catalytic enantioselective aldol addition reactions

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

[email protected] 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.

c01_tex 4/18/06 12:31 PM

(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%)


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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


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


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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


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

+

+


c01_tex 4/18/06 12:31 PM

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

+


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

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%)


c01_tex 4/18/06 12:31 PM

(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


c01_tex 4/18/06 12:31 PM

(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+


c01_tex 4/18/06 12:31 PM

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°


c01_tex 4/18/06 12:31 PM

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.


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

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%)


c01_tex 4/18/06 12:31 PM

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


BnO

(51-91%) 99% ee

+H

O

O

N N

O

t-Bu Bu-tCu2 OTf–

2+

4 (10 mol%)

1.


c01_tex 4/18/06 12:31 PM

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


1.

16 (10 mol%)

+

Cl ClSbF6

–

(Eq. 38)

O

EtO

SPh

OTMS

O

EtOSPh

OOH

(90%) 98% ee

+H

O


O

N N

O

Bn BnSn

2 OTf–

2+

7 (10 mol%)

1.


c01_tex 4/18/06 12:31 PM

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.


+

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


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

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°


c01_tex 4/18/06 12:31 PM

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+


c01_tex 4/18/06 12:31 PM

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°

+


c01_tex 4/18/06 12:31 PM

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


DMSO, rt

(97%) 96% ee

O+


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

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


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%)


c01_tex 4/18/06 12:31 PM

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


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°


c01_tex 4/18/06 12:31 PM

(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%)


(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°


c01_tex 4/18/06 12:31 PM

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%)


Ph H

O+


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

(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


c01_tex 4/18/06 12:31 PM

(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


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


c01_tex 4/18/06 12:31 PM

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


(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–


1.

8 (10 mol%)

2+


c01_tex 4/18/06 12:31 PM

(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–


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


1.

16 (10 mol%)

+

Cl ClSbF6

–


c01_tex 4/18/06 12:31 PM

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+


c01_tex 4/18/06 12:31 PM

(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–


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


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

(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


c01_tex 4/18/06 12:31 PM

(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


c01_tex 4/18/06 12:31 PM

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%)


c01_tex 4/18/06 12:31 PM

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°


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

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

+


c01_tex 4/18/06 12:31 PM

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%)


c01_tex 4/18/06 12:31 PM

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


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

+


c01_tex 4/18/06 12:31 PM

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)


DMF, 4°

O

H

(80%) dr = 4:1, 99% ee

H

O


c01_tex 4/18/06 12:31 PM

(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


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

(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–


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

*


c01_tex 4/18/06 12:31 PM

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–


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°


c01_tex 4/18/06 12:31 PM

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 =


c01_tex 4/18/06 12:31 PM

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%)


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

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%


c01_tex 4/18/06 12:31 PM

(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


c01_tex 4/18/06 12:31 PM

(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


c01_tex 4/18/06 12:31 PM

(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


c01_tex 4/18/06 12:31 PM

(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


c01_tex 4/18/06 12:31 PM

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%)


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

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%)


c01_tex 4/18/06 12:31 PM

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°


c01_tex 4/18/06 12:31 PM

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.


c01_tex 4/18/06 12:31 PM

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°


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

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


BnO+

H

O

O

N N

O

t-Bu Bu-tCu 2 OTf–1.

(100%) 96% ee

4 (10 mol%) OH

2+


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

(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


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


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

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%)


c01_tex 4/18/06 12:31 PM

(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


DMSO, rt, 60 hC6H11-cH

O

(62%) dr = 20:1, >99% ee

+


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

(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%)


c01_tex 4/18/06 12:31 PM

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


c01_tex 4/18/06 12:31 PM

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(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

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

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

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

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

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

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

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

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

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

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

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

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

(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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[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

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

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

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

[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

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

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

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

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

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

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

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

[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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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(44)

I:

II =

0.8

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1% e

e I,

94%

ee

IIf

III

+

206

c01_tex 4/18/06 12:32 PM

O

O–

n

C14

-15

n

Ph

OH

O

Ph

n 1 2

[Rh(

CO

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l]2

(2.5

mol

%),

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INA

P (7

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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

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(88)

% e

e

77g

88g

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O

Ph

a The

rea

ctio

n w

as c

arri

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ut a

t –78

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yna/

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ers

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ajor

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er (

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iast

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y in

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ated

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y rh

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yzed

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gate

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ition

of

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) 2 to

the

corr

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g en

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CO

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%),

(R

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5 eq

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,

dio

xane

, 95°

n

207

c01_tex 4/18/06 12:32 PM

REFERENCES

1Heathcock, C. H. Science 1981, 214, 395. 2Mukaiyama, T. Org. React. 1982, 28, 203.3Evans, D. A. Aldrichimica Acta 1982, 15, 23.4Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1. 5Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1984;Vol. 3, p. 111.

6Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24, 1.7Heathcock, C. H. Aldrichimica Acta 1990, 23, 99. 8Gennari, C. In Comprehensive Organic Synthesis: Additions to C-X �-Bonds; Trost, B. M., Fleming,I., Heathcock, C. H., Eds.; Pergamon Press: New York, 1991, p. 629.

9Yamamoto, H.; Maruoka, K. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993,p. 413.

10Ito, Y.; Sawamura, M. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993,p. 367.

11Braun, M.; Sacha, H. J. Prakt. Chem. 1993, 335, 653.12Franklin, A. S.; Paterson, I. Contemporary Organic Synthesis 1994, 317.13Noyori, R. Asymmetric Catalysis in Organic Synthesis, Wiley: New York, 1994. 14Santelli, M.; Pons, J. M. Lewis Acids and Selectivity in Organic Synthesis; CRC: Boca Raton, 1995.15Groeger, H.; Vogl, E. M.; Shibasaki, M. Chem. Eur. J. 1998, 4, 1137. 16Bach, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 417.17Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; Wiley: New York, 1989. 18Crimmins, M. T.; King, B. W. J. Am. Chem. Soc. 1998, 120, 9084.19Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653.20Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108, 6757. 21Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1987, 109, 7151. 22Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem., Int. Ed. Engl. 2002, 41, 1062. 23Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61, 4192. 24Abiko, A. Acc. Chem. Res. 2004, 37, 387. 25Carreira, E. M. In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A., Yamamoto, H.,

Eds.; Springer: Stuttgart, 1999; Vol. 3, p. 997. 26Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed. Engl. 2000, 39, 1352. 27Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357. 28Mahrwald, R. Chem. Rev. 1999, 99, 1095.29Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041. 30Kobayashi, S.; Onozawa, S.; Mukaiyama, T. Chem. Lett. 1992, 2419.31Kobayashi, S.; Hayashi, T.; Iwamoto, S.; Furuta, T.; Matsumura, M. Synlett 1996, 672. 32Rychnovsky, S. D.; Khire, U. R.; Yang, G. J. Am. Chem. Soc. 1997, 119, 2058. 33Li, K. W.; Wu, J.; Xing, W. N.; Simon, J. A. J. Am. Chem. Soc. 1996, 118, 7237.34Kobayashi, S.; Matsumura, M.; Furuta, T.; Hayashi, T.; Iwamoto, S. Synlett 1997, 301.35Kim, Y.; Singer, R. A.; Carreira, E. M. Angew. Chem., Int. Ed. Engl. 1998, 37, 1261.36Denmark, S. E.; Su, X. P.; Winter, S. B. D.; Wong, K. T.; Stavenger, R. A. 213th ACS National Meet-

ing, San Francisco, Organic Division 607, 1997.37Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples,

R. J. J. Am. Chem. Soc. 1999, 121, 669.38Evans, D. A.; Kozlowski, M. C.; Tedrow, J. S. Tetrahedron Lett. 1996, 37, 7481.39Evans, D. A.; MacMillan, D. W. C.; Campos, K. R. J. Am. Chem. Soc. 1997, 119, 10859.40Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 10521.41Henderson, I.; Sharpless, K. B.; Wong, C. H. J. Am. Chem. Soc. 1994, 116, 558. 42Wong, C. H.; Halcomb, R. L.; Ichikawa, Y.; Kajimoto, T. Angew. Chem., Int. Ed. Engl. 1995, 34, 412.43Gijsen, H. J. M.; Qiao, L.; Fitz, W.; Wong, C. H. Chem. Rev. 1996, 96, 443.44Gijsen, H. J. M.; Wong, C. H. J. Am. Chem. Soc. 1995, 117, 7585.45Reymond, J. L.; Chen, Y. W. Tetrahedron Lett. 1995, 36, 2575.


c01_tex 4/18/06 12:32 PM

46Wagner, J.; Lerner, R. A.; Barbas, C. F., III Science 1995, 270, 1797.47Zhing, G.; Hoffman, T.; Lerner, R. A.; Danishefsky, S.; Barbas, C. F., III J. Am. Chem. Soc. 1997, 119,

8131. 48Barbas, C. F., III; Heine, A.; Zhing, G.; Hoffman, T.; Gramatikova, S.; Björnestedt, R.; List, B.;

Anderson, J.; Stura, E. A.; Wilson, E. A.; Lerner, R. A. Science 1997, 278 , 2085.49Reetz, M. T.; Rentzsch, M.; Pletsch, A. Chimia 2002, 56, 721.50Tielmann, P.; Boese, M.; Luft, M.; Reetz, M. T. Chem. Eur. J. 2003, 9, 3882. 51Taylor, S. J.; Morken J. P. Science 1998, 280, 267. 52Sigman, M. S.: Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.53Hoveyda, A. H. Chem. Biol. 1999, 6, 305. 54Stauffer, S. R.; Beare, N. A.; Stambuli, J. P.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4641.55Hayashi, T.; Sawamura, M.; Ito, Y. Tetrahedron 1992, 48, 1999.56Ito, Y.; Sawamura, M.; Hamashima, H.; Emura, T.; Hayashi, T. Tetrahedron Lett. 1989, 30, 4681.57Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405.58Ito, Y.; Sawamura, M.; Hayashi, T. Tetrahedron Lett. 1987, 28, 6215.59Ito, Y.; Sawamura, M.; Hayashi, T. Tetrahedron Lett. 1988, 29, 239.60Ito, Y.; Sawamura, M.; Kobayashi, M.; Hayashi, T. Tetrahedron Lett. 1988, 29, 6321.61Ito, Y.; Sawamura, M.; Shirakawa, E.; Hayashizaki, K.; Hayashi, T. Tetrahedron Lett. 1988, 29, 235.62Ito, Y.; Sawamura, M.; Shirakawa, E.; Hayashizaki, K.; Hayashi, T. Tetrahedron 1988, 44, 5253.63Soloshonok, V. A.; Hayashi, T. Tetrahedron: Asymmetry 1994, 5, 1091.64Soloshonok, V. A.; Hayashi, T. Tetrahedron Lett. 1994, 35, 2713.65Yoshikawa, N.; Suzuki, T.; Shibasaki, M. J. Org. Chem. 2002, 67, 2556.66List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573.67Mikami, K.; Takasaki, T.; Matsukawa, S.; Maruta, M. Synlett 1995, 1057.68Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date, T.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1996,

35, 104.69Krüger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837.70Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 1997, 119,

7893.71Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F. J. Am. Chem. Soc. 2001, 123, 5260.72Furuta, K.; Maruyama, T.; Yamamoto, H. J. Am. Chem. Soc. 1991, 113, 1041.73Furuta, K.; Maruyama, T.; Yamamoto, H. Synlett 1991, 439.74Evans, D. A.; Murry, J. A.; Kozlowski, M. C. J. Am. Chem. Soc. 1996, 118, 5814.75Denmark, S. E.; Ghosh, S. K. Angew. Chem., Int. Ed. Engl. 2001, 40, 4759.76Suga, H.; Ikai, K.; Ibata, T. J. Org. Chem. 1999, 64, 7040.77Mikami, K.; Matsukawa, S. J. Am. Chem. Soc. 1993, 115, 7039.78Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503. 79Krueger, C. R.; Rochow, E. G. J. Organomet. Chem. 1964, 1, 476. 80Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1973, 38, 3239.81Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615.82Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496. 83Kumagai, N.; Matsunaga, S.; Yoshikawa, N.; Ohshima, T.; Shibasaki, M. Org. Lett. 2001, 3, 1539.84Trost, B. M.; Silcoff, E. R.; Ito, H. Org. Lett. 2001, 3, 2497.85List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395.86Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798.87Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. Engl. 2001, 40, 3726.88Roush, W. R. J. Org. Chem. 1991, 56, 4151.89Gustin, D. J.; VanNieuwenhze, M. S.; Roush, W. R. Tetrahedron Lett. 1995, 36, 3443.90Gustin, D. J.; VanNieuwenhze, M. S.; Roush, W. R. Tetrahedron Lett. 1995, 36, 3447. 91Anh, N. T.; Eisenstein, O. Nouv. J. Chim. 1977, 1, 61. 92Heathcock, C. H.; Hug, K. T.; Flippin, L. A. Tetrahedron Lett. 1984, 25, 5973. 93Heathcock, C. H.; Davidsen, S. K.; Hug, K. T.; Flippin, L. A. J. Org. Chem. 1986, 51, 3027. 94Yanagisawa, A.; Matsumoto, Y.; Nakashima, H.; Asakawa, K.; Yamamoto, H. J. Am. Chem. Soc. 1997,

119, 9319.


c01_tex 4/18/06 12:32 PM

95Nakamura, E.; Shimizu, M.; Kuwajima, I.; Sakata, J.; Yokoyama, K.; Noyori, R. J. Org. Chem. 1983,48, 932.

96Ewing, W. R.; Harris, B. D.; Li, W. R.; Joullie, M. M. Tetrahedron Lett. 1989, 30, 3757. 97Carreira, E. M.; Singer, R. A. Tetrahedron Lett. 1994, 35, 4323.98Denmark, S. E.; Chen, C.-T. Tetrahedron Lett. 1994, 4327.99Hollis, T. K.; Bosnich, B. J. Am. Chem. Soc. 1995, 117, 4570.

100Ellis, W. W.; Bosnich, B. In Organic Synthesis via Organometallics OSM 5: Proceedings of the FifthSymposium in Heidelberg; Helmchen, G., Dibo, J., Flubacher, D., Wiese, B., Eds.; Vieweg Verlag:Braunschweig/Wiesbaden, 1996; p. 209.

101Ellis, W. W.; Bosnich, B. Chem. Commun. 1998, 193.102Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233.103Ishihara, K.; Hiraiwa, Y.; Yamamoto, H. Chem. Commun. 2002, 1564.104Ishihara, K.; Hiraiwa, Y.; Yamamoto, H. Synlett 2001, 1851.105Myers, A. G.; Widdowson, K. L. J. Am. Chem. Soc. 1990, 112, 9672.106Denmark, S. E.; Griedel, B. D.; Coe, D. M.; Schnute, M. E. J. Am. Chem. Soc. 1994, 116, 7026.107Myers, A. G.; Kephart, S. E.; Chen, H. J. Am. Chem. Soc. 1992, 114, 7922.108Myers, A. G.; Widdowson, K. L.; Kukkola, P. J. J. Am. Chem. Soc. 1992, 114, 2765.109Denmark, S. E.; Lee, W. J. Org. Chem. 1994, 59, 707.110Gung, B. W.; Zhu, Z. H.; Fouch, R. A. J. Org. Chem. 1995, 60, 2860.111Burkhardt, E. R.; Bergman, R. G.; Heathcock, C. H. Organometallics 1990, 9, 30. 112Burkhardt, E. R.; Doney, J. J.; Bergman, R. G.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 2022.113Burkhardt, E. R.; Doney, J. J.; Slough, G. A.; Stack, J. M.; Heathcock, C. H.; Bergman, R. G. Pure

Appl. Chem. 1988, 60, 1.114Slough, G. A.; Bergman, R. G.; Heathcock, C. H. J. Am. Chem. Soc. 1989, 111, 938.115Fleming, I. Chemtracts 1991, 4, 21. 116Keck, G. E.; Savin, K. A.; Cressman, E. N. K.; Abbott, D. E. J. Org. Chem. 1994, 59, 7889.117Keck, G. E.; Dougherty, S. M.; Savin, K. A. J. Am. Chem. Soc. 1995, 117, 6210.118Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Angew. Chem., Int. Ed. Engl. 1990, 29, 256. 119Keck, G.; Castellino, S. J. Am. Chem. Soc. 1986, 108, 3847. 120Denmark, S. E.; Henke, B. R.; Weber, E. J. Am. Chem. Soc. 1987, 109, 2512.121LePage, T. J.; Wiberg, K. B. J. Am. Chem. Soc. 1988, 110, 6642.122Corcoran, R. C.; Ma, J. J. Am. Chem. Soc. 1991, 11, 8973.123Delbecq, F.; Sautet, P. J. Am. Chem. Soc. 1992, 114, 2446.124Denmark, S. E.; Henke, B. R. J. Am. Chem. Soc. 1991, 113, 2177.125Corey, E. J.; Loh, T. P.; Roper, T. D.; Azimioara, M. D.; Noe, M. C. J. Am. Chem. Soc. 1992, 114, 8290.126Hawkins, J. M.; Loren, S.; Nambu, M. J. Am. Chem. Soc. 1994, 116, 1657.127Power, M. B.; Bott, S. G.; Atwood, J. L.; Barron, A. R. J. Am. Chem. Soc. 1990, 112, 3446.128Corey, E. J.; Rohde, J. J.; Fischer, A.; Azimioara, M. D. Tetrahedron Lett. 1997, 38, 33. 129Corey, E. J.; Rohde, J. J. Tetrahedron Lett. 1997, 38, 37.130Corey, E. J.; Barnes-Seeman, D.; Lee, T. W. Tetrahedron Lett. 1997, 38, 1699.131Corey, E. J.; Barnes-Seeman, D.; Lee, T. W.; Goodman, S. N. Tetrahedron Lett. 1997, 38, 6513.132Corey, E. J.; Barnes-Seeman, D.; Lee, T. W. Tetrahedron Lett. 1997, 38, 4351.133Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.134Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432. 135Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16.136Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475.137Mikami, K.; Matsukawa, S. J. Am. Chem. Soc. 1994, 116, 4077.138Mikami, K.; Matsukawa, S.; Nagashima, M.; Funabashi, H.; Morishima, H. Tetrahedron Lett. 1997, 38,

579.139Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 12360.140Parmee, E. R.; Hong, Y. P.; Tempkin, O.; Masamune, S. Tetrahedron Lett. 1992, 33, 1729.141Kobayashi, S.; Ohtsubo, A.; Mukaiyama, T. Chem. Lett. 1991, 831.142Eliel, E. L.; Frye, S. V. J. Am. Chem. Soc. 1992, 114, 1778. 143Fujimura, O. J. Am. Chem. Soc. 1998, 120, 10032.


c01_tex 4/18/06 12:32 PM

144Sodeoka, M.; Ohrai, K.; Shibasaki, M. J. Org. Chem. 1995, 60, 2648.145Sodeoka, M.; Tokunoh, R.; Miyazaki, F.; Hagiwara, E.; Shibasaki, M. Synlett 1997, 463.146Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1987, 463. 147Mukaiyama, T.; Kobayashi, S.; Tamura, M.; Sagawa, Y. Chem. Lett. 1987, 491.148Kobayashi, S.; Tamura, M.; Mukaiyama, T. Chem. Lett. 1988, 91.149Mukaiyama, T.; Shimpuku, T.; Takashima, T.; Kobayashi, S. Chem. Lett. 1989, 145.150Kobayashi, S.; Hachiya, I. J. Org. Chem. 1992, 57, 1324.151Mukaiyama, T.; Shiina, I.; Uchiro, H.; Kobayashi, S. Bull. Chem. Soc. Jpn. 1994, 67, 1708.152Akiyama, T.; Ishikawa, K.; Ozaki, S. Synlett 1994, 275.153Kobayashi, S.; Furuya, M.; Ohtsubo, A.; Mukaiyama, T. Tetrahedron: Asymmetry 1991, 2, 635.154Kobayashi, S.; Horibe, M. Synlett 1994, 147.155Kobayashi, S.; Horibe, M.; Hachiya, I. Tetrahedron Lett. 1995, 36, 3173.156Kobayashi, S.; Horibe, M.; Matsumura, M. Synlett 1995, 675.157Kobayashi, S.; Horibe, M.; Saito, Y. Tetrahedron 1994, 50, 9629.158Kobayashi, S.; Kawasuji, T. Tetrahedron Lett. 1994, 35, 3329.159Kobayashi, S.; Uchiro, H.; Fujishita, Y.; Shiina, I.; Mukaiyama, T. J. Am. Chem. Soc. 1991, 113, 4247.160Kobayashi, S.; Uchiro, H.; Shiina, I.; Mukaiyama, T. Tetrahedron 1993, 49, 1761.161Mukaiyama, T.; Anan, H.; Shiina, I.; Kobayashi, S. Bull. Soc. Chim. Fr. 1993, 130, 388.162Mukaiyama, T.; Asanuma, H.; Hachiya, I.; Harada, T.; Kobayashi, S. Chem. Lett. 1991, 1209.163Kobayashi, S.; Mukaiyama, T. Chem. Lett. 1989, 297.164Mukaiyama, T.; Shiina, I.; Kobayashi, S. Chem. Lett. 1991, 1901.165Mukaiyama, T.; Uchiro, H.; Kobayashi, S. Chem. Lett. 1990, 1147.166Fukuyama, T.; Lin, S. C.; Li, L. J. Am. Chem. Soc. 1990, 102, 7050.167Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497.168Matsukawa, S.; Mikami, K. Tetrahedron: Asymmetry 1995, 6, 2571.169Mikami, K.; Matsukawa, S.; Kayaki, Y.; Ikariya, T. Tetrahedron Lett. 2000, 41, 1931.170Keck, G. E.; Knutson, C. E.; Wiles, S. A. Org. Lett. 2001, 3, 707.171Keck, G. E.; Krishnamurthy, D. J. Am. Chem. Soc. 1995, 117, 2363.172Keck, G. E.; Li, X. Y.; Knutson, C. E. Org. Lett. 1999, 1, 411.173Keck, G. E.; Lundquist, G. D. J. Org. Chem. 1999, 64, 4482.174Keck, G. E.; Park, M.; Krishnamurthy, D. J. Org. Chem. 1993, 58, 3787.175Zimmer, R.; Collas, M.; Roth, M.; Reissig, H. U. Liebigs Ann. Chem. 1992, 709.176Zimmer, R.; Peritz, A.; Czerwonka, R.; Schefzig, L.; Reissig, H. U. Eur. J. Org. Chem. 2002, 3419.177Sinz, C. J.; Rychnovsky, S. D. Tetrahedron 2002, 58, 6561.178Carreira, E. M.; Lee, W.; Singer, R. A. J. Am. Chem. Soc. 1995, 117, 3649.179Ishitani, H.; Yamashita, Y.; Shimizu, H.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 5403.180Yamashita, Y.; Ishitani, H.; Shimizu, H.; Kobayashi, S. J. Am. Chem. Soc. 2002, 124, 3292.181Corey, E. J.; Cywin, C. L.; Roper, T. D. Tetrahedron Lett. 1992, 33, 6907.182Ishihara, K.; Maruyama, T.; Mouri, M.; Gao, Q. Z.; Furuta, K.; Yamamoto, H. Bull. Chem. Soc. Jpn.

1993, 66, 3483.183Itsuno, S.; Komura, K. Tetrahedron 2002, 58, 8237.184Kiyooka, S.; Kaneko, Y.; Kume, K. Tetrahedron Lett. 1992, 33, 4927.185Ishihara, K.; Kondo, S.; Yamamoto, H. Synlett 1999, 1283.186Mukaiyama, T.; Takashima, T.; Kusaka, H.; Shimpuku, T. Chem. Lett. 1990, 1777.187Carreira, E. M.; Singer, R. A. Drug Discov. Today 1996, 1, 145.188Singer, R. A.; Shepard, M. S.; Carreira, E. M. Tetrahedron 1998, 54, 7025.189Smith, A. B., III; Verhoest, P. R.; Minbiole, K. P.; Lim, J. J. Org. Lett. 1999, 1, 909.190Krüger, J.; Carreira, E. M. Tetrahedron Lett. 1998, 39, 7013.191Singer, R. A.; Carreira, E. M. Tetrahedron Lett. 1997, 38, 927.192Kobayashi, S.; Nagayama, S.; Busujima, T. Chem. Lett. 1999, 71.193Kobayashi, S.; Nagayama, S.; Busujima, T. Tetrahedron 1999, 55, 8739.194Manabe, K.; Mori, Y.; Nagayama, S.; Odashima, K.; Kobayashi, S. Inorg. Chim. Acta 1999, 296, 158.195Orlandi, S.; Mandoli, A.; Pini, D.; Salvadori, P. Angew. Chem., Int. Ed. Engl. 2001, 40, 2519.196Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033.


c01_tex 4/18/06 12:32 PM

197Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W. J. Am. Chem. Soc. 1999, 121, 686.198Evans, D. A.; Masse, C. E.; Wu, J. Org. Lett. 2002, 4, 3375.199Evans, D. A.; Wu, J.; Masse, C. E.; MacMillan, D. W. C. Org. Lett. 2002, 4, 3379.200Nishiyama, H.; Yamaguchi, S.; Park, S. B.; Itoh, K. Tetrahedron: Asymmetry 1993, 4, 143. 201Jørgensen, K. A.; Johannsen, M.; Yao, S. L.; Audrain, H.; Thorhauge, J. Acc. Chem. Res. 1999, 32, 605.202Reetz, M. T.; Raguse, B.; Marth, C. F.; Huegel, H. M.; Bach, T.; Fox, D. N. A. Tetrahedron 1992, 48,

5731. 203Evans, D. A.; Fitch, D. M. Angew. Chem., Int. Ed. Engl. 2000, 39, 2536. 204Evans, D. A.; Trotter, B. W.; Côté, B.; Coleman, P. J. Angew. Chem., Int. Ed. Engl. 1997, 36, 2741. 205Evans, D. A.; Trotter, B. W.; Côté, B.; Coleman, P. J.; Dias, L. C.; Tyler, A. N. Angew. Chem., Int. Ed.

Engl. 1997, 36, 2744. 206Denmark, S. E.; Winter, S. B. D.; Su, X. P.; Wong, K. T. J. Am. Chem. Soc. 1996, 118, 7404.207Denmark, S. E.; Wong, K. T.; Stavenger, R. A. J. Am. Chem. Soc. 1997, 119, 2333.208Denmark, S. E.; Wynn, T.; Beutner, G. L. J. Am. Chem. Soc. 2002, 124, 13405.209Denmark, S. E.; Fujimori, S. Org. Lett. 2002, 4, 3473.210Denmark, S. E.; Fujimori, S. Org. Lett. 2002, 4, 3477.211Denmark, S. E.; Pham, S. M. Org. Lett. 2001, 3, 2201.212Denmark, S. E.; Stavenger, R. A. J. Org. Chem. 1998, 63, 9524.213Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001, 123, 3367.214Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1997, 36,

1871.215Yoshikawa, N.; Shibasaki, M. Tetrahedron 2001, 57, 2569.216Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168.217Yamada, Y. M. A.; Shibasaki, M. Tetrahedron Lett. 1998, 39, 5561.218Shibasaki, M.; Kanai, M. Chem. Pharm. Bull. 2001, 49, 511. 219Suzuki, T.; Yamagiwa, N.; Matsuo, Y.; Sakamoto, S.; Yamaguchi, K.; Shibasaki, M.; Noyori, R. Tetra-

hedron Lett. 2001, 42, 4669.220Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003.221Izquierdo, I.; Plaza, M. T.; Robles, R.; Mota, A. J.; Franco, F. Tetrahedron: Asymmetry 2001, 12, 2749.222Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron 2002, 58, 8167.223Cordova, A.; Notz, W.; Barbas, C. F., III J. Org. Chem. 2002, 67, 301.224Kobayashi, S.; Hayashi, T.; Kawasuji, T. Tetrahedron Lett. 1994, 35, 9573.225Kobayashi, S.; Kawasuji, T. Synlett 1993, 911.226Kobayashi, S.; Kawasuji, T.; Mori, N. Chem. Lett. 1994, 217.227Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.; Kim, H. S.; Wataya, Y. J. Org. Chem. 1999, 64, 6833.228Mukaiyama, T.; Furuya, M.; Ohtsubo, A.; Kobayashi, S. Chem. Lett. 1991, 989.229Mukaiyama, T.; Kobayashi, S.; Uchiro, H.; Shiina, I. Chem. Lett. 1990, 129.230Mukaiyama, T.; Shiina, I.; Izumi, J.; Kobayashi, S. Heterocycles 1993, 35, 719.231Wakabayashi, T.; Mori, K.; Kobayashi, S. J. Am. Chem. Soc. 2001, 123, 1372.232The nomenclature adopted by Heathcock for enolate geometrical isomers is used throughout, see: ref. 5.233Ishii, A.; Kojima, J.; Mikami, K. Org. Lett. 1999, 1, 2013.234Kobayashi, S.; Mori, K.; Wakabayashi, T.; Yasuda, S.; Hanada, K. J. Org. Chem. 2001, 66, 5580.235Takao, K.; Tsujita, T.; Hara, M.; Tadano, K. J. Org. Chem. 2002, 67, 6690.236Iseki, K.; Kuroki, Y.; Asada, D.; Takahashi, M.; Kishimoto, S.; Kobayashi, Y. Tetrahedron 1997, 53,

10271.237Kiyooka, S.; Yamaguchi, T.; Maeda, H.; Kira, H.; Hena, M. A.; Horiike, M. Tetrahedron Lett. 1997, 38,

3553.238Parmee, E. R.; Tempkin, O.; Masamune, S.; Abiko, A. J. Am. Chem. Soc. 1991, 113, 9365.239Bolm, C.; Kasyan, A.; Heider, P.; Saladin, S.; Drauz, K.; Gunther, K.; Wagner, C. Org. Lett. 2002, 4,

2265.240Li, G. G.; Wei, H. X.; Phelps, B. S.; Purkiss, D. W.; Kim, S. H. Org. Lett. 2001, 3, 823.241Evans, D. A.; Janey, J. M.; Magomedov, N.; Tedrow, J. S. Angew. Chem., Int. Ed. Engl. 2001, 40, 1884.242Denmark, S. E.; Fujimori, S. Synlett 2001, 1024.243Nagayama, S.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 11531.


c01_tex 4/18/06 12:32 PM

244Yanagisawa, A.; Matsumoto, Y.; Asakawa, K.; Yamamoto, H. Tetrahedron 2002, 58, 8331.245Yanagisawa, A.; Nakatsuka, Y.; Asakawa, K.; Kageyama, H.; Yamamoto, H. Synlett 2001, 69.246Kobayashi, S.; Hamada, T.; Nagayama, S.; Manabe, K. Org. Lett. 2001, 3, 165.247Yanagisawa, A.; Matsumoto, Y.; Asakawa, K.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 892.248Ooi, T.; Doda, K.; Maruoka, K. Org. Lett. 2001, 3, 1273.249Sawamura, M.; Nakayama, Y.; Kato, T.; Ito, Y. J. Org. Chem. 1995, 60, 1727.250Kuwano, R.; Miyazaki, H.; Ito, Y. J. Organomet. Chem. 2000, 603, 18.251Ito, Y.; Higuchi, N.; Murakami, M. Heterocycles 2000, 52, 91.252Togni, A.; Pastor, S. D. Helv. Chim. Acta 1989, 72, 1038.253Togni, A.; Pastor, S. D. J. Org. Chem. 1990, 55, 1649.254Longmire, J. M.; Zhang, X. M.; Shang, M. Y. Organometallics 1998, 17, 4374.255Mahrwald, R.; Ziemer, B. Tetrahedron Lett. 2002, 43, 4459.256Ooi, T.; Taniguchi, M.; Kameda, M.; Maruoka, K. Angew. Chem., Int. Ed. Engl. 2002, 41, 4542.257List, B. Tetrahedron 2002, 58, 5573.258Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386.259Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483. 260Loh, T. P.; Feng, L. C.; Yang, H. Y.; Yang, J. Y. Tetrahedron Lett. 2002, 43, 8741.261Kotrusz, P.; Kmentova, I.; Gotov, B.; Toma, S.; Solcaniova, E. Chem. Commun. 2002, 2510.262Benaglia, M.; Celentano, G.; Cozzi, F. Adv. Synth. Catal. 2001, 343, 171.263Benaglia, M.; Cinquini, M.; Cozzi, F.; Puglisi, A.; Celentano, G. Adv. Synth. Cat. 2002, 344, 533.264Bogevig, A.; Kumaragurubaran, N.; Jørgensen, K. A. Chem. Commun. 2002, 620.265Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem. Commun. 2000, 2211.266Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Chem. Pharm. Bull. 1994, 42, 839.267Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Heterocycles 1995, 41, 1435.268Brennan, C. J.; Campagne, J. M. Tetrahedron Lett. 2001, 42, 5195.269Snider, B. B.; Song, F. B. Org. Lett. 2001, 3, 1817.270Fettes, A.; Carreira, E. M. Angew. Chem., Int. Ed. Engl. 2002, 41, 4098.271Bluet, G.; Bazan-Tejeda, B.; Campagne, J. M. Org. Lett. 2001, 3, 3807.272Bluet, G.; Campagne, J. M. Tetrahedron Lett. 1999, 40, 5507.273Bluet, G.; Campagne, J. M. Synlett 2000, 221.274Evans, D. A.; Cee, V. J.; Smith, T. E.; Fitch, D. M.; Cho, P. S. Angew. Chem., Int. Ed. Engl. 2000, 39,

2533. 275Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet, J. A.; Lautens, M. J. Am. Chem.

Soc. 1999, 121, 7540.276Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.; Charette, A. B.; Lautens, M. J. Angew. Chem.,

Int. Ed. Engl. 1998, 37, 2354.277Szlosek, M.; Franck, X.; Figadere, B.; Cave, A. J. Org. Chem. 1998, 63, 5169.278Szlosek, M.; Jullian, J. C.; Hocquemiller, R.; Figadere, B. Heterocycles 2000, 52, 1005.279Franck, X.; Araujo, M. E. V.; Jullian, J. C.; Hocquemiller, R.; Figadere, B. Tetrahedron Lett. 2001, 42,

2801.280Szlosek, M.; Figadere, B. Angew. Chem., Int. Ed. Engl. 2000, 39, 1799.281Szlosek, M.; Peyrat, J. F.; Chaboche, C.; Franck, X.; Hocquemiller, R.; Figadere, B. New J. Chem.

2000, 24, 337.282Mascarenhas, C. M.; Miller, S. P.; White, P. S.; Morken, J. P. Angew. Chem., Int. Ed. Engl. 2001, 40,

601.283Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc. 2001, 123, 7945.284Audrain, H.; Jørgensen, K. A. J. Am. Chem. Soc. 2000, 122, 11543.285Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am. Chem. Soc. 2000, 122, 4528.286Zhao, C. X.; Duffey, M. O.; Taylor, S. J.; Morken, J. P. Org. Lett. 2001, 3, 1829.287Duffey, M. O.; LeTiran, A.; Morken, J. P. J. Am. Chem. Soc. 2003, 125, 1458.288Cauble, D. F.; Gipson, J. D.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 1110.289Yamada, K.; Arai, T.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1998, 63, 3666.290Evans, D. A.; Côté, B.; Coleman, P. J.; Connell, B. T. J. Am. Chem. Soc. 2003, 125, 10893.291Gosh, A. K.; Kim, J.-H. Org. Lett. 2003, 5, 1063.


c01_tex 4/18/06 12:32 PM

292Paterson, I.; Wallace, D. J.; Velazquez, S. M. Tetrahedron Lett. 1994, 35, 9083. 293Yeung, K.-S.; Paterson, I. Angew. Chem., Int. Ed. Engl. 2002, 41, 4632.294Paterson, I.; Collett, L. A. Tetrahedron Lett. 2001, 42, 1187.295Galobardes, M.; Gascón, M.; Mena, M.; Romea, P.; Urpí, F.; Vilarrasa, J. Org. Lett. 2000, 2, 2599.296Paterson, I.; Donghi, M.; Gerlach, K. Angew. Chem., Int. Ed. Engl. 2000, 39, 3315.297Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett. 1996, 37, 8585.298Paterson, I.; Oballa, R. M.; Norcross, R. D. Tetrahedron Lett. 1996, 37, 8581.299Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.; McClure, C. K.; Norcross, R. D. Tetra-

hedron 1990, 46, 4663.300Goodman, J. M.; Kahn, S. D.; Paterson, I. J. Org. Chem. 1990, 55, 3295.301Li, Y.; Paddon-Row, M. N.; Houk, K. N. J. Org. Chem. 1990, 55, 481.302Hoffmann, R. W.; Ditrich, K.; Froech, S.; Cremer, D. Tetrahedron 1985, 41, 5517.303Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.304Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 83.305Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.; Sheppard, G. S. J. Am. Chem. Soc. 1990, 112,

866. 306Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem. Soc. 1991, 113, 1047. 307Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997, 119, 7883. 308Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56, 5747.309Van Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.; Heathcock, C. H. J. Org. Chem. 1991, 56, 2499.310Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119, 2586.311Ghosh, A. K.; Onishi, M. J. Am. Chem. Soc. 1996, 118, 2527.312Paterson, I.; Goodman, J. M. Tetrahedron Lett. 1989, 30, 997.313Corey, E. J.; Huang, H.-C. Tetrahedron Lett. 1989, 30, 5235.314Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier, I.; Scott, J. P.; Sereinig, N. Org. Lett. 2003, 5, 35.315Evans, D. A.; Siska, S. J.; Cee, V. J. Angew. Chem., Int. Ed. Engl. 2003, 42, 1761. 316Balog, A.; Harris, C.; Savin, K.; Zhang, X.-G.; Chou, X.-G.; Danishefsky, S. J. Angew. Chem., Int. Ed.

Engl. 1998, 37, 2675.317Braun, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24.318Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.; Inoue, T.; Hashimoto, K.; Fujita, E. J. Org. Chem.

1986, 51, 2391.319Wuts, P. G. M.; Putt, R. Synthesis 1989, 951.320Saito, S.; Hatanaka, K.; Kano, T.; Yamamoto, H. Angew. Chem., Int. Ed. Engl. 1998, 37, 3378.321Noyori, R. In Catalytic Asymmetric Synthesis (Second Edition); Ojima, I., Ed.; Wiley-VCH: New York,

2000, pp. 1–110.322Kitamura, M.; Ohkuma, S.; Inoue, N.; Sayo, H.; Kumobayashi, S.; Akutagawa, T.; Otha, H. T.;

Noyori, R. J. Am. Chem. Soc. 1988, 110, 629.323Rychnovsky, S. D.; Griesgraber, G.; Zeller, S.; Skalitzky, D. J. J. Org. Chem. 1991, 56, 5161. 324Hinterding, K.; Jacobsen, E. N. J. Org. Chem. 1999, 64, 2164.325Frater, G. Helv. Chim. Acta 1979, 62, 2825. 326Frater, G. Helv. Chim. Acta 1979, 62, 2829.327Zueger, M.; Welles, T.; Seebach, D. Helv. Chim. Acta 1980, 63, 2005. 328Seebach, D.; Wasmuth, D. Helv. Chim. Acta 1980, 63, 197.329Waltz, K. M.; Gavenonis, J.; Walsh, P. J. Angew. Chem., Int. Ed. Engl. 2002, 41, 3697. 330Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 7920.331Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1982, 22, 555.332Roush, W. R.; VanNieuwenhze, M. S. J. Am. Chem. Soc. 1994, 116, 8536. 333Scherdt, K. A.; Tasaka, A.; Bannister, T. D.; Wendt, M. D.; Roush, W. R. Angew. Chem., Int. Ed. Engl.

1999, 38, 1652. 334Chemler, S. R.; Roush, W. R. Tetrahedron Lett. 1999, 40, 4643.335Chemler, S. R.; Roush, W. R. J. Org. Chem. 1998, 63, 3800.336Roush, W. R.; Grover, P. T. J. Org. Chem. 1995, 60, 3806. 337Chemler, S. R.; Roush, W. R. J. Org. Chem. 2003, 68, 1319. 338Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467.


c01_tex 4/18/06 12:32 PM

339Keck, G. E.; Geraci, L. S. Tetrahedron Lett. 1993, 34, 7827. 340Bode, J. W.; Gauthier, D. R.; Carreira, E. M. Chem. Commun. 2001, 24, 2560. 341Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401. 342Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990, 112, 6348.343Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.; Halterman, R. L. J. Am. Chem. Soc. 1990,

112, 6339. 344Hoppe, D. Angew. Chem., Int. Ed. Engl. 1984, 23, 932. 345Panek, J. S.; Cirillo, P. F. J. Org. Chem. 1993, 58, 999. 346Marshall, J. A.; Bourdeau, M. P. Org. Lett. 2002, 4, 3931. 347Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. J. Am. Chem. Soc. 1993,

115, 7001.348Gauthier, D. R., Jr.; Carreira, E. M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2363.349Bode, J. W.; Gauthier, D. R., Jr.; Carreira, E. M. Chem. Commun. 2001, 2560.350Sarraf, S. T.; Leighton, J. L. Org. Lett. 2000, 2, 403.351Leighton, J. L.; O’Neil, D. N. J. Am. Chem. Soc. 1997, 119, 11118.352Dreher, S. D.; Leighton, J. L. J. Am. Chem. Soc., 2001, 123, 341.353Zacuto, M. J.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 8587.354Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.355Hanson, R. M. Chem. Rev. 1991, 91, 437. 356Rao, A. S.; Paknikar, S. K.; Kirtane, J. G. Tetrahedron 1983, 39, 2323. 357Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 7559.358Smith, A. B., III; Boldi, A. M. J. Am. Chem. Soc. 1997, 119, 6925.359Jung, M. E.; Damico, D. C. J. Am. Chem. Soc. 1993, 115, 12208.360Wang, L.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7568. 361Jung, M. E.; Lee, W. S.; Sun, D. Q. Org. Lett. 1999, 1, 307.362Jung, M. E.; Amico, D. C. D. J. Am. Chem. Soc. 1997, 119, 12150. 363Shibata, T.; Gilheary, D. G.; Blackburn, B. K.; Sharpless, K. B. Tetrahedron Lett. 1990, 31, 3817.364Kwong, H.-L.; Sorato, L.; Ogino, Y.; Chen, H.; Sharpless, K. B. Tetrahedron Lett. 1990, 31, 2999.365Rychnovsky, S. D.; Hoye, R. C. J. Am. Chem. Soc. 1994, 116, 1753. 366Smith, A. B., III; Pitram, S. M.; Boldi, A. M.; Gaunt, M. J.; Sfouggatakis, C.; Moser, W. H. J. Am.

Chem. Soc. 2003, 125, 14435. 367Bode, J. W.; Fraefel, N.; Muri, D.; Carreira, E. M. Angew. Chem., Int. Ed. Engl. 2001, 40, 2082. 368Bode, J. W.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 3611. 369Bode, J. W.; Carreira, E. M. J. Org. Chem. 2001, 66, 6410. 370Zhu, C.; Shen, X.; Nelson, S. G. J. Am. Chem. Soc. 2004, 126, 5352.371El-Sayed, E.; Anand, N. K., Carreira, E. M. Org. Lett. 2001, 3, 3017. 372Sinz, C. J.; Rychnovsky, S. D. Top. Curr. Chem. 2001, 216, 51.373Chiu, P.; Lautens, M. Top. Curr. Chem. 1997, 190, 1. 374Lautens, M., Tomislav, R. J. Am. Chem. Soc. 1997, 119, 11090.375Csaky, A. G.; Vogel, P. Tetrahedron: Asymmetry 2000, 11, 4935.376Hanessian, S.; Wang, W.; Gai, Y.; Olivier, E. J. Am. Chem. Soc. 1997, 119, 10034.377Hanessian, S.; Ma, J.; Wang, W. J. Am. Chem. Soc. 2001, 123, 10200.378Kimura, T.; Vassilev, V. P.; Shen, G.-J.; Wong, C.-H. J. Am. Chem. Soc. 1997, 119, 11734.379Brownbridge, P.; Chan, T. H.; Brook, M. A.; Kang, G. J. Can. J. Chem. 1983, 61, 688. 380Denmark, S. E.; Stavenger, R. A. J. Am. Chem. Soc. 2000, 122, 8837. 381Labadie, S. S.; Stille, J. K. Tetrahedron 1984, 40, 2329. 382Kobayashi, K.; Kawanisi, M.; Hiomi, T.; Kozima, S. Chem. Lett. 1984, 497. 383Pereyre, M.; Bellegarde, B.; Mendelsohn, J.; Valade, J. J. Organomet. Chem. 1968, 11, 97.384Davies, I. W.; Gerena, L.; Lu, N.; Larsen, R. D.; Reider, P. J. J. Org. Chem. 1996, 61, 9629.385Ohkouchi, M.; Masui, D.; Yamaguchi, M.; Yamagishi, T. J. Mol. Catal. A-Chem. 2001, 170, 1.386Imashiro, R.; Kuroda, T. Tetrahedron Lett. 2001, 42, 1313.387Iseki, K.; Kuroki, Y.; Kobayashi, Y. Tetrahedron 1999, 55, 2225.388Ishihara, K.; Kondo, S.; Yamamoto, H. J. Org. Chem. 2000, 65, 9125.389Wu, G. Z.; Tormos, W. J. Org. Chem. 1997, 62, 6412.


c01_tex 4/18/06 12:32 PM

390Evans, D. A.; Hu, E.; Burch, J. D.; Jaeschke, G. J. Am. Chem. Soc. 2002, 124, 5654.391Kobayashi, S.; Furuta, T. Tetrahedron 1998, 54, 10275.392Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Côté, B.; Dias, L. C.; Rajapakse, H. A.; Tyler, A. N. Tetra-

hedron 1999, 55, 8671.393Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew. Chem., Int. Ed. Engl. 2002, 41, 4569.394Roers, R.; Verdine, G. L. Tetrahedron Lett. 2001, 42, 3563.395Carreira, E. M.; Singer, R. A.; Lee, W. S. J. Am. Chem. Soc. 1994, 116, 8837.396Mikami, K.; Matsukawa, S.; Sawa, E.; Harada, A.; Koga, N. Tetrahedron Lett. 1997, 38, 1951.397Mukaiyama, T.; Inubushi, A.; Suda, S.; Hara, R.; Kobayashi, S. Chem. Lett. 1990, 1015.398Mandoli, A.; Pini, D.; Orlandi, S.; Mazzini, F.; Salvadori, P. Tetrahedron: Asymmetry 1998, 9, 1479.399De Rosa, M.; Dell’Aglio, R.; Soriente, A.; Scettri, A. Tetrahedron: Asymmetry 1999, 10, 3659.400De Rosa, M.; Soriente, A.; Scettri, A. Tetrahedron: Asymmetry 2000, 11, 3187.401Anne, S.; Yong, W.; Vandewalle, M. Synlett 1999, 1435.402Soriente, A.; De Rosa, M.; Stanzione, M.; Villano, R.; Scettri, A. Tetrahedron: Asymmetry 2001, 12,

959.403Yanagisawa, A.; Asakawa, K.; Yamamoto, H. Chirality 2000, 12, 421.404Uotsu, K.; Sasai, H.; Shibasaki, M. Tetrahedron: Asymmetry 1995, 6, 71.405Li, H. J.; Tian, H. Y.; Chen, Y. J.; Wang, D.; Li, C. J. Chem. Commun. 2002, 2994.406Manabe, K.; Kobayashi, S. Chem. Eur. J. 2002, 8, 4095.407Chen, C. T.; Chao, S. D.; Yen, K. C.; Chen, C. H.; Chou, I. C.; Hon, S. W. J. Am. Chem. Soc. 1997,

119, 11341.408Denmark, S. E.; Stavenger, R. A.; Wong, K. T. J. Org. Chem. 1998, 63, 918.409Shioiri, T.; Bohsako, A.; Ando, A. Heterocycles 1996, 42, 93.410Ando, A.; Miura, T.; Tatematsu, T.; Shioiri, T. Tetrahedron Lett. 1993, 34, 1507.411Togni, A.; Pastor, S. D. Chirality 1991, 3, 331.412Pastor, S. D.; Kesselring, R.; Togni, A. J. Organomet. Chem. 1992, 429, 415.413Togni, A.; Pastor, S. D.; Rihs, G. Helv. Chim. Acta 1989, 72, 1471.414Toshikawa, N.; Shibasaki, M. Tetrahedron 2002, 58, 8289.415Gorla, F.; Togni, A.; Venanzi, L. M.; Albinati, A.; Lianza, F. Organometallics 1994, 13, 1607.416Trost, B. M.; Yeh, V. S. C. Org. Lett. 2002, 4, 3513.417Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am.

Chem. Soc. 2001, 123, 2466.418Chowdari, N. S.; Ramachary, D. B.; Cordova, A.; Barbas, C. F. Tetrahedron Lett. 2002, 43, 9591.419Cortez, G. S.; Oh, S. H.; Romo, D. Synthesis 2001, 1731.420Yoshida, K.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 2002, 124, 10984.


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aldol tandem reactions

organic reactions

furan52domino reactions

methyl ketone

enoxysilanes of acetoacetate

unsubstituted dienolates

synthesis attest