ee9284
(Eq. 122)
R H
O O O
OTMS R O
OH
(20 mol%),
OOTHF, –78°, slow addition
acidic work up
OO
TiCl
Cl
+
RPhn-Bu
(38%)(55%)
% ee8892
(Eq. 121)O O
OTMS R O
OH OO
(50 mol%),O
O CO2H
CH2Cl2, –78°, slow addition
acidic work up
MeO
OMe OB
O
OH
+R H
O
RPhn-Bu
(69%)(52%)
% ee6770
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 53
c01_tex 4/18/06 12:31 PM Page 53
Figure 23. Use of �-stannylpropenal as starting material in the synthesis of macrolactin A.
Bisphosphine copper(I) complexes are also efficient in mediating dienolate addi-tions to aldehydes. Thus, the complex that is generated upon mixing Tol-BINAP,Cu(OTf)2, and (Bu4N)Ph3SiF2 effects the rapid addition reaction of acetoacetate-derived dienolates to aldehydes to give adducts in high yield and with high selectiv-ity (Eq. 124).69,190,268,269 The addition of these dienolates to crotonaldehyde and otherunsaturated aldehydes serves as an important launching point in a total synthesis ofleucascandrolide A (Fig. 24),270 salicylhalamide A (Fig. 25),271 and madumycin 1(Fig. 26).268
Figure 24. Application of the copper-catalyzed aldol reaction to the synthesis of leucascandrolide A.
O
O OOH
H
O
OTMS
O O+
O O
O
O
OMe
O
O
NON
OMeO
H
leucascandrolide A
1. (R)-Tol-BINAP (2.1 mol%), Cu(OTf)2 (2.0 mol%),
(48%) 91% ee
3
3 Bu4N+Ph3SiF2
– (4.0 mol%), THF, –78°2. TFA
(Eq. 124)OTMS
O O
Bu4N+Ph3SiF2– (4 mol%),
THF, –78°
O
O
OOH+
SH
O
S(98%) 95% ee
(S)-Tol-BINAP (2.1 mol%), Cu(OTf)2 (2 mol%)
OTMS
OOBu3Sn
TMSO
O
O O
Bu3Sn
O
H
SnBu3
TMSO
O
OO
(80%) 92% ee
+
5 (2 mol%)
OH
O O
HO
HOmacrolactin A
1711
11
17
39
39
ent-5 (2 mol%)
(80%) 92% ee
54 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 54
Figure 25. Application of the copper-catalyzed aldol reaction to the synthesis of salicylhalamide A.
Figure 26. Application of the copper-catalyzed aldol reaction of enoxysilane to the synthesis of madumycin 1.
The copper-BINAP system has been examined in the addition reactions of �-substituted 3-pentenoic acid-derived dienolates (Eq. 125).272 In these addition reac-tions, useful levels of stereoinduction are observed, thus considerably expanding thescope of the acetoacetate aldol addition reactions. In studies aimed at the synthesisof octalactin A, the catalytic system afforded a useful intermediate (Eq. 126). 273
(Eq. 125)
OMe
OTMS
n-Bu4N+Ph3SiF2– (20 mol%), THF, rtPh H
O
(80%) 70% ee* not defined
+Ph OMe
OOHCu(OTf)2 (10 mol%),
(S)-Tol-BINAP (11 mol%)
*
OHO
O
O
NO
HN
O
O
BocHNH
O O O
OTMS
+1. CuF, THF, –78°
2. PPTS, MeOH, rt
BocHNOH OO
O
(80%) 81% ee
madumycin 1
14
14
(R)-Tol-BINAP
O
O OOHH
O
OTMS
O O+
salicylhalamide A
(64%) dr = 4.2:1
O OH
HN
OOOH
9
9
1. (R)-Tol-BINAP (2.1 mol%), Cu(OTf)2 (2.0 mol%),
Bu4N+Ph3SiF2– (4.0 mol%),
THF, –78°2. TFA
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 55
c01_tex 4/18/06 12:31 PM Page 55
(Eq. 126)
The catalytic systems that have been shown to effectively mediate additions tochelating aldehydes, such as benzyloxyacetaldehyde, have also been examined in thecontext of dienolate additions.37,74 The additions have been investigated with bothacetoacetate-derived enoxysilanes (Eq. 127) as well as the bis-silyldienolate pre-pared directly from acetoacetate derivatives 20 and 21. The addition has been usedin the preparation of the C4-C9 subunit of phorboxazole B (Eq. 128)274 as well as akey fragment in bryostatin 2 (Fig. 27).275,276
(Eq. 127)
(Eq. 128)
Figure 27. Application of the copper-catalyzed aldol reaction of dienolate in the synthesis of bryostatin 2.
OOMeO2C
O
O
O CO2Me
HO H
HOOH
OH O
O
OH
bryostatin 2
OBu-t
TMSO OTMSBnO
O
OBu-t
OOHBnO
1. ent-8 (5 mol%), CH2Cl2, –78°
2. acidic workup
(85%) 99% ee
+H
O
21
OMe
TMSO OTMSBnO
OH
OMe
OOHBnO
1. 8 (0.5 mol%), CH2Cl2, –78°
(98%) 97% ee
+H
O
20
2. acidic workup3. Me4N(OAc)3BH
OTMS
O O
O
O OBnO
OH
(94%) 92% ee
BnO +H
O
NNN Cu
OO
Ph Ph
2 SbF6–
CH2Cl2, –78°2. aq. HCl, THF
1.
8 (5 mol%)
2+
(90%) 80% ee* not defined
OEt
OTMS+
i-Pr OMe
OOH
n-Bu4N+Ph3SiF2– (20 mol%), THF, rt
Cu(OTf)2 (10 mol%), (S)-Tol-BINAP (11 mol%)
i-Pr H
O
*
56 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 56
Silyloxyfurans are synthetically useful equivalents of �-alkoxysubstituted �,�-unsaturated ester enolates. Their use in aldehyde additions has been documentedusing simple catalyst systems derived from titanium(IV) and BINOL (Eq. 129).277 – 280
The adducts are obtained in modest levels of simple diastereoselectivity and up to90% ee. The use of this system has been documented in a total synthesis of 4-de-oxygigantecin (Fig. 28).281 Bisoxazoline copper(II) complexes are effective in medi-ating these addition reactions as well. Thus, the addition of 1-trimethylsilyloxyfuranto pyruvate (Eq. 130) and benzyloxyacetaldehyde (Eq. 131) employing 10 mol%copper(II) catalyst affords adducts in high diastereoselectivity and 99% ee.197
(Eq. 129)
Figure 28. Use of silyloxyfurans in the synthesis of 4-deoxygigantecin.
(Eq. 130)
(Eq. 131)
O OTMS O
HO
BnO(93%) dr = 91:9, 92% ee
OBnO+
H
O
NNN Cu
OO
Ph Ph
2 SbF6–
CH2Cl2, –78°2. aq. HCl, THF
1.
8 (10 mol%)
2+
MeO
O
O
O OTMS O
HO
MeOO
O
THF, –78°
2. aq. HCl
(99%) dr = 95:5, 99% ee
+
O
N N
O
t-Bu Bu-tCu 2 OTf–
2+
4 (10 mol%)
1.
OOH
O O(R)-BINOL (40 mol%)
Ti(OPr-i)4 (20 mol%), Et2O, –20°+
(80%) dr = 60:40, >96% ee
HC11H23
O
OTMS
OO C11H23O
O OH
OH4-deoxygigantecin
C11H23
O OTMS
Ph
OHO O
Ph
OHO O+
I II
(R)-BINOL (40 mol%), Ti(OPr-i)4 (20 mol%)
Ph H
O+
(99%) I:II = 24:76, I 60% ee, II 90% ee
Et2O, –20°
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 57
c01_tex 4/18/06 12:31 PM Page 57
Domino Reactions Involving Aldol Additions. Among the various excitingnew developments involving enantioselective aldol addition reactions is their use inthe context of domino processes. Although there are only a few examples, these arequite innovative and promising, as a consequence of the ability of such processes topotentially lead to powerful simplifications in synthetic planning and execution.Domino enantioselective processes involving aldol additions can be grouped intotwo general classifications on the basis of whether the aldol reaction is the first stepor the subsequent in a series.
There are several reports of domino sequences in which an aldol addition is theleading step. In these, aldolization is followed by either C=O reduction or ring for-mation. In the first of these, 2 mol% of a chiral yttrium complex effects the crossedaldol addition reaction between non-enolizable aldehydes and isobutyraldehyde.282
In the presence of excess aldehyde, the �-hydroxyaldehyde aldol adduct subse-quently undergoes Tishchenko reduction to afford a selectively protected 1,3-diolwhich is isolated in up to 84% ee (Eq. 132).
Another process in which an asymmetric aldol addition leads the sequence is theintramolecular version of the catalytic, enantioselective Wynberg �-lactone synthe-sis, giving rise to bicyclic lactones through a sequence involving intramolecularaldol and lactone formation (Eq. 133).283 Thus, the formylacid initially undergoesconversion into the corresponding formylketene via chemoselective formation of theacid chloride. The ketene is then suggested to undergo reaction with the cinchona alkaloid catalyst to form a chiral enolate, which subsequently participates in aldoladdition and ring closure. The products formed from these reactions are isolatedenantioselectively in up to 92% ee.
(Eq. 133)
i-Pr2NEt (4 equiv), MeCN, rt, slow addition
NCHO
OHO
ClMe I– (3 equiv)
N
H
HN
MeOAcO
(10 mol%)
OO
(54%) 92% ee
CHO+
•O
(Eq. 132)i-Pr
Ph
O
O
Pr-iOHY5O(OPr-i)13 (2 mol%),
CH2Cl2, 4 Å MS
N NAr Ar
Ph PhH H (13 mol%),
Ph H
O
(70%) 84% ee
+H
O
HO
adamantyl
Ar =
58 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 58
A third example of aldehyde addition as the leading step in a domino sequenceinvolves the addition of two equivalents of diethylketene acetal to phenyl pyruvatein the presence of 20 mol% of a copper-bisoxazoline catalyst (Eq. 134).284 Aldol-likeaddition to the ketone by the electron-rich diethyl ketene acetal leads to the forma-tion of an oxonium intermediate, which is attacked by a second equivalent of the nucleophile to give yet another oxonium intermediate, which is trapped by the newlyformed copper alkoxide, leading to the formation of a densely funtionalized pyran inup to 93% ee.
There are a number of processes wherein aldol addition follows a different initialreaction whose outcome is the generation of an enolate intermediate. Such processeshave been documented in the context of conjugate additions. The reduction ofenones and enoates generally proceeds through the intermediacy of metal enolates.When the conjugate additions are carried out with chiral metal complexes, they pro-vide chiral metal enolates which can subsequently participate in enantioselectivealdol addition reactions. In this respect, the reaction of methyl acrylate with benzyl-oxyacetaldehyde, in the presence of a chiral tridentate bisoxazoline ligand 22, andIr(COD)Cl dimer, and a silane reductant leads to formation of propionate aldoladducts (Eq. 135).285,286 The adduct is formed diastereoselectively with a preferencefor the syn diastereomer (up to 10�1) in up to 96% ee. With certain chiral substratesthe reaction process can display a significant amount of matching/mismatching.Thus, the addition of the acrylate-derived propionate enolate to both enantiomers of3-benzyloxybutyraldehyde using the same catalyst affords complementary products
(Eq. 135)
OMe
O
OMe
OOH
NO
N N
O
22 (3 mol%)BnO
(84%) dr = 8:1, 96% ee
BnOH
O+
1.
[(COD)IrCl]2 (1 mol%), Et2MeSiH, rt, 24 h2. aq. HCl
(Eq. 134)EtO
EtOPh
OOEt
O
OEtO
OEt OEtOEt
PhO
OEt Et2O, –15°
+
(80%) 93% ee
O
N N
O
t-Bu Bu-tCu
2 OTf–
2+
4 (20 mol%)
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 59
c01_tex 4/18/06 12:31 PM Page 59
in equally good selectivities (Eq. 136). However, for a given catalyst enantiomeronly one enantiomer of the chiral 2-benzyloxypropionaldehyde undergoes addition.The reaction process has been applied in the synthesis of borrelidin 1 (Fig. 29), acomplex natural product macrolide isolated from Streptomyces.287
(Eq. 136)
Figure 29. Conjugate reduction/aldol sequence in the synthesis of borrelidin 1.
Enone acceptors can also lead to the formation of enolates through asymmetricmetal-mediated conjugate addition reactions of carbon nucleophiles. The rhodium-catalyzed addition reaction of phenylboronic acid to aryl enones affords an interme-diate rhodium enolate which participates in a subsequent intramolecular aldoladdition reaction, giving cyclic adducts in high yield and up to 95% ee (Eq. 137).288
(Eq. 137)
[Rh(COD)Cl]2 (2.5 mol%),(R)-BINAP (7.5 mol%)
Et
Ph
OHO
Ph
(88%) 94% ee
O
+
O
PhPh(BOH)2H2O (5 equiv), dioxane, 95°
OMe
O
OMe
OOHPMBO
(84%), dr = 6:1, >90% ee
PMBOH
O+
OH
O
O
NC
OH
CO2H
borrelidin 1
1. ent-2 (3 mol%), [(COD)IrCl]2 (1 mol%)
Et2MeSiH, rt, 24 h2. aq. HCl
OMe
O
R OMe
OOH
R(R)-MeCH(OBn)(S)-MeCH(OBn)(R)-MeCH(OBn)CH2
(S)-MeCH(OBn)CH2
(50%)(<5%)(65%)(57%)
syna:synb
>95:5n.d.
89:1188:12
syn:anti>95:5n.d.
2.7:13.0:1
1. 22 (7.5 mol%), [(COD)IrCl]2 (2.5 mol%)
+R OMe
OOH
R OMe
OOH
syna
synbanti
+
+
R H
O
Et2MeSiH, rt, 24 h2. aq. HCl
60 ORGANIC REACTIONS
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In another domino process involving conjugate addition followed by aldol addi-tion, the enolate formed upon asymmetric 1,4-addition of diethyl methylmalonatecarbanion to cyclopentanone participates in an intermolecular aldol addition, afford-ing adducts in up to 89% ee and good yields (Eq. 138).68,289 The catalyst used in thisprocess is the multifunctional complex 23 conveniently formed from LiAlH4 andBINOL. This cascade process has been elegantly employed in a synthesis of 11-deoxy-PGF1� (Fig. 30).
(Eq. 138)
Figure 30. Conjugate addition/aldol reaction sequence in the synthesis of 11-deoxy-PGF1�.
COMPARISON WITH OTHER METHODS
The advances in asymmetric synthesis have been so dramatic and pervasive thatthere are typically numerous approaches available for the synthesis of any givenbuilding block. This should not be perceived as unneccessary duplication or overlap,but is, on the contrary, indispensable for the field and the synthesis of complex organic molecules. Despite the general desire of every methods chemists to developreactions that display broad substrate scope, in reality no method can provide access
HOCO2H
HOH
11-deoxy-PGF1α
OO
CO2Bn
CO2Bn
2. OHC(CH2)5CO2Me3. MsCl, DMAP, toluene4. Al2O3 (73%) 92% ee
CO2Me1. 23 (10 mol%)/ ,
CO2Bn
CO2BnTHF, rt, 72 h
O O
CO2Bn
CO2Bn
OO
AlOO
Li
NaOBu-t, THF, rt
(75%) dr = 12:1, 97% ee
1.
23 (10 mol%),
2.
CO2Bn
CO2Bn
TBDMSOOHC CO2Me
5
CO2MeOH
TBDMSO
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 61
c01_tex 4/18/06 12:31 PM Page 61
to the endless structural space of chiral building blocks. In this respect, even when amethod displays the broadest scope, access to subclasses of starting materials maybe sufficiently laborious that the use of the method may be precluded. In consider-ing the preparation of aldol fragments, one cannot escape considering the use of diastereoselective chiral auxiliary-based methods. The development of asymmetricaldol addition processes has been most thoroughly and successfully studied in thecontext of diastereoselective methods, wherein the stereochemical induction is derived from previously existing stereogenic centers in the nucleophilic enolate,electrophilic aldehyde or ketone component,290,291 or metal fragment.292 – 302 In thisrespect, addition reactions in which the stereochemical outcome of the reaction isderived from a chiral enolate component are most common. In particular, chiral car-boxylic acid derivatives have proven most versatile and general. Hydrolysis of thealdol product affords the �-hydroxy carboxylic acid (or ester) and the conjugate acidof the chiral controlling group. The most common of these relies on the use of chiral imides (Eq. 139).303 – 306 Recent exciting developments in such processes havepermitted considerable expansion in the stereochemical outcome of the reaction by subtle variations in the nature of the auxiliary and conditions employed(Eq. 140)307 – 309 Additionally, the use of readily available ester-derived auxiliaries
has made possible convenient access to anti aldol adducts (Eqs. 141 and 142).310,311
A particularly attractive feature of the use of a chiral auxiliary is undeniable: the factthat the products are diastereomeric allows for ease of isomer purification by simplechromatographic means.
(Eq. 141)O
PhO
NBnMesSO2
(c-C6H11)2BOTf, Et3N
CH2Cl2, –78°, 2 hO
O
NBnMesSO2
OH
H
O+
(90%) dr >96:4
Ph
(Eq. 140)N O
O S
Bn
i-Pr N
OH
O
Bn
O S
(87%) dr >95%i-Pr H
O
1. TiCl4, (i-Pr)2NEt, CH2Cl2, 0°
2.
(Eq. 139)N O
O O
Bn
O
HPh+ N O
O O
Bn
OH
Phn-Bu2BOTf, i-Pr2NEt,
Et2O
(84%) dr >97%
62 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 62
(Eq. 142)
In parallel with the developments in imide-derived chiral auxiliaries, there havebeen exciting advances in the use of chiral boron reagents which allow for the for-mation of chiral enolates (Eqs. 143 and 144).312 – 314 These permit efficient stereose-lective coupling of ketone enolate and aldehyde fragments and are particularlynoteworthy in the context of complex fragment couplings, imparting a great degreeof convergency in the assembly of polyketides.
(Eq. 144)
There has been a dramatic increase in the understanding of the various factors inthe aldol addition reaction involving chiral enolate and chiral aldehyde coupling reactions. The nature of these processes makes them particularly amenable to mech-anistic studies and analysis, and consequently it is possible to carry out numerousfragment coupling reactions that lead to stereochemically dense polyketide frag-ments (Eqs. 145–147).292,314 However, it should be noted that periodically one findsunexpected results even in chiral auxiliary-mediated aldol addition reactions, whichrequire reevaluation of the accepted models in this area (Eq. 148).315,316
(Eq. 145)n-Bu2BOTf
(i-Pr)2NEt, Et2O, –78°
(89%) anti:syn = 95:5
+H
O
Ph
O OPMB O OPMBOH
Ph
SPh
OH
OMeO
TBSO
+
NB
N
PhPh
Br
Ar Ar
(i-Pr)2NEt
OHMeO
TBSO
SPh
O
(85%) 96% dsAr = 4-O2NC6H4O2S
(Eq. 143)H
O O (–)-Ipc2BCl
(i-Pr)2NEt, Et2O
OH O
(68%) 78% ee
+
O
O NHTs
+
(63%) I:II = 99:1
H
O
Ph+
TiCl4, (i-Pr)2NEt
CH2Cl2, rt
I II
O
O NHTsOH
Ph O
O NHTsOH
Ph
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 63
c01_tex 4/18/06 12:31 PM Page 63
(Eq. 147)
(Eq. 148)
An overview of the aldol reaction in its various incarnations reveals an interest-ing dichotomy in the development of the two general class types for stereocontrolwith respect to the family of ketides they provide access to. Thus, although chiral-auxiliary controlled diastereoselective aldol processes that afford syn or anti �-substituted �-hydroxy carbonyl compounds allow the ready synthesis of propionatefragments, they in general do not work well, with some exceptions (Eqs. 149 and150),317 – 320 in furnishing acetate adducts. Yet, this latter case of aldol processes canbe effected by employing a number of different enantioselective catalysts. It can be said with some confidence that further developments in the field will fill in the respective gaps of each strategy providing versatile, enabling reactions for the syn-thetic chemist.
(Eq. 149)
LDA, –100°
(89%) dr = 50:1
Ph H
OO
O
OPh
O Ph
OHPh
OHPhPh
OH
Ph+
Ph
OBu-t
OOLi OTES
THF, –120°
OBu-t
OO OTES
OBu-t
OO OTES
+OH OH
H
O
(68%) I:II = 5:1
+
I II
+(c-C6H11)2BCl
Et3N, Et2OO
TBSO OTBS
OHTBSO
(84%) syn:anti = 82:18
TBSO O
H O
OTBSTBSO
(Eq. 146)+
H
O O
OBz
(c-C6H11)2BCl
Me2NEt, Et2O
OH O
OBz(97%) dr = 98:2
64 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 64
(Eq. 150)
There are alternatives in catalytic asymmetric synthesis methods that do not involve aldol coupling reactions and furnish access to hydroxycarbonyl compounds.These can be highly effective means of accessing polyketide fragments. The prepa-ration of both acetate and propionate fragments can be effected by catalytic, asym-metric hydrogenation of �-diketones and �-keto esters (Eq. 151).321,322 Applicationsof these highly effective processes are numerous. A particularly innovative applica-tion involves the asymmetric reduction of 1,5-dichloro-2,4-pentanone to an opticallyactive diol and conversion of the diol product to the corresponding diepoxide, whichserves as a useful starting material (Eq. 152).323 Optically active monosubstitutedepoxides can be directly converted into �-hydroxycarbonyl compounds (Eq 153).324
These serve as entry points for the preparation of anti-propionate subunits via thealkylation of �-alkoxyenolate dianions.325 – 328
(Eq. 152)
The allylation reaction of aldehydes leading to the formation of homoallylic alcohols has long been recognized as a useful, practical alternative for the genera-tion of aldol fragments.329,330 Convenient access to �-hydroxycarbonyl compoundsis available from optically active homoallylic alcohols by oxidative olefin function-alization. These alcohols are readily accessed through asymmetric allylation reac-tions of aldehydes.331 – 340 The use of chiral allylboron reagents is most common
(Eq. 153)Co2(CO)8 (5%), 3-HO-pyr (10%)
CO, MeOH, THF, 60°O OH
OMe
O(92%)
O OOH OHClCl KOH 1. Li2NiBr4
2. acetone, CSA O OBrBr
(79%) overall from diol
(Eq. 151)O (S)-BINAP-Ru
50 atm H2, rtBnO OMe
O OH
BnO OMe
O
(94%) 99% ee
O
O
Pr-i
Pr-i LDA/THF O
O
Pr-i
Pr-iPh
OH
Ph H
O
O
O
Pr-i
Pr-iLi
(62%) dr >99:1
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 65
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(Eqs. 154 and 155).341 – 343 Chiral allyllithium reagents generated in the presence ofsparteine have also been documented (Eq. 156).344 Optically active allylsilanes havebeen cleverly utilized in the synthesis of complex polyketides (Eqs. 157 and158).345,337 A particularly attractive feature of these processes is that alteration of thereaction conditions can lead to divergent stereochemical patterns in the products. Re-lated methods commencing with chiral propargyl mesylates (Eq. 159) and allenyl-stannanes (Eq. 160) have been described and elegantly employed in complexmolecule assembly.346
(Eq. 155)
(Eq. 156)
(Eq. 158)CO2MeSiPhMe2
O
HBnO +
MgBr2
CH2Cl2, –78° CO2Me
OHBnO
(59%) syn:anti = 1:12.2
(Eq. 157)CO2MeSiPhMe2
O
HBnO +
BF3MOEt2
CH2Cl2, –78° CO2Me
OHBnO
(68%) syn:anti = 6.5:1
i-Pr H
O
O N(Pr-i)2
O (–)-sparteine
s-BuLi O N(Pr-i)2
OLi
i-Pr
OHO N(Pr-i)2
O(95%) 83% ee
+
N
NO
O
O
OBTBDPSO H
TESO OPhMe, sieves, –78°
TBDPSO
TESO OH
TBDPSO
TESO OH
I III:II = 9:1
+
CF3
CF3
(Eq. 154)B
2
H
O+
OHEt2O, –100°(82%) >99% ee
66 ORGANIC REACTIONS
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The catalytic, enantioselective allylation of aldehydes has been examined anddocumented. The use of allyl stannanes in combination with a catalyst system derivedfrom BINOL and Ti(IV) has proven highly effective for the synthesis of homoallylicalcohols (Eq. 161).338,347 The catalytic, enantioselective addition of allyltrimethylsi-lane has been effected with a catalyst derived from TiF4 � BINOL.348,349
(Eq. 162)
There are new developments in the use of homoallylic alcohols for the synthesisof polyketide fragments. Treatment of a homoallylic alcohol with acetone in the pres-ence of mercury leads to the formation of an alkyl mercurial intermediate that cansubsequently undergo carbonylation to afford an aldehyde (Eq. 163).350 – 352 The silyl
(Eq. 163)
Rh(acac)(CO)2 (3 mol%),P(OC6H4Bu-t-2)3 (6 mol%),
i-Pr
PMBO OHYb(OTf)3 (20 mol%)
HgCl(OAc), acetone i-Pr
PMBO O OHgCl
i-Pr
PMBO O O
H
O
800 psi H2/CO, DABCO, EtOAc
(75%)
(—)
1. (S)-1,1'-BINOL (10 mol%), TiF4 (5 mol%), CH2Cl2, MeCN, 0°
(90%) 94% ee
H
O+ TMS
OH
2. Bu4NF, THF, 0°
(Eq. 161) (+)-1,1'-BINOL (10 mol%)
Ti(OPr-i)4, (10 mol%), CH2Cl2, –20°(88%) 95% ee
Ph H
O
Ph+ SnBu3
OH
(Eq. 160)
O
H+
OTES
(88%) syn:anti = 94:6
BnO•
HH
n-Bu3Sn 2. TESOTf, Et3N
BnO1. BF3MOEt2, CH2Cl2, –78°
(Eq. 159)+
H
TBSO O OMs Pd(OAc)2, Ph3P
Et2Zn, THF
TBSO OH
(76%)
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 67
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ethers derived from homoallylic alcohols and diallylchlorosilane participate in adomino sequence of reactions involving directed hydrocarbonylation and intramole-cular allylation of the aldehyde product, providing rapid entry into polyketides sub-units (Eq. 164).353
The ability to prepare optically active epoxy alcohols as well as glycidate deriva-tives provides additional access to ketide fragments (Eqs. 165–167).354 – 358 Chiralepoxy alcohols have been shown to undergo pinacol rearrangements to furnish �-hydroxy aldehydes.359 – 362 Regioselective nucleophilic opening by carbon nucle-ophiles (or hydride) subsequently affords useful ketides.363 – 366
(Eq. 165)
A number of alternative approaches provide access to polyketide fragments andsubunits. The recent development of highly diastereoselective dipolar cycloadditionreactions of nitrile oxides and chiral allylic alcohols furnishes a wide range of sub-stituted isoxazolines that can be easily reductively opened to the corresponding hydroxy ketones (Eq. 168).367 – 369 The cycloaddition reaction of aldehydes withketenes derived from acid bromides is catalyzed by a chiral aluminum complex,
(Eq. 167)S S
TBS
t-BuLi, HMPA
THFS S
TBS Li
BnOO
(2.5 equiv)
BnO OBnSS
OTBSHO
(86%)
(Eq. 166)
OO
BnO
N
O
cumene hydroperoxideTHF/toluene, rt, 7 h
OO
BnO
N
OO
(80%) dr >99:1
OO
BnO
N
OOH
H8-BINOL (5 mol%),Sm(OPr-i)3 (5 mol%)
C3H7
OH
t-BuOOH, Ti(OPr-i)4
D-(–)-diisopropyl tartrateC3H7
OHO
TBSOTf, i-Pr2NEt
(94%) 95% ee
C3H7
OTBSO
H
(78%)
(Eq. 164)H
SiO
1. Rh(acac)(CO)2 (3 mol%), 1000 psi CO, C6H6
OHOH
(55%) dr >10:1
2. H2O2, NaHCO3
OH
68 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 68
which furnishes �-lactones in high selectivity and yield (Eq. 169).370 These lactoneshave been converted into the corresponding aldol fragments.371 Propargylic alcoholshave also been converted into hydroxy carbonyl compounds in high optical purity.372 The alkylation of acetonides has been effectively employed in the synthe-sis of skipped polyols and can be relied upon to provide polyol stretches efficientlywith high levels of induction (Eq. 170).373 In a unique approach to �-hydroxy ketoneand ester fragments, oxabicyclooctanes have been functionalized and cleverly manipulated to furnish long stretches of polyketide subunits (Eq. 171).374 – 376 The
(Eq. 170)
(Eq. 171)
OH Pd(NCMe)2Cl2 (5 mol%), ligand (5 mol%)
Zn(OTf)2 (10 mol%), Me2Zn, (CH2Cl)2, refluxO
OH
HO(90%) 88% ee
1. TBSCl
2. PMBBr
OTBS
PMBOOO
PMP
OTBS
OH
1. O3, NaBH4
2. DDQ
O O
CNCl LiNEt2
O O
•Cl
NLi O O
CNI
O OCl
O O
CNCN H
(45%)
(Eq. 169)
Br
OH
O
C6H11-c
+
N Al N
NBn
Pr-ii-Pr
MeTfTf
(10 mol%)
(i-Pr)2NEt, CH2Cl2
OO
C6H11-c
H
(85%) 94% ee
(Eq. 168)TBSON
O–
+i-PrOH
CH2Cl2OMgBr TBSO
ON
OH
+
(83%)
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 69
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tandem sequence of reactions involving the diastereoselective conjugate addition reaction of cuprates to �-alkoxy-�,�-unsaturated enoates followed by stereoselectiveoxidation of the ensuing enolate is also a powerful approach to polyketides(Eq. 172).376,377
Advances in bioorganic chemistry and biochemistry have resulted in the identifi-cation and engineering of novel enzymatic (Eq. 173 and 174)42 – 44,378 and anti-body45 – 47 catalysts that provide access to aldolate fragments. The processes arenotable by the fact that they are carried out under aqueous conditions and that theyfurnish polar products rich in functionality free of protecting groups.
(Eq. 173)
A number of the aldol addition reactions presented in this chapter are unique inthat other direct routes to hydroxycarbonyl compounds are not easily envisioned be-cause they would require laborious, multi-step synthetic sequences. In this categoryare found the acetoacetate and furan aldol addition reactions, additions affordingisoxazolines, and, significantly, the domino processes that incorporate an aldol addition reaction as part of a multi-step sequence of reactions.
EXPERIMENTAL CONDITIONS
The traditional catalytic aldol addition reactions have involved the use of enoxy-trialkylsilanes. These are conveniently prepared from the corresponding ketone,ester, or thioester for which a number of procedures have been described: ketones379
and esters,37 halo esters,237 acetoacetate,380 substituted acetoactetates,271 and dioxoli-none.266 The preparation of the corresponding trialkoxyenoxysilanes has been de-scribed.246 Trichlorosilyl enolates of aldehydes, ketones, and esters are accessed
(Eq. 174)+ H2N
OH
O L-threonine aldolaseOH
OOH
NH2H
O
(35%) dr >99:1
HON3
OH
2-deoxyribose-5-phosphate aldolase
(70%)
O OH
N3HHO
H
OH
O
HO
+
(Eq. 172)TBSO OMe
BOMO
O
1. Me2CuLi, TMSCl, THF, –78°
TBSO OMeBOMO
O
OH
(86%) ds >50:1
2. KHMDS, THF, Davis oxaziridine, –78°
70 ORGANIC REACTIONS
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from the corresponding enoxysilane or stannyl derivates and have been carefullydocumented.75,207,208,381 The stannane-derived enolates are prepared from the corre-sponding O-enol acetates.381,382 Small amounts of the C-silylated derivative can accompany the desired O-enoxysilane; however, few reports comment on this and,in general, no additional manipulation is undertaken to remove this by-product priorto use. The enol silanes tend to be moisture sensitive and are used unpurified or following distillation under reduced pressure.
The experimental conditions and catalysts vary widely. Although some of thetransition-metal-catalyzed processes can be sensitive to moisture, it is difficult togeneralize, as some are tolerant of moisture and benefit from the addition of smallamounts of water. The amine-catalyzed aldol addition reactions can provide usefulalternatives to the transition-metal-catalyzed processes that form the majority ofprocesses that have been documented. They offer a particular advantage in that theadditional steps typically required to prepare the enoxysilanes are obviated.
So fundamental a reaction as the aldol addition can expect to be the subject of additional scrutiny and study for the foreseeable future. When compared to otherwell-studied processes in catalytic asymmetric synthesis, catalytic, enantioselectivealdol addition reactions are in general far from ideal. In this respect, although impressive enantioinduction has been achieved (99%), the important reaction parameters such as catalytic loading, turn-over numbers, and volumetric efficiencyrequire additional improvement. Advances in this respect will necessitate mechanis-tic insight and reaction innovation.
EXPERIMENTAL PROCEDURES
Phenyl (2R,3S)-2-(Benzyloxy)-5-(tert-butyldimethylsiloxy)-3-hydroxypen-tanoate (Tin-catalyzed Aldol Reaction).227 To a solution of Sn(OTf)2 (0.16 mmol)and SnO (0.16 mmol) in n-PrCN (2.0 mL) was added a solution of (R)-1-methyl-2-(5,6,7,8-tetrahydro-1-naphthylaminomethyl)pyrrolidine (0.19 mmol) in EtCN(2.0 mL). The mixture was cooled to �78° and the aldehyde (0.77 mmol) in EtCN(1.0 mL) and the silylenol ether (0.93 mmol) in EtCN (1.0 mL) were slowly addedto the catalyst over 4 hours. The reaction mixture was further stirred for 2 hours atthe same temperature and then quenched with saturated aqueous NaHCO3. The or-ganic layer was separated and the aqueous layer was extracted with CH2Cl2. Thecombined organic layers were dried over Na2SO4, filtered, and evaporated. Thecrude product was treated with THF/1N HCl (20�1) at 0°. After the usual workup,the crude aldol was purified by chromatography on silica gel to afford the title com-
OTMS
OPh
O
OPh
OH
OBnBnO+
(70%) dr = 95:5, >96% ee
H
OSn(OTf)2 (20 mol%), SnO (20 mol%)
NMe
HN
1-tetrahydronaphthyl (25 mol%),
TBSOTBSO
EtCN, –78°, slow addition2. THF/HCl, 0°
1.
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 71
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pound in 70% yield. The diastereomer ratio was determined by 1H NMR analysis(syn/anti � 95�5). The enantiomeric excess of the syn adduct was determined to be96% ee by HPLC analysis using Daicel Chiralcel AD [hexane/i-PrOH (9�1), flowrate 1.0 mL�minutes, tR � 8.2 minutes (2S,3R), 15.6 minutes (2R,3S)]. syn: [�]25
D
58.0° (c 2.0, CHCl3); IR (neat) 3478, 2928, 1771, 1594, 1493, 1093 cm�1; 1HNMR (CDCl3) � 0.00 (s, 6H), 0.83 (s, 9H), 1.65–1.95 (m, 2H), 2.96 (d, J � 5.6 Hz,1H), 3.66–3.85 (m, 2H), 4.09 (d, J � 3.96 Hz, 1H), 4.26 (m, 1H), 4.52 (d, J �11.6 Hz, 1H), 4.85 (d, J � 11.6 Hz, 1H), 7.04–7.35 (m, 10H); 13C NMR (CDCl3) �–5.5, 18.2, 25.8, 35.4, 60.8, 71.3, 72.9, 80.6, 121.3, 121.4, 126.0, 128.2, 128.3,128.4, 128.5, 129.4, 136.9, 150.4, 169.6. HRMS: [M] calcd for C24H34O5Si,430.2176; found, 430.2169.
Phenyl (2S,3S)-3-Hydroxy-2-methyl-3-(4-methoxyphenyl)propanoate (Zirco-nium-catalyzed Aldol Reaction).180 To a suspension of (R)-3,3�-diiodo-1,1�-bi-naphthalene-2,2�-diol (0.048 mmol) in toluene (1.0 mL) was added Zr(OBu-t)4
(0.040 mmol) in toluene (1.0 mL) at room temperature and the solution was stirredfor 30 minutes. Then n-PrOH (0.32 mmol) and H2O (0.080 mmol) in toluene(0.5 mL) were added, and the reaction mixture was stirred for 3 hours at room tem-perature. After cooling at 0°, benzaldehyde (0.40 mmol) in toluene (0.75 mL) andsilyl enol ether (0.48 mmol) in toluene (0.75 mL) were added successively. The mix-ture was stirred for 18 hours and saturated aqueous NaHCO3 solution (10 mL) wasadded to quench the reaction. After CH2Cl2 (10 mL) was added the organic layer wasseparated and the aqueous layer was extracted with CH2Cl2 (2 � 10 mL). The or-ganic layers were combined and dried over Na2SO4. After filtration and concentra-tion under reduced pressure, the residue was treated with THF/1 N HCl (20�1) for 1 hour at 0°. The solution was then made alkaline with saturated NaHCO3 and ex-tracted with CH2Cl2. The organic layers were combined and dried over Na2SO4.After filtration and concentration under reduced pressure, the crude product was purified by preparative TLC [C6H6/EtOAc (20�1)] to afford the title compound. Theoptical purity was determined by HPLC analysis using a chiral column. HPLC (afteracetylation), Daicel Chiralcel OD, hexane/i-PrOH (30�1), flow rate � 0.5 mL�minute:syn isomer tR � 17.8 minutes (major), tR � 22.5 minutes (minor); anti isomer tR �19.7 minutes (major), tR � 24.3 minutes (minor); IR (neat) 3491, 1756, 1611, 1592,1514, 1493, 1457, 1375, 1304, 1250 cm�1; 1H NMR (CDCl3) anti isomer � 1.14 (d, J � 7.0 Hz, 3H), 2.74 (br, 1H), 3.03 (dq, J � 8.8, 7.3 Hz, 1H), 3.81 (s, 3H), 4.82 (d, J � 8.6 Hz, 1H), 6.91 (d, J � 8.8 Hz, 2H), 7.08 (m, 2H), 7.21–7.40 (m, 5H); de-tectable peaks of syn isomer � 1.34 (d, J � 7.1 Hz, 3H), 5.07 (d, J � 5.6 Hz, 1H);13C NMR (CDCl3) anti isomer � 14.3, 47.5, 55.2, 76.0, 113.8, 121.5, 125.8, 127.9,129.3, 133.5, 150.5, 159.4, 174.4; detectable peaks of syn isomer � 11.9, 47.1, 55.2,
OTMS
OPh
(R)-3,3'-I2BINOL (12 mol%), Zr(OBu-t)4 (10 mol%)
O
OPh
OH
H
O
(94%), dr = 95.5, 99% ee
+
MeO MeOn-PrOH (80 mol%),
H2O (20 mol%), PhMe, 0°
72 ORGANIC REACTIONS
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74.0, 113.7, 121.3, 127.4, 129.3, 129.4, 133.6, 150.3, 159.1, 173.8. HRMS (m�z):[M] calcd for C17H18O4, 286.1205; found, 286.1202.
(R)-1-Hydroxy-1-phenyl-3-heptanone (Boron-catalyzed Aldol Reaction).181
To a solution of catalyst (0.056 mmol) in 0.5 mL of EtCN at �78° in a dry 25-mLround-bottom flask was added benzaldehyde (0.028 mL, 0.28 mmol) followed by 2-trimethylsiloxy-1-hexene (0.080 mL, 0.41 mmol). The reaction mixture was stirredfor 14 hours at �78° and then quenched by the addition of saturated aqueous NaHCO3
solution (10 mL). The mixture was extracted with Et2O (4 � 20 mL) and the com-bined organic phases were dried (MgSO4) and concentrated. The residue was dis-solved in THF (4 mL) and aqueous 1 M HCl (2 mL), and the resulting solution leftstanding for 30 minutes. Saturated aqueous NaHCO3 solution (20 mL) was addedand the mixture was extracted with Et2O (4 � 25 mL). The combined organic phaseswere dried (MgSO4) and concentrated to an oily residue. Silica gel chromatography(5–20% EtOAc/hexane) afforded 0.058 g (100%) of the known title compound.HPLC analysis (Chiralcel AD column with 5% i-PrOH/hexane) indicated an enan-tiomeric excess of 90% (tr major � 11.5 minutes; minor � 13.8 minutes).
Methyl (R)-3-Hydroxy-8-phenyloct-4-ynoate (Titanium-catalyzed Aldol Re-action).188 To a solution of the chiral Schiff base ligand (5.0 mM, 0.066 equiv) intoluene was added Ti(OPr-i)4 (0.030 equiv). The orange solution was stirred for 1 hour at room temperature and 3,5-di-tert-butylsalicylic acid (0.060 equiv, 0.1 M intoluene) was added. Stirring was continued for an additional hour at room tempera-
OMe
OTMSOMe
OOH
(84%) 96% ee
2,6-lutidine (40 mol%), Et2O, 0°2. TBAF, THF
+H
O
Ph(CH2)3 Ph(CH2)3
N
Bu-t
BrO O
O
t-Bu
Bu-t
OO
Ti
(3 mol%)
1.
Bu-n
OTMS
NH
NTs
BBuO
O
(20 mol%),
EtCN, –78°, 14 h
Ph
OH
Bu-n
O
2. 1 M HCl+
Ph H
O
1.
(100%) 90% ee
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 73
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ture. The solvent was removed in vacuo and the orange solid was dissolved in Et2Oto give a 5.0 mM solution (relative to chiral ligand). After cooling the solution to 0°,2,6-lutidine (0.40 equiv) was added, followed by the sequential addition of 6-phenyl-hex-2-ynal (100 mg, 0.581 mmol, 1 equiv) and (1-methoxyvinyloxy)trimethylsilane(102 mg, 0.697 mmol, 1.2 equiv). The reaction mixture was stirred at 0° for 4 hoursbefore it was poured into water. The organic phase was dried over Na2SO4 and con-centrated in vacuo. The residue was dissolved in THF and treated with excess Bu4NF(2–3 equiv). The solution was partitioned between Et2O and 1 M aqueous HCl. Theorganic layer was washed with 5% aqueous NaHCO3 solution and then brine, dried(Na2SO4), and concentrated in vacuo. Purification by chromatography on silica gelusing CH2Cl2/hexanes (10�1) to elute the ligand, followed by CH2Cl2 /Et2O (10�1)afforded 119 mg (84%) of methyl (R)-3-hydroxy-8-phenyloct-4-ynoate, [�]D
19.3° (c 1.01, CHCl3); IR (thin film) 3448, 3026, 2948, 2860, 1739, 1602, 1496,1454, 1438, 1356, 1278, 1167, 1055, 1028, 747, 701 cm�1; 1H NMR (300 MHz,CDCl3) � 1.82 (dt, J � 7.4 Hz, 7.0, 2H), 2.22 (t, J � 7.0 Hz, 2H), 2.70 (t, J � 7.4 Hz,2H), 3.08 (d, J � 6.1 Hz, 2H), 3.73 (s, 3H), 4.77 (q, J � 6.1 Hz, 1H), 7.37–7.17 (m, 5H); 13C NMR (75 MHz, CDCl3) � 18.0, 29.9, 34.6, 42.1, 58.9, 79.8, 85.4,125.8, 128.3, 128.4, 141.4, 171.8; HRMS-EI: [M] calcd for C15H18O3, 246.1256;found, 246.1243.
(R)-S-tert-Butyl 4-Benzyloxy-3-hydroxybutanethioate (Copper-catalyzedAldol Reaction).74 To a 5-mL round-bottom flask equipped with a magnetic stir-ring bar and fitted with a septum was added 200 L (2.5 mol, 0.5 mol%) of a0.0125 M solution of the catalyst in CH2Cl2. After cooling to �78°, benzyloxyac-etaldehyde (74.8 mg, 0.50 mmol, 70.0 L) was added followed by (1-tert-butylsul-fanylvinyloxy)-trimethylsilane (122 mg, 0.60 mmol, 153 L). The resulting solutionwas stirred at �78° until the aldehyde was completely consumed, as determined byTLC (30% EtOAc/hexanes). The reaction mixture was then filtered through silicagel (1.5 � 8 cm plug) with Et2O (50 mL). Concentration of the ether solution gavea clear oil which was dissolved in THF solution (10 mL) and 1 N HCl (2 mL). Afterstanding at room temperature for 15 minutes, the solution was poured into a separa-tory funnel and diluted with Et2O (10 mL) and H2O (10 mL). After mixing, the aque-ous layer was discarded and the ether layer was washed with saturated aqueousNaHCO3 solution (10 mL) and brine (10 mL). The resulting ether layer was driedover MgSO4, filtered, and concentrated to provide pure title compound in 100%yield (141 mg, 0.50 mmol). [�]rt
D �10.9° (c 3.0, CH2Cl2); [�]26D (lit.) 10.0° (c 1.0,
CHCl3) 96% ee (R). The enantiomeric excess was determined by HPLC with a Chi-ralcel OD-H column [hexanes:i-PrOH:EtOAc (94.2�0.8�5.0), 1.0 mL�minute] R
BnOSBu-t
O
SBu-t
OTMS
CH2Cl2, –78°2. aq. HCl, THF
BnO+
H
O
O
N N
O
t-Bu Bu-tCu 2 OTf–1.
(100%) 96% ee
4 (10 mol%) OH
2+
74 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 74
enantiomer tr � 16.3 minutes, S enantiomer tr � 17.9 minutes, 99% ee. 1H NMR,13C NMR, IR, and HRMS were identical to that previously reported.
(S)-4-Hydroxy-4-phenyl-2-butanone (Organocatalyzed Aldol Reaction).383
The trichlorosilyl enolate (421.3 mg, 2.2 mmol, 1.1 equiv) was added quickly to acold (�74°) solution of the S,S-catalyst (37.3 mg, 0.1 mmol, 0.05 equiv) in CH2Cl2
(2 mL). A solution of benzaldehyde (203 L, 2.0 mmol) in CH2Cl2 (2 mL) was cooled to �78° and was added quickly via a short cannula to the first solution.During the addition the temperature rose to �67°. The reaction mixture was stirredat �75° for 2 hours, then was quickly poured into cold (0°) saturated aqueousNaHCO3 solution and the resulting slurry was stirred for 15 minutes. The two-phasemixture was filtered through Celite, the phases were separated, and the aqueousphase was extracted with CH2Cl2 (3 � 50 mL). The organic phases were combined,dried over Na2SO4, filtered, and concentrated, and the residue was purified by col-umn chromatography [SiO2, pentane/Et2O (1�1)] to give 321.6 mg (98%) of the titlecompound as a clear, colorless oil. TLC: Rf 0.16 [hexane/EtOAc (3�1)]; [�]24
D
�51.4° (c 1.47, CHCl3); IR (neat) 3466, 3424, 2910, 1710, 1417, 1361, 1062, 756,701 cm�1; 1H NMR (500 MHz) � 2.19 (s, 3H), 2.81 (ABX, JAB � 17.5 Hz,JBX � 2.7 Hz, 1H), 2.88 (ABX, JAB � 17.5 Hz, JAX � 9.5 Hz, 1H), 3.30 (s, 1H), 5.15(dd, J � 9.1, 3.3 Hz, 1H), 7.36–7.27 (m, 5H); 13C NMR (126 MHz) � 30.7, 51.6,69.8, 125.6, 127.7, 128.5, 142.7, 209.1; MS (CI, CH4) M 164 (19), 147 (30), 146(18), 107 (100), 106 (21), 105(15), 79 (26), 59 (27). Anal. Calcd for C10H12O2: C,73.15; H, 7.37. Found: C, 72.97; H, 7.43.
(R)-4,4-Dimethyl-1-hydroxy-1-phenyl-3-pentanone (Silver-catalyzed Aldol Re-action).94 A mixture of AgOTf (26.7 mg, 0.104 mmol) and (R)-BINAP (64.0 mg,0.103 mmol) was dissolved in dry THF (3 mL) under argon atmosphere and with di-rect light excluded, and stirred at 20° for 10 minutes. To the resulting solution wasadded dropwise a THF solution (3 mL) of benzaldehyde (100 L, 0.98 mmol), andthen 3,3-dimethyl-1-tributylstannyl-2-butanone (428.1 mg, 1.10 mmol) was addedover a period of 4 hours with a syringe pump at �20°. The mixture was stirred for 4 hours at this temperature and treated with MeOH (2 mL). After warming to roomtemperature, the mixture was treated with brine (2 mL) and solid KF (ca. 1 g). Theresulting precipitate was removed by filtration and the filtrate was dried over Na2SO4
Ph H
O
Bu-t
O
Ph
OH
(78%) 95% eeBu-t
O+
Bu3Sn(R)-BINAP (11 mol%)/Ag(OTf) (11 mol%)
THF, –20°, 8 h
OSiCl31.
O
Ph
OHN
PON
NPh
Ph
Me
Me
(98%) 87% eePh H
O+
(5 mol%)
CH2Cl22. aq. NaHCO3
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 75
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and concentrated in vacuo. The crude product was purified by column chromatogra-phy on silica gel to afford the title compound (161.7 mg, 78% yield) as a colorlessoil: TLC Rf 0.22 [EtOAc/hexane (1�5)]; [�]30
D 61.5° (c 1.3, CHCl3); IR (neat)3625–3130, 3063, 3033, 2971, 2907, 2872, 1701, 1605, 1495, 1478, 1455, 1395,1368, 1073, 1057, 1011, 984, 914, 878, 760, 747, 700 cm�1; 1H NMR (CDCl3) �1.14 (s, 9H), 2.89 (d, J � 5.7 Hz, 2H), 3.59 (d, J � 3.0 Hz, 1H), 5.13 (m, 1H),7.29–7.39 (m, 5H). The enantioselectivity was determined to be 95% ee by HPLCanalysis using a chiral column (Chiralcel OD-H, hexane/i-PrOH (20�1), flowrate � 0.5 mL�minute) tminor � 17.7 minutes, tmajor � 20.2 minutes. The absoluteconfiguration of the product was unknown and assigned to be R by analogy.
(S)-3-Hydroxy-4-methyl-1-(3-nitrophenyl)-1-pentanone (Heterobimetallic-catalyzed Aldol Reaction).216 To a stirred solution of potassium bis(trimethylsi-lyl)amide (KHMDS, 43 L, 0.0216 mmol, 0.5 M in toluene) at 0°, was added asolution of water (48.0 L, 0.048 mmol, 1.0 M in THF). The solution was stirred for20 minutes at 0° and then catalyst (400 L, 0.024 mmol, 0.06 M in THF) was addedand the mixture was stirred at 0° for 30 minutes. The resulting pale yellow solutionwas then cooled to �20°, and 3-nitroacetophenone (175 L, 1.5 mmol) was added.The solution was stirred for 20 minutes at this temperature, and then 2,2-dimethyl-3-phenylpropanal (49.9 L, 0.3 mmol) was added and the reaction mixture wasstirred for 28 hours at �20°. The mixture was quenched by addition of 1 N HCl(1 mL), and the aqueous layer was extracted with Et2O (2 � 10 mL). The combinedorganic layers were washed with brine and dried over Na2SO4. The solvent was re-moved under reduced pressure, and the residue was purified by flash chromatogra-phy [SiO2, Et2O/hexane (1�12)] to give the title compound (72 mg, 85%, 89% ee);[�]28
D �40.8° (c 0.56, CHCl3) (70% ee); IR (neat) 3541, 1688, 1535, 1351 cm�1; 1HNMR (CDCl3) � 1.01 (d, J � 7.0 Hz, 3H), 1.02 (d, J � 7.0 Hz, 3H), 1.82 (m, 1H),2.85 (d, J � 3.5 Hz, 1H), 3.13 (d, J � 5.0 Hz, 1H), 3.14 (d, J � 7.0 Hz, 1H), 4.04(m, 1H), 7.69 (m, 1H), 8.31–8.29 (m, 1H), 8.44–8.42 (m, 1H), 8.77 (m, 1H); 13CNMR (CDCl3) � 17.7, 18.5, 33.2, 42.6, 72.3, 123.0, 127.6, 129.9, 133.6, 138.2,148.5, 198.7; MS m�z 237 (M�CH3), 165 (M�i-PrCHO), 150 (ArC�O, basepeak); HPLC [Chiralpak AS, 2-PrOH/hexane (1�9), flow 1.0 mL�minute] tR � 16.1and 18.4 minutes. Anal. Calcd for C12H15NO4: C, 60.75; H, 6.37; N, 5.90. Found: C,60.49; H, 6.51; N, 5.71.
+
O OOHNO2 NO2
(85%) 89% ee
OO O
OOOLi Li
Li
La
(R)-LLB (8 mol%)
H
O
KHMDS (7.2 mol%)H2O (16 mol%), THF, –20°
Ph Ph
76 ORGANIC REACTIONS
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(R)-3-Cyclohexyl-3-hydroxy-1-phenylpropan-1-one (Zinc-catalyzed Aldol Reaction).220 Under an argon atmosphere, a solution of diethylzinc (1 M inhexane, 0.2 mL, 0.2 mmol) was added to the solution of ligand 11 (64 mg, 0.1 mmol)in THF (1 mL) at room temperature. After stirring for 30 minutes (evolution ofethane gas), the resulting solution was used as catalyst for the aldol reaction (ca0.09 M solution). To a suspension of cyclohexylcarboxaldehyde (0.5 mmol), triph-enylphosphine sulfide (22.1 mg, 0.075 mol), powdered 4 Å molecular sieves(100 mg, dried at 150° under vacuum overnight) and acetophenone (5 mmol) in THF(0.8 mL) was added the solution of catalyst (0.025 mmol) at 0°, and the mixture wasstirred at 5° for 2 days. The resulting mixture was poured onto 1 N HCl and extractedwith Et2O. After normal workup, the crude product was purified by silica gel columnchromatography using a mixture of petroleum ether and Et2O. The title compoundwas obtained in 60% yield and 98% ee.
(R)-4-Hydroxy-5-methylhexan-2-one (L-Proline-catalyzed Aldol Reaction).85
L-Proline (0.03–0.04 mmol) was stirred in 1 mL of DMSO/acetone (4�1) for15 minutes. Isobutyraldehyde (0.1 mmol) was added and the mixture was stirred for4–24 hours. The mixture was treated with saturated aqueous NH4Cl solution and ex-tracted with EtOAc. The organic layer was dried (MgSO4), filtered, and concentratedto give the title compound after column chromatography [hexanes/EtOAc (3�1)].
S-tert-Butyl (3S)-3-Hydroxy-3-methoxycarbonyl-2-butanethioate (Copper-catalyzed Aldol).197 To a 10-mL round-bottom flask were added, in an inert
MeO
O
O
SBu-t
OTMS
O
MeOSBu-t
OOH
(88%) dr = 97:3, 99% ee
THF, –78°2. aq. HCl
+
O
N N
O
t-Bu Bu-tCu 2 OTf–1.
4 (10 mol%)
2+
O
i-Pr
OHL-proline (25 mol%)
DMSO, rti-Pr H
O
(97%) 96% ee
+O
Ph
O
c-C6H11 Ph
O
Et2Zn (10 mol%), 4 Å MS, THF, 5°
(60%) 98% ee
c-C6H11 H
O+
NNPhPh OH HO
PhPh
OH
11 (5 mol%) OH
, Ph3P=S
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 77
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atmosphere box, ligand (15 mg, 0.050 mmol) and Cu(OTf)2 (18 mg, 0.050 mmol).The flask was charged with 1.5 mL of THF and the resulting suspension was stirred rapidly for 1 hour to give a clear dark green solution. The catalyst solution wascooled to �78° and methyl pyruvate (45 L, 0.50 mmol) was added, followed bythe silylketene thioacetal (153 L, 0.60 mmol). The resulting solution was stirred at�78° until the pyruvate was completely consumed (0.5–24 hours), as determined byTLC (2.5% Et2O/CH2Cl2). The reaction mixture was then filtered through a 2–4 cmplug of silica gel with Et2O (60 mL). Concentration of the solution gave the crudesilyl ether, which was dissolved in THF (5 mL) and treated with 1 N HCl (1 mL).After being stirred at room temperature for 1–5 hours this solution was poured intoa separatory funnel and diluted with Et2O (20 mL) and H2O (10 mL). After mixing,the aqueous layer was discarded and the ether layer was washed with saturated aque-ous NaHCO3 solution (10 mL) and brine (10 mL). The resulting ether layer wasdried over Na2SO4, filtered, and concentrated to provide the title compound as aclear oil in 88% yield (112 mg, 0.48 mmol) after flash chromatography (10–20%EtOAc/hexanes). Enantiomeric excess was determined by HPLC [Chiralcel OD-Hcolumn (hexanes/2-propanol (99�1), flow � 0.5 mL�minute]: 2S,3S enantiomertr � 13.4 minutes, 2R,3R enantiomer tr � 12.7 minutes, 99% ee; [�]rt
D 25.1° (c5.2, CHCl3); IR (CH2Cl2) 3534, 2967, 1738, 1678 cm�1; 1H NMR (400 MHz, CDCl3)� 1.36 (s, 3H). 1.40 (s, 9H), 2.79 (d, J � 15.8 Hz, 1H), 3.02 (d, J � 15.8 Hz, 1H),3.70 (br s, 1H), 3.75 (s, 3H); 13C NMR (100 MHz, CDCl3) � 26.0, 29.6, 48.6, 52.7,52.9, 72.9, 175.7, 198.1; LRMS (CI/NH3) (m�z): 235 (MH), 252 (M NH4);HRMS (CI/NH3) (m�z): calcd for (C10H18O4S NH4), 252.1270; found, 252.1268.
(2S,1�R)-2-(Hydroxyphenylmethyl)cyclohexanone (Silver-catalyzed Aldol Reac-tion).245–247 A mixture of AgOTf (12.9 mg, 0.050 mmol) and (R)-p-Tol-BINAP(37.3 mg, 0.055 mmol) was dissolved in dry THF (6 mL) under argon atmosphereand with direct light excluded, and stirred at 20° for 10 minutes. To the resulting solution were added dropwise MeOH (81 L, 2.00 mmol), benzaldehyde (100 L,0.98 mmol), 1-trichloroacetoxycyclohexene (243.2 mg, 1.00 mmol), and trimethyl-tin methoxide (0.52 M in THF, 100 L, 0.052 mmol) successively at �20°. Afterbeing stirred for 4 hours at this temperature and then for 12 hours at room tempera-ture, the mixture was treated with MeOH (2 mL). The mixture was treated with brine(2 mL) and KF (ca. 1 g) at ambient temperature for 30 minutes. The resulting pre-cipitate was removed by filtration using a glass filter funnel filled with Celite and sil-ica gel. The filtrate was dried over Na2SO4 and concentrated in vacuo after filtration.The residual crude product was purified by column chromatography on silica gel toafford a mixture of aldol adducts I and II (172.8 mg, 86% yield) as a colorless oil.The anti/syn ratio was determined to be 94�6 by 1H NMR analysis. The enantiose-lectivities of the anti and syn isomers were determined to be 96% ee and 18% ee,respectively, by HPLC [Chiralcel OD-H, hexane/i-PrOH (9�1), flow rate � 0.5 mL�
O
HPh
O(R)-p-Tol-BINAP/Ag(OTf) (5 mol%),
Me3SnOMe (5 mol%), MeOH
CCl3
OO
Ph
OH O
Ph
OH
(86%) I:II = 94:6, I 96% ee, II 18% ee
++THF, –20°-rt, 8 h
I II
78 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 78
minutes]: 2S,1�S enantiomer tsyn-minor � 14.2 minutes, 2R,1�R enantiomer tsyn-major � 15.7 minutes, 2S,1�R enantiomer tanti-major � 17.4 minutes, 2R,1�S enan-tiomer tanti-minor � 24.2 minutes. Spectral data of the anti isomer (oil, 96% ee): TLCRf 0.11 [EtOAc/hexane (1�5)]; [�]32
D 19.7° (c 1.0, CHCl3). IR (neat) 3700–3140,2940, 2863, 1700, 1605, 1497, 1453, 1401, 1312, 1296, 1227, 1204, 1130, 1042,702 cm�1; 1H NMR (300 MHz, CHCl3) � 1.22–1.37 (m, 1H), 1.47–1.81 (m, 4H),2.05–2.13 (m, 1H), 2.31–2.42 (m, 1H), 2.45–2.52 (m, 1H), 2.57–2.67 (m, 1H),3.96 (d, J � 2.8 Hz, 1H), 4.79 (dd, J � 2.8, 8.8 Hz, 1H), 7.28–7.40 (m, 5H,); 13CNMR (75 MHz, CDCl3) � 24.5, 27.6, 30.6, 42.4, 57.3, 74.5, 126.9 (2 C), 127.7,128.3 (2 C), 140.9, 215.3. Spectral data of the syn isomer (white solid, 18% ee): TLCRf 0.13 [EtOAc/hexane (1�5)]; [�]33
D 37.6° (c 1.0, CHCl3); IR (KBr) 3600–3125,2940, 2855, 1701, 1603, 1495, 1449, 1406, 1320, 1132, 1063, 986, 696 cm�1; 1HNMR (300 MHz, CDCl3) � 1.47–1.80 (m, 4H), 1.81–1.91 (m, 1H), 2.04–2.15 (m,1H), 2.32–2.51 (m, 2H), 2.56–2.65 (m, 1H), 3.01 (d, J � 3.2 Hz, 1H), 5.40 (d, J � 2.4, 3.2 Hz, 1H), 7.25–7.37 (m, 5H); 13C NMR (75 MHz, CDCl3) � 24.7,25.9, 27.8, 42.5, 57.1, 70.5, 125.7 (2 C), 126.8, 128.0 (2 C), 141.5, 214.5.
(4S,5R)-4-(Methoxycarbonyl)-5-phenyl-2-oxazoline (Gold-catalyzed Aldol Re-action).253 To a solution of ligand (37.5 mg, 0.055 mmol) in CH2Cl2 (6 mL) wasadded the gold complex (25.1 mg, 0.05 mmol). The reaction mixture was stirred for10 minutes, and then to the resultant solution were added sequentially methyl iso-cyanoacetate (0.45 mL, 5 mmol) and benzaldehyde (0.56 mL, 5.5 mmol). The reactionmixture was stirred for 18 hours at room temperature. The solvent was removed invacuo, and the residue was dissolved in Et2O (20 mL). Any precipitate formed was removed by filtration, and the solvent was removed in vacuo. The residue wasbulb-to-bulb distilled (Kugelrohr), to give a 90�10 cis/trans mixture of the title com-pound in 99% combined yield, which was analyzed by GLC using a Chirasil-L-Valcolumn and by 1H NMR with the chiral shift reagent ()-2,2,2-trifluoro-1-(9-anthryl)-ethyl alcohol.
O
OO
O
OZn
Zn
10 (1 mol%)
THF, –20°, 18 h;then acetone, H+
H
OO
OH
OMe
+
(83%) dr = 89:11, 96% ee
Ph
Ph
O
MeO
OO
[Au(C6H11CN)2]BF4 (1.0 mol%),CH2Cl2 (1 mol%), rt, 18 h
OMe
OCN
O N
PhO
OMeO N
PhO
OMe
I II
Fe PPh2
PPh2
MeN N
O
Ph H
O
(99%) I:II = 90:10, I 91% ee, II 7% ee
+ +(1.1 mol%)
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 79
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(2R,3S)-2,3-Dihydroxy-2,3-O-isopropylidene-1-(2-methoxyphenyl)-5-phenyl-1-pentanone (Zinc-catalyzed Aldol Reaction of a Hydroxyketone).83
Molecular sieves (3 Å, 200 mg, powder) in a test tube were activated prior to useunder reduced pressure (ca. 0.7 kPa) at 160° for 3 hours. After cooling, a solution of(S,S)-ligand (1.54 mg, 0.0025 mmol) in THF (0.6 mL) was added under Ar. Themixture was cooled to �20°. To the mixture was added Et2Zn (10 L, 0.01 mmol,1.0 M in hexanes) at �20°. After the mixture had been stirred for 10 minutes at�20°, a solution of hydroxyketone (182.8 mg, 1.1 mmol) in THF (1.1 mL) wasadded. Hydrocinnamaldehyde (1.0 mmol) was added, and the mixture was stirred at�20°. After 18 hours, the mixture was quenched with 1 M HCl (2 mL). The mixturewas extracted with EtOAc and the combined organic layers were washed with satu-rated aqueous NaHCO3 solution and brine, and dried over MgSO4. Evaporation ofsolvent gave a crude mixture of the title compound. The diastereomeric ratio of thealdol product was determined by 1H NMR of the crude product. After purificationby silica gel flash column chromatography [hexanes/acetone (8�1-4�1)], the titlecompound was obtained (269.6 mg, 0.898 mmol, 90%, dr syn/anti � 89�11, 96% eesyn). Spectral data were collected after conversion into the acetonide. colorless oil;[�]21
D �39.4° (c 0.52, CH2Cl2) (92% ee). HPLC (for diol) [Daicel Chiralcel OD,i-PrOH/hexane (20�80), flow 1.0 mL�minute, detection at 254 nm]: tR � 13.6 min-utes (minor) and 15.9 minutes (major); IR (neat) 2936, 1685, 1598, 1247 cm�1; 1HNMR (CDCl3) � 1.34 (s, 3H), 1.49 (s, 3H), 1.87–1.99 (m, 2H), 2.65 (ddd, J � 6.9,9.8 Hz, 14.1Hz, 1H), 2.80 (ddd, J � 5.5, 10.0 Hz, 14.1 Hz, 1H), 3.82 (s, 3H),4.21–4.23 (m, 1H), 4.95 (d, J � 6.7 Hz, 1H), 6.92 (brd, J � 8.3 Hz, 1H), 6.99 (ddd,J � 0.9, 7.5, 7.5 Hz, 1H), 7.10–7.12 (m, 2H), 7.14–7.17 (m, 1H), 7.22–7.25 (m, 2H), 7.42–7.48 (m, 2H); 13C NMR (CDCl3) � 26.1, 27.5, 31.8, 35.6, 55.6, 77.7,84.7, 110.3, 111.5, 120.8, 125.8, 127.5, 128.3, 128.3, 130.3, 133.3, 141.5, 157.8,201.5. EIMS (m�z): 340 [M], 135 [ArCO]; HRMS-FAB (m�z): [M H] calcdfor C21H25O4, 341.1753; found, 341.1743.
(3S,4S)-4-Cyclohexyl-3,4-dihydroxybutan-2-one (L-Proline-catalyzed AldolReaction of a Hydroxyketone).257 To a mixture of anhydrous DMSO (4 mL) andhydroxyacetone (1 mL) was added cyclohexanecarboxaldehyde (0.5 mmol) fol-lowed by L-proline (25 mol%), and the resulting homogeneous reaction mixture wasstirred at room temperature for 60 hours. Then half-saturated NH4Cl solution andEtOAc were added with vigorous stirring, the layers were separated, and the aque-ous phase was extracted thoroughly with EtOAc. The combined organic phases were dried (MgSO4), concentrated, and purified by flash column chromatography(silica gel, mixtures of hexanes/EtOAc) to afford the title compound. HPLC [Chiralpak AS, hexane/i-PrOH (85�15), flow rate � 1.0 mL�minute, � � 285 nm]:tR � 6.22 minute; [�]D 83° (c 1, CHCl3); IR (NaBr): 3445, 2922, 2351, 1730,1640, 1456, 1373, 1253, 1045, 736 cm�1; 1H NMR: � 0.99–1.37 (m, 1H), 1.58–1.84(m, 1H), 1.92 (m, 1H), 2.31 (s, 4H), 3.52–3.60 (m, 2H), 4.24 (m, 1H); 13C NMR: �
O
OH
O
C6H11-cOH
OHL-proline (25 mol%)
DMSO, rt, 60 hC6H11-cH
O
(62%) dr = 20:1, >99% ee
+
80 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 80
25.8, 26.1, 26.2, 72.4, 29.7, 39.7, 77.5, 78.3, 209.9; HRMS (m�z): [M Na] calcdfor C10H18O3, 209.1148; found, 209.1157.
(R)-6-(2-Hydroxy-4-phenylbut-3-enyl)-2,2-dimethyl-[1,3]-dioxin-4-one (Titanium-catalyzed Aldol Reaction of a Dienolate).139 To a solution of the chi-ral Schiff base ligand (5.5 mM, 0.022 equiv) in toluene was added Ti(OPr-i)4 (0.010equiv). The orange solution was stirred for 1 hour at room temperature and a solu-tion of 3,5-di-tert-butylsalicylic acid (0.020 equiv; 20 mM in toluene) was added.Stirring was continued for an additional hour at room temperature. The solvent wasremoved in vacuo and the orange solid was dissolved in Et2O to give a 5.5 mM solution (relative to chiral ligand). After cooling the solution to 0°, 2,6-lutidine (0.40 equiv) was added to the solution, followed by the sequential addition of cin-namaldehyde (1.0 equiv) and the dienolate (1.5 equiv). After the reaction mixturewas stirred for 4 hours at 0°, it was poured into water. The mixture was extractedwith Et2O. The organic extracts were dried over Na2SO4 and concentrated in vacuo.The residue was treated with 10% TFA in THF. After desilylation was complete thesolution was partitioned between Et2O and water. The organic layer was washedtwice with a 5% aqueous NaHCO3 solution and then with brine. The solution wasdried over Na2SO4 and concentrated in vacuo. Purification by chromatography onsilica gel [hexane/EtOAc (2�1)] afforded the aldol adduct. A portion of the aldoladduct was converted into the corresponding (S)-MTPA ester as follows. To a solutionof the alcohol (0.010 mmol, 1 equiv) and DMAP (10 mg) in CH2Cl2 (1 mL) wasadded (R)-MTPA-Cl (0.011 mmol, 1.1 equiv). The MTPA ester was purified bychromatography on silica gel [hexane/EtOAc (2�1)]. The enantiomeric excess of theproduct was determined by integration of the 1H NMR (300 MHz, CDCl3). The titlecompound was isolated (88%) as a white crystalline solid, mp 85–86°; [�]6.2°(c 1.0, CHCl3). IR (thin film) 3420, 1728 cm�1; 1H NMR (300 MHz, CHCl3) � 1.68(s, 3H), 1.68 (s, 3H), 2.24 (br s, 1H), 2.54 (m, 2H), 4.59 (q, J � 6.6 Hz, 1H), 5.36(s, 1H), 6.20 (dd, J � 15.9, 6.6 Hz, 1H), 6.63 (d, J � 15.9 Hz, 1H), 7.38–7.27 (m, 5H); 13C NMR (75 MHz, CHCl3) � 24.8, 25.3, 41.5, 69.7, 95.3, 106.7, 126.5,128.1, 128.6, 130.2, 131.4, 136.0, 161.1, 168.3; HRMS-FAB (m�z): [M H] calcdfor C16H19O4, 275.1283; found 275.1285. (S)-MTPA ester data: 1H NMR (CHCl3)vinyl resonances at � 5.30 and 5.19 ppm in ratio of 24.4�1 (92% ee). After crystal-lizing 90 mg of the title product from hexane/EtOAc (6�1), 55 mg (61% yield) ofwhite needle crystals (mp 88–89�) were obtained which were found to be 99% ee byintegration of the 1H NMR of the (S)-MTPA ester.
OTMS
O O
O
OOOH
2,6-lutidine (40 mol%), Et2O, 0°2. TFA, THF
+
PhPh H
O
N
Bu-t
BrO O
O
t-Bu
Bu-t
OO
Ti
(2 mol%)
1.
(88%) 92% ee
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 81
c01_tex 4/18/06 12:31 PM Page 81
(2S,3S)-Methyl-4-benzyloxy-3-hydroxy-2-methylbutanoate (Iridium-cat-alyzed Aldol Reaction).286 A flask was charged with [Ir(COD)Cl]2 (20.0 mg,0.030 mmol), the ligand384 (35.0 mg, 0.089 mmol), and CH2Cl2 (850 L). The resulting solution was stirred at room temperature. After 1 hour CH2Cl2 (644 L)and diethylmethylsilane (207 L, 1.43 mmol) were added to the mixture and the reaction mixture was stirred for an additional 30 minutes. Stock aldehyde/methylacrylate solution (1.7 mL, 0.7 M in aldehyde and 0.84 M in acrylate, 1.19 mmolaldehyde, 1.43 mmol acrylate) was added dropwise. The vessel was then sealed andthe contents stirred for 24 hours. The solvent was then evaporated from the reactionmixture and 1 mL each of THF, MeOH, and 4 N HCl were added. The solution wasstirred at room temperature for an additional 30 minutes. The product was extractedwith EtOAc (3 � 7 mL), and the combined organic layers were washed with satu-rated NaHCO3 solution (2 � 20 mL), dried over MgSO4, and filtered. The solventwas removed by rotary evaporation to give the crude product, which was purified viaflash chromatography (10�1 then 8�1 hexanes:EtOAc) to yield 131 mg (0.6 mmol,49% yield) of the title compound (94% ee, GC Alltech Chiraldex GTA column). IR(neat) 3462, 3032, 2950, 1961, 1869, 1731, 1203, 1101 cm�1; 1H NMR � 1.22 (d,J � 7.2 Hz, 3H), 2.70 (m, 1H), 2.72 (d, J � 4.8 Hz, 1H), 3.48 (dd, J � 3.4, 7.0 Hz,1H), 3.53 (dd, J � 1.9, 8 Hz, 1H), 3.67 (s, 3H), 4.07 (m, 1H), 4.55 (s, 2H), 7.34 (m, 5H); 13C NMR: � 12.2, 42.2, 52.0, 71.1, 71.8, 73.7, 128.0, 128.0, 128.7, 138.0,175.8. Anal. Calcd for C13H18O4: C, 65.53; H, 7.61. Found: C, 65.31; H, 7.51.
TABULAR SURVEY
The literature search for the tabular survey takes into account publications on cat-alytic asymmetric aldol addition reactions—meaning catalytic in the enantioinducingchiral species—until January 2003 and was effected using Beilstein and SciFinder.Given the complexity of the subject, different organizations of this tabular surveywere conceivable. The finally adopted structure is based on the differentiation be-tween direct aldol reactions and Mukaiyama-type additions. Each section is furthersubdivided into organocatalysis and metal-catalyzed reactions according to the nature of the metal used.
Within a subtable, entries are sorted by increasing number of carbon atoms in thenucleophilic component (not taking into consideration protective groups), followedby the increasing number of hydrogen atoms. For a given nucleophile, the same criteria were applied to the electrophiles and also for subtables within an entry.
Yields are given in parentheses, and (—) indicates that no information was givenin the original report.
NN
OO
N1.
[(cod)IrCl]2 (2.5 mol%), Et2MeSiH2. H3O+
OOBn
HMeO
O+
MeOOBn
O OH
(49%) 94% ee
(7.5 mol%)
82 ORGANIC REACTIONS
c01_tex 4/18/06 12:31 PM Page 82
The following abbreviations were used in the tabular survey.Ac acetylacac acetylacetonylatm atmosphereBBN borabicyclo[3.3.1]nonylBINAP 2,2�-bis(diphenylphosphino)-1,1�-binaphthylBINOL 1,1�-bi-2-naphtholBn benzylBoc tert-butyoxycarbonylBu butylBz benzoylcod cyclooctadienede diastereomeric excessDMF N,N-dimethylformamideDMSO dimethyl sulfoxidedr diastereomeric ratioee enantiomeric excessKHMDS potassium hexamethyldisilazideLLB lithium lanthanum binaphthoxide complexMOM methoxymethylMs methanesulfonylMS molecular sievesNs 4-nitrophenylsulfonylPCC pyridinium chlorochromatePh phenylPiv pivaloylPMB p-methoxybenzylPMP p-methoxyphenylPy pyridinerac racemicrt room temperaturesc supercriticalTaddol �,�,��,��-tetraaryl-1,3-dioxolan-4,5-dimethanolTBAF tetra-n-butylammonium fluorideTBAI tetra-n-butylammonium iodideTBDPS tert-butyldiphenylsilylTBS tert-butyldimethylsilylTES triethylsilylTf trifluoromethanesulfonylTFA trifluoroacetic acidTHF tetrahydrofuranTIPS triisopropylsilylTMEDA N,N,N,N-tetramethylethylenediamineTMS trimethylsilylTol 4-methylphenylTr tritylTs 4-methylbenzenesulfonyl
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS 83
c01_tex 4/18/06 12:31 PM Page 83
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
Ele
ctro
phile
TA
BL
E 1
A. S
ILV
ER
-CA
TA
LY
ZE
D M
UK
AIY
AM
A-T
YPE
AL
DO
L A
DD
ITIO
NS
R1
OSn
(Bu-
n)3
R2 C
HO
(R)-
BIN
APM
AgO
Tf
(10
mol
%),
TH
F, –
20°,
8 h
O
R1
OH
R2
C3–
8
R1
Me
Me
Me
t-B
u
t-B
u
t-B
u
Ph Ph Ph
R2
Ph (E)-
PhC
H=
CH
Ph(C
H2)
2
Ph (E)-
PhC
H=
CH
Ph(C
H2)
2
Ph (E)-
PhC
H=
CH
Ph(C
H2)
2
(73)
(83)
(61)
(78)
(69)
(75)
(57)
(33)
(40)
% e
e
77 53 59 95 86 94 71 41 50
94
PhC
HO
C4
(R)-
Tol
-BIN
APM
AgO
Tf
(22
mol
%),
Bu 2
Sn(O
Me)
2 (2
0 m
ol%
),
MeO
H (
2 eq
uiv)
, TH
F,
–20
°, 7
2 h
247
(59)
84
% e
eaO
O
MeO
Ph
OO
OH
PhC
HO
OSn
(Bu-
n)3
(R)-
BIN
APM
AgO
Tf
(10
mol
%),
TH
F, –
20°,
8 h
O
Ph
OH
O
Ph
OH
+94
(92)
I:I
I =
89:
11, 9
2% e
e I
C5
III
OC
OC
Cl 3
RC
HO
C6
(R)-
Tol
-BIN
APM
AgO
Tf
(5 m
ol%
),
Me 3
SnO
Me
(5 m
ol%
),
MeO
H (
2 eq
uiv)
, TH
F, –
20°
O
R
OH
O
R
OH
244
III
+
84
c01_tex 4/18/06 12:31 PM Page 84
R (E)-
n-Pr
CH
=C
H
Ph 4-M
eOC
6H4
(E)-
PhC
H=
CH
Ph(C
H2)
2
1-C
10H
7
(61)
(86)
(66)
(49)
(76)
(29)
(74)
I:II
76:2
4
94:6
94:6
80:2
0
78:2
2
84:1
6
96:4
% e
e I
83 96 95 77 90 79 92
OO
RC
HO
OSi
(OM
e)3
(R)-
Tol
-BIN
APM
AgF
(10
mol
%),
MeO
H, –
78°
O
R
OH
245
R Ph 4-B
rC6H
4
4-M
eOC
6H4
(78)
(87)
(86)
syn:
anti
84:1
6
76:2
4
75:2
5
% e
e sy
na
87 90 92
PhC
HO
OSn
(Bu-
n)3
(R)-
BIN
APM
AgO
Tf
(10
mol
%),
TH
F, –
20°,
8 h
O
Ph
OH
O
Ph
OH
+94
(94)
I:I
I =
92:
8, 9
3% e
e I
III
t-B
u
OSi
(OM
e)3
RC
HO
(R)-
Tol
-BIN
APM
AgF
(10
mol
%),
MeO
H, –
78°
R Ph 4-B
rC6H
4
4-M
eOC
6H4
(E)-
PhC
H=
CH
1-C
10H
7
(84)
(64)
(76)
(56)
(63)
syn:
anti
> 9
9:1
> 9
9:1
> 9
9:1
> 9
9:1
94:6
% e
e sy
na
97 87 96 85 95
245
C7
t-B
u
O
R
OH
85
c01_tex 4/18/06 12:31 PM Page 85
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
Ele
ctro
phile
TA
BL
E 1
A. S
ILV
ER
-CA
TA
LY
ZE
D M
UK
AIY
AM
A-T
YPE
AL
DO
L A
DD
ITIO
NS
(Con
tinu
ed)
PhC
HO
OSn
(Bu-
n)3
(R)-
BIN
APM
AgO
Tf
(10
mol
%),
TH
F, –
20°,
8 h
O
Ph
OH
O
Ph
OH
+94
(90)
I:I
I =
85:
15, 9
6% e
e I
III
94
C7–
8
t-B
u
OSn
(Bu-
n)3
R1
R1
Me
Me
Et
R2
Ph Ph(C
H2)
2
Ph
O
t-B
u
OH
R2
R1
R2 C
HO
O
t-B
u
OH
R2
R1
+
III
(81)
(77)
(98)
I:II
> 9
9:1
> 9
9:1
> 9
9:1
% e
e I
95 95 91
OT
MS
Ph
C8
RC
HO
R
OH
Ph
OR Ph Ph c-
C6H
11
1-C
10H
7
2-C
10H
7
(10
0)
(36
)
(83
)
(82
)
(10
0)
% e
e
69 80b
47a
54a
58a
385
AgP
F 6 (
2 m
ol%
),
(S)
-BIN
AP
(2 m
ol%
), D
MF,
rt
R
OH
Ph
OR Ph Ph c-
C6H
11
1-C
10H
7
2-C
10H
7
(10
0)
(10
0)
(10
0)
(10
0)
(10
0)
% e
e
11 11b
6a
17a
15a
385
AgO
Ac
(2 m
ol%
),
(S)
-BIN
AP
(2 m
ol%
), D
MF,
rt
(R)-
BIN
APM
AgO
Tf
(10
mol
%),
TH
F, –
20°,
8h
C7
RC
HO
86
c01_tex 4/18/06 12:31 PM Page 86
OT
MS
Ph
C9
PhC
HO
Ph
OH
Ph
O
385
(98)
syn
:ant
i = 8
4:16
, 23%
ee
Ia
a The
abs
olut
e co
nfig
urat
ion
was
not
det
erm
ined
.b
The
rea
ctio
n w
as c
arri
ed o
ut a
t –30
°.
AgO
Ac
(2 m
ol%
),
(S)
-BIN
AP
(2 m
ol%
), D
MF,
rt
87
c01_tex 4/18/06 12:31 PM Page 87
C2
OM
e
OT
MS
Cl
Cl
CH
O
MeO
2-O
2NC
6H4
SN
B H
OOi-
Pr
CH
2Cl 2
, –78
°, 7
h
MeO
OH
Cl
Cl
386
(88)
77%
ee
OM
e
O
OO
(20
mol
%),
OE
t
OT
MS
F
Br
RC
HO
R
OH
OE
t
O
Br
F
387
R BnO
CH
2
n-Pr
i-B
u
Et 2
CH
Ph c-C
6H11
(E)-
PhC
H=
CH
Ph(C
H2)
2
(81)
(90)
(96)
(70)
(90)
(74)
(96)
(89)
I:II
57:4
3
46:5
4
48:5
2
54:4
6
69:3
1
52:4
8
57:4
3
46:5
4
Pr-i
NH
Ts
(20
mol
%),
BH
3MT
HF
(22
mol
%),
EtN
O2,
–78
°
(E/Z
= 6
2:38
)
% e
e I
97 97 98 99 98 94 83 98
% e
e II
97a
98a
98a
98a
90 89a
83a
98a
R
OH
OE
t
O
FB
r
III
R
OH
OE
t
O
Br
F
387
Pr-i
NH
TsO
H
O(2
0 m
ol%
),
BH
3MT
HF
(22
mol
%),
EtN
O2,
–20
°
R
OH
OE
t
O
FB
r
III
+ +
OH
O
TA
BL
E 1
B. B
OR
ON
-CA
TA
LY
ZE
D M
UK
AIY
AM
A-T
YPE
AL
DO
L A
DD
ITIO
NS
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
Ele
ctro
phile
RC
HO
88
c01_tex 4/18/06 12:31 PM Page 88
R BnO
CH
2
n-Pr
i-B
u
Et 2
CH
Ph c-C
6H11
Ph(C
H2)
2
(80)
(87)
(83)
(85)
(89)
(90)
(85)
I:II
26:7
4
11:8
9
14:8
6
23:7
7
49:5
1
20:8
0
13:8
7
% e
e I
29 49 21 21 13 18 48
% e
e II
72a
93a
88a
74a
13b
81a
92a
OE
t
OT
MS
F
F
RC
HO
R
OH
OE
t
O
FF
236
R BnO
CH
2
n-Pr
i-B
u
Et 2
CH
Ph c-C
6H11
(E)-
PhC
H=
CH
Ph(C
H2)
2
n-C
9H19
(94)
(91)
(85)
(81)
(99)
(87)
(99)
(98)
(93)
% e
ea
98 97 82 64 97c
76 96 76 92
Pr-i
NH
TsO
H
O(2
0 m
ol%
),
BH
3MT
HF
(22
mol
%),
EtN
O2,
–78
°
RC
HO
R
OH
OE
t
O
FF
236
R BnO
CH
2
n-Pr
i-B
u
Et 2
CH
Ph c-C
6H11
(E)-
PhC
H=
CH
Ph(C
H2)
2
n-C
9H19
(60)
(90)
(85)
(90)
(96)
(97)
(65)
(99)
(90)
% e
ea
54 94 96 95 65c
94 26d
70 63
(20
mol
%),
BH
3MT
HF
(22
mol
%),
EtN
O2,
–45
°OH
Ot-
Bu
NH
Ns
89
c01_tex 4/18/06 12:32 PM Page 89
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
Ele
ctro
phile
SEt
OT
MS
RC
HO
R
OH
SEt
OR Ph Ph
(CH
2)2
(89)
(82)
% e
e
89 89
1.
(20
mol
%),
B
H3M
TH
F (2
0 m
ol%
), E
tCN
, –78
°
2. 1
N H
Cl/T
HF
140
OPr
-i
OT
MS
F
Br
OH
OPr
-i
O
Br
F
387
Pr-i
NH
TsO
H
O(2
0 m
ol%
),
(E/Z
= 6
2:38
)
OH
OPr
-i
O
FB
rI
II
BH
3MT
HF
(22
mol
%),
EtN
O2,
–78
°
PhC
HO
PhPh
NsH
N23
7C
O2H
1. B
H3M
TH
F (2
0 m
ol%
), E
tNO
2,
–7
8°, 1
h
2. N
i 2B
/H2
(20
mol
%),
OT
MS
OE
tS
S
PhC
HO
PhC
O2E
t
OH
(86)
>
98%
ee
237
Ph
TB
SO(>
77)
100
% d
ePh
CH
O
OT
BS
CO
2Et
OH
+
Pr-i
NH
TsO
H
OC
2
TA
BL
E 1
B. B
OR
ON
-CA
TA
LY
ZE
D M
UK
AIY
AM
A-T
YPE
AL
DO
L A
DD
ITIO
NS
(Con
tinu
ed)
237
Ph
TB
SO(>
77)
100
% d
eC
O2E
t
OH
NsH
N
B
H3M
TH
F (2
0 m
ol%
), E
tNO
2,
–7
8°, 1
h
2. N
i 2B
/H2C
O2H
1.(2
0 m
ol%
),Ph
CH
O
OT
BS
NsH
NC
O2H
1. B
H3M
TH
F (2
0 m
ol%
), E
tNO
2,
–7
8°, 1
h
2. N
i 2B
/H2
(20
mol
%),
(89)
I:I
I =
39:
61, 9
5% e
e I,
95%
ee
II
90
c01_tex 4/18/06 12:32 PM Page 90
3
,5-(
CF 3
) 2C
6H3B
Cl 2
(10
mol
%),
E
tCN
, –20
°
2. 2
N H
Cl
183
1.
(12
mol
%),
(99)
37
% e
eO
TM
S
SBu-
nPh
CH
On-
BuS
Ph
OO
H
N H
OH
O
TsH
N
183
1. P
hB(O
H) 2
(20
mol
%),
EtC
N, –
78°
2. 2
N H
Cl
(99)
0%
ee
n-B
uSPh
OO
H
183
1. BH
3MT
HF
(20
mol
%),
EtC
N, –
78°
2. 2
N H
Cl
n-B
uSPh
OO
H
NsH
NC
O2H
(20
mol
%),
NsH
NC
O2H
(20
mol
%),
SBu-
t
OT
MS
RC
HO
R
OH
SBu-
t
O1.
(2
0 m
ol%
),
B
H3M
TH
F (2
0 m
ol%
), E
tCN
, –78
°
2. 1
N H
Cl/T
HF
R n-Pr
2-C
4H3O
(E)-
i-Pr
CH
=C
H
Ph c-C
6H11
Ph(C
H2)
2
(91)
(98)
(91)
(86)
(75)
(77)
% e
e
92 85 82 87 81 91
140
Pr-i
NH
TsO
H
O
OPh
OT
MS
RC
HO
R
OH
OPh
O1.
(20
mol
%),
B
H3M
TH
F (2
0 m
ol%
), E
tCN
, –78
°
2. 1
N H
Cl/T
HF
R Ph c-C
6H11
Ph(C
H2)
2
(77)
(87)
(78)
% e
e
93 84 85
140
Pr-i
NH
TsO
H
O
(90)
66
% e
e
PhC
HO
PhC
HO
91
c01_tex 4/18/06 12:32 PM Page 91
RC
HO
O
OPh
OH
R
R n-Pr
Ph
% e
e
76 84
73(4
9)
(63)
OPr
-i
OPr
-iO
CO
2HO
CO
2H
OH
1. B
H3M
TH
F (2
0 m
ol%
), E
tCN
, –78
°
2. T
BA
F/T
HF
(20
mol
%),
RC
HO
B
H3M
TH
F (2
0 m
ol%
), E
tNO
2,
–
78°,
1–3
h
2. T
BA
F
R i-Pr
Ph
(60)
(66)
184
% e
e
70a
80
1.
OPh
R
OO
H
C3
NsH
NC
O2H
(20
mol
%),
SEt
OT
MS
PhC
HO
Ph
OH
SEt
O1.
(20
mol
%),
B
H3M
TH
F (2
0 m
ol%
), E
tCN
, –78
°
2. 1
M T
BA
F, T
HF
(84)
I:I
I =
55:
45, >
98%
ee
I
140
Ph
OH
SEt
O
III
+
Pr-i
NH
TsO
H
O
C2
SEt
OT
MS
RC
HO
R
OH
SEt
O
R 2-C
4H3O
(E)-
Me(
CH
2)2C
H=
CH
Ph 4-M
eOC
6H4
(94)
(80)
(89)
(78)
% e
e I
89 60 80 75
I:II
66:3
3
80:2
0
87:1
3
89:1
1
140
R
OH
SEt
O
III
+
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
Ele
ctro
phile
TA
BL
E 1
B. B
OR
ON
-CA
TA
LY
ZE
D M
UK
AIY
AM
A-T
YPE
AL
DO
L A
DD
ITIO
NS
(Con
tinu
ed)
OPh
OT
MS
1.
(20
mol
%),
B
H3M
TH
F (2
0 m
ol%
), E
tCN
, –78
°
2. 1
M T
BA
F, T
HF
Pr-i
NH
TsO
H
O
92
c01_tex 4/18/06 12:32 PM Page 92
RC
HO
R
OH
SEt
O1.
(20
mol
%),
B
H3M
TH
F (2
0 m
ol%
), E
tCN
, –78
°
2. 1
M T
BA
F, T
HF
MeO
MeO
CO
2H
NH
Ts
R n-Pr
Ph(C
H2)
2
(81)
(85)
% e
e I
70 82
I:II
88:1
2
91:9
140
R
OH
SEt
O
III
OT
MS
OR
1R
2 CH
O73
R1
Et
Ph Ph Ph Ph Ph Bn
R2
Ph Ph n-Pr
i-Pr
(E)-
MeC
H=
CM
e
(E)-
n-Pr
CH
=C
H
Ph
(51)
(83)
(57)
(45)
(86)
(97)
(72)
I:II
50:5
0
79:2
1
65:3
5
64:3
6
> 9
5:5
96:4
50:5
0
O
OR
1
OH
R2
O
OR
1
OH
R2
III %
ee
I
61 92 88 79 94 97 68
% e
e II
47 6 71 29 10 — 57
OPr
-i
OPr
-iO
CO
2HO
CO
2H
OH
1. B
H3M
TH
F (2
0 m
ol%
), E
tCN
, –78
°
2. T
BA
F/T
HF
(20
mol
%),
+ +
SBu-
t
OT
MS
RC
HO
R
OH
SBu-
t
O1.
(
20 m
ol%
),
B
H3M
TH
F (2
0 m
ol%
), E
tCN
, –78
°
2. 1
M T
BA
F, T
HF
R 2-C
4H3O
Ph
(54)
(78)
% e
e I
79 82
I:II
88:1
2
94:6
140
R
OH
SBu-
t
O
III
+
Pr-i
NH
TsO
H
O
93
c01_tex 4/18/06 12:32 PM Page 93
OPh
OT
MS
PhC
HO
Ph
OH
OPh
O (77)
I:I
I =
77:
23, 8
7% e
e I
140
Ph
OH
OPh
O
III
OH
OPh
O1.
(20
mol
%),
B
H3M
TH
F (2
0 m
ol%
), E
tCN
, –78
°
2. 1
M T
BA
F, T
HF
MeO
MeO
CO
2H
NH
Ts
Ph
(72)
I:I
I =
90:
10, >
75%
ee
I
140
PhC
HO
OH
OPh
O
Ph
III
73
O
OPh
OH
Ph
O
OPh
OH
Ph
III
(73)
I:I
I =
79:
21, 9
2% e
e I,
3%
ee
II
OPr
-i
OPr
-iO
CO
2HO
CO
2H
OH
1. B
H3M
TH
F (2
0 m
ol%
), E
tCN
, –78
°
2. T
BA
F/T
HF
(20
mol
%),
+
+
+
C3
RC
HO
B
H3M
TH
F (2
0 m
ol%
), E
tNO
2,
–
78°,
1-3
h
2. T
BA
FR n-
Pr
i-Pr
Ph
(60)
(64)
(91)
184
% e
e I
60 90 66
OPh
R
OO
H
OPh
R
OO
H
III
I:II
60:4
0
65:3
5
76:2
4
% e
e II
91 97 90
1.
NsH
NC
O2H
(20
mol
%),
+
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
Ele
ctro
phile
TA
BL
E 1
B. B
OR
ON
-CA
TA
LY
ZE
D M
UK
AIY
AM
A-T
YPE
AL
DO
L A
DD
ITIO
NS
(Con
tinu
ed)
1.
(
20 m
ol%
),
B
H3M
TH
F (2
0 m
ol%
), E
tCN
, –78
°
2. 1
M T
BA
F, T
HF
Pr-i
NH
TsO
H
O
PhC
HO
94
c01_tex 4/18/06 12:32 PM Page 94
OM
e
OT
MS
RC
HO
N H
N Ts
BB
u-n
OO
(20
mol
%),
1.O
O
C4
181
R c-C
3H5
2-C
4H3O
Ph c-C
6H11
Ph(C
H2)
2
(87
)
(83
)
(10
0)
(80
)
(57
)
% e
e
73 67 82 76 69
EtC
N, –
78°,
14
h
2. C
F 3C
O2H
OM
e
OT
MS
OH
OM
e
O
236
Tem
p
–78°
–45°
–30° 0°
(97)
(88)
(70)
(70)
% e
ea
83 52 53 35
Pr-i
NH
TsO
H
O(2
0 m
ol%
),
BH
3MT
HF
(22
mol
%),
EtN
O2
CH
OB
nO
3
,5-(
CF 3
) 2C
6H3B
Cl 2
(10
mol
%),
E
tCN
, –20
°
2. 2
N H
Cl
183
1.
(12
mol
%),
(99)
65
% e
e
OT
MS
SEt
PhC
HO
SEt
Ph
OO
H
N H
OH
O
TsH
N
R
BnO
P
hB(O
H) 2
(20
mol
%),
C
H2C
l 2, –
78°
2. 2
N H
Cl
183
(87)
24
% e
e
1.
NsH
NC
O2H
(20
mol
%),
I
I
3
,5- (C
F 3) 2
C6H
3BC
l 2 (
20 m
ol%
),
C
H2C
l 2, –
78°
2. 2
N H
Cl
183
(29)
50
% e
e
1.
NsH
NC
O2H
(20
mol
%),
I
PhC
HO
PhC
HO
95
c01_tex 4/18/06 12:32 PM Page 95
OE
t
OT
MS
RC
HO
R
OH
OE
t
O1.
(
20 m
ol%
),
B
H3M
TH
F (2
0 m
ol%
), E
tCN
, –78
°
2. 1
N H
Cl/T
HF
R n-Pr
i-B
u
Ph c-C
6H11
Ph(C
H2)
2
(82)
(89)
(83)
(59)
(83)
% e
e
> 9
8a
> 9
8a
91 96
> 9
8a
R
OH
OE
t
OR B
nO(C
H2)
2
n-Pr
i-B
u
Ph c-C
6H11
Ph(C
H2)
2
(86)
(81)
(87)
(80)
(68)
(83)
% e
e
99a
> 9
8a
97a
84 91
> 9
8a
1.
(20
mol
%),
B
H3M
TH
F (2
0 m
ol%
), E
tCN
, –78
°
2. 1
N H
Cl/T
HF
MeO
MeO
CO
2H
NH
Ts
238
238
Pr-i
NH
TsO
H
OC
4
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
Ele
ctro
phile
TA
BL
E 1
B. B
OR
ON
-CA
TA
LY
ZE
D M
UK
AIY
AM
A-T
YPE
AL
DO
L A
DD
ITIO
NS
(Con
tinu
ed)
PhC
HO
CO
2HT
MS
OH
(10
mol
%),
OE
t
O
Ph
OH
239
(92)
86
% e
e
1. B
H3M
TH
F (1
0 m
ol%
), E
tCN
,
–
78°,
3 h
2. p
H 7
buf
fer
R2 C
HO
B
H3M
TH
F (2
0 m
ol%
), E
tNO
2,
–
78°,
1–4
h
2. T
BA
F
R2
Ph Ph Ph(C
H2)
2
(E)-
PhC
H=
CH
(92)
(65)
(97)
(63)
184
% e
e
90 96 95 81
OT
MS
OR
1R
1 OR
2
OO
H
R1
Et
Ph Et
Ph
1.
NsH
NC
O2H
(20
mol
%),
(+)
RC
HO
96
c01_tex 4/18/06 12:32 PM Page 96
RC
HO
OM
e
OM
eO
CO
2HO
R n-B
u
n-C
5H11
Ph (E)-
PhC
H=
CH
(52)
(44)
(69)
(56)
266
% e
ea
70 73e
67 73e
CO
2H
OH
1. B
H3M
TH
F (5
0 m
ol%
),
C
H2C
l 2, –
78°
2. H
Cl
(50
mol
%),
OO
OT
MS
OO
OR
OH
PhO
CO
2HO
B
H3M
TH
F (5
0 m
ol%
),
C
H2C
l 2, –
78°
2. H
Cl
266
CO
2H
OH
1.
(50
mol
%),
OO
OPh
OH
OPr
-i
OPr
-iO
CO
2HO
B
H3M
TH
F (5
0 m
ol%
),
C
H2C
l 2, –
78°
2. H
Cl
R n-B
u
Ph (E)-
PhC
H=
CH
(45)
(74)
(63)
266
% e
ea
64 52 38
CO
2H
OH
1.
(50
mol
%),
OO
OR
OH
PhC
HO
RC
HO
(79)
46
% e
ea
97
c01_tex 4/18/06 12:32 PM Page 97
R1
Me
Me
Me
Me
n-Pr
n-Pr
Ph Ph Ph 4-M
eC6H
4
R2
Ph 4-M
eC6H
4
4-M
eOC
6H4
(E)-
PhC
H=
CH
i-B
u
Ph Et
n-Pr
i-B
u
i-B
u
(71)
(68)
(67)
(75)
(63)
(65)
(63)
(62)
(60)
(61)
I:II
1:2
1:1.
9
1:1.
8
< 1
:20
< 1
:20
1:6.
3
1:2.
5
1:5
< 1
:20
< 1
:20
% e
e Ia
85 98 94 — — 81 98 97 — —
% e
e II
a
70 66 69 72 97 61 88 73 98 97
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
Ele
ctro
phile
TA
BL
E 1
B. B
OR
ON
-CA
TA
LY
ZE
D M
UK
AIY
AM
A-T
YPE
AL
DO
L A
DD
ITIO
NS
(Con
tinu
ed)
C4–
10
TM
SOR
1
I
R2
OH
O
R1
I
R2
OH
O
R1
I
III
240
N H
O
n-C
3F7
CO
2H
Bn
(20
mol
%),
B
H3M
TH
F (2
0 m
ol%
), E
tCN
,
–
78°,
7 h
2. a
q H
Cl
1.
+
OT
MS
PhC
HO
OO
H
Ph
OO
H
Ph18
1
N H
N Ts
BB
u-n
OO
(40
mol
%),
1.
III
(71)
I:
II =
94:
6, 9
2% e
e I
C5
E
tCN
, –7
8°, 1
4 h
2. 1
M H
Cl
+
R2 C
HO
•
98
c01_tex 4/18/06 12:32 PM Page 98
(74)
I:
II =
88:
12, 3
3% e
e I,
12%
ee
II38
8Ph
CH
OI
+ I
I
N H
OH
O
TsH
N
3
,5-(
CF 3
) 2C
6H3B
Cl 2
(10
mol
%),
E
tCN
, –78
°, 1
2 h
2. 1
N H
Cl/T
HF,
rt
1.
(10
mol
%),
OT
MS
Et
RC
HO
O
Et
OH
R72
O
Et
OH
R
III
PhC
HO
O
Et
OH
Ph72
O
Et
OH
Ph
III
(99)
I:
II =
94:
6, 9
6% e
e I
R n-Pr
(E)-
MeC
H=
CH
Ph
I:II
80:2
0
> 9
4:6
94:6
% e
e I
88 93 96
(61)
(79)
(96)
OPr
-i
OPr
-iO
CO
2HO
B
H3M
TH
F (2
0 m
ol%
),
E
tCN
, –78
°
2. 1
N H
Cl
CO
2H
OH
1.
(20
mol
%),
OPr
-i
OPr
-iO
CO
2HO
B
H3M
TH
F (2
0 m
ol%
),
E
tCN
, –78
°
2. 1
N H
Cl
CO
2H
OH
1.
(20
mol
%),
+
+
RC
HO
O
Et
OH
R
R (E)-
MeC
H=
CH
Ph
O
Et
OH
R
I:II
94:6
91:9
% e
e I
93 95
III (9
5)
(81)
182
OPr
-i
OPr
-iO
CO
2HO
3
,5-(
CF 3
) 2C
6H3B
(OH
) 2
(
20 m
ol%
), E
tCN
, –78
°
2. 1
N H
Cl
CO
2H
OH
1.
(20
mol
%),
+
99
c01_tex 4/18/06 12:32 PM Page 99
OH
i-Pr
O
Et
(99)
sy
n:an
ti =
48:
52, 9
5% e
e I,
93%
ee
II
388
OH
i-Pr
O
Et
III
N H
OH
O
TsH
N
3
,5-(
CF 3
) 2C
6H3B
Cl 2
(10
mol
%),
E
tCN
, –78
°, 1
2 h
2. 1
N H
Cl/T
HF,
rt
1.
(10
mol
%),
PhC
HO
OM
e
OM
eO
CO
2HO
B
H3M
TH
F (5
0 m
ol%
),
C
H2C
l 2, –
78°
2. H
Cl
267
CO
2H
OH
1.
(50
mol
%),
III
(100
) I
:II
= 2
5:75
, 80%
ee
I, 6
3% e
e II
OO
OT
MS
OO
OPh
OH
OO
OPh
OH
TM
SO
OB
n
OT
BS
OO
TB
S
OB
nPh
OH
(29)
>
95%
de
177
OPr
-i
OPr
-iO
CO
2HO
3
,5-(
CF 3
) 2C
6H3B
(OH
) 2
(
50 m
ol%
), E
tCN
, –78
°
2. H
+
CO
2H
OH
1.
(50
mol
%),
CH
O+
+
C5
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
Ele
ctro
phile
TA
BL
E 1
B. B
OR
ON
-CA
TA
LY
ZE
D M
UK
AIY
AM
A-T
YPE
AL
DO
L A
DD
ITIO
NS
(Con
tinu
ed)
OT
MS
Et
C5–
9
OT
MS
R1
R2 C
HO
O
R1
OH
R2
R1
Et
Ph Ph
R2
Ph n-Pr
Ph
72
O
R1
OH
R2
I:II
93:7
88:1
2
95:5
% e
e I
94 80 95
III
(97)
(62)
(86)
OPr
-i
OPr
-iO
CO
2HO
B
H3M
TH
F (2
0 m
ol%
), E
tCN
, –78
°
2. 1
N H
Cl
CO
2H
OH
1.
(20
mol
%),
+
PhC
HO
100
c01_tex 4/18/06 12:32 PM Page 100
OT
MS
OO
H
R38
8
C6
RC
HO
OO
H
R
III
R i-Pr
Ph
(36)
(> 9
9)
I:II
77:2
3
78:2
2
% e
e I
96 89
% e
e I
96 5
N H
OH
O
TsH
N
3
,5-(
CF 3
) 2C
6H3B
Cl 2
(10
mol
%),
E
tCN
, –78
°, 1
2 h
2. 1
N H
Cl/T
HF,
rt
1.
(10
mol
%),
PhC
HO
OO
H
Ph72
III
(57)
I:
II >
95:
5, >
95%
ee
I
OO
H
Ph
OPr
-i
OPr
-iO
CO
2HO
B
H3M
TH
F (2
0 m
ol%
), E
tCN
, –78
°
2. 1
N H
Cl
CO
2H
OH
1.
(20
mol
%),
++
OO
H
Ph18
2
III
(83)
I:
II >
95:
5, 9
7% e
e I
OO
H
Ph
OPr
-i
OPr
-iO
CO
2HO
3
,5-(
CF 3
) 2C
6H3B
(OH
) 2
(
20 m
ol%
), E
tCN
, –78
°
2. H
Cl
CO
2H
OH
1.
(20
mol
%),
+Ph
CH
O
N H
OH
O
TsH
N
3
,5-(
CF 3
) 2C
6H3B
Cl 2
(
5–10
mol
%),
EtC
N, –
78°,
12
h
2. 1
N H
Cl/T
HF,
rt
R1
OT
MS
O
R1
OH
R2
388
1.O
R1
OH
R2
III
(5–1
0 m
ol%
),
+
R1
Et
Et
Ph Ph Ph Ph
R2
n-Pr
i-Pr
n-Pr
i-Pr
(E)-
MeC
H=
CH
PhC
C
(> 9
9)
(94)
(> 9
9)
(> 9
9)
(85)
(92)
I:II
62:3
8
83:1
7
> 9
9:1
97:3
95:5
89:1
1
% e
e I
92 92 > 9
9
98 97 90
% e
e I
77 91 — — — 58
R2 C
HO
101
c01_tex 4/18/06 12:32 PM Page 101
C6–
8O
TM
S
R1
R2 C
HO
O
R1
OH
R2
R1
n-B
u
n-B
u
Ph Ph
R2
n-B
u
Ph Ph (E)-
PhC
H=
CH
(70)
(96)
(99)
(88)
182
% e
e
77 83 88 91
OPr
-i
OPr
-iO
CO
2HO
3
,5-(
CF 3
) 2C
6H3B
(OH
) 2
(
20 m
ol%
), E
tCN
, –78
°
2. 1
N H
Cl
CO
2H
OH
1.
(20
mol
%),
OPr
-i
OPr
-iO
CO
2HO
B
H3M
TH
F (2
0 m
ol%
), E
tCN
, –78
°
2. 1
N H
Cl
72C
O2H
OH
1.
(20
mol
%),
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
Ele
ctro
phile
TA
BL
E 1
B. B
OR
ON
-CA
TA
LY
ZE
D M
UK
AIY
AM
A-T
YPE
AL
DO
L A
DD
ITIO
NS
(Con
tinu
ed)
R1
n-B
u
n-B
u
Ph Ph
R2
n-B
u
Ph Ph (E)-
PhC
H=
CH
(70)
(81)
(98)
(88)
% e
e
80 85 85 83
R1
n-B
u
Ph Ph
R2
Ph Ph (E)-
PhC
H=
CH
(91)
(93)
(93)
182
% e
e
88 91 94
OPr
-i
OPr
-iO
CO
2HO
2
-PhO
C6H
4B(O
H) 2
(20
mol
%),
E
tCN
, –78
°
2. H
Cl
CO
2H
OH
1.
(20
mol
%),
I
I I
R2 C
HO
R2 C
HO
n-B
u
OT
MS
RC
HO
R Ph c-C
6H11
(100
)
(56)
% e
e
90 86
N H
N Ts
BB
u-n
OO
(20
mol
%),
1.
R
OH
n-B
u
O18
1
E
tCN
, –78
°, 1
4 h
2. 1
M H
Cl
C6
102
c01_tex 4/18/06 12:32 PM Page 102
OT
MS
C7
CH
O
OO
Bz
(85)
sy
n:an
ti =
10:
1, 9
9% e
e
OPr
-i
OPr
-iO
CO
2HO
2
-PhO
C6H
4B(O
H) 2
(20
mol
%),
E
tCN
, –78
°
2. B
zCl,
Py
CO
2H
OH
1.
235
(20
mol
%),
OT
MS
OO
H
Ph
(85)
I:
II =
66:
34, 2
9% e
e I,
14%
ee
II
388
PhC
HO
OO
H
Ph
III
N H
OH
O
TsH
N
3
,5-(
CF 3
) 2C
6H3B
Cl 2
(10
mol
%),
E
tCN
, –78
°, 1
2 h
2. 1
N H
Cl/T
HF,
rt
1.
(10
mol
%),
B
H3M
TH
F (4
5 m
ol%
), E
tCN
,
–
78°,
slo
w a
dditi
on
2. T
BA
F/T
HF
389
OT
MS
OE
t(9
0)
91%
ee
CH
O
O
OB
nOO
O
OE
t
O
HO
OB
n
1.
NsH
NC
O2H
(40
mol
%),
+
N H
OH
O
TsH
N
B
uB(O
H) 2
(20
mol
%),
E
tCN
, –78
°
2. 1
N H
Cl/T
HF,
rt
1.
PhC
HO
Ph
OT
MS
O
Ph
OH
Ph(8
2)
89%
ee
185
C8
(20
mol
%),
103
c01_tex 4/18/06 12:32 PM Page 103
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
Ele
ctro
phile
TA
BL
E 1
B. B
OR
ON
-CA
TA
LY
ZE
D M
UK
AIY
AM
A-T
YPE
AL
DO
L A
DD
ITIO
NS
(Con
tinu
ed)
PhC
HO
O
Ph
OT
MS
Ph(8
8)
79%
ee
185
185
N H
OH
O
TsH
N
PhB
Cl 2
(10
mol
%),
EtC
N, –
78°
(10
mol
%),
N H
OH
O
TsH
N
3,5
-(C
F 3) 2
C6H
3BC
l 2 (
10 m
ol%
),
EtC
N, –
78°
(10
mol
%),
RC
HO
R n-Pr
2-C
4H3O
Ph c-C
6H11
(94)
(100
)
(82)
(67)
% e
e
89 92 89 93N H
N Ts
BB
u-n
OO
(20
mol
%),
1.
R
OH
Ph
O18
1
E
tCN
, –78
°, 1
4 h
2. 1
M H
Cl
3
,5-(
CF 3
) 2C
6H3B
Cl 2
(10
mol
%),
E
tCN
, –78
°
2. 2
N H
Cl
183
1.
(12
mol
%),
(99)
93
% e
eO
TE
S
PhPh
CH
OPh
Ph
OH
N H
OH
O
TsH
NO
I
I
(91)
93
% e
e
Ph
OT
MS
C8
PhC
HO
104
c01_tex 4/18/06 12:32 PM Page 104
C9
OT
MS
PhR
CH
O
O
Ph
OH
R
R n-Pr
Ph
O
Ph
OH
R
I:II
94:6
99:1
% e
e I
80 96
III
(55)
(92)
182
OPr
-i
OPr
-iO
CO
2HO
3
,5-(
CF 3
) 2C
6H3B
(OH
) 2
(
20 m
ol%
), E
tCN
, –78
°
2. T
BA
F, T
HF
CO
2H
OH
1.
(20
mol
%),
3
,5-(
CF 3
) 2C
6H3B
Cl 2
(10
mol
%),
E
tCN
, –78
°, 3
h
2. 2
N H
Cl
183
1.
(12
mol
%),
(74)
94
% e
e
OT
ES
PhC
HO
(1
equi
v)N H
OH
O
TsH
N
OT
ES
O
O
Ph
OH
C10
+
183
(93)
—
PhC
HO
(2
equi
v)
O
O
Ph
Ph
OH
OH
a The
abs
olut
e co
nfig
urat
ion
was
not
det
erm
ined
.b T
he c
onfi
gura
tion
of th
e sy
n pr
oduc
t is
2S,3
R.
c The
pro
duct
has
the
R c
onfi
gura
tion.
d The
rea
ctio
n w
as c
arri
ed o
ut a
t –20
°.e T
he p
roto
col i
nvol
ves
slow
add
ition
of
the
reag
ents
.
3
,5-(
CF 3
) 2C
6H3B
Cl 2
(10
mol
%),
E
tCN
, –78
°, 3
h
2. 2
N H
Cl
1.
(12
mol
%),
N H
OH
O
TsH
N
105
c01_tex 4/18/06 12:32 PM Page 105
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
C. C
OPP
ER
-CA
TA
LY
ZE
D M
UK
AIY
AM
A-T
YPE
AL
DO
L A
DD
ITIO
NS
Ele
ctro
phile
CH
OB
nOX
OT
MS
X OE
t
SEt
SBu-
t
BnO
X
OO
H37
(99)
(95)
(99)
% e
e
98 98 99
C2
CH
2Cl 2
, –78
°
(0.5
mol
%),
CH
OR
OSB
u-t
OT
MS
RO
SBu-
t
OO
H37
(—)
(—)
(—)
% e
e
88 99 56
R n-B
u
PMB
TB
S
CH
2Cl 2
, –78
°
2. a
q H
Cl,
TH
F
(10
mol
%),
1.
CH
OB
nOB
nOSB
u-t
OT
MSO
37
CH
2Cl 2
, –78
°, 1
2 h
(5 m
ol%
),(—
) d
r =
1:1
CH
OB
nOB
nOSB
u-t
OT
MSO
37(—
) d
r =
98.
5:1.
5
CH
2Cl 2
, –78
°, 1
2 h
(5 m
ol%
),
N
NN
Cu
OO
PhPh
2 Sb
F 6–
2+
N
NN
Cu
OO
PhPh
2 Sb
F 6–
2+
N
NN
Cu
OO
PhPh
2 Sb
F 6–
2+
N
NN
Cu
OO
PhPh
2 Sb
F 6–
2+
106
c01_tex 4/18/06 12:32 PM Page 106
O
NN
O
t-B
uB
u-t
Cu
2 O
Tf–
2+
O
R1 O
O
R2
O
R1 O
SBu-
t
OH
OR
2R
1
Me
Me
Me
Et
t-B
u
Bn
R2
Me
Et
i-B
u
i-Pr
Me
Me
(96)
(84)
(94)
(84)
(91)
(95)
% e
e
99 94 94 36 99 99
70(1
0 m
ol%
),
1. T
HF,
–78
°
2. a
q H
Cl
195
SBu-
t
OH
O
SBu-
t
OT
MSO
O
N
OO
N
t-B
uB
u-t
III
3
(97)
93
% e
e I
195
O
SBu-
t
OH
O
SBu-
t
OT
MSO
BnO
N
OO
N
t-B
uB
u-t
III
3
(100
) 9
2% e
e I
Cu(
OT
f)2
(7 m
ol%
), 3
Å M
S,
TH
F, 0
°
(7.7
mol
%),
(12.
4 m
ol%
),
Cu(
OT
f)2
(7 m
ol%
), 3
Å M
S, T
HF,
0°
MeO
OO
MeO
O
MeO
O
MeO
O
MeO
OT
MS
SEt
OB
n
BnO
OB
n
SEt
OO
H
37
Z/E
90:1
0
25:7
5
(21
)
(11
)
% e
e
76 63
dr
74:2
6
86:1
4
CH
OB
nO
+ +
O
MeO
O
C
H2C
l 2, –
78°
2. a
q H
Cl,
TH
F
(10
mol
%),
1.
N
NN
Cu
OO
PhPh
2 Sb
F 6–
2+
107
c01_tex 4/18/06 12:32 PM Page 107
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
C. C
OPP
ER
-CA
TA
LY
ZE
D M
UK
AIY
AM
A-T
YPE
AL
DO
L A
DD
ITIO
NS
(Con
tinu
ed)
Ele
ctro
phile
BnO
X
OO
H
X
OT
MS
X Me
OE
t
SBu-
t
Ph
(—)
(—)
(—)
(—)
% e
e
38a
50 91 51a
37
C2–
8
C
H2C
l 2, –
78°
2. a
q H
Cl,
TH
F
(10
mol
%),
1.
CH
OB
nOO
NN
O
t-B
uB
u-t
Cu
2 O
Tf–
2+
MeO
O
OX M
e
Me
SEt
SEt
Ph Ph
(76)
(81)
(97)
(83)
(77)
(80)
% e
e
93 94b
97 86b
99 92b
197
O
MeO
X
OH
O
O
NN
O
t-B
uB
u-t
Cu
2 O
Tf–
2+
(10
mol
%),
1. T
HF,
–78
°
2. a
q H
Cl
MeO
O
O
OE
t
OT
MS
C3
(—)
dr
= 8
6:14
, 39%
ee
197
O
NN
O
t-B
uB
u-t
Cu
2 O
Tf–
2+
(10
mol
%),
1. C
H2C
l 2, –
78°
2. a
q H
Cl
MeO
O
OE
t
OO
H
CH
OB
nOSB
u-t
OT
MS
SBu-
t
OO
H
BnO
(50)
dr
= 8
1:19
, 84%
ee
37O
NN
O
t-B
uB
u-t
Cu
2 O
Tf–
2+
(10
mol
%),
1. C
H2C
l 2, –
78°
2. a
q H
Cl
108
c01_tex 4/18/06 12:32 PM Page 108
MeO
O
O
SR2
OT
MS
R1
O
MeO
SR2
OO
H R1
C3–
6
R1
Me
Me
Me
Me
Me
Me
Me
Me
i-Pr
i-Pr
i-B
u
i-B
u
R2
t-B
u
t-B
u
t-B
u
t-B
u
Et
Et
Et
Et
Et
t-B
u
Et
t-B
u
Geo
met
ry
Z Z E E Z Z E E Z Z Z Z
Solv
ent
CH
2Cl 2
TH
F
CH
2Cl 2
TH
F
CH
2Cl 2
TH
F
CH
2Cl 2
TH
F
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
CH
2Cl 2
dr 94:6
90:1
0
95:5
97:3
90:1
0
94:6
98:2
98:2
90:1
0
66:3
4
90:1
0
93:7
(96
)
(93
)
(90
)
(88
)
(95
)
(90
)
(78
)
(91
)
(80
)
(71
)
(88
)
(58
)
% e
e
96 93 98c
99c
95 93 98d
98 99e
97f
93g
97
197
O
NN
O
t-B
uB
u-t
Cu
2 O
Tf–
2+
(10
mol
%),
1. C
H2C
l 2, –
78°
2. a
q H
Cl
Et
O
O
O
Et
SBu-
t
OO
H
70(8
5) d
r =
93:
7, 9
7% e
eO
NN
O
t-B
uB
u-t
Cu
2 O
Tf–
2+
(10
mol
%),
1. C
H2C
l 2, –
78°
2. a
q H
Cl
109
c01_tex 4/18/06 12:32 PM Page 109
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
C. C
OPP
ER
-CA
TA
LY
ZE
D M
UK
AIY
AM
A-T
YPE
AL
DO
L A
DD
ITIO
NS
(Con
tinu
ed)
Ele
ctro
phile
MeO
O
O
OT
MSO
C4
O(9
9)
dr =
95:
5, 9
9% e
eh19
7O
O
NN
O
t-B
uB
u-t
Cu
2 O
Tf–
2+
(10
mol
%),
1. T
HF,
–78
°
2. a
q H
Cl
(93)
dr
= 9
1:9,
92%
ee
37C
HO
BnO
CO
2Me
HO
OO
OH
OB
n
O
OH
BnO
(95)
dr
= 9
6:4,
95%
ee
74C
HO
BnO
OT
MSO
O
X
OT
MS
R
BnO
R
X
OO
HC
3–8
37C
HO
BnO
X OE
t
OE
t
SEt
SEt
SEt
SBu-
t
SBu-
t
R Me
Ph Me
Me
i-B
u
Me
Me
(60)
(—)
(90)
(48)
(85)
(86)
(14)
dr
84:1
6
50:5
0
97:3
86:1
4
95:5
85:1
5
85:1
5
% e
e
87 9 97 85 95 99 97
Z/E
15:8
5
30:7
0
95:5
1:99
90:1
0
95:5
4:96
C
H2C
l 2, –
78°
2. a
q H
Cl,
TH
F
(10
mol
%),
1.N
NN
Cu
OO
PhPh
2 Sb
F 6–
2+
C
H2C
l 2, –
78°
2. a
q H
Cl,
TH
F
(10
mol
%),
1.N
NN
Cu
OO
PhPh
2 Sb
F 6–
2+
C
H2C
l 2, –
78°
2. a
q H
Cl,
TH
F
(10
mol
%),
1.N
NN
Cu
OO
PhPh
2 Sb
F 6–
2+
110
c01_tex 4/18/06 12:32 PM Page 110
OT
MS
OO
(S)-
Tol
-BIN
AP
(2.1
mol
%),
Cu(
OT
f)2
(2
mol
%),
n-B
u 4N
+Ph
3SiF
– (4
mol
%),
TH
F, –
78°
RC
HO
O
O
O
R
OH
R 2-C
4H3O
2-C
4H3S
(E)-
MeC
H=
CH
Me 2
C=
CH
Ph 4-M
eOC
6H4
(E)-
PhC
H=
CH
(E)-
PhC
H=
CM
e
(E)-
2-M
eOC
6H4C
H=
CH
2-C
10H
7
(91)
(98)
(48)
(81)
(92)
(93)
(83)
(74)
(82)
(86)
% e
e
94 95 91 83 94 94 85 65 90 93
69
SEt
OT
MS
199
CH
OE
tO
O(6
0)
94%
ee
O
O
OH
CH
2Cl 2
, –78
°, 1
6 h
2. R
aney
Ni
O
NN
O
Bn
Bn
Sn
2+
2 T
fO–
(10-
15 m
ol%
),
1. CH
OB
ocH
NO
O
OO
H(8
0)
81%
ee
268
Boc
HN
"
N
O
N
O
i-Pr
Pr-i
Cu(
OT
f)2
(20
mol
%),
Tri
ton
X-1
00 (
3 m
ol%
), H
2O, 0
°
OT
MS
OM
ePh
CH
O
O
OM
e
OH
Ph19
3(8
6)
53%
eei
(20
mol
%),
111
c01_tex 4/18/06 12:32 PM Page 111
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
C. C
OPP
ER
-CA
TA
LY
ZE
D M
UK
AIY
AM
A-T
YPE
AL
DO
L A
DD
ITIO
NS
(Con
tinu
ed)
Ele
ctro
phile
OR
TM
SOO
TM
S
R Me
t-B
u
BnO
O
OR
OO
H
(96)
(85)
% e
e
97 99
O
OO
BnO
OH
(94)
92
% e
e74
CH
OB
nO
37
C4
C5
OT
MS
OO
H
BnO
37(9
5)
dr =
95:
5, 9
5% e
e
CH
OB
nO
CH
OB
nO
CH
OO
O
OO
H26
9(6
4)
72%
de
(S)-
Tol
-BIN
AP
(2.1
mol
%),
Cu(
OT
f)2
(2
mol
%),
n-B
u 4N
+Ph
3SiF
– (4
mol
%),
TH
F, –
78°
OT
MS
OO
C
H2C
l 2, –
78°
2. a
q H
Cl,
TH
F
(5 m
ol%
),
1.
N
NN
Cu
OO
PhPh
2 Sb
F 6–
2+
C
H2C
l 2, –
78°
2. A
cidi
c w
orku
p
(0.5
mol
%),
1.
N
NN
Cu
OO
PhPh
2 Sb
F 6–
2+
C
H2C
l 2, –
78°
2. a
q H
Cl,
TH
F
(10
mol
%),
1.
N
NN
Cu
OO
PhPh
2 Sb
F 6–
2+
112
c01_tex 4/18/06 12:32 PM Page 112
OM
e
OT
MS
RC
HO
R i-B
u
2-C
4H3O
Ph (E)-
PhC
H=
CH
2,3-
(MeO
) 2C
6H3
2-C
10H
7
(61)
(30)
(73)
(42)
(71)
(76)
dr
> 9
8:2
> 9
8:2
> 9
8:2
> 9
8:2
> 9
8:2
> 9
8:2
% e
e
91 86 87 82 91 85
271
O
R
Cu(
OT
f)2
(10
mol
%),
(S)
-Tol
-BIN
AP
(11
mol
%),
n-B
u 4N
+Ph
3SiF
2– (20
mol
%),
TH
F, r
t
O
N
O
N
O
i-Pr
Pr-i
Cu[
O2S
(OC
12H
25-n
) 2]
(20
mol
%),
n-C
11H
23C
O2H
(10
mol
%),
H2O
, rt
OT
MS
Et
PhC
HO
O
Et
OH
Ph(2
4 m
ol%
),19
4(7
6)
syn:
anti
= 2
.8:1
, 69%
eei
N
O
N
O
i-Pr
Pr-i
Cu(
OT
f)2
(x m
ol%
),
H2O
/EtO
H (
1:9)
, 20
h
OT
MS
Et
RC
HO
O
Et
OH
R
R Ph Ph Ph 4-C
lC6H
4
2-M
eOC
6H4
2-C
10H
7
2-C
10H
7
2-C
4H3O
2-C
4H3O
(E)-
PhC
H=
CH
Ph(C
H2)
2
(64)
(81)
(34)
(88)
(87)
(91)
(87)
(86)
(78)
(94)
(37)
% e
ei
80 81 76 76 75 79 76 76 75 57 59
syn:
anti
3.7:
1
3.5:
1
3.7:
1
2.6:
1
2.9:
1
4.0:
1
4.0:
1
4.0:
1
5.7:
1
2.3:
1
4.6:
1
192
x 10 20 5 10 10 20 10 20 10 20 20
Tem
p
–15°
–15°
–15°
–10°
–10°
–10°
–10°
–10°
–10°
–10°
–5°
(x m
ol%
),
113
c01_tex 4/18/06 12:32 PM Page 113
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
C. C
OPP
ER
-CA
TA
LY
ZE
D M
UK
AIY
AM
A-T
YPE
AL
DO
L A
DD
ITIO
NS
(Con
tinu
ed)
Ele
ctro
phile
OE
t
OT
MS
CH
OPM
BO
PMB
O
OH
OE
t
O(9
3)
95%
ee
390
C5
273
OH
OE
t
OC
u(O
Tf)
2 (1
0 m
ol%
),
(S)
-Tol
-BIN
AP
(11
mol
%),
n-B
u 4N
+Ph
3SiF
2– (20
mol
%),
TH
F, 0
°, 2
4 h
CH
O(9
0)
80%
eei
271
O
O
TB
DPS
OC
HO
TB
DPS
O
(60)
dr
> 9
5:5
271
Cu(
OT
f)2
(10
mol
%),
(R
)-T
ol-B
INA
P (1
1 m
ol%
),
n-B
u 4N
+Ph
3SiF
2– (20
mol
%),
TH
F, r
t
OE
t
OT
MS
RC
HO
R i-Pr
Ph (E)-
PhC
H=
CH
2-C
10H
7
(68)
(80)
(35)
(70)
% e
ei
77 70 56 48
272
Cu(
OT
f)2
(10
mol
%),
(S)
-Tol
-BIN
AP
(11
mol
%),
n-B
u 4N
+Ph
3SiF
2– (20
mol
%),
TH
F, r
t
R
OH
OE
t
O
I
I
(50
) d
r =
9:1
Cu(
OT
f)2
(10
mol
%),
(S)
-Tol
-BIN
AP
(11
mol
%),
n-B
u 4N
+Ph
3SiF
2– (20
mol
%),
TH
F, r
t
TB
DPS
OC
HO
OM
e
OT
MS
C
H2C
l 2, –
78°
2. a
q H
Cl,
EtO
Ac,
rt
(2.5
mol
%),
1.
N
NN
Cu
OO
PhPh
2 Sb
F 6–
2+
H2O
OH
2
114
c01_tex 4/18/06 12:32 PM Page 114
O
NN
O
t-B
uB
u-t
Cu
2+
SEt
OT
MS
EtO
O
OH
SEt
O
199
CH
OE
tO
O2
TfO
–
(10–
15 m
ol%
),
CH
2Cl 2
, –78
°, 1
6 h
N
OA
rO
Me
C9
O
N
Ar
CO
2Et
CO
2Me
Ar
= 4
-MeO
C6H
4
241
O
NN
O
t-B
uB
u-t
Cu
+T
fO-
OT
f2
H2O
(1 m
ol%
),
3 Å
MS,
TH
F, –
20°,
24
h
(> 9
9)
dr =
95:
5, 9
7% e
eC
HO
EtO
O
Pr-i
OT
MS
(90)
(10)
BnO
Pr-i
OO
H
dr 95:5
38:6
2
% e
e
90 28
C6
Z/E
90:1
0
10:9
0
37C
HO
BnO
(61)
98
% e
e
N
O
N
O
i-Pr
Pr-i
Cu(
OT
f)2
(20
mol
%),
H2O
/EtO
H (
1:9)
, 20
h
OT
MS
Pr-i
RC
HO
O
Pr-i
OH
R19
2(2
0 m
ol%
),
R Ph 2-C
10H
7
(95)
(97)
syn:
anti
4.0:
1
4.0:
1
% e
ei
77 81
C
H2C
l 2, –
20°,
2 d
2. a
q H
Cl,
TH
F
(10
mol
%),
1.
N
NN
Cu
OO
PhPh
2 Sb
F 6–
2+
115
c01_tex 4/18/06 12:32 PM Page 115
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
C. C
OPP
ER
-CA
TA
LY
ZE
D M
UK
AIY
AM
A-T
YPE
AL
DO
L A
DD
ITIO
NS
(Con
tinu
ed)
Ele
ctro
phile
O
NN
O
t-B
uB
u-t
Cu
2+
199
CH
OE
tO
OPh
OT
MS
Ph
OO
H
EtO
O2
TfO
–
(10–
15 m
ol%
),
CH
2Cl 2
, –78
°, 1
6 h
a The
rea
ctio
n w
as c
arri
ed o
ut a
t –20
°.b T
he r
eact
ion
was
car
ried
out
in d
ichl
orom
etha
ne.
c The
am
ount
of
TM
SOT
f ad
ded
was
0.9
equ
ival
ents
.d T
he a
mou
nt o
f ca
taly
st u
sed
was
2.5
mol
%.
e The
rea
ctio
n w
as c
arri
ed o
ut a
t –50
°.f T
he r
eact
ion
was
car
ried
out
at r
oom
tem
pera
ture
.g T
he a
mou
nt o
f T
MSO
Tf
adde
d w
as 0
.5 e
quiv
alen
ts.
h The
sam
e re
sult
was
obt
aine
d w
ith d
ichl
orom
etha
ne a
s so
lven
t.i T
he a
bsol
ute
conf
igur
atio
n w
as n
ot d
eter
min
ed.
N
OA
rO
Me
C10
O
N
Ar
CO
2Et
CO
2Me
Ar
= 4
-MeO
C6H
4
241
CH
OE
tO
O
O
NN
O
t-B
uB
u-t
Cu
+
2 T
fO–
(1 m
ol%
),
TH
F, –
40°,
17
h
(94)
dr
= 9
4:6,
99%
ee
(< 5
) 9
5% e
e
N
O
N
O
Bn
Bn
Cu(
OT
f)2
(20
mol
%),
H2O
/EtO
H (
1:9)
, 0°,
20
h
OT
MS
PhR
CH
O
O
Ph
OH
R19
2
R Ph 4-C
lC6H
4
c-C
6H11
(98)
(56)
(77)
% e
e
61 67i
42i
syn:
anti
2.6:
1
1.6:
1
4.6:
1
(20
mol
%),
C9
116
c01_tex 4/18/06 12:32 PM Page 116
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
D. T
IN-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S
Ele
ctro
phile
C2
OT
MS
SEt
(20
mol
%),
Sn(
OT
f)2
(20
mol
%),
EtC
N, –
78°,
slo
w a
dditi
on
O
SEt
OH
141
N Me
H NR
OT
BS
CH
OR
OT
BS
O
SEt
OH
R
OT
BS
R Me
Ph
(84)
(85)
I:II
94:6
94:6
III
O
SEt
OH
141
R
OT
BS
CH
OR
OT
BS
O
SEt
OH
R
OT
BS
R Me
Ph
(86)
(85)
I:II
96:4
96:4
III
(20
mol
%),
Sn(
OT
f)2
(20
mol
%),
EtC
N, –
78°,
slo
w a
dditi
on
O
SEt
OH
141
N Me
H NR
OT
BS
CH
OR
OT
BS
O
SEt
OH
R
OT
BS
R Me
Ph
(85)
(86)
I:II
4:96
5:95
III
O
SEt
OH
141
R
OT
BS
CH
OR
OT
BS
O
SEt
OH
R
OT
BS
III
+ + + +
R Me
Ph
(85)
(90)
I:II
6:94
5:95
(20
mol
%),
Sn(
OT
f)2
(20
mol
%),
EtC
N, –
78°,
slo
w a
dditi
on
N Me
H N
(20
mol
%),
Sn(
OT
f)2
(20
mol
%),
EtC
N, –
78°,
slo
w a
dditi
on
N Me
H N
117
c01_tex 4/18/06 12:32 PM Page 117
(20
mol
%),
Sn(
OT
f)2
(20
mol
%),
EtC
N, –
78°
slo
w a
dditi
on
O
SEt
TM
SO
R15
3N M
e
NH
R TM
SC
C
i-Pr
n-B
u
n-B
uC
C
c-C
6H11
n-C
7H15
PhC
C
(75)
(48)
(79)
(68)
(81)
(79)
(71)
% e
e
77a,
b
90 91 88b
92 93b
79b
RC
HO
(20
mol
%),
Sn(
OT
f)2
(20
mol
%),
SnO
(20
mol
%),
EtC
N, –
78°,
slo
w a
dditi
on
O
SEt
OH
n-C
6H13
391
N Me
H Nn-
C6H
13C
HO
(87)
94
% e
e
CH
ON O
Ph
SBu-
t
TM
SON O
Ph
OH
SBu-
t
O
(91)
94
% e
e19
6O
NN
O
PhPh
Sn
2 O
Tf–
2+ (10
mol
%),
1. C
H2C
l 2, –
78°
2. a
q H
Cl
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
Ele
ctro
phile
TM
SO
SEt
TA
BL
E 1
D. T
IN-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
C2
(20
mol
%),
Sn(
OT
f)2
(20
mol
%),
EtC
N, –
78°,
slo
w a
dditi
on
O
SEt
TM
SO
R
N Me
NH
RC
HO
R (E)-
n-Pr
CH
=C
H
C6F
5
(65)
(90)
% e
e
72 68
153
118
c01_tex 4/18/06 12:32 PM Page 118
TM
SO
OPh
(20
mol
%),
Sn(
OT
f)2
(20
mol
%),
SnO
(20
mol
%),
EtC
N, –
78°,
slo
w a
dditi
on
O
OPh
TM
SO
R22
5N M
e
H NR
CH
O
R CH
2=C
H
(E)-
MeC
H=
CH
(E)-
n-Pr
CH
=C
H
n-C
5H11
Ph
(80)
(87)
(68)
(85)
(81)
% e
e
96 92 93 95 89
OB
n
syn:
anti
> 9
8:2
97:3
97:3
> 9
8:2
90:1
0
BnO
O
OPh
TM
SO
224
OB
n
(87)
sy
n:an
ti =
97:
3, 9
1% e
eC
HO
TM
S
TM
S
(24
mol
%),
Sn(
OT
f)2
(20
mol
%),
SnO
(20
mol
%),
EtC
N, –
78°,
slo
w a
dditi
on
31N M
e
H N
(87)
sy
n:an
ti =
97:
3, 9
1% e
e
(20
mol
%),
Sn(
OT
f)2
(20
mol
%),
SnO
(20
mol
%),
EtC
N, –
78°,
slo
w a
dditi
on
N Me
H N
CH
OT
MS
O
OPh
TM
SO
OB
nT
MS
(20
mol
%),
Sn(
OT
f)2
(20
mol
%),
EtC
N, –
78°,
SnO
(20
mol
%),
slo
w a
dditi
on
O
OPh
TM
SO
227
N Me
H N
OB
n
(70)
sy
n:an
ti =
95:
5, 9
6% e
eT
BSO
TB
SOC
HO
CH
OO
OPh
TM
SO
OB
n
(70)
sy
n:an
ti >
98:
2, 8
0% e
e22
5
"
119
c01_tex 4/18/06 12:32 PM Page 119
C2–
3T
MSO
SEt
(20
mol
%),
Sn(
OT
f)2
(20
mol
%),
SnO
(40
mol
%),
EtC
N, –
78°,
slo
w a
dditi
on
O
SEt
TM
SO
R2
226
N Me
H NR
2 CH
O
R1
R2
i-Pr
n-B
u
(E)-
n-Pr
CH
=C
H
c-C
6H11
(E)-
MeC
H=
CH
(E)-
n-Pr
CH
=C
H
Ph n-C
7H15
(50)
(71)
(83)
(78)
(85)
(81)
(78)
(81)
% e
e
92 92 84 94 95 94 93 > 9
8
R1
syn:
anti
— — — — 99:1
100:
0
95:5
100:
0
R1
H H H H Me
Me
Me
Me
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
Ele
ctro
phile
TA
BL
E 1
D. T
IN-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
(20
mol
%),
Sn(
OT
f)2
(20
mol
%),
CH
2Cl 2
,
–78
°, s
low
add
ition
O
SEt
TM
SO
R2
228
N Me
H NR
2 CH
O
R2
n-B
uC
C
TM
SC
C
MeC
C
n-B
uC
C
PhC
C
(63)
(73)
(77)
(67)
(82)
% e
e
88 91 88 91 86
R1
syn:
anti
— 95:5
86:1
4
93:7
90:1
0
R1
H Me
Me
Me
Me
CH
O
O
EtO
SR2
TM
SO
O
EtO
SR2
OO
H
O
NN
O
R3
R3
Sn
2 O
Tf–
2+
R1
R1
R1
H Me
Me
Et
i-Pr
i-B
u
i-B
u
i-B
u
R2
Ph Ph Ph Ph Ph Et
t-B
u
Ph
(90)
(97)
(97)
(90)
(72)
(83)
(83)
(88)
dr — 96:4
94:6
92:8
93:7
92:8
94:6
92:8
% e
e
98 94 95c
95 95 92 96 98
C2–
6
(10
mol
%),
1. C
H2C
l 2,–
78°
2. a
q H
Cl
R3
Bn
Ph Bn
Bn
Bn
i-Pr
i-Pr
Bn
39 392
393
39 39 39 39 39
120
c01_tex 4/18/06 12:32 PM Page 120
C3
TM
SO
SEt
(50
mol
%),
SnO
(1
equi
v),
TM
SOT
f (6
5 m
ol%
), C
H2C
l 2,
–78
°, s
low
add
ition
O
SEt
TM
SO
R16
5R
CH
ON M
e
H N
O
SEt
TM
SO
RI
II
+
R Et
i-B
u
Ph c-C
6H11
n-C
7H15
(65)
(70)
(82)
(58)
(65)
% e
e
67 94 91 68 85
I:II
94:6
98:2
94:6
91:9
98:2
(20
mol
%),
Sn(
OT
f)2
(20
mol
%),
EtC
N, –
78°,
slo
w a
dditi
on
O
SEt
TM
SO
R
R (E)-
MeC
H=
CH
(E)-
n-Pr
CH
=C
H
Ph 4-C
lC6H
4
c-C
6H11
4-M
eC6H
4
n-C
7H15
(76)
(73)
(77)
(83)
(71)
(75)
(80)
% e
ed
93 93 90 90 > 9
8
91 > 9
8
160
N Me
H Nsy
n:an
ti
96:4
93:7
93:7
87:1
3
100:
0
89:1
1
100:
0
RC
HO
(20
mol
%),
Sn(
OT
f)2
(20
mol
%),
CH
2Cl 2
,
–78
°, s
low
add
ition
O
SEt
TM
SO
R
R (E)-
MeC
H=
CH
(E)-
n-Pr
CH
=C
H
Ph 4-C
lC6H
4
c-C
6H11
4-M
eC6H
4
n-C
7H15
(51)
(62)
(86)
(80)
(31)
(82)
(75)
% e
e
77 74 91 93 74 80 > 9
8
160
RC
HO
N Me
H Nsy
n:an
ti
84:1
6
81:1
9
93:7
93:7
99:1
78:2
2
100:
0
(24
mol
%),
Sn(
OT
f)2
(20
mol
%),
SnO
(20
mol
%),
CH
2Cl 2
, –78
°,
slo
w a
dditi
on
O
SEt
OH
n-C
9H19
231
N Me
H N(8
3)
syn:
anti
= 9
7:3,
94%
ee
n-C
9H19
CH
O
121
c01_tex 4/18/06 12:32 PM Page 121
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
Ele
ctro
phile
TA
BL
E 1
D. T
IN-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
O
Et
O
39SB
u-t
TM
SO
O
Et
SBu-
t
OH
O
(—)
dr
= 9
9:1,
98%
ee
O
MeO
O
39
O
MeO
SBu-
t
OH
O
(94)
dr
= 9
9:1,
99%
ee
C3
TM
SO
SEt
(22
mol
%),
Sn(
OT
f)2
(20
mol
%),
CH
2Cl 2
,
–
78°,
slo
w a
dditi
on
O
SEt
TM
SO
R
R Ph 4-C
lC6H
4
c-C
6H11
n-C
7H15
(86)
(80)
(64)
(76)
% e
ed
91 93 92a
> 9
8
229
RC
HO
N Me
H Nsy
n:an
ti
93:7
93:7
> 9
9:1
100:
0
TM
SO
OPr
-i(2
0 m
ol%
),
Sn(
OT
f)2
(20
mol
%),
EtC
N, –
78°,
slo
w a
dditi
on
O
OPr
-i
OH
Ph23
0Ph
CH
O
OB
n
N Me
H N
OB
n
(60)
I:
II =
90:
10, 9
6% e
e I
I
O
OPr
-i
OH
Ph
OB
n
II
+
E:Z
= 7
1:29
C
H2C
l 2, –
78°
2. a
q H
Cl
(10
mol
%),
1.
N
NN
SnO
O
PhPh
2 T
fO–
2+
C
H2C
l 2, –
78°
2. a
q H
Cl
(10
mol
%),
1.
N
NN
SnO
O
PhPh
2 T
fO–
2+
122
c01_tex 4/18/06 12:32 PM Page 122
O
MeO
O
39X
TM
SO
O
MeO
X
OO
H
RR
R Me
Me
Me
Et
Et
i-B
u
i-B
u
X SEt
SBu-
t
SBu-
t
SEt
SBu-
t
SEt
SBu-
t
(91
)
(84
)
(94
)
(94
)
(84
)
(76
)
(81
)
dr 95:5
99:1
99:1
99:1
98:2
99:1
99:1
% e
e
92 96 99 97 97 97 99
C3–
6
Geo
met
ry
Z E Z Z Z Z Z
a The
am
ount
of
cata
lyst
use
d w
as 3
0 m
ol%
.b D
ichl
orom
etha
ne w
as u
sed
as th
e so
lven
t.c
The
R,R
-cat
alys
t was
use
d.d T
he a
bsol
ute
conf
igur
atio
n w
as n
ot d
eter
min
ed.
O
EtO
O
394
SEt
TM
SO
O
EtO
SEt
OO
HC
6
(85)
91
% e
e
SEt
TM
SO
199
CH
OE
tO
O(6
0)
94%
ee
O
O
OH
CH
2Cl 2
, –78
°, 1
6 h
2. R
aney
Ni
O
NN
O
Bn
Bn
Sn
2+
2 T
fO–
(10-
15 m
ol%
),
1.C
4
C
H2C
l 2, –
78°
2. a
q H
Cl
(10
mol
%),
1.
N
NN
SnO
O
PhPh
2 T
fO–
2+
T
HF
–78°
, 48
h
2. a
q H
Cl
(10
mol
%),
1.
N
NN
SnO
O
PhPh
2 T
fO–
2+
123
c01_tex 4/18/06 12:32 PM Page 123
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
E. T
ITA
NIU
M-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S
Ele
ctro
phile
OM
e
TM
SOR
CH
OR
OM
e
OO
HC
2R T
IPSC
C
(E)-
MeC
H=
CH
n-Pr
TB
SOC
H2C
C
TB
SOC
Me 2
C C
Ph c-C
6H11
PhC
C
(E)-
PhC
H=
CH
Ph(C
H2)
2
(E)-
PhC
H=
CM
e
Ph(C
H2)
3C C
(88)
(82)
(76)
(91)
(88)
(94)
(81)
(96)
(95)
(98)
(89)
(84)
% e
e
97a
97 95 99 96a
96 95 94a
98 93 97 96a
188
395
395
191
188
191
395
188
191
191
191
188
OB
nO
TB
S32
—(8
4)
N
Bu-
t
Br
OO
O
t-B
u
Bu-
tOO
Ti
(2
mol
%),
Et 2
O, –
10°
2. T
BA
F, T
HF
1.
O OT
iO
PhM
e, –
23°
TM
SO
SRPh
CH
OO
SR
TM
SO
Ph39
7(2
0 m
ol%
),
NC
l
MO
MO
CH
ON
Cl
MO
MO
OM
e
OO
H
22(9
0)
94%
ee
R Et
t-B
u
Ph Ph3C
(61)
(87)
(38)
(35)
% e
eb
31 44 37 42
N
Bu-
t
Br
OO
O
t-B
u
Bu-
tOO
Ti
(
2 m
ol%
),
Et 2
O, –
10°
2. T
BA
F, T
HF
1.
124
c01_tex 4/18/06 12:32 PM Page 124
OT
MS
SR1
SR1
R2
OT
MS
O13
7R
2 CH
O
R1
Et
Et
Et
Et
Et
Et
Et
t-B
u
t-B
u
R2
ClC
H2
Boc
NH
CH
2
BnO
CH
2
n-B
uO2C
(E)-
MeC
H=
CH
i-Pr
n-C
8H17
ClC
H2
n-C
8H17
Solv
ent
CH
2Cl 2
CH
2Cl 2
PhM
e
PhM
e
PhM
e
PhM
e
PhM
e
PhM
e
PhM
e
(47)
(64)
(81)
(84)
(60)
(61)
(67)
(61)
(60)
% e
e
80c
88c
94 95 81 85 86 91 91
(R)-
BIN
OL
/TiC
l 2(O
Pr-i
) 2
(5
mol
%),
0°
OR
1 XX
OH
OC
HO
OB
n
R1
TM
S
TM
S
TM
S
X OE
t
OPh
SBu-
t
OB
n
X
OH
O
OB
n
III
(71)
(45)
(61)
I:II
17:8
3
18:8
2
18:8
2
% e
e
— — —
396
1. (
R)-
BIN
OL
/TiC
l 2(O
Pr-i
) 2
(2
0 m
ol%
), P
hMe,
0°
2. H
+
+
X
OH
O
R1
TM
S
TM
S
TE
S
TM
S
X OE
t
SBu-
t
SBu-
t
OPh
OB
n
X
OH
O
OB
n
+
III
(73)
(68)
(66)
(65)
I:II
98:2
98:2
97:3
97:3
% e
e
— — — —
396
1. (
S)-B
INO
L/T
iCl 2
(OPr
-i) 2
(2
0 m
ol%
), P
hMe,
0°
2. H
+
CH
O
OB
n
125
c01_tex 4/18/06 12:32 PM Page 125
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
E. T
ITA
NIU
M-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
OT
MS
SBu-
tR
CH
OR
OH
SBu-
t
OR B
nOC
H2
2-C
4H3O
Ph c-C
6H11
(E)-
PhC
H=
CH
Ph(C
H2)
2
n-C
8H17
(82
)
(88
)
(90
)
(70
)
(76
)
(80
)
(74
)
% e
e
> 9
8
> 9
8
97 89 89 97 98
(S)-
BIN
OL
(20
mol
%),
Ti(
OPr
-i) 4
(20
mol
%),
4 Å
MS,
Et 2
O, –
20°,
12
h
171
CH
O
OB
n
(R)-
BIN
OL
, Ti(
OPr
-i) 4
4 Å
MS,
Et 2
O, –
20°
SBu-
t
OO
Bn
OH
(47)
dr
= 2
:117
7
1. (
R)-
BIN
OL
/Ti(
OPr
-i) 4
(
10 m
ol%
), P
hOH
(10
mol
%),
E
t 2O
, 0°;
then
0°
to r
t
2. 2
N H
Cl
(65)
96
% e
e17
6M
eO2C
(CH
2)4C
HO
SBu-
t
OO
H
MeO
2C(C
H2)
4
C2
1. (
R)-
BIN
OL
/Ti(
OPr
-i) 4
(
10 m
ol%
), P
hOH
(50
mol
%),
4
Å M
S, E
t 2O
; 0°,
then
0°
to r
t
2. 2
N H
Cl
(76)
>
97%
ee
176
n-Pr
O2C
(CH
2)4C
HO
1. (
R)-
BIN
OL
/Ti(
OE
t)4
(
10 m
ol%
), E
t 2O
, 0°,
5 h
;
th
en 0
° to
rt,
16 h
2. 2
N H
Cl
176
SBu-
t
OO
H
n-Pr
O2C
(CH
2)4
I
I (
66)
> 9
7% e
en-
PrO
2C(C
H2)
4CH
O
126
c01_tex 4/18/06 12:32 PM Page 126
1. (
R)-
BIN
OL
/Ti(
OPr
-i) 4
(
10 m
ol%
), P
hOH
(50
mol
%),
E
t 2O
, 0°;
then
0°
to r
t
2. 2
N H
Cl
RC
HO
SBu-
t
OO
H
R
R i-B
u
Ph n-C
6H13
Bn
Ph(C
H2)
2
(58)
(71)
(76)
(73)
(85)
% e
e
53 96 93 96 92
SBu-
t
OO
HC
HO
(31)
—
NO
2N
O2
1. (
R)-
BIN
OL
/Ti(
OPr
-i) 4
(
10 m
ol%
), P
hOH
(20
mol
%),
E
t 2O
, 0°;
then
0°
to r
t
2. 2
N H
Cl
RC
HO
SBu-
t
OO
H
R
R EtO
2C
TB
SO(C
H2)
5
(65)
(22)
% e
e
63 95
1. (
R)-
BIN
OL
/Ti(
OPr
-i) 4
(
10 m
ol%
), E
t 2O
, 0°;
th
en 0
° to
rt
2. 2
N H
Cl
SBu-
t
OO
H
CH
O(2
3)
62%
ee
OO
OO
176
176
176
176
OH
(76)
95
% e
e
O
N
Ph
CH
O
O
N
Ph
SBu-
t
OO
H
MeO
2CC
HO
MeO
2C(4
0)
—
176
176
OSB
u-t
1. (
R)-
BIN
OL
/Ti(
OPr
-i) 4
(
10 m
ol%
), P
hOH
(50
mol
%),
E
t 2O
, 0°;
then
0°
to r
t
2. 2
N H
Cl
1. (
R)-
BIN
OL
/Ti(
OPr
-i) 4
(
10 m
ol%
), E
t 2O
, 0°;
th
en 0
° to
rt
2. 2
N H
Cl
1. (
R)-
BIN
OL
/Ti(
OPr
-i) 4
(
10 m
ol%
), E
t 2O
, 0°;
th
en 0
° to
rt
2. 2
N H
Cl
127
c01_tex 4/18/06 12:32 PM Page 127
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
E. T
ITA
NIU
M-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
SBu-
t
TM
SOO
137
(80)
96
% e
e
1. (
R)-
BIN
OL
/Ti(
OPr
-i) 4
(5
mol
%),
a
dditi
ve (
1 eq
uiv)
, 4 Å
MS,
P
hMe,
0°
2. H
+
t-B
uSC
8H17
-n
OH
On-
C8H
17C
HO
168
addi
tive
PhO
H
C6F
5OH
(61)
(62)
% e
e
96 97
BnO
CH
O(S
)-B
INO
L/T
iCl 2
(OPr
-i) 2
(5
mol
%),
PhM
e, 0
°B
nO
SBu-
tF 2
HC
OH
O(4
7)
96%
ee
OH
CH
F 2E
tO67
1. (
R)-
BIN
OL
/TiC
l 2(O
Pr-i
) 2
(
20 m
ol%
), 5
Å M
S, P
hMe,
0°,
2
h
2. H
+
1. (
R)-
BIN
OL
/TiC
l 2(O
Pr-i
) 2
(
5 m
ol%
), 4
Å M
S, s
cCH
F 3,
1
00 a
tm, 3
4°
2. H
+
SBu-
tn-
C8H
17
OH
On-
C8H
13C
HO
169
(46)
88
% e
e
C2
OT
MS
SBu-
t
O
SBu-
tSB
u-t
R
OO
RC
HO
168
SiM
e
R BnO
CH
2
n-C
8H17
(95)
(83)
% e
e
98 97
(R)-
BIN
OL
/TiC
l 2(O
Pr-i
) 2
(5
mol
%),
PhM
e, 0
°, 2
h
Si
OT
MS
SRC
F 3C
HO
67SR
CF 3
OH
O
R t-B
u
Ph
(56)
(38)
% e
e
90 96
1. (
R)-
BIN
OL
/TiC
l 2(O
Pr-i
) 2
(
20 m
ol%
), P
hMe,
0°
2. H
+
Me
128
c01_tex 4/18/06 12:32 PM Page 128
O OT
iO
PhM
e, –
78°
TB
SO
SRPh
CH
OO
SR
TM
SO
Ph39
7
R Et
t-B
u
Bn
Ph2C
H
(92)
(91)
(89)
(60)
% e
eb
35 60d
40 45
(20
mol
%),
OH
N
HO
Br
Sxy
x =
5, y
= 6
0O
Bn
TM
SO
PhO
Bn
OO
H(—
) 2
6% e
e39
8
Ti(
OPr
-i) 4
(2
mol
%),
PhM
e,
0°,
36
h
(2 m
ol%
),n
RC
HO
RO
Bn
OO
HR T
BSO
CH
2C C
Ph (E)-
PhC
H=
CH
Ph(C
H2)
2
3,4-
(MeO
) 2C
6H3
(E)-
PhC
H=
CM
e
(99)
(94)
(98)
(95)
(81)
(91)
% e
e
99 96 96 91 95 97
191
TrS
CH
O
TrS
OH
(99)
>
98%
ee
33
N
Bu-
t
Bu-
tO
O
O
t-B
u
Bu-
tOO
Ti
(2
mol
%),
E
t 2O
, –10
°
2. T
BA
F, T
HF
1.
OB
n
O
PhC
HO
= X
1. e
nt-X
(2
mol
%),
Et 2
O, –
10°
2. T
BA
F, T
HF
129
c01_tex 4/18/06 12:32 PM Page 129
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
E. T
ITA
NIU
M-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
TM
SOR
CH
OR
OO
H
R TB
SOC
H2C
C
Ph c-C
6H11
PhC
C
Ph(C
H2)
2
Ph(C
H2)
3C C
(85)
(83)
(79)
(99)
(98)
(99)
% e
e
93 66 75 91 90 98
178
C3
1. X
(2
mol
%),
Et 2
O, 0
° to
rt
2. 2
.N H
Cl,
Et 2
O
(84)
> 9
8% e
e18
9N
O
CH
O
OPM
B
N
O
OH
OB
n
O
OPM
B
C2
OB
n
TM
SO
TM
SO
SR1
R2 C
HO
137
SR1
R2
TM
SOO
I
SR1
R2
TM
SOO
IIR
1
Et
Et
t-B
u
R2
BnO
CH
2
n-B
uO2C
n-B
uO2C
(85)
(64)
(57)
I:II
72:2
8
92:8
57:4
3% e
e I
90 98 88T
MSO
SR1
137
SR1
R2
TM
SOO
I
SR1
R2
TM
SOO
IIR
1
Et
t-B
u
t-B
u
R2
BnO
CH
2
BnO
CH
2
n-B
uO2C
(80)
(72)
(81)
I:II
48:5
2
8:92
20:8
0
% e
e I
I
86 90 86
(R)-
BIN
OL
/TiC
l 2(O
Pr-i
) 2
(5
mol
%),
PhM
e, 0
°
+ +(R
)-B
INO
L/T
iCl 2
(OPr
-i) 2
(5
mol
%),
PhM
e, 0
°
R2 C
HO
N
Bu-
t
Br
OO
O
t-B
u
Bu-
tOO
Ti
(2
mol
%),
E
t 2O
, –10
°
2. T
BA
F, T
HF
1.
= X
130
c01_tex 4/18/06 12:32 PM Page 130
(64)
I:
II =
48:
52, 5
5% e
e I,
64%
ee
II
(48)
I:
II =
44:
56, 8
9% e
e I,
83%
ee
II
1. (
R)-
BIN
OL
/TiC
l 2(O
Pr-i
) 2
(
10 m
ol%
), C
H2C
l 2, 0
°, 3
h
2. H
Cl,
MeO
H
TM
SO
SEt
SEt
CF 3
OH
O
I
SEt
CF 3
OH
O
II
CF 3
CH
O67
1. (
R)-
BIN
OL
/TiC
l 2(O
Pr-i
) 2
(
20 m
ol%
), P
hMe,
0°
2. H
+
TM
SO
SEt
SEt
CF 3
OH
O
I
SEt
CF 3
OH
O
II
CF 3
CH
O67
1. (
R)-
BIN
OL
/TiC
l 2(O
Pr-i
) 2
(
20 m
ol%
), P
hMe,
0°
2. H
+
+ +
(R)-
BIN
OL
/TiC
l 2(O
Pr-i
) 2
(5
mol
%),
CH
2Cl 2
, 0°
OT
BS
R Me
n-B
uR
O2C
OH
OT
BS
(71)
(73)
% e
e
> 9
9
> 9
9
77R
OC
HO
O
CO
2Me
OH
O13
8M
eO2C
OH
(—)
> 9
9% d
e, >
99%
ee
MeO
CH
O
O
OO
TM
SR
CH
OR
OH
OO
R Ph n-C
7H15
n-C
7H15
n-C
12H
25
n-C
12H
25
(70
)
(95
)
(50
)
(80
)
(20
)
I:II
70:3
0
70:3
0
53:4
7
60:4
0
70:3
0
R
OH
OO
% e
e I
54b
57 87e
80 90e
277
III
+
(R)-
BIN
OL
(40
mol
%),
Ti(
OPr
-i) 4
(20
mol
%),
C
H2C
l 2, –
20°
C4
131
c01_tex 4/18/06 12:32 PM Page 131
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
E. T
ITA
NIU
M-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
OO
TM
S
C4
n-C
12H
25C
HO
n-C
12H
25
OH
OO
n-C
12H
25
OH
OO
278
III
addi
tive
none
(+)-
Tad
dol (
20 m
ol%
)
none
(R)-
BIN
OL
(40
mol
%),
Ti(
OPr
-i) 4
(20
mol
%),
add
itive
,
Et 2
O, –
20°
(20
)
(72
)
(80
)
I:II
60:4
0
70:3
0
60:4
0
% e
e I
90 93f
> 9
6g
+
RC
HO
R
OH
OO
R
OH
OO
280
III
R Ph c-C
6H11
(E)-
n-C
6H13
CH
=C
H
(E)-
n-C
5H11
CH
=C
H(C
H2)
2
n-C
12H
25
(R)-
BIN
OL
(40
mol
%),
Ti(
OPr
-i) 4
(20
mol
%),
Et 2
O, –
20°
dr
24:7
6
65:3
5
30:7
0
53:4
7
60:4
0
(99
)
(70
)
(70
)
(99
)
(80
)
% e
e I
60 71 52 94 > 9
6
% e
e II
90b
79 24 90 90
+
CH
O
OT
BS
OO
OT
BS
OH
OO
OT
BS
OH
OO
OT
BS
OH
OO
OT
BS
OH
III
I
IIIV
279
1. T
i(O
Pr-i
) 4 (
20 m
ol%
),
li
gand
(40
mol
%),
Et 2
O, –
20°
2. H
F, T
HF
Lig
and
(S)-
BIN
OL
(R)-
BIN
OL
(50
)
(50
)
I:II
:III
:IV
26:9
:55:
10
15:3
5:10
:40
+
+
55
5
55
132
c01_tex 4/18/06 12:32 PM Page 132
RC
HO
R n-B
u
Ph (E)-
PhC
H=
CH
(55)
(38)
(32)
267
% e
e
92 88 33
1. (
R)-
BIN
OL
/Ti(
OPr
-i) 4
(
20 m
ol%
), 4
Å M
S, T
HF,
–
78°
to r
t
2. N
aHC
O3
OO
OR
OH
OT
MS
OO
R
OH
O
O
O (
65)
(42
)
(63
)
(72
)
(59
)
(39
)
% e
e
89 80h
92 75 98 89
Ti(
OPr
-i) 4
(50
mol
%),
(R
)-B
INO
L (
50 m
ol%
), 4
Å M
S,
TH
F, –
78°
RC
HO
R 3-C
4H3O
3-C
4H3O
Ph 4-O
2NC
6H4
4-M
eOC
6H4
n-C
9H19
399
399
400
400
400
400
O
OO
R
OH
R TIP
SC C
(Z)-
TB
SOC
H2C
H=
CH
n-B
u 3Sn
CH
=C
H
(E,E
)-M
eCH
=C
H-C
H=
CH
Ph (E)-
PhC
H=
CH
Ph(C
H2)
2
(86)
(97)
(79)
(95)
(83)
(88)
(97)
% e
e
91 94 92 92 96 99 80
139
RC
HO
N
Bu-
t
Br
OO
O
t-B
u
Bu-
tOO
Ti
(2 m
ol%
),
Et 2
O, 0
°
2. T
FA, T
HF
1.
133
c01_tex 4/18/06 12:32 PM Page 133
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
E. T
ITA
NIU
M-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
O
OO
OH
401
CH
O(7
9)
97.5
% e
e
N
Bu-
t
Br
OO
O
t-B
u
Bu-
tOO
Ti
(2 m
ol%
),
Et 2
O, 0
°, 5
.5 h
2. T
FA, T
HF
1.
OT
MS
OO
C4
OM
e
TM
SOO
TM
S
R
OH
O
OM
e
O1.
Ti(
OPr
-i) 4
(8
mol
%),
(
R)-
BIN
OL
(8
mol
%),
T
HF,
–78
°
2. T
FA
(67
)
(65
)
(86
)
(68
)
(31
)
(92
)
% e
e
99 88 90 91 92 99
R 3-C
4H3O
Ph 4-O
2NC
6H4
4-M
eOC
6H4
n-C
7H15
(E)-
PhC
H=
CH
RC
HO
402
1. T
i(O
Pr-i
) 4 (
2 m
ol%
),
(R
)-B
INO
L (
2 m
ol%
),
T
HF,
–78
°
2. T
FA
(82
)
(94
)
(84
)
(70
)
% e
e
99 92 99 98
R 3-C
4H3O
Ph (E)-
PhC
H=
CH
n-C
9H19
RC
HO
402
I
I
134
c01_tex 4/18/06 12:32 PM Page 134
OT
MS
OO
R
OH
O
O
O
(59)
(89)
(69)
(76)
(55)
(30)
(37)
% e
e
87 94i
92 90 95 90 36
Ti(
OPr
-i) 4
(17
mol
%),
(R
)-B
INO
L (
17 m
ol%
),
TH
F, –
78°
RC
HO
R 3-C
4H3O
3-C
4H3O
Ph 4-O
2NC
6H4
4-M
eOC
6H4
(E)-
PhC
H=
CH
n-C
9H19
399
399
400
400
400
400
400
R n-B
u
Ph (E)-
PhC
H=
CH
(37)
(93)
(58)
267
% e
e
76 92 79
1. (
R)-
BIN
OL
/Ti(
OPr
-i) 4
(
20 m
ol%
), 4
Å M
S, T
HF,
–
78°
to r
t
2. N
aHC
O3
I
IR
CH
O
OT
MS
Pr-n
n-B
uO2C
OH
OT
MS
(67)
Z
:E =
95:
5, >
99%
ee
Et
OT
MS
Et
MeO
2C
OH
OT
MS
(54)
Z
:E =
96:
4, d
r =
98:
2, 9
9% e
e
77 77
n-B
uOC
HO
O
MeO
CH
O
O
(R)-
BIN
OL
/TiC
l 2(O
Pr-i
) 2
(5
mol
%),
CH
2Cl 2
, 0°
(R)-
BIN
OL
/TiC
l 2(O
Pr-i
) 2
(5
mol
%),
CH
2Cl 2
, 0°
C5
135
c01_tex 4/18/06 12:32 PM Page 135
C5
OR
1 Et
R2 O
2C
OH
OR
1
Me
R1
TM
S
TM
S
TB
S
R2
Me
n-B
u
Me
Z:E
94:6
99:1
84:1
6
dr 98:2
99:1
73:2
7
% e
e
99 99 77
(58)
(63)
(73)
77R
2 OC
HO
O
OE
t
OT
MS
RC
HO
R i-Pr
Ph 2-C
10H
7
(E)-
PhC
H=
CH
(18)
(45)
(25)
(45)
% e
eb
70 75 75 60
272
Ti(
Oi-
Pr) 4
(20
mol
%),
(R
)-B
INO
L (
40 m
ol%
),
CH
2Cl 2
, rt
R
OH
OE
t
O
OT
MS
OO
R
OH
O
O
O40
0
Ti(
Oi-
Pr) 4
(50
mol
%),
(R
)-B
INO
L (
50 m
ol%
),
TH
F, –
78°
RC
HO
(40)
(41)
(45)
(73)
% e
e
67h
72 73 62
R 3-C
4H3O
3-C
4H3O
Ph 4-O
2NC
6H4
(R)-
BIN
OL
/TiC
l 2(O
Pr-i
) 2
(5
mol
%),
CH
2Cl 2
, 0°
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
E. T
ITA
NIU
M-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
1. (
R)-
BIN
OL
/Ti(
OPr
-i) 4
(
20 m
ol%
), 4
Å M
S, T
HF,
–
78°
to r
t
2. N
aHC
O3
PhC
HO
267
(62)
I:I
I =
51:
11, 1
00%
ee
I, 2
6% e
e II
OO
OT
MS
III
OO
OPh
OH
OO
OPh
OH
+
136
c01_tex 4/18/06 12:32 PM Page 136
OT
BS
CO
2Me
OH
O13
8M
eO2C
OH
CO
2Me
OH
% e
e
98.5
95.9
Con
figu
ratio
n
R S
(47)
(44)
CO
2Me
OH
O
MeO
2C
OH
I
III:
II
98.4
:1.6
5.9:
94.1
% e
e I
99.6
—
MeO
CH
O
O
1. (
R)-
BIN
OL
/TiC
l 2(O
Pr-i
) 2
(10
mol
%),
CH
2Cl 2
, 0°
2. H
Cl/M
eOH
+
PhC
HO
OC
OC
Cl 3
M
eOH
(1
equi
v), T
HF,
rt
Ti
OM
e
Cl
(10
mol
%),
(55)
sy
n:an
ti =
79:
21, 5
8% e
eb
C6
403
O
Ph
OH
OR
3 R1
C8–
10
R1
CF 3
OH
OR
3
R2
I
R1
CF 3
OH
O
R2
II
CF 3
CH
O23
3R
2(R
)-B
INO
L/T
iCl 2
(OPr
-i) 2
(x
mol
%),
CH
2Cl 2
, 0°,
15
min
+
R1
Ph Ph 4-M
eC6H
4
4-M
eC6H
4
4-M
eOC
6H4
4-M
eSC
6H4
R2
H H Me
Me
Me
Me
R3
TB
S
TIP
S
TM
S
TB
S
TB
S
TB
S
x 5 1 20 20 20 20
E:Z
I
1:5
1:5
— 1:6
1:5
1:6
syn:
anti
II
— — — 1:1
5:3
2:1
% e
e (Z
)-I
98 96 — 94 95 95
I
(67)
(90)
(0)
(77)
(68)
(72)
II (14)
(4)
(27)
j
(10)
(22)
(18)
137
c01_tex 4/18/06 12:32 PM Page 137
a The
am
ount
of
cata
lyst
use
d w
as 3
mol
%.
b The
abs
olut
e co
nfig
urat
ion
was
not
det
erm
ined
.c T
he r
eact
ion
was
car
ried
out
at –
20°.
d The
rea
ctio
n w
as c
arri
ed o
ut a
t –43
°.e
Die
thyl
eth
er w
as u
sed
as th
e so
lven
t.f T
he a
mou
nt o
f (R
)-B
INO
L u
sed
was
20
mol
%.
g The
ald
ehyd
e an
d th
e si
lyl a
ceta
l wer
e ad
ded
in f
our
port
ions
.h F
or th
is r
eact
ion,
17
mol
% o
f T
i(O
Pr-i
) 4 a
nd 1
7 m
ol%
of
(R)-
BIN
OL
wer
e us
ed.
i For
this
rea
ctio
n, 5
0 m
ol%
of
Ti(
OPr
-i) 4
and
50
mol
% o
f (R
)-B
INO
L w
ere
used
.j P
rodu
ct I
I w
as o
btai
ned
as it
s si
lyl e
ther
.
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
E. T
ITA
NIU
M-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
138
c01_tex 4/18/06 12:32 PM Page 138
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
F. O
TH
ER
ME
TA
L-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S
Ele
ctro
phile
C2
OT
MS
SEt
(R)-
3,3'
-I2B
INO
L (
12 m
ol%
),
Zr(
OB
u-t)
4 (1
0 m
ol%
),
n-P
rOH
(80
mol
%),
H2O
(20
mol
%),
PhM
e, 0
°
O
SEt
OH
R18
0
180
180
180
179
RC
HO
R (E)-
MeC
H=
CH
Ph 4-M
eOC
6H4
(E)-
PhC
H=
CH
Ph(C
H2)
2
(76)
(91)
(92)
(94)
(69)
% e
e
97 95 96 95 81a
CH
OB
nOSB
u-t
OT
MS
BnO
SBu-
t
OO
H38
CH
2Cl 2
, –78
°
(10
mol
%),
R i-Pr
t-B
u
Ph Bn
(—)
(—)
(—)
(—)
% e
e
36 18 78 40
OT
BS
OR
1R
1
Et
Et
Bn
Bn
Bn
Bn
PhN
HT
f
CO
2TB
S(4
0 m
ol%
),
ZnE
t 2 (
20 m
ol%
), P
hMe,
–78
°
O
OR
1
OT
BS
R2
R2
CO
2Bn
Ph CC
l 3
CB
r 3
2-C
4H3O
c-C
6H11
(84)
(79)
(70)
(63)
(95)
(76)
% e
eb
49 60 72c
80c
47 23
186
CH
O
O
EtO
O
EtO
OH
O
SEt
198
SEt
OT
MS
OB
nO
Bn
(92)
d.r
. = 9
2:8,
95%
ee
R2 C
HO
N
NN
ScO
O
PhPh
C
H2C
l 2, –
78°
2. a
q H
Cl
1.+
Cl
Cl
SbF 6
–
(10
mol
%),
N
NN
Zn
OO
RR
2 Sb
F 6–
2+
139
c01_tex 4/18/06 12:32 PM Page 139
OT
BS
OR
1 R1
Bn
Bn
NH
Tf
CO
2TB
S
(40
mol
%),
ZnE
t 2 (
20 m
ol%
), P
hMe,
–78
°
O
OR
1
OH
R2
R2
CC
l 3
CB
r 3
(61)
(66)
% e
eb
88 93
186
CH
O
O
EtO
O
EtO
OH
O
SR2
198
SR2
OT
MS
R1
C2–
6
R1
H Me
Me
i-Pr
i-B
u
Et
R2
t-B
u
t-B
u
t-B
u
t-B
u
t-B
u
Ph
(92)
(93)
(90)
(90)
(94)
(90)
dr —
92:8
92:8
95:5
93:7
92:8
% e
e
90 95 93d
99 93 95
R1
C3
OT
MS
OR
1
(R)-
3,3'
-I2B
INO
L (
12 m
ol%
),
Zr(
OB
u-t)
4 (1
0 m
ol%
),
n-P
rOH
(80
mol
%),
H2O
(20
mol
%),
PhM
e, 0
°
O
OR
1
OH
R2
180
R2 C
HO
R2
Ph (E)-
MeC
H=
CH
Ph 4-C
lC6H
4
4-M
eOC
6H4
(E)-
PhC
H=
CH
Ph(C
H2)
2
(79)
(65)
(94)
(96)
(89)
(92)
(61)
% e
e
96 92 99 96 98 98 89
R1
Me
Ph Ph Ph Ph Ph Ph
syn:
anti
7:93
11:8
9
5:95
9:91
7:93
15:8
5
14:8
6
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
F. O
TH
ER
ME
TA
L-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
C2
R2 C
HO
N
NN
ScO
O
PhPh
C
H2C
l 2, –
78°
2. a
q H
Cl
1.
Cl
Cl
SbF 6
–
(10
mol
%),
+
140
c01_tex 4/18/06 12:32 PM Page 140
OT
MS
OPh
(R)-
3,3'
-I2B
INO
L (
24 m
ol%
),
Zr(
OB
u-t)
4 (2
0 m
ol%
),
n-P
rOH
(16
0 m
ol%
), H
2O (
20 m
ol%
),
PhM
e, 0
°
O
OPh
OH
R18
0R
CH
O
R n-Pr
i-B
u
n-C
5H11
i-B
uCH
2
c-C
6H11
CH
2
Ph(C
H2)
2
C6H
11(C
H2)
2
(71)
(16)
(64)
(56)
(14)
(71)
(52)
% e
e
81 28 85 89 31 82 78
syn:
anti
15:8
5
17:8
3
12:8
8
12:8
8
21:7
9
10:9
0
14:8
6
(R)-
3,3'
-I2B
INO
L (
12 m
ol%
),
Zr(
OB
u-t)
4 (1
0 m
ol%
),
n-P
rOH
(80
mol
%),
H2O
(20
mol
%),
PhM
e, 0
°
I23
4
O
OPh
OH
IC
HO
(79)
sy
n:an
ti =
20:
80, 9
6% e
e
O O
OT
MS
OM
eR
CH
OR
TM
SO
OM
e
O
143
C4
P PPt
Ph2
Ph2
Bu-
t
Bu-
t
(5 m
ol%
),
R
OH
OM
e
O
TfO
H (
5 m
ol%
), 2
,6-l
utid
ine
(5 m
ol%
),
CH
2Cl 2
, –25
°
III
+
(92)
(96)
(99)
(7)
(90)
(94)
% e
eb
91 88 59 — 46 95
I:II
55:4
5
82:1
8
65:3
5
65:3
5
65:3
5
51:4
9
R i-B
u
neo-
C5H
11
Ph c-C
6H11
(E)-
PhC
H=
CH
Ph(C
H2)
2
141
c01_tex 4/18/06 12:32 PM Page 141
R
TM
SO
OM
e
O
143
(99)
(66)
(99)
(5)
(92)
(96)
% e
eb
90 80 56 — 46 91
I:II
91:9
94:6
82:1
8
> 9
9:1
84:1
6
84:1
6
R i-B
u
neo-
C5H
11
Ph c-C
6H11
(E)-
PhC
H=
CH
Ph(C
H2)
2
R
OH
OM
e
O
O O
P PPt
Ph2
Ph2
(5 m
ol%
),I
II
(R)-
3,3'
-I2B
INO
L (
12 m
ol%
),
Zr(
OB
u-t)
4 (1
0 m
ol%
),
n-P
rOH
(80
mol
%),
H2O
(20
mol
%),
PhM
e, 0
°
O
MeO
OH
R
179
180
180
179
180
R (E)-
MeC
H=
CH
n-C
5H11
Ph 4-M
eOC
6H4
Ph(C
H2)
2
(74)
(93)
(95)
(90)
(92)
% e
e
90e
84 98 93 80
+
T
fOH
(5
mol
%),
2
,6-l
utid
ine
(5 m
ol%
), C
H2C
l 2, –
25°
RC
HO
RC
HO
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
F. O
TH
ER
ME
TA
L-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
TM
SO
OM
e
C4
142
c01_tex 4/18/06 12:32 PM Page 142
PhC
HO
OT
MS
O
Ph
OH
(56)
sy
n:an
ti =
44:
12, 7
0% e
eb14
5
[Pd(
(R)-
Tol
-BIN
AP)
(H2O
) 2](
BF 4
) 2
(1
mol
%),
4 Å
MS,
wet
DM
F,
20°
, 43
h
C6
O
Ph
OH
(58)
sy
n:an
ti =
43:
15, 7
2% e
eb14
4Pd
Cl 2
[(R
)-B
INA
P] (
5 m
ol%
),
AgO
TF,
4 Å
MS,
DM
F, H
2O, r
t
CH
O
O
EtO
199
SEt
OT
MS
EtO
O
OH
SEt
OR t-
Bu
Ph Ph
X Cl
OT
f
Cl
Y SbF 6
OT
f
SbF 6
(—
)
(—
)
(—
)
% e
e
62h
6 95
(10–
15 m
ol%
),
CH
2Cl 2
, –78
°, 1
6 h
TM
SO
OE
tR
CH
OO
Et
O
R
OH
404
R Ph Ph Ph Ph 4-O
2NC
6H4
4-O
2NC
6H4
4-M
eOC
6H4
4-M
eOC
6H4
OE
t
O
R
TM
SO
(71)
(84)
(82)
(72)
(98)
(93)
(55)
(36)
I:II
16:5
5
41:4
3
27:5
5
36:3
6
5:93
35:5
8
16:3
9
20:1
6
% e
e Ib
41 51 44 44 42 41 29 42
% e
e II
b
31 48f
17g
32f,g
44 41f
1 8f
Yb(
OT
f)3
(20
mol
%),
CH
2Cl 2
, –40
°
Ph Ph
NN
a
NN
a
Tf
Tf
(20
mol
%),
III
+
PhC
HO
N
NN
ScO
O
RR
+
Y–
XX
143
c01_tex 4/18/06 12:32 PM Page 143
SEt
OT
MS
199
CH
OE
tO
O(8
8)
92%
ee
O
OH
C7
O
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
F. O
TH
ER
ME
TA
L-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
O
OHO
(80)
95
% e
e19
9
(10
–15
mol
%),
C
H2C
l 2, –
78°,
16
h
2. R
aney
Ni
SEt
OT
MS
199
Et
Et
CH
OE
tO
O(7
6)
95%
ee
OO
OH
Et
Et
CH
O
O
EtO
TM
SO
C6
PhC
HO
Ph
OT
BS
PhPh
OO
H14
5
[Pd(
(R)-
Tol
-BIN
AP)
(H2O
) 2](
BF 4
) 2
(1
mol
%),
4 Å
MS,
DM
F, H
2O,
20°
, 17
h
(77)
74
% e
e
C8
N
NN
ScO
O
PhPh
1.
+
Cl
Cl
SbF 6
–
" "
144
c01_tex 4/18/06 12:32 PM Page 144
CH
O
O
EtO
Ar
R
R
OT
MS
Ar
R
O
EtO
O
OH
R
198
C8–
18
Ar
Ph Ph Ph 4-FC
6H4
4-B
rC6H
4
2,5-
Cl 2
C6H
3
R Me
n-C
5H11
n-C
4H9
Me
H H
(85)
(80)
(81)
(85)
(91)
(96)
% e
e
95 97 98 95 91 96
[Pd(
(R)-
Tol
-BIN
AP)
(H2O
) 2](
BF 4
) 2
(1
mol
%),
4 Å
MS,
wet
DM
F, r
t
R2 C
HO
R1
R2
OO
H
R1
Ph 2-C
10H
7
(78)
(82)
% e
e
74i
72
145
R2
Ph(C
H2)
2
Ph
PdC
l 2[(
R)-
BIN
AP]
(5
mol
%),
AgO
Tf
4 Å
MS,
DM
F, H
2O, r
t
R2 C
HO
R1
R2
OO
H (8
0)
(86)
% e
e
73 73
144
R2
Ph Ph(C
H2)
2
[Pd(
(R)-
Tol
-BIN
AP)
(H2O
) 2](
BF 4
) 2
(5
mol
%),
4 Å
MS,
1,1
,3,3
-tet
ram
ethy
lure
a, 0
°
R2 C
HO
R1
OT
MS
R1
R2
OO
H
R1
Ph Ph 2-C
10H
7
(92
)
(88
)
(89
)
% e
e
89 81 87
145
R2
Ph Ph(C
H2)
2
Ph
C8–
12
N
NN
ScO
O t-B
uB
u-t
T
MSC
l (2
equi
v), C
H2C
l 2, –
78°
2. a
q H
Cl
1.
Cl
Cl
SbF 6
–
(10
mol
%),
+
145
c01_tex 4/18/06 12:32 PM Page 145
CH
O
O
N
Ar
CO
2Me
O
N
Ar
CO
2Me
III
+24
1
R2
R1
R1
R2
R1
R2
R1
Cl
NO
2
Br
Me
(96
)
(93
)
(98
)
(86
)
I:II
> 9
9:1
93:7
96:4
> 9
9:1
% e
e I
> 9
9
> 9
9
95 > 9
9
R2
H H OM
e
H
X (
5 m
ol%
), L
iClO
4 (2
0 m
ol%
),
3 Å
MS,
PhM
e, r
t, 20
h
CH
ON
OA
rO
Me
R
C9
O
N
Ar
CO
2Me
O
N
Ar
CO
2Me
III
R H 4-F
3-C
l
3-N
O2
4-N
O2
3-O
Me
4-O
Ac
4-O
Ph
3-M
e
4-M
e
4-C
N
4-C
O2M
e
4-Ph
(99
)
(98
)
(93
)
(99
)
(99
)
(95
)
(95
)
(89
)
(98
)
(96
)
(96
)
(98
)
(10
0)
I:II
95:5
96:4
90:1
0
73:2
7
88:1
2
93:7
96:4
96:4
95:5
92:8
83:1
7
93:7
96:4
% e
e I
99 > 9
9j
99 91 97 99 > 9
9
> 9
9j
98 96 95 > 9
9
99
Ar
= 4
-MeO
C6H
4
241
NN
OO
Bu-
t
t-B
u
Bu-
t
Bu-
t
Al
SbF 6
(5 m
ol%
),
LiC
lO4
(20
mol
%),
3 Å
MS,
PhM
e, r
t, 20
h
R
+
R
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
F. O
TH
ER
ME
TA
L-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
= X
146
c01_tex 4/18/06 12:32 PM Page 146
OT
MS
PhR
CH
OPh
O
R
OH
Ph
O
R
OH
405
III
Bu-
t
NN
PhPhO
HH
OPhPh
OH
(20
mol
%),
R n-C
5H11
Ph 4-C
lC6H
4
4-O
2NC
6H4
4-M
eOC
6H4
4-M
eC6H
4
(E)-
PhC
H=
CH
1-C
10H
7
(82
)
(85
)
(77
)
(82
)
(80
)
(89
)
(90
)
(87
)
I:II
89:1
1
85:1
5
82:1
8
77:2
3
88:1
2
90:1
0
90:1
0
80:2
0
% e
e I
30 85 78 62 84 88 86 82
Ga(
OT
f)3
(20
mol
%),
H2O
/EtO
H (
9:1)
, 0–5
°, 3
6 h
+
C9
O
N
Ar
R
CO
2Me
O
N
Ar
R
CO
2Me
III
+24
1R
CH
O
R 2-C
4H3O
2,5-
(MeO
) 2-3
-NO
2C6H
2
(E)-
4-N
O2C
6H4C
H=
CH
1-C
10H
7
2-C
10H
7
(58
)
(96
)
(98
)
(97
)
(98
)
I:II
77:2
3
90:1
0
90:1
0
96:4
96:4
% e
e I
96 98 98 > 9
9
> 9
9
CH
O
O
N
Ar
CO
2Me
O
N
Ar
CO
2Me
III
R1
F OM
e
Cl
(10
0)
(90
)
(99
)
I:II
89:1
1
91:9
74:2
6
% e
e I
98 98 92
241
R2
Cl
Br
NO
2
R2
R1
R1
R1
R2
R2
+
X (
5 m
ol%
), L
iClO
4 (2
0 m
ol%
),
3 Å
MS,
PhM
e, r
t, 20
h
X (
5 m
ol%
), L
iClO
4 (2
0 m
ol%
),
3 Å
MS,
PhM
e, r
t, 20
h
147
c01_tex 4/18/06 12:32 PM Page 147
i-B
uCH
O
O
Ph
OH
Bu-
i40
6(9
9)
syn:
anti
= 9
4:6,
87%
ee
CH
O
O
EtO
199
R t-B
u
Ph Ph
X Cl
OT
f
Cl
Y SbF 6
OT
f
SbF 6
(—
)
(—
)
(—
)
% e
e
85h,
k
90 70
Ph
OT
MS
Ph
OO
H
OE
t
O
C10
(10–
15 m
ol%
),
CH
2Cl 2
, –78
°, 1
6 h
O O
O O
Pb(
OT
f)2
(20
mol
%),
H2O
/EtO
H (
1:9)
, 0°,
24
h
O O
(24
mol
%),
O
Ph
OH
Ph24
3O O
O O
Pb(
OT
f)2
(20
mol
%),
H2O
/EtO
H (
1:9)
, 0°,
24
h
(62)
sy
n:an
ti =
90:
10, 5
5% e
eO O
(24
mol
%),
PhC
HO
OT
MS
Ph
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
F. O
TH
ER
ME
TA
L-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
C9
PhC
HO
O
Ph
OH
Ph24
6
N
O O
O O
N
Pr(
OT
f)3
(20
mol
%),
H2O
/EtO
H (
1:9)
,
0°,
18
h
(85)
sy
n:an
ti =
91:
9, 8
2% e
e
(24
mol
%),
N
NN
ScO
O
RR
Y–
XX
+
148
c01_tex 4/18/06 12:32 PM Page 148
a The
rea
ctio
n w
as c
arri
ed o
ut a
t roo
m te
mpe
ratu
re.
b The
abs
olut
e co
nfig
urat
ion
was
not
det
erm
ined
.c T
he d
esily
late
d pr
oduc
t was
isol
ated
.d T
he a
mou
nt o
f ca
taly
st u
sed
was
5 m
ol%
.e n
-But
yl a
lcoh
ol (
50 m
ol%
) w
as a
dded
.f T
he p
roto
col i
nvol
ves
slow
add
ition
of
the
nucl
eoph
ile.
g Yb(
OPr
-i) 3
was
use
d in
stea
d of
Yb(
OT
f)3.
h The
pro
duct
has
the
S co
nfig
urat
ion.
i The
am
ount
of
cata
lyst
use
d w
as 2
.5 m
ol%
.j T
he a
mou
nt o
f ca
taly
st u
sed
was
10
mol
%.
k TM
SCl (
2 eq
uiva
lent
s) w
ere
adde
d an
d th
e re
actio
n w
as c
arri
ed o
ut a
t –35
°.l R
educ
tion
was
per
form
ed u
sing
Et 2
BO
Me/
NaB
H4
to g
ive
the
tran
s pr
oduc
t.
Ph
OT
MS
CH
OE
tO
O
O
HO
O
Ph(6
5)
98%
ee
199
C12
Ar
OT
MS
CH
OE
tO
O19
9
C10
–14
Ar
Ph Ph 4-FC
6H4
C10
H7
(60
)
(62
)
(60
)
(49
)
% e
e
95 95l
95 98
OH
O
O
Ar
N
NN
ScO
O
t-B
uB
u-t
T
MSC
l (2
equi
v), C
H2C
l 2,
–
78°,
16
h
2. M
e 4N
BH
(OA
c)3
3. T
sOH
1.
Cl
Cl
SbF 6
–
(10-
15 m
ol%
),
+
"
149
c01_tex 4/18/06 12:32 PM Page 149
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
G. N
ON
-ME
TA
L-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S
Ele
ctro
phile
OM
e
OSi
Cl 3
R1
O
R2
NN
Bu-
tn-
BuO
t-B
uO
Bu-
n
1. CH
2Cl 2
, –20
°, 1
2 h
2. a
q N
aHC
O3
R1
R2
OH
OM
e
OR
1
Et
c-C
3H5
t-B
u
2-C
4H3O
Ph Ph Ph 4-C
F 3C
6H4
4-M
eOC
6H4
c-C
6H11
PhC
C
(E)-
PhC
H=
CH
Ph(C
H2)
2
1-C
10H
7
R2
Me
Me
Me
Me
Me
Et
HC
C
Me
Me
Me
Me
Me
Me
Me
(84)
(84)
(87)
(87)
(96)
(90)
(89)
(91)
(94)
(91)
(94)
(87)
(97)
(89)
% e
ea
32 20 43e
49 83b
81 86b
76c
68 32 35 11 35 56c
OH
OO
Me
O
OH
OO
Me
O
C2
102
102
102
(90)
80%
eea
(86)
8%
eea
OO
(10
mol
%),
RC
HO
R
OH
OM
e
O20
6N
PN
O N
Me
Me
R t-B
u
Ph
(76)
(88)
% e
ea
26 20
(10
mol
%),
CH
2Cl 2
, –78
°
" "
150
c01_tex 4/18/06 12:32 PM Page 150
RC
HO
R
OH
OM
e
O20
6
R t-B
u
Ph Ph
(78)
(87)
(94)
% e
e
40 33 38d
(10
mol
%),
CH
2Cl 2
, –78
°NPO
N
NPh
Ph
Me
Me
N NP
Me
Me
NR
OH
OM
e
O20
6
R t-B
u
t-B
u
Ph
(75)
(78)
(91)
% e
e
49 50d
23
(10
mol
%),
CH
2Cl 2
, –78
°
OM
e
OT
BS
RC
HO
N NP
Me
Me
O
N Me
(CH
2)5
2
R
OH
OM
e
OR 2-
C4H
3O
Ph c-C
6H11
4-M
eC6H
4
4-C
F 3C
6H4
4-M
eOC
6H4
(E)-
PhC
H=
CH
Ph(C
H2)
2
(E)-
PhC
H=
CM
e
1-C
10H
7
2-C
10H
7
(94)
(97)
(86)
(97)
(97)
(97)
(95)
(72)
(98)
(98)
(98)
% e
e
87 93e
88e
94 91 97 94 81e
45 80 94
SiC
l 4, C
H2C
l 2, –
78°,
15
min
208
(5 m
ol%
),
OR
CH
O
151
c01_tex 4/18/06 12:32 PM Page 151
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
G. N
ON
-ME
TA
L-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
Ar
Ph Ph Ph Ph Ph 2,6-
(MeO
) 2C
6H3
4-t-
BuC
6H4
4-t-
BuC
6H4
4-t-
BuC
6H4
R Me
Me
Et
Et
Et
Et
Et
Et
Et
X TfO
ClO
4
ClO
4
ClO
4
ClO
4
SbC
l 6
ClO
4
PF6
SbC
l 6
(75
)
(92
)
(52
)
(67
)
(99
)
(53
)
(40
)
(20
)
(48
)
% e
e
3b
12b
24 16 11 22 38 32 6
Tim
e
3 h
6 h
3 h
4.5
h
6 h
4 h
3 h
3 h
4 h
C3
OR
OT
BS
PhC
HO
PhO
R
OO
H
208
R Me
Et
t-B
u
t-B
u
Ph
E/Z
82:1
8
95:5
95:5
12:8
8
94:6
(98)
(78)
(93)
(73)
(98)
% e
e
72 76 > 9
8
> 9
8
88
d.r.
99:1
98:2
99:1
99:1
94:6
N NP
Me
Me
O
N Me
(CH
2)5
2
SiC
l 4, C
H2C
l 2, –
78°,
3 h
(1 m
ol%
),
OT
BS
OE
tPh
CH
O
Ar
RR
+
X–
CH
2Cl 2
, –78
°
2. a
q H
F/C
H3C
N
OE
t
O
Ph
OH
407
(10–
20 m
ol%
),
1.C
2
152
c01_tex 4/18/06 12:32 PM Page 152
OB
u-t
OT
BS
RO
Bu-
t
OO
H
RC
HO
R Ph 4-C
F 3C
6H4
4-M
eOC
6H4
(E)-
PhC
H=
CH
PhC
CC
H2
(E)-
PhC
H=
CM
e
1-C
10H
7
2-C
10H
7
(93)
(93)
(88)
(98)
(92)
(90)
(98)
(95)
% e
e
> 9
8
92 98 > 9
8
68 92 94 > 9
8
dr 99:1
> 9
9:1
> 9
9:1
> 9
9:1
96:4
> 9
9:1
96:4
> 9
9:1
208
N NP
Me
Me
O
N Me
(CH
2)5
2
SiC
l 4, C
H2C
l 2, –
78°,
3 h
(1 m
ol%
),
R
OT
MS
R
O
Ph
OH
PhC
HO
C3–
6
380
1. H
g(O
Ac)
2, S
iCl 4
, CH
2Cl 2
2. (6
5)
(71)
% e
e
75 57
R Me
i-B
uN
PON
NPh
Ph
Me
Me
C
H2C
l 2, –
78°
3. a
q N
aHC
O3
(10
mol
%),
OE
t
OT
BS
RO
Et
OO
H
RC
HO
(29)
(49)
(55)
(71)
% e
e
—f
36f,g
89 88f
dr 92:8
89:1
1
93:7
91:9
208
N NP
Me
Me
O
N Me
(CH
2)5
2
SiC
l 4, C
H2C
l 2, –
78°,
24
h
(5 m
ol%
),
R c-C
6H11
c-C
6H11
Ph(C
H2)
2
Ph(C
H2)
2
153
c01_tex 4/18/06 12:32 PM Page 153
R1
Me
Me
Me
Me
Me
Me
Me
Me
Me
n-C
5H11
R2
(E)-
MeC
H=
CH
Ph c-C
6H11
PhC
C
(E)-
PhC
H=
CH
Ph(C
H2)
2
(E)-
PhC
H=
CM
e
1-C
10H
7
2-C
10H
7
Ph
(85)
(95)
(42)
(98)
(86)
(47)
(91)
(97)
(99)
(92)
I:II
99:1
98:2
97:3
98:2
99:1
95:5
97:3
98:2
99:1
99:1
% e
e I
5 81 44 7 42 8 68 54 86 90
R1
OSi
Cl 3
R2 C
HO
R2
OH
CH
O
R1
75R
2
OH
CH
O
R1
III
R1
Me
Me
Me
Me
Me
Me
Me
Me
Me
n-C
5H11
R2
(E)-
MeC
H=
CH
Ph C6H
11
PhC
C
(E)-
PhC
H=
CH
Ph(C
H2)
2
(E)-
PhC
H=
CM
e
1-C
10H
7
2-C
10H
7
Ph
(91)
(97)
(69)
(99)
(88)
(79)
(89)
(97)
(99)
(91)
I:II
98:2
99:1
99:1
98:2
99:1
99:1
99:1
98:2
98:2
97:3
% e
e I
52 59 19 76 26 66 90 70 53 82
+
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
G. N
ON
-ME
TA
L-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
C3–
7
R1
OSi
Cl 3
R2 C
HO
R2
OH
CH
O
R1
75R
2
OH
CH
O
R1
III
N NP
Me
Me
O
N Me
(CH
2)5
2
C
HC
l 3/C
H2C
l 2 (
4:1)
, –78
°, 6
h
2. M
eOH
(5 m
ol%
),
1.
+
"
154
c01_tex 4/18/06 12:32 PM Page 154
C3–
8
R
OSi
Cl 3
PhC
HO
1. C
H2C
l 2, –
78°,
2 h
2. a
q N
aHC
O3
R
O
Ph
OH
408
R Me
TB
SOC
H2
i-Pr
n-B
u
i-B
u
t-B
u
Ph
(98)
(94)
(97)
(98)
(95)
(95)
(93)
% e
e
87 86 81 85 82 52 49
NPO
N
NPh
Ph
Me
Me
(5 m
ol%
),
C4
212
OR
1O
R2
OH
OR
1O
R2
OH
III
R2
Ph Ph (E)-
MeC
H=
CH
(E)-
MeC
H=
CH
Ph Ph Ph Ph
(78
)
(78
)
(80
)
(81
)
(85
)
(85
)
(78
)
(77
)
OT
MS
OR
1
1. H
g(O
Ac)
2, S
iCl 4
, CH
2Cl 2
2.
NPO
N
NPh
Ph
Me
Me
C
H2C
l 2, –
78°
3. a
q N
aHC
O3
(5 m
ol%
),
R1
Piv
Piv
TB
S
TB
S
TB
S
TB
S
Bn
Bn
I:II
3.4:
1
20:1
h
1.3:
1
6.2:
1h
1.5:
1
73:1
h
1:1.
1
11:1
h
+
TB
SOO
SiC
l 3Ph
CH
OT
BSO
O
Ph
OH
210
(72)
(75)
I:II
1:2.
5
1.3:
1iTB
SOO
Ph
OH
III
CH
2Cl 2
, –78
°, 4
h
NPO
N
NPh
Ph
Me
Me
(10
mol
%),
+
C5
R2 C
HO
155
c01_tex 4/18/06 12:32 PM Page 155
dias
tere
omer
s
RC
HO
211
O
R
OH
I
II
R (E)-
MeC
H=
CH
2-C
4H3O
Ph PhC
C
(E)-
PhC
H=
CH
1-C
10H
7
2-C
10H
7
I:II
93:7
94:6
95:5
95:5
93:7
98:2
94:6
(85)
(82)
(88)
(79)
(81)
(72)
(71)
OT
MS
OT
BS
1. H
g(O
Ac)
2, S
iCl 4
, CH
2Cl 2
, rt
2.
NPO
N
NPh
Ph
Me
Me
CH
2Cl 2
, –78
°, 1
0 h
(5 m
ol%
),O
TB
S
OR
OT
MS
PhC
HO
RO
O
Ph
OH
210
RO
O
Ph
OH
III
R TB
S
TB
S
TIP
S
TIP
S
(61)
(58)
(89)
(86)
I:II
5.5:
1
1:4.
4i
1.8:
1
1:2.
3i
1. H
g(O
Ac)
2, S
iCl 4
, CH
2Cl 2
, rt
2.
NPO
N
NPh
Ph
Me
Me
CH
2Cl 2
, –78
°, 4
h
(10
mol
%),
+
+
242
O
R
OH
O
R
OH
I
II
R (E)-
MeC
H=
CH
CH
2=C
Me
(E)-
MeC
H=
CM
e
t-B
u
Ph C6H
11
PhC
C
(E)-
PhC
H=
CH
Ph(C
H2)
2
(E)-
PhC
H=
CM
e
1-C
10H
7
(85
)
(81
)
(78
)
(73
)
(80
)
(47
)
(83
)
(81
)
(34
)
(84
)
(85
)
OT
MS
I:II
4.88
:1
15.7
:1
24:1
27.9
:1
19:1
15.7
:1
3.35
:1
8:1
10.1
:1
10.1
:1
15.7
:1
TB
SOT
BSO
TB
SO
RC
HO
+
1. H
g(O
Ac)
2, S
iCl 4
, CH
2Cl 2
, rt
2.
NPO
N
NPh
Ph
Me
Me
CH
2Cl 2
, –78
°, 4
h
(10
mol
%),
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
G. N
ON
-ME
TA
L-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
C5
156
c01_tex 4/18/06 12:32 PM Page 156
242
O
R
OH
O
R
OH
III
1. H
g(O
Ac)
2, S
iCl 4
, CH
2Cl 2
2.
NPO
N
NPh
Ph
Me
Me
C
H2C
l 2, –
78°
3. a
q N
aHC
O3
(10
mol
%),
TB
SOT
BSO
RC
HO
+
OT
MS
TB
SO
R (E)-
MeC
H=
CH
CH
2=C
Me
(E)-
MeC
H=
CM
e
t-B
u
Ph c-C
6H11
PhC
C
(E)-
PhC
H=
CH
Ph(C
H2)
2
(E)-
PhC
H=
CM
e
1-C
10H
7
(83
)
(84
)
(75
)
(78
)
(75
)
(31
)
(82
)
(82
)
(22
)
(80
)
(83
)
I:II
1:2.
87
1:8.
09
1:4.
56
1:6.
51
1:7.
33
1:4
1:1.
32
1:4.
26
1:2.
45
1:6.
69
1:8.
09
C6
OSi
Cl 3
RC
HO
207
O
R
OH
O
R
OH
III
1. C
H2C
l 2, –
78°,
2 h
2. a
q N
aHC
O3
NPO
N
NPh
Ph
Me
Me
(10
mol
%),
R Ph PhC
C
(E)-
PhC
H=
CH
(E)-
PhC
H=
CM
e
1-C
10H
7
I:II
1:61
1:5.
3
< 1
:99
< 1
:99
< 1
:99
(95)
(90)
(94)
(98)
(94)
% e
e II
93 82 88 92 97
+
157
c01_tex 4/18/06 12:32 PM Page 157
PhC
HO
134
O
Ph
OH
O
Ph
OH
III
(94)
I:
II =
97:
1, 5
3% e
e I
+
n-B
u
OSi
Cl 3
RC
HO
n-B
u
O
R
OH
(81)
(79)
(94)
(95)
(92)
(95)
% e
e
92g
89g
84 91 86 85
R t-B
u
C6H
11
(E)-
PhC
H=
CH
(E)-
PhC
H=
CM
e
1-C
10H
7
4-Ph
C6H
4
408
1. C
H2C
l 2, –
78°,
2 h
2. a
q N
aHC
O3
NPO
N
NPh
Ph
Me
Me
(5 m
ol%
),
380
CH
O
OT
BS
OT
BS
OH
n-B
u
O
OT
BS
OH
n-B
u
O
III
Solv
ent
CH
2Cl 2
CH
2Cl 2
Et 2
O
PhM
e
EtC
N
(47
)
(50
)
(45
)
(40
)
(43
)
I:II
2.7:
1i
1:15
.6
1:9
1:6.
7
1:11
.5
1. –
78°,
6 h
2. a
q N
aHC
O3
NPO
N
NPh
Ph
Me
Me
(10
mol
%),
380
OT
BS
OH
n-B
u
O1.
CH
2Cl 2
, –78
°
2. a
q N
aHC
O3
NPO
N
NPh
Ph
Me
Me
(10
mol
%),
CH
OT
BSO
(88)
75
% e
e
+
1. C
H2C
l 2, –
78°,
2 h
2. a
q N
aHC
O3
NPO
N
NPh
Ph
Ph
Ph
(10
mol
%),
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
G. N
ON
-ME
TA
L-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
C6
OSi
Cl 3
158
c01_tex 4/18/06 12:32 PM Page 158
n-B
u
OT
MS
n-B
u
OO
H
408
PhC
HO
Ph(8
9) 9
2% e
e
1. H
g(O
Ac)
2, S
iCl 4
, CH
2Cl 2
2.
NPO
N
NPh
Ph
Me
Me
C
H2C
l 2, –
78°
3. a
q N
aHC
O3
(5 m
ol%
),
TIP
SOO
SiC
l 3R
CH
O
TIP
SOO
R
OH
210
TIP
SOO
R
OH
III
(79)
(83)
(83)
(81)
(84)
(86)
(83)
(81)
(80)
(75)
CH
2Cl 2
, –78
°, 8
h
NPO
N
NPh
Ph
Me
Me
(10
mol
%),
TIP
SOO
R
OH
TIP
SOO
R
OH
III
IV
I+II
:III
+IV
7:1
1:6
3:1
1:3
16:1
1:10
10:1
1:8
30:1
1:10
I+IV
:II+
III
28:1
37:1
i
> 5
0:1
> 5
0:1i
30:1
26:1
i
> 5
0:1
> 5
0:1i
17:1
18:1
i
R (E)-
MeC
H=
CH
(E)-
MeC
H=
CH
(E)-
MeC
H=
CM
e
(E)-
MeC
H=
CM
e
Ph Ph (E)-
PhC
H=
CH
(E)-
PhC
H=
CH
1-C
10H
7
1-C
10H
7
+
+
159
c01_tex 4/18/06 12:32 PM Page 159
OSi
Cl 3
TIP
SO
RC
HO
TB
AI
(20
mol
%),
CH
2Cl 2
,
–78
°, 8
h
NPO
N
NPh
Ph
Me
Me
(10
mol
%),
O
R
OH
I
TIP
SOO
R
OH
II
TIP
SO
O
R
OH
III
TIP
SOO
R
OH
IV
TIP
SO
+
+
209
R (E)-
MeC
H=
CH
(E)-
MeC
H=
CH
(E)-
MeC
H=
CM
e
(E)-
MeC
H=
CM
e
Ph Ph (E)-
PhC
H=
CH
(E)-
PhC
H=
CH
1-C
10H
7
1-C
10H
7
(90)
(85)
(85)
(80)
(84)
(82)
(88)
(75)
(71)
(79)
I+II
:III
+IV
15:1
1:5
13:1
1:5
24:1
1:8
14:1
1:6
89:1
1:17
I+IV
:II+
III
> 5
0:1
> 5
0:1i
13:1
19:1
i
53:1
j
32:1
i,j
9:1
15:1
i
14:1
14:1
i
OR
OSi
Cl 3
PhC
HO
RO
O
Ph
OH
210
RO
O
Ph
OH
III
CH
2Cl 2
, –78
°, 8
h
NPO
N
NPh
Ph
Me
Me
(10
mol
%),
+
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
G. N
ON
-ME
TA
L-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
C6
+
160
c01_tex 4/18/06 12:32 PM Page 160
R TB
S
TB
S
TIP
S
TIP
S
TIP
S
(59)
(60)
(84)
(86)
(80)
Z:E
12:1
12:1
16:1
16:1
1:15
I+II
:III
+IV
14:1
1:14
16:1
1:10 1:1
I+IV
:II+
III
6:1
12:1
i
30:1
26:1
i
3:1i
C6–
8
R
OT
MS
PhC
HO
NH
O
N
Ph+
F–
1. T
HF,
–70
°, 1
0 m
in
2. a
q H
Cl,
MeO
H
R
O
Ph
OH
409
R t-B
u
Ph 4-C
lC6H
4
4-M
eOC
6H4
2,4-
(MeO
) 2C
6H3
(62
)
(76
)
(55
)
(70
)
(73
)
% e
e
62 40 42 37 25
R
O
Ph
OH
409
R t-B
u
Ph
(55
)
(46
)
% e
e
39 36
(10
mol
%),
NH
O
N
Ph+
F–
1. T
HF,
–70
°, 1
0 m
in
2. a
q H
Cl,
MeO
H
(10
mol
%),
PhC
HO
RO
O
Ph
OH
RO
O
Ph
OH
III
IV
++
161
c01_tex 4/18/06 12:32 PM Page 161
C9
RC
HO
207
Ph
O
R
OH
Ph
O
R
OH
III
1. C
H2C
l 2, –
78°,
6–8
h
2. a
q N
aHC
O3N
PON
NPh
Ph
Me
Me
(15
mol
%),
Ph
OSi
Cl 3
+
R (E)-
MeC
H=
CH
Ph 4-B
rC6H
4
PhC
C
(E)-
PhC
H=
CH
1-C
10H
7
I:II
7:1
18:1
12:1
1:3.
5
9.4:
1
3:1
(94)
(95)
(89)
(92)
(97)
(96)
% e
e I
91 95 96 58 92 84
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 1
G. N
ON
-ME
TA
L-C
AT
AL
YZ
ED
MU
KA
IYA
MA
-TY
PE A
LD
OL
AD
DIT
ION
S (C
onti
nued
)
Ele
ctro
phile
C10
OT
MS
RC
HO
N
HSO
4–
(2 m
ol%
),
KFM
2H2O
(0.
5 eq
uiv)
, TH
F/Ph
Me
(2:1
),
–40
°, 0
.5–1
h
OO
H
R
R Ph Ph 1-C
10H
7
9-ph
enan
thry
l
(92)
(90)
(90)
(88)
dr
70:3
0
83:1
7
94:6
95:5
% e
e
76k
84 91 90
248
Ar
Ar Ar
=
CF 3
CF 3
+
162
c01_tex 4/18/06 12:32 PM Page 162
C11
OT
MS
R
PhC
HO
R
O
Ph
OH
R
O
Ph
OH
III
NH
O
N
Ph+
F– (12
mol
%),
1. T
HF,
–70
°, 6
h
2. a
q H
Cl,
MeO
H
410
+
R H H OM
e
Cl
Br
(74
)
(65
)
(73
)
(73
)
(67
)
I:II
70:3
0
73:2
7
76:2
4
82:1
8
81:1
9
% e
e I
70 44 68 66 66
% e
e II
20 6l
30 21 15
a The
abs
olut
e co
nfig
urat
ion
was
not
det
erm
ined
.b T
he p
rodu
ct h
as th
e S
conf
igur
atio
n.c T
he r
eact
ion
was
que
nche
d af
ter
20 h
ours
.d T
he p
roto
col i
nvol
ves
slow
add
ition
of
the
alde
hyde
.e T
he r
eact
ion
was
que
nche
d af
ter 32
hou
rs.
f TB
AI
(0.1
equ
ival
ents
) w
as a
dded
.g T
he a
mou
nt o
f ca
taly
st u
sed
was
10
mol
%.
h The
R,R
-cat
alys
t was
use
d.i T
he S
,S-c
atal
yst w
as u
sed.
j No
TB
AI
was
add
ed.
k The
rea
ctio
n w
as c
arri
ed o
ut in
TH
F at
roo
m te
mpe
ratu
re.
l TH
F/M
eCN
(3:
7) w
as u
sed
as th
e so
lven
t.
163
c01_tex 4/18/06 12:32 PM Page 163
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
A. G
OL
D-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
Ele
ctro
phile
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, 0°,
20–
100
h
OM
e
OC
3
64C
NR
CH
O
ON
R
O
OM
e
ON
R
O
OM
e
III
R Ph 2-FC
6H4
3-FC
6H4
4-FC
6H4
2,6-
F 2C
6H3
2,4,
6-F 3
C6H
2
2,3,
5,6-
F 4C
6H
C6F
5
(94)
(99)
(97)
(96)
(98)
(96)
(90)
(99)
I:II
94:6
89:1
1
94:6
94:6
75:2
5
67:3
3
47:5
3
57:4
3
% e
e I
95 90 95 96 86 73 48 36
% e
e II
49a
40 20 19 78 82 89 78
FePP
h 2
PPh 2M
eN
N (1.1
mol
%),
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, 0°,
20–
100
h
64
ON
R
O
OM
e
ON
R
O
OM
e
III
R Ph 4-FC
6H4
2,3,
5,6-
F 4C
6H
C6F
5
(93)
(92)
(93)
(92)
I:II
95:5
94:6
38:6
2
37:6
3
% e
e I
95 94 33 36
% e
e II
12b
25 90 86
FePP
h 2
PPh 2M
eN
NO
(1.1
mol
%),
+ +
59
ONO
OM
e
Fe
PPh 2
PPh 2
n-C
13H
27
(89)
93
% e
eM
eN
NO
n-C
13H
27C
HO
(1.1
mol
%),
RC
HO
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, rt,
25 h
164
c01_tex 4/18/06 12:32 PM Page 164
RC
HO
ON
R
O
OM
e
ON
R
O
OM
e
III
R Me
i-Pr
i-B
u
t-B
u
(E)-
n-Pr
CH
=C
H
Ph 4-C
lC6H
4
4-O
2NC
6H4
2-M
eC6H
4
2-M
eOC
6H4
3,4-
(BnO
) 2C
6H3
(99)
(100
)
(99)
(94)
(85)
(93)
(97)
(80)
(98)
(98)
(88)
I:II
89:1
1
99:1
96:4
100:
0
87:1
3
95:5
94:6
83:1
7
96:4
92:8
94:6
% e
e I
89 92 87 97 92 95 94 86 95 92 95
% e
e II
10 — 0 47c
12 17 75 20 73 32
FePP
h 2
PPh 2M
eN
NO
56O
NCO
2Me
III
FePP
h 2
PPh 2M
eN
NO
OM
e
O
O
MeO
2C
ONC
O2M
eM
eO2C
(90)
I:
II=
73:
23, 8
2% e
e I,
33%
ee
II
62 55 55 55 55 55 55 55 55 55 55
+
(0.5
mol
%),
(1.1
mol
%),
+
[A
u(C
6H11
CN
) 2]B
F 4 (
0.5
mol
%),
CH
2Cl 2
, rt,
12 h
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, rt,
20–7
0 h
165
c01_tex 4/18/06 12:32 PM Page 165
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
A. G
OL
D-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, rt,
16–4
0 h
ON
RO
Me
ON
RO
Me
I
II
R H Me
i-Pr
Ph
(89)
(100
)
(99)
(94)
I:II —
85:1
5
99:1
94:6
% e
e I
44 85 94 95
% e
e II
— 56 — 49
FePP
h 2
PPh 2M
eN
N
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, rt,
10–4
0 h
ON
R
O
OM
e
ON
R
O
OM
e
III
R Me
i-Pr
t-B
u
(E)-
n-Pr
CH
=C
H
Ph c-C
6H11
(100
)
(99)
(100
)
(83)
(98)
(95)
I:II
84:1
6
98:2
100:
0
81:1
9
89:1
1
97:3
% e
e I
72 90 97 84 93 90
% e
e II
44 — — 52 49 —
FePP
h 2
PPh 2H N
61 62 55 55
NE
t 2
58 58 57 57 58 57
+(1
.1 m
ol%
),
(1 m
ol%
),
O
O
55 55
+
OM
e
C3
CN
RC
HO
O
FeO O(8
6)
(80)
95:5
100:
0
96 89
0 —
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, rt,
20–4
0 h
FePP
h 2
PPh 2M
eN
NO
(1.1
mol
%),
RI:
II%
ee
I%
ee
II
ON
R
O
OM
e
ON
R
O
OM
e
III
+
RC
HO
RC
HO
166
c01_tex 4/18/06 12:32 PM Page 166
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, rt,
10–4
0 h
ON
R
O
OM
e
III
R Me
(E)-
MeC
H=
CH
(E)-
n-Pr
CH
=C
H
Ph c-C
6H11
(94)
(89)
(97)
(91)
(96)
I:II
78:2
2
91:9
80:2
0
90:1
0
98:2
% e
e I
37 95 81 91 81
% e
e II
0 31 0 4 —
FePP
h 2
PPh 2H N
NM
e 2
58 57 58 58 57
Fe
PPh 2
PPh 2Me
NN
Me 2
OR
1
O
CN
ON
R2
O
OR
1
R2 C
HO
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, rt,
18–9
4 h
(1.1
mol
%),
I
ON
R2
O
OR
1
II
R2
Ph 2-M
eC6H
4
2-C
F 3C
6H4
3-C
F 3C
6H4
4-C
F 3C
6H4
CH
2=C
(Me)
Ph
(28)
(72)
(72)
(94)
(92)
(89)
(90)
(95)
I:II
95:5
90:1
0
93:7
84:1
6
81:1
9
85:1
5
68:3
2
92:8
% e
e I
51 90 92 88 84 85 54 93
R1
Me
Me
Et
Et
Et
Et
t-B
u
t-B
u
% e
e II
59d,
e
12 21d,
f
86d,
g
62d
57d
79d
47d
OO25
3
253
253
253
253
253
252
252
Fe
PPh 2 M
eN
NM
e 2O
Me
O
CN
ON
Ph
O
OM
ePh
CH
O
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
ClC
H2C
H2C
l, 50
°, 5
h
(1.1
mol
%),
I
ON
Ph
O
OM
e
II
253
(85)
I:
II =
74:
26, 2
1% e
e I,
4%
ee
II
(1 m
ol%
),O
N
R
O
OM
e
+
+
+R
CH
O
167
c01_tex 4/18/06 12:32 PM Page 167
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
A. G
OL
D-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
OR
O41
1C
N
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, rt
FePP
h 2XN
Me 2
(1.1
mol
%),
PhC
HO
ON
Ph
O
OR
I
ON
Ph
O
OR
IIPP
h 2
Ph
OR
O41
1C
N
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, rt
FePP
h 2XN
Me 2
(1.1
mol
%),
ON
Ph
O
OR
I
ON
Ph
O
OR
IIPP
h 2
Ph
X S O
(> 8
5)
(> 8
5)
I:II
72:2
8
70:3
0
% e
e I
13 7
% e
e II
22 43
R Me
Et
X S O
(> 8
5)
(> 8
5)
I:II
83:1
7
77:2
3
% e
e I
84 80
% e
e II
71 61
R Me
Et
+ +
OR
1
O25
2C
N
ON
R2
O
OR
1
R2 C
HO
R2
CH
2=C
Me
Ph 2,5-
Me 2
C6H
3
CH
2=C
Me
Ph
(56)
(99)
(84)
(69)
(88)
I:II
92:8
90:1
0
93:7
91:9
89:1
1
% e
e I
72 91 95 78 93
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, rt,
18–7
2 h
FePP
h 2
PPh 2M
eN
NM
e 2
(1.1
mol
%),
R1
Me
Me
Me
Et
Et
% e
e II
13d
7d 7d 6d
17d
I
ON
R2
O
OR
1
II
+
C3
PhC
HO
168
c01_tex 4/18/06 12:32 PM Page 168
OR
O41
1C
N
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, rt
FePP
h 2XN
Me 2
(1.1
mol
%),
PhC
HO
ON
Ph
O
OR
I
ON
Ph
O
OR
IIPP
h 2
Ph
411
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, rt
FePP
h 2XN
Me 2
(1.1
mol
%),
ON
Ph
O
OR
I
ON
Ph
O
OR
IIPP
h 2
Ph
X S O
(> 8
5)
(> 8
5)
I:II
88:1
2
81:1
9
% e
e I
89 67
% e
e II
16 10
R Me
Et
X S O
(> 8
5)
(> 8
5)
I:II
74:2
6
67:3
3
% e
e I
17 22
% e
e II
18 43
R Me
Et
+
OE
t
O25
2C
N
ON
R
O
OE
tR
CH
O
R 2-C
4H3O
3-C
4H3O
2-C
4H3S
3-C
4H3S
2-C
5H4N
3-C
5H4N
4-C
5H4N
2,4,
6-M
e 3C
6H2
(62)
(80)
(90)
(78)
(45)
(55)
(38)
(57)
I:II
68:3
2
86:1
4
95:5
97:3
75:2
5
88:1
2
88:1
2
100:
0
% e
e I
32 87 33 78 6 79 75 91d
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
ClC
H2C
H2C
l, 50
°, 2
.5–2
4 h
FePP
h 2
PPh 2M
eN
NM
e 2
(1.1
mol
%),
% e
e II
83d
7d
17d
1d
84d
62d
78d
—
I
ON
R
O
OE
t
II
+
+
PhC
HO
169
c01_tex 4/18/06 12:32 PM Page 169
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
A. G
OL
D-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
252
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, rt,
24 h
FePP
h 2
PPh 2M
eN
NM
e 2
(1.1
mol
%),
(88)
I:
II =
89:
11, 9
3% e
e I,
18%
ee
II
PhC
HO
ON
Ph
O
OE
t
IO
N
Ph
O
OE
t
II
253
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
ClC
H2C
H2C
l, 50
°, 2
0 h
FePP
h 2Me
NN
Me 2
(1.1
mol
%),
(34)
I:
II =
77:
23, 1
6% e
e I,
1%
ee
IId
ONO
OE
t
IO
NO
OE
t
II
+
412
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
ClC
H2C
H2C
l, 50
°, 2
0 h
FePP
h 2NN
(1.1
mol
%),
ON
Ph
O
OE
t
IO
N
Ph
O
OE
t
II
+
R1
PPh 2
R1
OH N
O
R4
R2R
3
R1
Me
Me
Me
Bn
Bn
Bn
R2
Me
Me
n-C
17H
35
Me
Me
n-C
17H
35
R3
H 1-C
10H
7
H H 1-C
10H
7
H
R4
1-C
10H
7
H H 1-C
10H
7
H H
(96)
(88)
(84)
(35)
(44)
(33)
I:II
89:1
1
90:1
0
90:1
0
68:3
2
64:3
6
67:3
3
% e
e I
95 95 96 15 16 26
% e
e II
35 34 40 6 8 11
+
C3
OE
t
O
CN
ONO
OE
t
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
ClC
H2C
H2C
l, 40
°
FePP
h 2
PPh 2M
eN
NM
e 2
(1.1
mol
%),
CH
O(6
5)41
3
PhC
HOC
HO
170
c01_tex 4/18/06 12:32 PM Page 170
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, 20–
50 h
NM
e 2
O63
CN
RC
HO
ON
R
O
NM
e 2
ON
R
O
NM
e 2
III
R Ph 2-FC
6H4
4-FC
6H4
2,6-
F 2C
6H3
2,4,
6-F 3
C6H
2
2,3,
5,6-
F 4C
6H
2,3,
5,6-
F 4C
6H
C6F
5
C6F
5
(74)
(87)
(89)
(84)
(83)
(88)
(78)
(82)
(87)
I:II
94:6
83:1
7
92:8
77:2
3
85:1
5
89:1
1
84:1
6
77:2
3
81:1
9
% e
e I
94 93 94 93 91 77 84 80 68
% e
e II
— — — 64 48 28 26 20 24
FePP
h 2
PPh 2M
eN
N
Tem
p
rt 22°
20°
20°
10°
20°
15°
15°
rt
(1.1
mol
%),
+
ONO
OE
t(6
9)41
3Fe
PPh 2
PPh 2Me
NN
Me 2
(1.1
mol
%),
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
ClC
H2C
H2C
l, 40
°
[
Au(
C6H
11C
N) 2
]BF 4
(1
mol
%),
C
H2C
l 2, r
t, 20
–108
h
2. H
Cl/M
eOH
3. B
zCl,
NE
t 3, C
HC
l 3
56
III
FePP
h 2
PPh 2M
eN
NO
RX
O
O
R Me
Me
i-B
u
Ph
X Me
OM
e
OM
e
OM
e
(65)
(78)
(82)
(59)
% e
e I
75 90 76 42
% e
e II
74 36 84 74
1.
XN
Me 2
O
NH
Bz
O
OH
RX
NM
e 2
O
NH
Bz
O
OH
R
(1.1
mol
%),
+
CH
O
I:II
57:4
3
86:1
4
87:1
3
71:2
9
171
c01_tex 4/18/06 12:32 PM Page 171
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
A. G
OL
D-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
[A
u(C
6H11
CN
) 2]B
F 4 (
0.5–
1 m
ol%
),
CH
2Cl 2
, rt,
40–8
0 h
60Fe
PPh 2
PPh 2M
eN
NR M
e
Et
i-B
u
Ph 4-B
nOC
6H4C
H2
(85)
(84)
(92)
(74)
(84)
% e
e
98.6
96.3
97.3
94.1
94.5
tran
s:ci
s
91:9
95:5
94:6
94:6
> 9
5:5
ON
R
O
NM
e 2R
CH
O
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, rt,
20–4
8 h
N Me
O
249
CN
ON
R
O
N Me
RC
HO
(1.1
mol
%),
R Me
(E)-
MeC
H=
CH
i-Pr
Ph (E)-
BnO
CH
2CH
=C
H
(—)
(94)
(90)
(86)
(82)
tran
s:ci
s
95:5
97:3
98:2
97:3
96:4
% e
e
97 99 97 96 95
OM
e
FePP
h 2
PPh 2M
eN
NO
OM
e
(0.5
–1 m
ol%
),
C3
[A
u(C
6H11
CN
) 2]B
F 4 (
0.5–
1 m
ol%
),
CH
2Cl 2
, rt,
20–5
0 h
N
O
60C
N
FePP
h 2
PPh 2M
eN
NR M
e
Ph
(84)
(73)
% e
e
96.1
93.9
tran
s:ci
s
94:6
95:5
ON
RO
NR
CH
O
O
O25
2C
N(—
) a
nti:s
yn >
99:
1, 8
0% d
eC
HO
PhO
N
O
OPh
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
ClC
H2C
H2C
l, 40
°, 2
0 h
(1.1
mol
%),
Fe
PPh 2
PPh 2Me
NN
Me 2
(0.5
–1 m
ol%
),
NM
e 2
O
CN
172
c01_tex 4/18/06 12:32 PM Page 172
252
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
ClC
H2C
H2C
l, 40
°, 2
0 h
FePP
h 2
PPh 2M
eN
NM
e 2
(1.1
mol
%),
(—)
I:I
I =
98:
2, 8
1% d
e I,
40%
de
II
CH
O
ON
O
O
II
ON
O
O
I
PhPh
O
O25
2C
N
ON
O
O
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
ClC
H2C
H2C
l, 50
°, 2
0 h
FePP
h 2
PPh 2M
eN
NM
e 2
(1.1
mol
%),
II
(—)
I:I
I =
97:
3, 8
8% d
e I,
15%
de
II
CH
O
ON
O
O
I
++
252
ON
O
O
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
ClC
H2C
H2C
l, 50
°, 2
0 h
(1.1
mol
%),
II
(—)
I:I
I =
97:
3, 8
9% d
e I,
33%
de
II
ON
O
O
I
Fe
PPh 2
PPh 2Me
NN
Me 2
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, rt,
20–9
0 h
OM
e
OC
3-9
CN
(CH
2O) n
ON
O
OM
eFe
PPh 2
PPh 2M
eN
NM
e 2
R
R
R H Me
Et
i-Pr
Ph
(99)
(100
)
(89)
(99)
(75)
% e
e
52 64 70 71 67d
61
+
(1.1
mol
%),
CH
O
173
c01_tex 4/18/06 12:32 PM Page 173
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
A. G
OL
D-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, rt,
41–3
30 h
OM
e
OC
4-6
CN
R2 C
HO
ON
R2
O
OM
e
ON
R2
O
OM
e
III
FePP
h 2
PPh 2M
eN
NO
R1
R1
R1
R1
Me
Me
Et
i-Pr
i-Pr
R2
Me
Ph Me
Me
Ph
(86)
(97)
(92)
(100
)
(86)
I:II
56:4
4
93:7
54:4
6
24:7
6
62:3
8
% e
e I
86 94 87 26 88
% e
e II
54 53 66h
51 17
62+
(1.1
mol
%),
[A
u(C
6H11
CN
) 2]B
F 4 (
1 m
ol%
),
CH
2Cl 2
, rt,
20–2
90 h
OM
e
O
CN
R2 C
HO
ON
R2
O
OM
e
ON
R2
O
OM
e
III
FePP
h 2
PPh 2M
eN
N
R1
R1
R1
R1
Me
Me
Me
Et
i-Pr
i-Pr
i-Pr
R2
H Me
Ph H H Me
Ph
(95)
(94)
(92)
(89)
(96)
(100
)
(86)
I:II —
44:5
6
88:1
2
— —
22:7
8
54:4
6
% e
e I
63 44 90 66 81 35 92
% e
e II
6 5 23b
28b
61 62 62 61 61 62 62
+
(1.1
mol
%),
a The
rea
ctio
n w
as c
arri
ed o
ut a
t roo
m te
mpe
ratu
re.
b The
abs
olut
e co
nfig
urat
ion
of I
I is
4S,
5S.
c The
abs
olut
e co
nfig
urat
ion
of I
I is
4R
,5R
.d T
he a
bsol
ute
conf
igur
atio
n w
as n
ot d
eter
min
ed.
e The
rea
ctio
n w
as c
arri
ed o
ut a
t 50°
.f P
Ph3
was
add
ed.
g TM
ED
A w
as a
dded
.h T
he a
mou
nt o
f ca
taly
st u
sed
was
0.7
mol
%.
174
c01_tex 4/18/06 12:32 PM Page 174
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
B. N
ON
-GO
LD
ME
TA
L-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
Ele
ctro
phile
Ar
NC
O2R
Ar
C2
CH
OC
O2R
OH
NH
2
CO
2R
OH
NH
2
414
1. (
S)-L
LB
(20
mol
%),
LiO
H (
18 m
ol%
),
H
2O (
22 m
ol%
), T
HF,
–50
°
2. C
itric
aci
d, T
HF/
H2O
, rt
III
R Me
CH
Ph2
N(M
e)O
Me
(58
)
(56
)
(98
)
I:II
89:1
1
78:2
2
20:8
0
ee %
I
38 47 33
ee %
II
— 42 3a
Ar
NC
O2B
u-t
Ar
RC
HO
CO
2Bu-
t
OH
NH
2
CO
2Bu-
t
OH
NH
2
414
1. (
S)-L
LB
(20
mol
%),
LiO
H (
18 m
ol%
),
H
2O (
22 m
ol%
), T
HF,
–50
°
2. C
itric
aci
d, T
HF/
H2O
, 40°
III
(82
)
(71
)
(89
)
(73
)
I:II
61:3
9
86:1
4
28:7
2
70:3
0
ee %
I
19 76 42 69
ee %
II
2b
—b
1b
18b
RR
R 2-C
4H3O
t-B
u
n-C
5H11
c-C
6H11
NC
O2B
u-t
Ar
CH
OC
O2B
u-t
OH
NH
2
CO
2Bu-
t
OH
NH
2
414
1. (
S)-L
LB
(20
mol
%),
LiO
H (
18 m
ol%
),
H
2O (
22 m
ol%
), T
HF,
–50
°
2. C
itric
aci
d, T
HF/
H2O
, rt
III
+
+
+
Ar
= 4
-ClC
6H4
Ar
= 4
-ClC
6H4
Ar
Ph 4-FC
6H4
4-C
lC6H
4
4-M
eC6H
4
4-C
F 3C
6H4
4-C
F 3C
6H4
(94
)
(87
)
(93
)
(85
)
(50
)
(43
)
I:II
62:3
8
53:4
7
59:4
1
63:3
7
56:4
4
44:5
6
ee %
I
47 64 74 42 61 68
ee %
II
3a 8 20 0a
43c
51b
Ar
175
c01_tex 4/18/06 12:32 PM Page 175
C3
OR
CH
OR
OO
HR n-
Pr
i-Pr
i-B
u
t-B
u
Ph 4-O
2NC
6H4
c-C
6H11
Ph(C
H2)
2
Ph2C
H
Ph2C
H
(56)
(80)
(24)
(76)
(55)
(62)
(85)
(59)
(79)
(72)
ee % 84 87 76 86 88 78 93
d
89 82 87d
84N
N
PhPhO
HH
OPhPh
OH
(5 m
ol%
),
Et 2
Zn
(10
mol
%),
4 Å
MS,
TH
F, 5
°
R n-Pr
n-Pr
i-Pr
i-B
u
t-B
u
Ph 4-O
2NC
6H4
c-C
6H11
Ph(C
H2)
2
Ph2C
H
(69)
(72)
(89)
(59)
(72)
(78)
(54)
(89)
(76)
(84)
ee % 89 84
e
91 84 94 83 76 92 82 91
84N
N
PhPhO
HH
OPhPh
OH
(10
mol
%),
Et 2
Zn
(20
mol
%),
4 Å
MS,
TH
F, 5
°
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
B. N
ON
-GO
LD
ME
TA
L-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
I
IR
CH
O
176
c01_tex 4/18/06 12:32 PM Page 176
R Et
2-C
5H4N
3-C
5H4N
4-C
5H4N
Ph 2-C
lC6H
4
3-C
lC6H
4
4-C
lC6H
4
2-O
2NC
6H4
3-O
2NC
6H4
4-O
2NC
6H4
c-C
6H11
2-M
eC6H
4
3-M
eC6H
4
4-M
eC6H
4
2,4,
6-M
e 3C
6H2
1-C
10H
7
2-C
10H
7
(91)
(82)
(80)
(82)
(85)
(90)
(91)
(87)
(82)
(73)
(60)
(97)
(90)
(87)
(80)
(84)
(73)
(81)
I:II
91:9
74:2
6
71:2
9
79:2
1
78:2
2
67:3
3
83:1
7
75:2
5
45:5
5
72:2
8
74:2
6
72:2
8
79:2
1
80:2
0
82:1
8
86:1
4
88:1
2
81:1
9
ee %
I
30 0 16 16 24 19 15 30 1 12 21 11 3 12 11 26 4 23
ee %
II
70 53 61 49 67 49 42 65 56 45 57 74 50 60 61 71 53 66
AgO
Tf
(1 m
ol%
),
NE
t(Pr
-i) 2
(10
mol
%),
TH
F, r
t
OM
e
O25
4C
NR
CH
O
ON
R
O
OM
e
ON
R
O
OM
e
PtPP
h 2Ph
2PC
l
III
(1 m
ol%
),+
177
c01_tex 4/18/06 12:32 PM Page 177
R H Me
Et
i-Pr
2-C
4H3O
2-C
5H4N
3-C
5H4N
4-C
5H4N
Ph c-C
6H11
2-M
eC6H
4
4-C
F 3C
6H4
2-M
eOC
6H4
3-M
eOC
6H4
4-M
eOC
6H4
2,4,
6-M
e 3C
6H2
1-C
10H
7
2-C
10H
7
(91)
(93)
(92)
(94)
(96)
(90)
(91)
(89)
(96)
(95)
(96)
(95)
(97)
(97)
(89)
(65)
(84)
(94)
(95)
I:II —
69:3
1
75:2
5
90:1
0
73:2
7
66:3
4
56:4
4
65:3
1
70:3
0
93:7
85:1
5
65:3
5
69:3
1
68:3
2
72:2
8
90:1
0
68:3
2
87:1
3
69:3
1
% e
e I
15 14 18 29 62 13 41 20 65 39 61 41 58 49 64 15 54 54 52
% e
e II
— 24 32 32 14 29 25 22 3 — 9 20 31 17 24 22 6 8 6
O O
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
B. N
ON
-GO
LD
ME
TA
L-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
NE
t(Pr
-i) 2
(10
mol
%),
CH
2Cl 2
, 20°
RC
HO
ON
R
O
OM
e
ON
R
O
OM
e
PtPP
h 2Ph
2PC
lI
II
(1.5
mol
%),
OO
OO
415
+O
Me
O
CN
C3
178
c01_tex 4/18/06 12:32 PM Page 178
[R
h(ac
ac)(
CO
) 2]
(1 m
ol%
),
Bu 2
O, 5
–100
h
X
OC
4
250
HC
HO
(1.1
mol
%),
X OM
e
OE
t
OPr
-i
OB
u-t
OC
H(i
-Pr)
2
OC
H(t
-Bu)
2
OC
HPh
2
N(O
Me)
Me
(67)
(85)
(86)
(80)
(82)
(86)
(96)
(80)
% e
e
35 74 78 82 91 93 87 61
CN
FeFe
Ph2P
PPh 2
H
H
HO
X
CNO
Tem
p
–30°
–30°
–30°
–30°
–10°
–10°
–10° 0°
R1
OR
2 CH
O(R
)-L
LB
(20
mol
%),
TH
F, –
20°
R2
R1
OO
H21
4
C3–
4
R1
Me
Me
Et
R2
t-B
u
BnC
Me 2
BnC
Me 2
(53
)
(82
)
(71
)
% e
e
73 74 94
OO
O
NN
O
t-B
uB
u-t
Cu
2 O
Tf–
2+ (10
mol
%),
1. N
,N-d
imet
hyla
nilin
e (5
mol
%),
Et 2
O, r
t
2. E
t 3N
, TB
SCl
265
(48)
96
% e
e
OO
OT
BS
OM
e
O
OM
e
OM
eO
O
179
c01_tex 4/18/06 12:32 PM Page 179
OH
OH
HO
(20
mol
%),
La(
OPr
-i) 3
(20
mol
%),
BuL
i (60
mol
%),
LiI
(10
mol
%),
PhM
e, –
20°
C4–
8
O
R R Et
i-Pr
Me 2
C=
CH
Me 2
C=
CH
Ph
(71)
(62)
(70)
(66)
(70)
% e
e
40 45 52 60f
67f
O
OH
HO
HO
PhC
HO
215
PhR
OO
H
PhC
HO
OO
H
Ph21
6
OC
5
(R)-
LL
B (
8 m
ol%
), K
HM
DS
(7.2
mol
%),
H2O
(16
mol
%),
TH
F, –
20°,
99
h
OH
Ph
O
III
(95)
I:
II =
93:
7, 7
6% e
e I,
88%
ee
II
+
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
B. N
ON
-GO
LD
ME
TA
L-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
[R
h(ac
ac)(
CO
) 2]
(1 m
ol%
),
Bu 2
O, 2
4–88
h
OR
1
O
250
R2 C
HO
(1.1
mol
%),
R1
Et
i-Pr
CH
(Pr-
i)2
CH
(Pr-
i)2
CH
(i-P
r)2
(63)
(61)
(67)
(76)
(88)
ee %
I
31 55 86 57 91
CN
FeFe
Ph2P
PPh 2
H
H
R2
OR
1
CNO
OH
I
R2
OR
1
CNO
OH
II
I:II
45:5
5
47:5
7
81:1
9
75:2
5
68:3
2
ee %
II
23 50 33 10 63
R2
Me
Me
Me
Et
EtO
2C
+
C4
180
c01_tex 4/18/06 12:32 PM Page 180
RC
HO
RE
t
OO
HR E
t
i-Pr
t-B
u
Ph PhC
C
(78)
(43)
(71)
(85)
(68)
dr
72:2
8
79:2
1
88:1
2
91:9
73:2
7
% e
e
74 71 93 91 78
255
rac-
BIN
OL
2-T
i 2(O
Pr-i
) 3/
(R
)-m
ande
lic a
cid
(10
mol
%),
rt
RE
t
OO
H
255
R Et
i-Pr
t-B
u
Ph PhC
C
(75)
(39)
(70)
(68)
(71)
dr
76:2
4
71:2
9
81:1
9
85:1
5
75:2
5
% e
e
76 74 86 88 81
OH
O
O21
3
C6
RC
HO
OH
O
OR
OH
R c-C
6H11
Ph(C
H2)
2
(90)
(97)
% e
e
96 95
dr 6:1
3.4:
1N
N
PhPhO
HH
OPhPh
OH
(5 m
ol%
),
Et 2
Zn
(10
mol
%),
4 Å
MS,
TH
F, –
35°,
24
h
rac-
BIN
OL
2-T
i 2(O
Bu-
t)3/
(R
)-m
ande
lic a
cid
(10
mol
%),
rt
OH
OH
HO
(20
mol
%),
La(
OPr
-i) 3
(20
mol
%),
BuL
i (60
mol
%),
LiI
(60
mol
%),
PhM
e, –
20°,
141
h
Et
O
Et
O
OH
HO
HO
BnO
CH
O21
5B
nOE
t
OO
H
BnO
Et
OO
H
III
(5)
I:I
I =
60:
40, 5
1% e
e I,
9%
ee
II
+
RC
HO
181
c01_tex 4/18/06 12:32 PM Page 181
CH
O
R
OO
H
R
OC
6–12
220
R 2-C
4H3O
2-M
eOC
6H4
4-M
eOC
6H4
2-C
10H
7
(66)
(48)
(36)
(40)
% e
eb
97 97 98 96
NN
PhPhO
HH
OPhPh
OH
(5 m
ol%
)
Et 2
Zn
(10
mol
%),
Ph 3
P=S
(15
mol
%),
4 Å
MS,
TH
F, 5
°, 2
d
Ar
Ph 2-C
10H
7
4-Ph
C6H
4
(94)
(92)
(90)
% e
e I
97 93 97
I:II
78:1
6
77:1
5
78:1
2
% e
e II
84 83 86
O
RC
HO
(R)-
LL
B (
8 m
ol%
), K
HM
DS
(7.2
mol
%),
H2O
(16
mol
%),
TH
F, –
20°
R
OO
H
216
(90)
(75)
(91)
(85)
(68)
(55)
(60)
(50)
C8
% e
e
33f
88 90 89 70g
42h
80i
30a
X H H H H 3-N
O2
3-N
O2
3-N
O2
3-N
O2
R i-Pr
t-B
u
BnO
CH
2CM
e 2
BnC
Me 2
i-Pr
n-C
5H11
Et 2
CH
Ph(C
H2)
2
X
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
B. N
ON
-GO
LD
ME
TA
L-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
416
n-B
uCH
O
OH
O
On-
Bu
OH
NN
Ar
Ar
OH
HO
Ar
Ar
OH
(5 m
ol%
),
Et 2
Zn
(10
mol
%),
4 Å
MS,
TH
F, –
35°,
12
h
OH
O
On-
Bu
OH
III
+
OH
O
O
C6
X
182
c01_tex 4/18/06 12:32 PM Page 182
PhC
HO
OH
O
Ph
(33)
I:I
I =
66:
34, 7
8% e
e I,
95%
ee
II
216
DD
O
NO
2N
O2 O
HO
Ph
D
NO
2
(R)-
LL
B (
8 m
ol%
),
KH
MD
S (
7.2
mol
%),
H2O
(16
mol
%),
TH
F, –
40°,
48
h
I
II
217
RC
HO
R
OH
Ph
OR i-
Pr
BnO
CM
e 2
t-B
u
BnO
CH
2CM
e 2
BnO
CH
2CM
e 2
c-C
6H11
BnC
Me 2
(91)
(99)
(77)
(83)
(86)
(87)
(77)
% e
e
50 70 67 69 70d,
j
54 56
O
Ph
OM
eO
H(1
2.5
mol
%),
Ba(
OPr
-i) 2
(5
mol
%),
DM
E, –
20°,
18–
48 h
R
OH
Ph
O21
9O
H
OH
Ca[
N{S
i(C
H3)
3}2]
2(T
HF)
2, K
SCN
,
EtC
N/T
HF
(4:1
), –
20°
R t-B
u
BnO
CH
2CM
e 2c-
C6H
11
Ph(C
H2)
2
PhC
H2C
Me 2
(87)
(76)
(88)
(13)
(75)
% e
e
86 91 66 15k
87
+
(3 m
ol%
),R
CH
O
183
c01_tex 4/18/06 12:32 PM Page 183
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
CH
O
OT
BS
OH
Ph
O
216
OT
BS
(R)-
LL
B (
8 m
ol%
),
KH
MD
S (7
.2 m
ol%
),
H2O
(16
mol
%),
TH
F, –
20°,
48
h
OH
Ph
O
OT
BS
III
(85)
I:
II =
73:
12, 9
9% e
e I,
93%
ee
II
CH
O
OO
(R)-
LL
B (
20 m
ol%
),
KH
MD
S (1
8 m
ol%
),
H2O
(40
mol
%),
TH
F, –
20°
OO
OH
Ph
O40
(±)
OO
OH
Ph
O
(59)
I:
II =
1:1
, 89%
ee
I, 8
8% e
e II
I
II
RPh
OO
H22
0R
CH
O
R n-Pr
n-Pr
i-Pr
i-B
u
TB
SOC
H2C
Me 2
c-C
6H11
PhC
HM
e
Ph2C
H
(33)
(24)
(62)
(49)
(61)
(60)
(67)
(79)
% e
e
56l
74m
98 68b,
l
93b,
n
98 94b,
o
99b
NN
PhPhO
HH
OPhPh
OH
(5 m
ol%
),
Et 2
Zn
(10
mol
%),
Ph 3
P=S
(15
mol
%),
4 Å
M.S
., T
HF,
5°,
2 d
+
+
Nuc
leop
hile
Ref
s.C
ondi
tions
TA
BL
E 2
B. N
ON
-GO
LD
ME
TA
L-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
O
Ph
C8
184
c01_tex 4/18/06 12:32 PM Page 184
Ph
O
OH
RC
HO
(S)-
LL
B (
10 m
ol%
),
KH
MD
S (9
mol
%),
H2O
(20
mol
%),
TH
F, –
50°
RPh
O
OH
OH
65
R i-B
u
n-C
5H11
Ph(C
H2)
2
Ph(C
H2)
3
Ph(C
H2)
3
(86)
(84)
(89)
(84)
(78)
(90)
I:II
65:3
5
74:2
6
69:3
1
84:1
6
78:2
2
72:2
8
RPh
O
OH
OH
III
% e
e II
83 84 87 74 70a,
p
83
% e
e I
90 94 95 95 92 94
417
O
O O
O OZ
n
Zn
RPh
O
OH
OH R i-Pr
i-B
u
n-C
5H11
Et 2
CH
c-C
6H11
Ph(C
H2)
2
(92)
(80)
(80)
(79)
(89)
(89)
(81)
I:II
5:1
2:1
2:1
7:1
6:1
3:1
2:1
RPh
O
OH
OH
III
% e
e I
86 83 77 79 85 81 79
% e
e II
67 79 73 72 78 81 75
(10
mol
%),
TH
F, –
40°,
36–
60 h
+ +R
CH
O
185
c01_tex 4/18/06 12:32 PM Page 185
O
OH
RC
HO
O
O O
O OZ
n
Zn
83R
O
OH
OH
R
O
OH
OH
III
(1 m
ol%
),
TH
F, –
30°,
16–
24 h
XX
X
RC
HO
RPh
OO
H
OH
R i-Pr
i-B
u
i-B
u
c-C
6H11
c-C
6H11
n-C
7H15
Ph(C
H2)
2
Ph(C
H2)
2
CH
2=C
H(C
H2)
8
Ph2C
H
(89)
(65)
(96)
(83)
(97)
(89)
(78)
(98)
(91)
(74)
% e
e I
93 94 88p
92 90p
86p
91 90p
87 96
dr 13:1
35:1
3:1
30:1
5:1
5:1
9:1
3:1
5:1
> 9
9:1
213
NN
Ar
Ar
OH
HO
Ar
Ar
OH
(2.5
mol
%),
Et 2
Zn
(10
mol
%),
4 Å
MS,
TH
F, –
35°,
24
h
+
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
B. N
ON
-GO
LD
ME
TA
L-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
Ph
O
OH
C8
X 2-M
eO
2-M
eO
2-M
eO
2-M
eO
2-M
eO
2-M
eO
2-M
eO
2-M
eO
2-M
eO
R BnO
CH
2
BnO
(CH
2)2
i-Pr
i-B
u
n-C
5H11
Et 2
CH
c-C
6H11
n-C
6H13
Ph(C
H2)
2
(84)
(81)
(83)
(84)
(88)
(92)
(95)
(84)
(94)
% e
e I
96 95 98 93 95 99 98 96 92
% e
e II
93 90 — 87 91 — — 87 89
I:II
72:2
8
86:1
4
97:3
84:1
6
88:1
2
96:4
97:3
87:1
3
89:1
1
186
c01_tex 4/18/06 12:32 PM Page 186
O
OH
RC
HO
(S)-
LL
B (
10 m
ol%
),
KH
MD
S (9
mol
%),
H2O
(20
mol
%),
TH
F, –
40°,
12–
35 h
R
O
OH
OH
65
(90)
(96)
(96)
(69)
(82)
(50)
(76)
(42)
I:II
77:2
3
82:1
8
75:2
5
76:2
4
77:2
3
81:1
9
67:3
3
74:2
6
C8–
9
R
O
OH
OH
III
% e
e II
57 83 89 74 83 79 91 41
% e
e I
84 96 96 95 95 98 93 80
X
X 2-M
e
4-M
e
4-M
e
2-M
eO
3-M
eO
4-M
eO
4-M
eO
2,5-
(MeO
) 2
R Ph(C
H2)
3
Ph(C
H2)
3
n-C
5H11
Ph(C
H2)
3
Ph(C
H2)
3
Ph(C
H2)
3
Ph(C
H2)
3
XX
+
Ph(C
H2)
2
Ph(C
H2)
2
(94)
(85)
(73)
86:1
4
70:3
0
60:4
0
87 77 86
92 77d
86d,
q
2-M
eO
3-M
eO
4-M
eO
Ar
OR
CH
O(R
)-L
LB
(20
mol
%),
TH
F, –
20°
RA
r
OO
H21
4C
8–12
Ar
Ph Ph Ph Ph Ph 1-C
10H
7
R i-Pr
t-B
u
c-C
6H11
Ph(C
H2)
2
BnC
Me 2
t-B
u
(59
)
(81
)
(72
)
(28
)
(90
)
(55
)
% e
e
54 91f
44 52 69 76f
187
c01_tex 4/18/06 12:32 PM Page 187
a The
rea
ctio
n w
as c
arri
ed o
ut a
t –40
°.b T
he a
bsol
ute
conf
igur
atio
n w
as n
ot d
eter
min
ed.
c The
rea
ctio
n w
as c
arri
ed o
ut at
–60
°.d T
he a
mou
nt o
f ca
taly
st u
sed
was
10
mol
%.
e Ph 3
P=S
(0.5
equ
ival
ents
) w
as a
dded
.f T
he r
eact
ion
was
car
ried
out
at –
30°.
g The
rea
ctio
n w
as c
arri
ed o
ut at
–50
°.h F
or th
is r
eact
ion,
30
mol
% o
f L
LB
, 27
mol
% o
f K
HM
DS
and
60 m
ol%
of
H2O
wer
e us
ed, a
nd th
e re
actio
n w
as c
arri
ed o
ut at
–50
°.i F
or th
is r
eact
ion,
15
mol
% o
f L
LB
, 13.
5 m
ol%
of
KH
MD
S an
d 30
mol
% o
f H
2O w
ere
used
, and
the
reac
tion
was
car
ried
out
at –
45°.
j The
rea
ctio
n w
as c
arri
ed o
ut at
–25
°.k T
he p
rodu
ct h
as th
e S
conf
igur
atio
n.l T
he r
eact
ion
was
car
ried
out
at –
5°.
m T
he r
eact
ion
was
car
ried
out
at –
15°.
n The
rea
ctio
n w
as q
uenc
hed
afte
r 4
days
.o T
he d
iast
ereo
mer
ic r
atio
of
the
prod
ucts
for
this
ent
ry is
2:1
.p T
he a
mou
nt o
f ca
taly
st u
sed
was
5 m
ol%
.q T
he r
eact
ion
was
car
ried
out
at –
20°.
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
B. N
ON
-GO
LD
ME
TA
L-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
188
c01_tex 4/18/06 12:32 PM Page 188
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
C. N
ON
-ME
TA
L-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
Ele
ctro
phile
C2
MeC
HO
MeC
HO
L-P
rolin
e (1
.7 m
ol%
), s
olve
nt,
rt,
14 h
OH
223
Solv
ent
DM
SO
TH
F
(13
)
(10
)
% e
e
57 90a
CH
O
OB
u-t
O
NR
CH
OO
Bu-
t
O
R
OH
NH
2
256
N
HSO
4–
(2 m
ol%
),
aq
NaO
H (
1 m
ol%
), P
hMe,
0°
Ar
Ar
Ar
=
CF 3
CF 3
R Me
CH
2=C
H(C
H2)
2
c-C
6H11
c-C
6H11
Ph(C
H2)
2
(58)
(71)
(40)
(78)
(76)
dr
2.3:
1
2.4:
1
2.8:
1
1.2:
1
3.3:
1
% e
e
92 90 95 93b
91
256
N
HSO
4–
(2 m
ol%
),
aq
NaO
H (
1 m
ol%
), P
hMe,
0°
Ar
Ar
Ar
=F 3C
CF 3
CF 3
CF 3
R TIP
SOC
H2
CH
2=C
H(C
H2)
2
n-C
6H13
Ph(C
H2)
2
(72)
(62)
(65)
(71)
dr 20:1
6.3:
1
10:1
12:1
% e
e
98 80 91 96
+ +
Ph
Ph
I
IR
CH
O
189
c01_tex 4/18/06 12:32 PM Page 189
C3
OR
CH
O
R i-Pr
n-C
4H9
Ph 2-C
lC6H
4
4-B
rC6H
4
4-A
cHN
C6H
4
4-O
2NC
6H4
c-C
6H11
2-C
10H
7
(61
)
(75
)
(60
)
(71
)
(65
)
(60
)
(60
)
(45
)
(60
)
% e
e
94 73 89 74 67 80 86 83 88
R
OO
H71
S
N HC
O2H
(20
mol
%),
DM
SO, r
t, 24
–48
h
R i-Pr
n-C
4H9
Ph 2-C
lC6H
4
4-B
rC6H
4
4-A
cHN
C6H
4
4-O
2NC
6H4
c-C
6H11
2-C
10H
7
(97
)
(56
)
(62
)
(94
)
(74
)
(62
)
(68
)
(60
)
(54
)
% e
e
96 68 60 69 65 69 76 85 77
71L
-Pro
line
(20
mol
%),
DM
SO,
rt,
24–4
8 h
L-P
rolin
e (3
0 m
ol%
), D
MSO
, rt
R i-Pr
t-C
4H9
Ph 2-C
lC6H
4
4-B
rC6H
4
4-O
2NC
6H4
c-C
6H11
CH
2=C
HC
H2C
Me 2
2-C
10H
7
(97)
(81)
(62)
(94)
(74)
(68)
(63)
(85)
(54)
% e
e
96 > 9
9
60 69 65 76 84 > 9
9
77
85 257
85 85 85 85 257
257
85
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
C. N
ON
-ME
TA
L-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
I
I I
RC
HO
RC
HO
190
c01_tex 4/18/06 12:32 PM Page 190
R n-C
4H9
n-C
4H9
i-B
u
i-B
u
CH
2=C
H(C
H2)
2
n-C
5H11
neo-
C5H
11
(31)
(29)
(34)
(23)
(34)
(35)
(22)
% e
e
67 70d
73 61d
72d
73 36d
66O
R
OH
L-P
rolin
e (1
0–20
mol
%),
ace
tone
, rt
X
OO
HX H 4-
F
2-B
r
2-N
O2
3-N
O2
4-N
O2
2-O
Me
4-O
Me
4-C
F 3
4-C
N
(55)
(90)
(61)
(93)
(94)
(68)
(69)
(69)
(91)
(74)
% e
e
76 68 63 82 70 65e
68 50 73f
70
X
CH
OL
-Pro
line
(30
mol
%),
NB
u-n
MeN
+PF
6– ,26
1
24
h, r
t
O
O
OO
O
OH
C
L-P
rolin
e (3
0 m
ol%
), D
MSO
, rt
O
O
OO
O
OO
H
(—)
> 9
9% d
e22
1
RC
HO
O
R
OH
R Ph 4-B
rC6H
4
c-C
6H11
2-C
10H
7
(58)
(72)
(65)
(60)
% e
e
71 67 89 69
260
RC
HO
L-P
rolin
e (3
0 m
ol%
),
NB
u-n
MeN
+PF
6– ,
24
h, r
t
191
c01_tex 4/18/06 12:32 PM Page 191
OR
CH
OR
OO
H26
2
R Ph 4-B
rC6H
4
4-O
2NC
6H4
c-C
6H11
(45)
(55)
(68)
(81)
% e
e
59 63 77
> 9
8g
O
O
ON
H
CO
2H D
MF,
rt
(30
mol
%),
N H
N
Chi
ral d
iam
ine
(3 m
ol%
),
2,4
-(N
O2)
2C6H
3SO
3H•2
H2O
(3
mol
%),
ace
tone
, rt
CH
O
O2N
O2N
OO
H
222
N H
N
N H
N
N H
N
N H
N
OM
e
Chi
ral d
iam
ine
(61)
(41)
(72)
(50)
(8)
83 84 93 84 89% e
ei
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
C. N
ON
-ME
TA
L-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
C3
O
192
c01_tex 4/18/06 12:32 PM Page 192
N H
N
H2N
N
PhN H
N
O
N H
NH
2
H2N
N
Ph
H2N
N
Ph N H
H N
N H
H N
(3)
(15)
(52)
(25)
(71)
(88)
(81)
(84)
58 83 81 66 76 63 81 81
N H
H N(7
)84
N H
NH
Bu-
t(7
2)11
193
c01_tex 4/18/06 12:32 PM Page 193
Chi
ral d
iam
ine
(10
mol
%),
2,4
-(N
O2)
2C6H
3SO
3HM2H
2O
(10
mol
%),
ace
tone
, rt
CH
OO
OH
222
N H
N
N H
N
Chi
ral d
iam
ine
N H
NH
2
N H
N
N H
N
N H
N
OM
e
% e
ei
(6)
(2)
(13)
(7)
(1)
(3)
80 69 91 76 74 78
H2N
N
Ph
68(2
7)
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
C. N
ON
-ME
TA
L-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
C3
O
194
c01_tex 4/18/06 12:32 PM Page 194
H2N
N
Ph
H2N
N
Ph N H
H N
N H
H N
N H
H N
N H
NH
Bu-
t
(56)
(69)
(58)
(16)
(39)
(12)
72 45 74 54 52 15
Chi
ral d
iam
ine
(15
mol
%),
2,4
-(N
O2)
2C6H
3SO
3HM2H
2O
(15
mol
%),
ace
tone
, rt
CH
OO
OH
222
Chi
ral d
iam
ine
H2N
N
Ph
(8)
28% e
ei
H2N
N
Ph
(32)
42h
195
c01_tex 4/18/06 12:32 PM Page 195
H2N
N
Ph N H
H N
N H
H N
N H
H N
N H
NH
Bu-
t
(66)
(64)
(40)
(60)
(40)
46h
80 83 80 80
RC
HO
EtC
HO
L-P
rolin
e (1
0 m
ol%
),
DM
F, –
4° to
rt,
72 h
OR
OH
HO
R Et
i-Pr
i-B
u
% e
e
11c
12 11
418
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
C. N
ON
-ME
TA
L-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
Chi
ral d
iam
ine
(15
mol
%),
2,4
-(N
O2)
2C6H
3SO
3HM2H
2O
(15
mol
%),
ace
tone
, rt
CH
OO
OH
222
C3
O
Chi
ral d
iam
ine
% e
ei
(53)
(32)
(34)
α:ß
1:2.
2
1:2
1:2.
5
196
c01_tex 4/18/06 12:32 PM Page 196
RC
HO
R i-Pr
neo-
C5H
11
Ph 2-C
lC6H
4
c-C
6H11
PhC
HM
e
2-C
10H
7
(<
5)
(<
5)
(<
5)
(26)
(36)
(45)
(<
5)
(29
)
dr — — — 1:1
3:2
> 2
0:1
— 1:1
R
OO
H
71S
N HC
O2H
(20
mol
%),
DM
SO, 3
7°, 2
4–48
h
OO
% e
e
— — — 95 92 95 — 91
OH
O
OH
R
OO
H
71
OH
L-P
rolin
e (2
0 m
ol%
), D
MSO
,
rt,
24–4
8 h
R i-Pr
neo-
C5H
11
Ph 2-C
lC6H
4
c-C
6H11
PhC
HM
e
2-C
10H
7
(27)
(62)
(24)
(42)
(57)
(60)
(51)
(47)
dr 2:1
> 2
0:1
1.7:
1
1:1
3:2
> 2
0:1
> 2
0:1
3:1
OO
% e
e
> 9
7
> 9
9
> 9
7
80 67 > 9
9
> 9
5
79
RC
HO
CH
OR
OH
R Et
i-Pr
i-B
u
Ph c-C
6H11
(80)
(82)
(88)
(81)
(87)
dr 4:1
24:1
3:1
3:1
14:1
% e
e
99 > 9
9
97 99 99
L-P
rolin
e (1
0 m
ol%
), D
MF,
4°
86
RC
HO
197
c01_tex 4/18/06 12:32 PM Page 197
O
OO
H
262
O
O
ON
H
CO
2H D
MF,
rt,
48 h
(30
mol
%),
OH
(48)
dr
> 2
0:1,
> 9
8% e
eC
HO
RC
HO
O
R
OH
OH
R i-Pr
t-B
uCH
2
2-C
lC6H
4
c-C
6H11
PhC
HM
e
(40)
(62)
(38)
(95)
(60)
(51)
dr 2:1
> 2
0:1
1.7:
1
1.5:
1
> 2
0:1
> 2
0:1
% e
e
> 9
7
> 9
9
> 9
7
67 > 9
9
> 9
5
258
L-P
rolin
e (2
0–30
mol
%),
DM
SO,
rt,
24–7
2 h
OO
C3–
8
OC
HO
R
OH
C
OH
R
CO
2Et
CO
2Et
264
L-P
rolin
e (5
0 m
ol%
), C
H2C
l 2,
rt,
3 h
(90
)
(91
)
(88
)
(94
)
(91
)
% e
ei
90 85 85 88 84
R Me
Et
i-Pr
CH
2=C
HC
H2
n-C
6H13
CO
2Et
EtO
2C
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
C. N
ON
-ME
TA
L-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
O
OH
C3
198
c01_tex 4/18/06 12:32 PM Page 198
C4
OH
CH
OL
-Pro
line
(30
mol
%),
NB
u-n
MeN
+PF
6– ,26
1
CF 3
CF 3
(53)
I:
II =
6:1
, 10%
ee
I, 8
% e
e II
OO
OH
CF 3
O
III
24
h, r
t
71L
-Pro
line
(20
mol
%),
DM
SO,
rt,
24–4
8 h
R i-Pr
n-B
u
4-O
2NC
6H4
(60
)
(65
)
(65
)
% e
e
80 58 77
Et
OR
CH
OR
Et
OO
H71
R i-Pr
n-B
u
4-O
2NC
6H4
(< 5
)
(< 5
)
(57)
% e
e
— — 74
S
N HC
O2H
(20
mol
%),
DM
SO, r
t, 24
–48
h
Et
OO
HC
HO
261
CF 3
CF 3
(59)
76
% e
e
+
(5 m
ol%
),
OO
OH
C5
CH
O
O2N
(5 m
ol%
),N H
N
cyc
lope
ntan
one,
30°
N H
N
M2
TfO
H
O2N
(88)
an
ti:sy
n =
43:
57, 8
4% e
e an
ti,i 5
% e
e sy
ni
222
i-B
uCH
O66
L-P
rolin
e (2
0 m
ol%
), C
HC
l 3,
rt,
72 h
O
Bu-
i
OH
O
Bu-
i
OH
+
III
(77)
I:
II =
2.5
:1, 9
5% e
e I,
20%
ee
II
RC
HO
I
I
L-P
rolin
e (3
0 m
ol%
),
NB
u-n
MeN
+PF
6– ,
24
h, r
t
199
c01_tex 4/18/06 12:32 PM Page 199
PhC
HO
Ph
OH
NB
u-n
MeN
+PF
6– ,
L-P
rolin
e (3
0 m
ol%
),
260
O
rt,
25 h
OH
CH
O26
1
CF 3
CF 3
(94)
I:
II =
1:1
, 32%
ee
I, 8
6% e
e II
III
OO
H
CF 3
O
+
(5 m
ol%
),
OO
OH
CH
O
O2N
(5 m
ol%
),N H
N
3-p
enta
none
, 30°
N H
N
M2
TfO
H
O2N
(81)
an
ti:sy
n =
54:
46, 8
4% e
e an
ti, 1
6% e
e sy
n
222
Et
Et
Et
C5–
6
O
n
CH
O
O2N
O
nN
O2
OH
O
nN
O2
OH
71S
N HC
O2H
(20
mol
%),
DM
SO, r
t, 24
–48
hI
IIn 1 2
(63
)
(56
)
I:II
24:3
9
21:3
5
% e
e I
60 69
% e
e II
63 90
+
(83)
dr
= 6
1:39
, —
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
C. N
ON
-ME
TA
L-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
OC
5
NB
u-n
MeN
+PF
6– ,
L-P
rolin
e (3
0 m
ol%
),
rt,
24 h
200
c01_tex 4/18/06 12:32 PM Page 200
O
nN
O2
OH
O
nN
O2
OH
71
III
n 1 2
(73
)
(65
)
I:II
27:4
6
24:4
1
% e
e I
63 67
% e
e II
69 89
L-P
rolin
e (2
0 m
ol%
), D
MSO
,
rt,
24–4
8 h
RC
HO
C6
257
L-P
rolin
e (2
0 m
ol%
), C
HC
l 3,
rt,
72 h
O
III
O
R
OH
O
R
OH
R i-Pr
i-B
u
Ph
(68)
(41)
(85)
I:II
> 2
0:1
7:1
1:1
% e
e I
97 86 85
% e
e II
— 89 76
OH
CH
OL
-Pro
line
(30
mol
%),
NB
u-n
MeN
+PF
6– ,26
1
CF 3
CF 3
(91)
I:I
I 20
:1, 9
3% e
e I
IIIO
H
CF 3
OO
rt,
24 h
+
+
+
(5 m
ol%
),
OO
HC
HO
O2N
(5 m
ol%
),N H
N
cyc
lohe
xano
ne, 3
0°
N H
NO
2N
(97)
ant
i:syn
= 7
4:26
, 96
% e
e an
ti,i 6
1% e
e sy
ni
222
CH
O
O2N
M2T
fOH
201
c01_tex 4/18/06 12:32 PM Page 201
i-P
r 2N
Et (
4 eq
uiv)
, MeC
N, r
t,
slo
w a
dditi
on
419
N+
(54)
(37)
(48)
(39)
(37)
(45)
(42)
% e
e
92 92 89 90 87 90 92
Cl
Me
I–
(3 e
quiv
),NH
HN
MeO
O(1
0 m
ol%
),
OO
R
O
R Me
n-Pr
t-B
u
i-B
uO
Ph PhN
H
n-C
9H19
CH
O
OH
O
i-P
r 2N
Et (
4 eq
uiv)
, MeC
N, r
t,
slo
w a
dditi
on
419
NC
lM
eI–
(3 e
quiv
),NH
HN
MeO
AcO
(10
mol
%),
+
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 2
C. N
ON
-ME
TA
L-C
AT
AL
YZ
ED
AL
DO
L A
DD
ITIO
NS
OF
UN
MO
DIF
IED
NU
CL
EO
PHIL
ES
(Con
tinu
ed)
Ele
ctro
phile
i-P
r 2N
Et (
4 eq
uiv)
, MeC
N, r
t,
slo
w a
dditi
on
419
NC
lM
eI–
(3 e
quiv
),
N
HN
OM
eO
Ac
(10
mol
%),
OO
(51)
86
% e
eH
+
C6
I
I (
8) 1
1% e
e
I
202
c01_tex 4/18/06 12:32 PM Page 202
i-P
r 2N
Et (
4 eq
uiv)
, MeC
N, r
t,
slo
w a
dditi
on
418
NC
lM
eI–
(3 e
quiv
),N
HN
MeO
O
(10
mol
%),
n-C
5H11
CH
Oi-
PrC
HO
L-P
rolin
e (1
0 m
ol%
), D
MF,
rt
CH
O
Bu-
n
i-Pr
OH
(80)
dr
= 2
4:1,
98%
ee
86
O
O
C7
O
O
O
ON
H
CO
2H D
MSO
, rt,
90 h
(35
mol
%),
O
O
(55)
75
% e
e26
3O
+
Ph(C
H2)
2CH
Oi-
PrC
HO
L-P
rolin
e (1
0 m
ol%
), D
MF,
rt
(75)
dr
= 1
9:1,
91%
ee
C9
86
a The
rea
ctio
n w
as c
arri
ed o
ut a
t 0°
for
5 ho
urs.
b Di-
n-bu
tyl e
ther
was
use
d as
the
solv
ent.
c Aft
er 1
0 ho
urs
at 4
°, th
e en
antio
mer
ic e
xces
s w
as 4
7%.
d Tri
chlo
rom
etha
ne w
as u
sed
as th
e so
lven
t.e T
he a
ldeh
yde
was
add
ed a
fter
pre
mix
ing
prol
ine,
ace
tone
, and
ioni
c liq
uid.
f The
sam
e re
sult
was
obt
aine
d us
ing
10 m
ol%
of
cata
lyst
.g D
MSO
was
use
d as
the
solv
ent.
h Tw
enty
mol
% o
f ca
taly
st w
as u
sed.
CH
O
Bn
i-Pr
OH
I (
42)
90%
ee
203
c01_tex 4/18/06 12:32 PM Page 203
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 3
. AL
DO
L T
AN
DE
M R
EA
CT
ION
S
Ele
ctro
phile
C2
OE
tE
tOR
1
O
R2
O
O
NN
O
t-B
uB
u-t
Cu
2 O
Tf–
2+
(20
mol
%),
1.
O
EtO
OE
tO
Et O
Et
R1 O
R2
284
R1
Me
Me
Me
Me
BrC
H2
Et
i-Pr
Ph (E)-
PhC
H=
CH
R2
Me
OM
e
Et
Ph OE
t
OM
e
OE
t
OE
t
OM
e
(71)
(74)
(70)
(58)
(55)
(70)
(58)
(80)
(80)
% e
e
95 83a
90 90 53 77 80 93a
85a
Et 2
O, –
15°
C3
OM
e
OR
CH
OR
OM
e
OO
HR T
BSO
CH
2
BnO
CH
2
BnO
(CH
2)2
Ph
(47)
(59)
(65)
(68)
dr
8.2:
1
9.5:
1
2.7:
1
6.6:
1
% e
e
96 96 82 94
286
[(
cod)
IrC
l]2
(2.5
mol
%),
Et 2
MeS
iH,
r
t, 24
h
2. a
q H
Cl
NO
NN
O(7
.5 m
ol%
),
1.
OM
e
OO
H
287
NO
NN
O(3
mol
%),
PMB
O(7
6) d
r =
6:1
, > 9
0% e
eC
HO
PMB
O
[
(cod
)IrC
l]2
(1 m
ol%
), E
t 2M
eSiH
,
r
t, 24
h
2. a
q H
Cl
1.
204
c01_tex 4/18/06 12:32 PM Page 204
RC
HO
RO
Me
OO
H R (R)-
MeC
H(O
Bn)
(S)-
MeC
H(O
Bn)
(R)-
MeC
H(O
Bn)
CH
2
(S)-
MeC
H(O
Bn)
CH
2
(50)
(< 5
)
(65)
(57)
syn a
:syn
bb
> 9
5:5
—
89:1
1
88:1
2
syn:
antic
> 9
5:5
— 2.7:
1
3.0:
1
286
NO
NN
O(7
.5 m
ol%
),
[
(cod
)IrC
l]2
(2.5
mol
%),
Et 2
MeS
iH,
r
t, 24
h
2. a
q H
Cl
OPh
OR
CH
OR
OPh
OO
HR E
t
t-B
u
Ph c-C
6H11
1-C
10H
7
(59)
(48)
(72)
(54)
(82)
dr
5.1:
1
1.8:
1
3.4:
1
3.9:
1
3.8:
1
% e
e
88 45 87 84 80
1. [
(cod
)RhC
l]2
(2.5
mol
%),
(
R)-
BIN
AP
(6.5
mol
%),
Et 2
MeS
iH,
C
H2C
l 2, r
t, 24
h
2. a
q H
Cl
285
1.
CH
OR
CH
O
R
O
O
Pr-i
OH
C4
Y5O
(OPr
-i) 1
3 (2
mol
%),
CH
2Cl 2
,
4 Å
MS,
rt,
15 h
NN
OH
OH
adam
anty
l
adam
anty
l
PhPh
HH
(13
mol
%),
R Ph 4-B
rC6H
4
4-M
eOC
6H4
(E)-
PhC
H=
CH
2-C
10H
7
(70)
(55)
(21)
(50)
(50)
% e
e
74 70 72 10 64
282
205
c01_tex 4/18/06 12:32 PM Page 205
Nuc
leop
hile
Ref
s.C
ondi
tions
Prod
uct(
s), Y
ield
(s)
(%)
and
Ster
eose
lect
ivity
TA
BL
E 3
. AL
DO
L T
AN
DE
M R
EA
CT
ION
S (C
onti
nued
)
Ele
ctro
phile
OA
l(lig
ands
)
CO
2Et
CO
2Et
C9
O
CO
2Et
CO
2Et
PhPh
CH
O
OH
H
68O O
Al
O O
Li
(10
mol
%),
TH
F, r
t, 36
h
(64)
91
% e
ed
O
CO
2Et
CO
2Et
PhPh
CH
O
OH
68O O
Al
O O
Li
(10
mol
%),
TH
F, r
t, 72
h
2. P
CC
(82)
89
% e
ed
1.
OA
l(lig
ands
)
CO
2Bn
CO
2Bn
O
CO
2Bn
CO
2Bn
MeO
2CC
HO
OH
H
289
O OA
lO O
Li
(10
mol
%),
NaO
Bu-
t, 4
Å M
S, T
HF,
rt
(75)
97
% e
ee
TB
SO
5
CO
2Me
5
TB
SO
O–
t-B
u
C13
1. [
Rh(
OH
)((S
)-B
INA
P)] 2
(3
mol
%),
D
MF,
20°
, 12
h
2. H
2O2/
NaO
H
420
F
EtC
HO
O
t-B
u
F
Et
OH
O
t-B
u
F
Et
OH
(44)
I:
II =
0.8
:1, 4
1% e
e I,
94%
ee
IIf
III
+
206
c01_tex 4/18/06 12:32 PM Page 206
O
O–
n
C14
-15
n
Ph
OH
O
Ph
n 1 2
[Rh(
CO
D)C
l]2
(2.5
mol
%),
(R
)-B
INA
P (7
.5 m
ol%
), H
2O (
5 eq
uiv)
,
dio
xane
, 95°
288
(88)
(69)
% e
e
94g
95g
O
O–
Ph
n
C19
-20
Ph n 1 2
288
(78)
(88)
% e
e
77g
88g
Ph
OH
O
Ph
a The
rea
ctio
n w
as c
arri
ed o
ut a
t –78
°.b S
yna/
syn b
ref
ers
to th
e ra
tio o
f th
e m
ajor
syn
dia
ster
eom
er (
show
n) to
the
min
or s
yn d
iast
ereo
mer
.c S
yn/a
nti r
efer
s to
the
colle
ctiv
e sy
n di
aste
reom
ers/
colle
ctiv
e an
ti di
aste
reom
ers.
d The
eno
late
was
gen
erat
ed b
y in
-situ
con
juga
te a
dditi
on to
cyc
lope
nten
one.
e The
eno
late
was
gen
erat
ed b
y in
-situ
con
juga
te a
dditi
on to
the
subs
titut
ed c
yclo
pent
enon
e.f T
he e
nola
te w
as g
ener
ated
by
rhod
ium
-cat
alyz
ed in
-situ
con
juga
te a
dditi
on o
f 4-
FC6H
4-9-
BB
N to
the
corr
espo
ndin
g en
one.
g The
eno
late
was
gen
erat
ed b
y rh
odiu
m-c
atal
yzed
in-s
itu c
onju
gate
add
ition
of
PhB
(OH
) 2 to
the
corr
espo
ndin
g en
one.
[Rh(
CO
D)C
l]2
(2.5
mol
%),
(R
)-B
INA
P (7
.5 m
ol%
), H
2O (
5 eq
uiv)
,
dio
xane
, 95°
n
207
c01_tex 4/18/06 12:32 PM Page 207
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