Catalytic Enantioselective Aldol Addition Reactions

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CHAPTER 1
CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS ERICK M. CARREIRA, ALEC FETTES, AND CHRISTIANE MARTI Laboratory of Organic Chemistry, Swiss Federal Institute of Technology (ETH-Z), HCI H337 ETH-Hnggerberg, CH 8093 Zrich, Switzerland
CONTENTS PAGE 2 6 8 8 11 15 15 15 28 30 30 48 52 58 61 70 71 71 72 73 73 74 75 75 76 77 77 77
INTRODUCTION . . . . . . . . . . . . Background . . . . . . . . . . . . MECHANISM AND STEREOCHEMISTRY . . . . . . . . . General Aspects . . . . . . . . . . . Catalyst Turnover . . . . . . . . . . . SCOPE AND LIMITATIONS . . . . . . . . . . . Acetate, Methyl Ketone, and Unsubstituted Dienolates . . . . . Enoxysilanes and Stannanes . . . . . . . . . Direct Aldol Addition Reactions of Unsubstituted Systems . . . Propionates and Substituted Enolates . . . . . . . . Enoxysilanes and Stannanes . . . . . . . . . Direct Aldol Addition Reactions of Substituted Systems . . . . Enoxysilanes of Acetoacetate and Furan . . . . . . . Domino Reactions Involving Aldol Additions . . . . . . COMPARISON WITH OTHER METHODS . . . . . . . . . EXPERIMENTAL CONDITIONS . . . . . . . . . . EXPERIMENTAL PROCEDURES . . . . . . . . . . Phenyl (2R,3S)-2-(Benzyloxy)-5-(tert-butyldimethylsiloxy)-3-hydroxypentanoate Phenyl (2S,3S)-3-Hydroxy-2-methyl-3-(4-methoxyphenyl)propanoate . . (R)-1-Hydroxy-1-phenyl-3-heptanone . . . . . . . . Methyl (R)-3-Hydroxy-8-phenyloct-4-ynoate . . . . . . (R)-S-tert-Butyl 4-Benzyloxy-3-hydroxybutanethioate . . . . . (S)-4-Hydroxy-4-phenyl-2-butanone . . . . . . . . (R)-4,4-Dimethyl-1-hydroxy-1-phenyl-3-pentanone . . . . . (S)-3-Hydroxy-4-methyl-1-(3-nitrophenyl)-1-pentanone . . . . (R)-3-Cyclohexyl-3-hydroxy-1-phenylpropan-1-one . . . . . (R)-4-Hydroxy-5-methylhexan-2-one . . . . . . . . S-tert-Butyl (3S)-3-Hydroxy-3-methoxycarbonylbutanethioate . . .
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carreira@org.chem.ethz.ch Organic 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. 1
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ORGANIC REACTIONS . . . . . . . . . . . . . . . . . . . 78 79 80 80 81 82 82 84 88 106 117 124 139 150 164 175 189 204 208
(2S,1R)-2-(Hydroxyphenylmethyl)cyclohexanone . . . . . . . (4S,5R)-4-(Methoxycarbonyl)-5-phenyl-2-oxazoline . . . . . . . (2R,3S)-2,3-Dihydroxy-2,3-O-isopropylidene-1-(2-methoxyphenyl)-5-phenyl-1-pentanone (3S,4S)-4-Cyclohexyl-3,4-dihydroxybutan-2-one . . . . . . . . (R)-6-(2-Hydroxy-4-phenylbut-3-enyl)-2,2-dimethyl-[1,3]-dioxin-4-one . . . (2S,3S)-Methyl 4-Benzyloxy-3-hydroxy-2-methylbutanoate . . . . . . TABULAR SURVEY . . . . . . . . . . . . . . Table 1A. Silver-Catalyzed Mukaiyama-Type Aldol Additions . . . . . Table 1B. Boron-Catalyzed Mukaiyama-Type Aldol Additions . . . . . Table 1C. Copper-Catalyzed Mukaiyama-Type Aldol Additions . . . . . Table 1D. Tin-Catalyzed Mukaiyama-Type Aldol Additions . . . . . . Table 1E. Titanium-Catalyzed Mukaiyama-Type Aldol Additions . . . . . Table 1F. Other Metal-Catalyzed Mukaiyama-Type Aldol Additions . . . . Table 1G. Non-Metal-Catalyzed Mukaiyama-Type Aldol Additions . . . . Table 2A. Gold-Catalyzed Aldol Additions of Unmodified Nucleophiles . . . Table 2B. Non-Gold Metal-Catalyzed Aldol Additions of Unmodified Nucleophiles . Table 2C. Non-Metal-Catalyzed Aldol Additions of Unmodified Nucleophiles . . Table 3. Aldol Tandem Reactions . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . .
INTRODUCTION
The aldol addition reaction has become a strategically important, reliable transformation that is widely employed in the asymmetric synthesis of complex molecules (Eq. 1).1 17 It can be counted upon not only to provide access to polyketide fragments with their characteristic 1,3-oxygenation pattern,18 but also to numerous other 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 versatile role of this reaction in the pantheon of organic transformations.12
O R H O R2 XR1 R R2 OH O XR1
(Eq. 1)
R2 = H Acetate Aldol R2 = Me Propionate Aldol
Two general approaches have emerged for the asymmetric aldol reaction: (1) diastereoselective additions, wherein stoichiometric quantities of a covalently bound, chiral controlling element shepherds the stereochemical course of the reaction,3 8,11,14 and, alternatively, (2) enantioselective methods, wherein a chiral catalyst functions as the stereochemical controlling element, preferably in substoichiometric amounts.15,24 29 Given the intensive research activities in this area by numerous groups over the last three decades, diastereoselective methods remain dominant in practice to date with respect to the frequency of use. This is hardly surprising as such methods have enjoyed a long period of intense scrutiny and possess a high degree of predictability and reliability. By comparison, useful catalytic, enantioselective methods are fairly
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CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS
recent arrivals on the scene. Nonetheless, explosive developments in the field are beginning to provide the practitioner with additional useful tools for complex molecule assembly via catalytic asymmetric aldol transformations.30 40 In this respect, it is important to note that enantioselective asymmetric, catalytic aldol addition methods can furnish ketide fragments such as polyacetate or unsubstituted skipped polyol fragments that have not otherwise been conveniently accessible through more traditional diastereoselective approaches. Enantioselective aldol methods use small-molecule (often termed chemical catalysts) as well as macromolecule catalysis (commonly referred to as biological catalysts, such as enzymes or antibodies).41 48 The origins of the differentiation between chemical or biological is likely historical. It is debatable whether such a categorization is at all reasonable, because the only obvious differentiation between catalysts of either group is molecular weight or, correspondingly, size, properties that vary continually. Moreover, the advances in mutagenesis techniques, library synthesis, and high-throughput screening methods49 54 for the generation of non-natural catalysts in both classes serve to further blur the distinction between bio- and abiological catalysis. It is certainly the case that members of either group share many more features 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 established that catalytic enantioselective aldol additions could be carried out with in-situ generation of an enolate (Eq. 2),55 64 and the commonly held distinction that only
Me N
PhCHO + CN
N Fe PPh2 PPh2 1 (1.1 mol%) OMe [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, 0, 20-100 h
O Ph O OMe Ph + O N
O OMe N
I II I:II 94:6, 95% ee
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. Certain classes 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 catalytic methods for asymmetric aldol reactions is best when it is focused. Consequently, the coverage in this chapter is limited to catalytic enantioselective aldol addition methods using small-molecule catalysts, wherein the products in general
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ORGANIC REACTIONS
Li O O Li O La O O O Li
O Ph(CH2)3CHO + OH Ar = 4-MeOC6H4 Ar
2 (S)-LLB (10 mol%) KHMDS (9 mol%), H2O (20 mol%), THF, 40 OH O Ph(CH2)3 + OH O
(Eq. 3)
Ar Ph(CH2)3 Ar OH OH (50%) I II I:II = 81:19, I 98% ee, II 79% ee
OH F F
+
OTMS
1. (R)-BINOL/TiCl2(OPr-i)2, (20 mol%), PhMe, 0
OH O F F
(47%) 96% ee
OEt
SBu-t 2. H+
SBu-t
(Eq. 4)
CO2Et CO2Et Li O O Al O O O O (10 mol%) THF, rt, 72 h; then PhCHO 2. PCC H O Ph CO2Et CO2Et (82%) 89% ee
1.
(Eq. 5)
P(Ar)2 P(Ar)2 3 (2.1 mol%) OTMS Cu(OTf)2 (2 mol%), n-Bu4NPh3SiF (4 mol%), THF, 78 Ar = 4-MeC6H4
RCHO +
TMSO R
O O
(Eq. 6)
(98%) 95% ee R = 2-thienyl
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retain -hydroxycarbonyl functionality. For historical reasons there are three exceptions to such boundary conditions on the topical discussion, namely the aldol addition reactions leading to oxazoline products (Eq. 2),55 64,76 aldehyde ene addition reactions of enol silanes,77 and domino processes (cf Eq. 5).65 In the aldol reactions that 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 considered best classified with processes that rely on the use of chiral auxiliaries or stoichiometric controlling groups or additives.
2+ O 1. O + O OTMS SBu-t O N N 2 OTf Cu Bu-t t-Bu 4 (10 mol%)
OH O SBu-t O (85%) dr = 93:7, 97% ee
(Eq. 7)
CH2Cl2, 78 2. aq. HCl
O t-Bu H +
L-proline (30 mol%)
OH O t-Bu (81%) 99% ee
DMSO, rt
(Eq. 8)
Bu-t N Br O Ti O O O O t-Bu O Cl MOMO N H + OTMS OMe Bu-t 5 (1.1 mol%) Et2O, 10 MOMO (90%) 94% ee TMSO N O OMe
Cl
(Eq. 9)
i-PrO 1. O O CO2H CO2H OH OH O Ph Ph (93%) 94% ee
O Ph H
OTMS Ph
OPr-i 6
(Eq. 10)
2-PhOC6H4B(OH)2 (20 mol%), EtCN, 78 2. HCl
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ORGANIC REACTIONS
2+ O 1. O EtO O H + Bn OTMS SPh N Sn N O 2 OTf OH O EtO SPh O (90%) 98% ee Bn 7 (10 mol%)
(Eq. 11)
2+ O N O 2 SbF6 N Cu N Ph Ph 8 (10 mol%) BnO
1. OTMS BnO CHO + O
(Eq. 12)
OH O O
CH2Cl2, 78 2. aq. HCl, THF
(95%) dr = 96:4, 95% ee
1.
Me O N P N N (CH2)5 Me Me
2
O Ph
+ C5H11 H
OSiCl3
9 (5 mol%), CHCl3/CH2Cl2 (4:1), 78, 6 h 2. MeOH Ph
OH CHO + Ph
OH CHO
C5H11 C5H11 (92%) dr = 99:1, 90% ee
(Eq. 13)
Background The use of catalysts to channel the stereochemical outcome of the aldol addition reaction process is feasible because the aldol addition reaction is overall an atomtransfer reaction (Fig. 1).78 In the reactions involving enolate additions to aldehydes,
R3Si R1 R O + R H R3Sn R1 R2 O H R1 R2 XR1 R R1 R2
2
O XR1 O XR1 R3Si or R3Sn R R1 R2 OH O XR1 O O XR1
Figure 1. Aldol addition reactions as atom transfer 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 electrophile and C =C in the enolate component for a C C bond and a new C=O in the adduct.79 In aldol additions involving direct addition of enolizable carbonyls, the C 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 involve the use of enoxysilanes, the direct addition of enolizable ketones and esters to aldehydes and ketones in aldol additions have been documented as well. The classic in this respect is rooted in the proline-catalyzed Robinson annulation reaction (Eq. 14)
O + O O (S)-proline (3 mol%) MeCN O O
(Eq. 14)
OH (97%) 93% ee
for the preparation of the Wieland-Miescher ketone80 82 and the direct addition of isocyanoacetates to aldehydes to give isoxazolines catalyzed by gold complexes prepared from 1 (Eq. 2).55 64 More recently, impressive advances have been made in catalytic, enantioselective aldol reactions involving the direct addition of enolizable carbonyls 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 like 11.15,55 65,82 87
O O O Zn O O Zn O i-Pr H O + OH OMe 10 (1 mol%) THF, 30, 16-24 h i-Pr OH (83%) dr = 97:3, 98% ee OH O OMe
(Eq. 15)
Ph Ph
OH N
HO OH N
Ph Ph
(Eq. 16)
O + c-C6H11 H O 11 (10 mol%) Et2Zn (20 mol%), 4 MS, THF, 5 c-C6H11 (85%) 93% ee OH O
O i-Pr H +
L-proline (30 mol%)
OH O i-Pr (97%) 96% ee
DMSO, rt
(Eq. 17)
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8
O + i-Pr H H
ORGANIC REACTIONS
OH i-Pr CHO
L-proline (10 mol%)
DMF, 4
(Eq. 18)
(82%) dr = 24:1, >99% ee
MECHANISM AND STEREOCHEMISTRY
General Aspects. The diastereoselective aldol addition reactions that are best understood and provide adducts with a high degree of stereochemical control and predictability are those proceeding from a metal enolate through closed, ZimmermanTraxler-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 lack thorough mechanistic understanding. Earlier analyses suggesting open transition states (Fig. 2, A-C),92 96 despite their historical importance and utility, are likely oversimplifications, because at the very least they tend to ignore the fate of the silyl group in the course of C =O addition and C C bond formation. Given the inherent high energy of a trialkylsilyl cation, its formation in the course of the aldol process is unlikely. In this respect, it is interesting to note that more recent models (D-H) take into account the silicon in the transition state.97 101 Indeed, focusing on the fate of the silyl group can lead to useful new catalytic processes.102 110
O MXLn R1 H OSiR3 A R R H Si R O O R MXL E R1 R R2 B R3 R4X H Si X O R2 O MLn R R1 F H C MXLn OSiR3 XR4 H R4X R3SiO R R1 MXLn R2 H H 4 XR MXLn R O R2 OSiR3 R1 D
R2 R R4X
R4X R2 R1
Ln R XR4 R4X H R Si Y O M X O Y R2 O R R2 O R 1 SiR 1 3 R R H G R
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-silacyclobutanes,105 109 and trihalosilyl enolates.102 The typical lack of reactivity for the parent trialkylsilyl enolates is critical, as it ensures that the uncatalyzed background aldol additions are precluded. The enoxytrihalosilanes represent an interesting exception. Thus, although their reactions with aldehydes are fast even at low temperature, the Lewis base catalyzed processes are even faster.75 In the simplest analysis, the enoxysilanes and aldehydes can be induced to react by either of two fundamentally different mechanisms: electrophilic activation of the C=O component25 or nucleophilic activation of the enolate15,57,69,111 114 or enol surrogate (Fig. 3).71 In reality, it is likely that mechanistic pathways form a continuum
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of possibilities and possess some component of both activation modes.115 117 Recent reports involving the use of enolizable carbonyl substrates that undergo in situ conversion to the corresponding enolate or enamine provide new mechanistic options for this transformation. Moreover, these add to the class of traditional closed cyclic transition-state arrangements found in the aldol addition reactions such as those of alkali, alkaline earth, and boron enolates.
A + R2 O OH O R O R2 XR1
O O R H + R2 O XR1 R
XR1 H electrophilic activation + H XR1 R nucleophilic activation Y B
R2
Figure 3. Electrophilic vs. nucleophilic activation of an enolate intermediate.
Close inspection of the few cases that have been studied in some detail reveals that the mechanistic possibilities are as numerous as the catalysts and conditions that have been described for this venerable reaction. Given the complexity of the reaction, there are a number of important issues that can be examined in the process: substrate binding and activation (C =O electrophile, enolate nucleophile, or both), C=O face differentiation, as well as catalyst turnover. With respect to the activation and facial differentiation of the electrophilic C=O component, little detailed structural information is available at the kind of resolution that would permit generalization and/or understanding at a fundamental level.118 However, a number of binding modes of aldehydes to Lewis acidic centers have been proposed and are worth examining because of their great value in formulating the binding event (Fig. 4).119 124 In the most general mode of C=O activation, a Lewis acidic center (or Brnsted 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 this arrangement sets the position of the metal in the plane defined by the aldehyde, it leaves ill-defined the dihedral angle X M O=C, which is critical to understanding the facial differentiation event, assuming that C=O addition is the stereochemically determining step. A number of intriguing hypotheses have been proffered dealing with factors that may be operating in constraining the critical dihedral angle. These include secondary contacts between the polarized coordinated aldehyde and aromatic surfaces on the ligand (A1 in Fig. 4).125,126 Indeed, examination of the crystal structure of benzyloxyacetaldehyde bound to a bisoxazoline-copper complex strongly 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 the formyl C H and a heteroatom ligating group (A3 in Fig. 4).128 132
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ORGANIC REACTIONS
R L X M L X RCHO H O L M X L X A R H L M X L X A1 X A2 L X A3 M X O H
R O L M L X H L O
Figure 4. Possible binding modes of aldehydes to Lewis acid centers.
Special classes of substrates such as -alkoxy or -amino carbonyls and 1,2dicarbonyls that bind to activating metal centers via chelate formation have been investigated and developed to furnish aldol adducts in high selectivity.133 The details of how the chiral metal complex binds and activates substrates have been the subject of structural studies. It has been suggested that the subtle differences in the various binding modes arise from the differences in the Lewis basicity between the carbonyl and ether oxygens. The more basic ether oxygen is bound at the site that displays the complementary 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 acidic catalysts. 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 and studied, such as those proceeding via metalloenolates and those catalyzed by Lewis bases or amines (e.g., proline), the collection of transition states for the aldol addition processes is dramatically augmented (Fig. 5). Reactions proceeding through metalloenolate intermediates have numerous options available that require additional 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 involvement of multiple metal sites. Much remains to be learned about the new Lewis base catalyzed processes of trihalosilyl enolates. In this respect, the reactions of trichloroenoxysilanes are currently believed to proceed through hexavalent silicon intermediates G, wherein the high degree of stereoselectivity results from a closed Zimmerman-Traxler-like arrangement with the silicon serving as an organizational locus.134 Although the amine-catalyzed aldol addition reactions have been known for some time, it is only recently that computational studies have shed some light on the nature of the transition state in these processes. Thus, it has been suggested that the hydrogen bond formed between the carboxylic acid and the ensuing aldol alcohol in structure H is critical to the organization in the transition state and accounts for the sense of induction.135,136
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Y metalloenolate: R O A O O R O C Lewis base catalysis: L2 L1 + L3 R H O N H O H M X R O M X O M M Y O X R O B O O R O M X X H O O O O O M O O M O O Ln O O O O Y M F
11
amine catalysis:
R3
R4
P 1 L L2 R5 1 Cl O R P L3 Si O O O Cl
G
H O
R2
Figure 5. Transition states for asymmetric, catalytic aldol addition processes.
Catalyst Turnover. The general aspects of turnover in the catalytic, enantioselective aldol addition reaction have been discussed (Figs. 6 and 7).25 Depending on the aldol type, namely electrophile versus nucleophile activation, various possibilities for turnover exist. The proline-catalyzed processes provide additional features to consider in the catalytic turnover. For the aldol additions involving enoxysilanes that undergo additions via Lewis acid coordinated aldehydes, three distinct mechanistic possibilities may be postulated. In the first of these, silyl transfer takes place from a silylated oxonium species, the first formed adduct, to the newly installed -alkoxide in a distinct step subsequent to the C C bond formation. Such silicon transfer may be imagined to occur via either direct transfer of the silicon moiety from C=O to the metal alkoxide in the product in an intramolecular manner (A, Fig. 6), or alternaO R R3SiO R O R2 X4M R R3 Si + O R2 H + O MX4 R H X4M vs R OSiR3 R2 O O B + SiR3 O R2
X3M O vs R C
O + R SiX 3 R2
Figure 6. Catalytic cycle of the Lewis acid catalyzed aldol reaction.
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ORGANIC REACTIONS
O OTMS OPh O Ar TsN B H O Ar O TMS TsN B O +O H R OPh Ar OTMS TsN O B O O H R OPh OTMS Ar O TsN B O H R
RCHO +
TMSO R
O OPh
O OPh
RCHO + OTMS OMe R
R O
R O O O Ti X X L R TMSO R O OMe
O O TMS X Ti O +O L X R OMe R R O O O+ Ti X O L X R
R O O TMS O OMe
O X L Ti X O R TMS O OMe
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 intramolecular 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 R3SiNTf2catalyzed additions.104 In a related process (Fig. 7), the intramolecular transfer of the silyl group is suggested to occur through an intermediate, wherein the ligand associated with the metal complex serves as a shuttle, undergoing silylation transiently.139,140 This option has been hypothesized to occur in the aldol addition reactions involving boron and titanium complexes. The alternative third option, wherein silyl transfer occurs in an intermolecular fashion has been proffered in the context of aldol addition reactions catalyzed by chiral copper-bisoxazoline complexes (Fig. 8).74,141 The silylating species is presumably R3SiOTf. The Cu-catalyzed
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2+ 2+ O N t-Bu BnO Cu N O H
+
13
O N O BnO H t-Bu
2 OTf N Cu Bu-t 4
O 2 OTf Bu-t
O kcat OTMS
+
O N Cu N O Bu-t O X OTf + TMSOTf
t-Bu
BnO
O N t-Bu BnO Cu N O
O OTf Bu-t O X O kturnover TMSOTf TMS BnO O O
+ 4 X
BnO
+ H
OTMS X
kSi-cat TMSOTf
TMS BnO
O X
racemic kcat and kturnover >> kSi-cat
Figure 8. Intermolecular silyl group transfer in copper-catalyzed aldol reactions.
process74 is rather interesting, as it represents a case wherein the metal activation of the aldehyde substrate and the subsequent turnover is faster than a potentially competing stereorandom silicon-catalyzed process. This situation may be the result of two key features of the system. The fact that chelating substrates are employed in this reaction may considerably favor activation of the substrate by the metal complex over the silyl triflate. Indeed, it is well known that chelation of electrophilic substrates leads to significant rate acceleration as compared to the monodentate substrates.142 Additionally, the metal aldolate that is first formed in these addition reactions is a copper alkoxide, which may be silylated at considerably faster rates than harder metal alkoxides derived from early transition metals such as titanium(IV). The operation of intermolecular silylation in the turnover event is consistent with double-labeling experiments.97 When the reactions involve the use of enolsilanes that in turn produce an intermediate metalloenolate, the key turnover event is likely the silylation of the aldolate product by the starting enoxysilane (Fig. 9).114 Such an event is necessarily intermolecular; given the metals that are involved in such systems (e.g., soft metals such as platinum,143 copper,69 and palladium144,145) the process is driven by the exchange of a weak metal oxygen bond in the first formed adduct for a strong Si O bond in the silylated product.
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ORGANIC REACTIONS
O OTMS
initiation LnMF TMSF
TMS R
O O
O M
O O RCHO O O
O OTMS
M R
Figure 9. Catalytic cycle of the aldol reaction of enoxysilane.
Commentary on the turnover step in the recently reported systems involving direct addition of ketones and aldehydes to aldehyde electrophiles is warranted. These generally fall into two categories: metal-mediated enolization and addition or, alternatively, amine-mediated additions via formation of an enamine. Turnover in the first of these systems is possible, because the pKa values of the alcohol adducts are within range of the starting ketone or aldehyde. Thus, for the lanthanide BINOL complexes65 and zinc(II)-mediated aldol additions84 involving the direct addition of ketones to aldehydes, the product metal alkoxide may effect direct deprotonation of the ketone subsequent to aldol addition to furnish the aldol product and regenerate a ketone enolate. For the amine-catalyzed aldol addition processes (Fig. 10), modeling suggests that the proton transfer that occurs from the carboxylic acid to the aldol adduct is crucial for selectivity.80 82,135,136 Thus, in the course of the enamine addition to aldehyde substrates, a carboxylic acid surrenders its proton to the more basic oxygen acceptor in the adduct. Of greater significance in these processes with respect to turnover is the hydrolytic cleavage of the enamine in the adduct to release the amine for a subsequent round of CC bond formation. The precarious balance in these systems is manifest in the conditions that are used in the amine-catalyzed crossed aldol addition reactions, where it is worth noting that the experimental procedures prescribe long reaction times and highlight the importance in proper selection of polar solvents, where presumably the requisite enamine forming and cleavage
(S)-proline
HO2C
RCHO N
R H
N H O
H O
HO2C
OH R
OH R
Figure 10. Amine-catalyzed aldol addition processes.
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steps are facilitated. The prescription for slow addition of aldehyde substrates in some of the reported processes highlights another aspect of these systems, wherein the adduct as an enamine could itself participate in aldol addition chemistry, as such slow addition of substrate is necessary to allow sufficient time for enamine exchange between product and reactant. Nonetheless, it is important to note that even in the earliest reports of this process in the 1970s, aldol addition reactions could be conducted with low catalytic loadings of proline.
SCOPE AND LIMITATIONS
Acetate, Methyl Ketone, and Unsubstituted Dienolates Reports of catalytic, enantioselective aldol addition reactions involving unsubstituted enolates (acetate aldol) are far fewer than the corresponding additions involving substituted enolates (e.g., propionates). Some of the more prominent examples for both categories are selected in this section for discussion. Enoxysilanes and Stannanes. The classic examples in the area of catalytic enantioselective aldol addition methodology originate from the work involving the addition of enol silanes under the influence of tin catalysts.146 165 The tin(II) complexes are typically assembled from Sn(OTf)2 and optically active diamine ligands such as 12, in particular, in the early work those derived from proline. These early examples involve the addition of thioacetate-derived O-silyl ketene acetals to a wide range of aldehydes (Eqs. 19 21).141,153 The additions are typically conducted at low
N Me O
6
H N
OTMS H + SEt
(20 mol%) Sn(OTf)2 (20 mol%), CH2Cl2, 78, slow addition
TMSO
6
O SEt
(Eq. 19)
(79%) 93% ee
temperature (78) with 20 30 mol% loadings of catalysts 12 or ent-12. The thioester-derived enoxysilanes are optimal for these systems. Of additional benefit is the presence of a thioester in the product as it is conveniently converted directly into an aldehyde.166,167 This catalytic system has been extensively studied, and much information is available concerning the effect of numerous additives and variations in a number of reaction parameters on the reaction selectivity, rates, and catalyst turnover. One particular aspect of the process that is worth noting is the fact that the reactions can be carried out under reagent control. Thus, in additions to the enantiomers of 2-silyloxypropionaldehyde, both diastereomeric adducts can be obtained in high selectivities (Eqs. 20 and 21).141
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ORGANIC REACTIONS
H N 1-naphthyl N Me ent-12 (20 mol%) Sn(OTf)2 (20 mol%), EtCN, 78, slow addition
O H OTBS +
OTMS SEt
OH O SEt OTBS +
OH O SEt OTBS
(85%) dr = 96:4
(Eq. 20)
O R H OTBS
+
OTMS SEt
ent-12 (20 mol%) Sn(OTf)2 (20 mol%), EtCN, 78, slow addition
OH O R OTBS SEt
+ R
OH O SEt
OTBS dr R Me (85%) 94:6 Ph (86%) 94:6
(Eq. 21)
Aldol addition reactions employing BINOL/TiClx(OPr-i)4-x complexes as catalysts 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 preparation.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 either TiCl2(OPr-i)2137 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
O BnO
+
OTMS H SEt
(S)-BINOL/TiCl2(OPr-i)2 (5 mol%) PhMe, 0
TMSO BnO
SEt (80%) 96% ee
(Eq. 22)
O BnO H OTMS + SBu-t (S)-BINOL (20 mol%) Ti(OPr-i)4 (20 mol%), 4 MS, Et2O, 20 BnO OH O SBu-t (82%) >98% ee
(Eq. 23)
TiCl2(OPr-i)2 system is the fact that the addition to a wide range of functionalized aldehydes has been documented, such as trifluoro- (Eq. 24),67 chloro- (Eq. 25),137 and azido acetaldehydes, all of which are rare substrates in catalytic, enantioselective aldol addition reactions. It is worth noting that these titanium catalysts are also quite general with respect to the enolate component, thus both silyl ketene and thioketene acetals in addition to ketone-derived enol ethers have been employed
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1. (R)-BINOL/TiCl2(OPr-i)2 (20 mol%) PhMe, 0 2. H+
17
O + CF3 H
OTMS SPh
OH O CF3 SPh (38%) 96% ee
(Eq. 24)
O Cl + H
OTMS SBu-t
(R)-BINOL/TiCl2(OPr-i)2 (5 mol%) PhMe, 0
TMSO Cl
O SBu-t
(Eq. 25)
(61%) 91% ee
(Eq. 26).77,175,176 They have been utilized in the context of a complex natural product synthesis, namely that of dermostatin A (Fig. 11).177 These reactions are best considered as aldehyde ene additions in which the C=C of the ketone-derived enol ether has undergone a shift in the product. The ease with which the product silyl enol ethers are hydrolyzed to the corresponding hydroxycarbonyl compound renders these synthetically equivalent to aldol addition reactions.178 The addition reactions are reported to give adducts in high selectivity in a procedure that prescribes 20 to 0 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 reaction rate and product selectivity not only being dramatically sensitive to solvent and reaction temperature, but also to catalyst concentration and loading.
O + MeO2C H OTBS (R)-BINOL/TiCl2(OPr-i)2, (5 mol%) CH2Cl2, 0 MeO2C (71%) 99% ee OH OTBS
(Eq. 26)
BnO
35
O H
+
OTMS SBu-t
(R)-BINOL (20 mol%) Ti(OPr-i)4 (20 mol%), 4 MS, Et2O, 20, 12 h
BnO
35
OH O
31
SBu-t
(47%) dr = 2:1 OH
O O
35 31
OH
OH OH OH OH OH OH OH dermostatin A
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 mediate enantioselective 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
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ORGANIC REACTIONS
the reactions are carried out under optimal conditions in aqueous 2-propanol/toluene solvent mixtures. As such, it is remarkable that the process is tolerant and indeed thrives in the presence of water.
O + H SEt OTMS (R)-3,3'-I2BINOL (12 mol%) Zr(OBu-t)4 (10 mol%), n-PrOH (80 mol%), H2O (20 mol%), PhMe, 0 OH O SEt (76%) 97% ee
(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 or amino acids as donors for metals, such as boron or zinc, with the former being most common (Eqs. 28 32).72,73,140,181 184 The typical boron catalyst is assembled upon mixing 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 the ligands are straightforward and convenient to access permits a number of ligand variations 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) and non-natural amino acids, such as C-substituted amino acids (14, Eqs. 30 31).140 In general, the addition reactions are conducted at 78 with 20 30 mol% of catalyst to give adducts in useful levels of enantioselectivity. One particularly attractive feature of these catalysts is that they allow considerable flexibility in the types of enolates that can be employed, such as enol silanes derived from methyl ketones (Eq. 29), alkyl thioacetates (Eq. 30), and phenyl acetate (Eq. 31).
i-PrO O O O Ph H OTMS Ph CO2H CO2H OH OH O Ph Ph (93%) 94% ee
OPr-i 6
(Eq. 28)
1. 2-PhOC6H4B(OH)2 (20 mol%), EtCN, 78 2. HCl
O 1. O + c-C6H11 H OTMS Ph O TsN BBu N H 13 (20 mol%) c-C6H11
(Eq. 29)
OH O Ph
EtCN, 78, 14 h 2. 1 M HCl
(67%) 93% ee
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19
1. O Ph H OTMS SBu-t
i-Pr 14 (20 mol%) BH3MTHF (20 mol%), 78, 2. 1 N HCl/THF Ph
NHTs CO2H
(Eq. 30)
OH O SBu-t (77%) 91% ee
O Ph H
OTMS OPh
1. 14 (20 mol%), BH3MTHF (20 mol%), 78 2. 1 N HCl/THF
OH O OPh Ph (77%) 93% ee
(Eq. 31)
The related complexes prepared from Et2Zn have also been reported.186 Although these do not have the broad substrate scope displayed by the boron complexes, there are some remarkable aldol addition reactions that have been described, such as those with trihaloacetaldehydes (Eq. 32).
O R H
OTBS OBn
1.
NHTf CO2TBS
(40 mol%) R
OH O OBn
ZnEt2 (20 mol%), PhMe, 78 2. H3O+
(Eq. 32)
% ee R CCl3 (61%) 88 CBr3 (66%) 93
A complex derived from titanium(IV), a tridentate Schiff base ligand, and di-tertbutylsalicylic acid is effective in catalyzing the addition of the trimethylsilyl ketene acetal derived from methyl acetate or other simple alkyl acetates (Eqs. 33 and 34).187,188
Bu-t N Br O Ti O O O O t-Bu O R H OTMS OMe Bu-t ent-5 (2 mol%) 1. Et2O, 10 2. TBAF, THF R OH O OMe
(Eq. 33)
% ee R (E)-PhCH=CH (81) 98 TBSOCH2CC (95) 99
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ORGANIC REACTIONS
The reaction is typically conducted at 0 with 2 5 mol% catalyst loadings to give acetate aldol adducts in high selectivities for a broad range of aldehydes. There are a number of unique features of this catalyst system that are worth noting: (1) the reaction does not require the use of low temperatures, (2) the additions can be conducted
O H TIPS +
OTMS OMe
1. ent-5 (2 mol%), Et2O, 10 2. TBAF, THF TIPS
OH O OMe (88%) 97% ee
(Eq. 34)
with as little as 0.5 mol% catalyst, and (3) the additions are effected with methyl or ethyl 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-butylsalicylaldehyde. Treatment of the Schiff base with Ti(OPr-i)4 and di-tert-butylsalicylic acid followed by evaporation of the solvent with concomitant azeotropic removal of 2-propyl alcohol affords an orange crystalline solid which can be used as a catalyst in 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 dichloromethane and dichloroethane significant reduction in the reaction enantioselectivity is observed. The catalytic aldol addition reaction may be conducted between the temperature range of 20 to 23 without adversely affecting the reaction rate (2 8 hours) or enantioselectivity (90% ee). For the aldol addition reaction of the methyl acetate-derived silyl ketene acetal and aldehydes mediated by 5, no diminution in the optical purity of the aldol products is observed throughout the catalyst range of 0.5 10 mol%. The complex 5 has been shown to perform well in the synthesis of a variety 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
TrtS
CHO +
OTMS OBn
1. ent-5 (2 mol%), Et2O, 10 2. TBAF, THF S O i-Pr NH HN O O HN HN Pr-i S 3 O O H FR-9001,228 O TrtS
OH CO2Bn 3 (99%) >98% ee
Figure 12. Application of the titanium-catalyzed aldol reaction to the synthesis of FR-9001,228.
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1. ent-5 (1.1 mol%), Et2O 2. TBAF
21
H + BnO TBSO O
OTMS OMe
35
31
29
CO2Me
BnO
TBSO
OH
(84%)
35 O
OH O
31 29
OH OH OH OH OH O roflamycoin
OH
Figure 13. Application of the titanium-catalyzed aldol reaction to the synthesis of roflamycoin.
O Cl MOMO i-PrO MeO OMe HN O N Cl O O O O OH O NMe2 OH N H + OTMS OMe MOMO (90%) 94% ee 5 (1.1 mol%), Et2O Cl TMSO N O OMe
HO
OH O O
kedarcidin
Figure 14. Application of the titanium-catalyzed aldol reaction to the synthesis of kedarcidin.
O N H PMBO O N
15
PMBO
OTMS OBn
ent-5 (2 mol%), Et2O
OH O OBn
(84%) 99% ee OH O
15
OMe HO H H O HO MeO Br phorboxazole A N O O H O
N H O O H O
H H
Figure 15. Application of the titanium-catalyzed aldol reaction to the synthesis of phorboxaxole A.
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ORGANIC REACTIONS
The protocol most widely employed for the preparation of catalyst 5 prescribes the co-mixing of the various catalyst components, as described above, followed by evaporation of solvent and released isopropanol. A simplified experimental protocol for the preparation of the active catalyst has been developed.191 Thus, the addition of 20 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 in the aldol addition reaction (Eq. 35). This in situ procedure leads to substantial simplification of the overall protocol, because it obviates the need to remove isopropanol. Importantly, the efficiency of the catalytic process (high ees and yields with low catalyst loads) is not jeopardized by the presence of the Et3NHCl and TMSOPr-i byproducts. Moreover, the in situ procedure described provides in principle a useful alternative to the more commonly employed methods for the removal of isopropanol released in the preparation of Ti(IV) complexes with Ti(OPr-i)4 (evaporation and addition of 4 sieves). As an application of the catalytic, enantioselective aldol addition employing the in situ catalyst preparation procedure, the synthesis of (R)-()-epinephrine has been carried out through a convenient sevenstep sequence from commercially available veratraldehyde (Eq. 35).191
H 1. N OH HO Bu-t + HO2C HO Bu-t Bu-t
O MeO MeO OH O MeO MeO (81%) 95% ee OBn H + OTMS OBn
Br 15 (4.4 mol%) Et3N (1 equiv) 2. TFA (work up) HO HO HO
Ti(OPr-i)4 (2 mol%), TMSCl (20 mol%),
(Eq. 35)
NHMe
(R)-()-epinephrine
Aldehyde and ketone substrates incorporating an oxygenated C substituent that can participate in metal chelation, such as -alkoxyacetaldehydes, pyruvates, and diketones, have been shown to be ideal substrates in a class of highly selective aldol addition 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 Two general ligand classes have been examined: bidentate bisoxazolines prepared from malonate esters, and the complementary tridentate bisoxazoline-derived ligands accessed from 2,6-dicarboxypyridine (PYBOX).200 Some general comments can be made about these ligand classes and their corresponding metal complexes as catalysts 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
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2+ O 1. O BnO OTMS + H X X = SBu-t, OEt, Me, Ph t-Bu N Cu N O 2 OTf OH O BnO X (51-91%) 99% ee Bu-t 4 (10 mol%)
23
(Eq. 36)
2+ O N O 2 SbF6 N Cu N Ph Ph 8 (0.5 mol%) CH2Cl2, 78 BnO
(Eq. 37)
OH O X (95-100%) 98-99% ee
O BnO H
OTMS
X X = SBu-t, SEt, OEt
are the counterions accompanying the metal centers, although other non-participating counterions 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 ketonederived enol silanes. The typical protocol for catalyst generation proceeds by addition of ligand to a solution of a metal triflate; after allowing a brief time for complexation the subtrates are then added. A highly attractive feature of this system is the fact that a meticulous study of the process and a range of reaction parameters have been undertaken. In this respect, catalyst preparation time, catalyst hydration state, catalyst loading, time, solvent, and temperature, along with the typical scope has been the subject of in-depth investigations, which are well worth consulting for the practical and mechanistic insight they provide.133 For a broad range of complexation times, 15 minutes to 4 hours, no difference in catalytic efficiency or selectivity was observed. Only at extended complexation times (12 hours) were some deleterious effects in efficiency observed. The fact that catalyst activity and efficiency can be regained on addition of molecular sieves strongly implies catalyst hydration as the culprit in deactivation; indeed, studies have revealed that the bishydrates are less efficient catalysts than their anhydrous counterparts. The reactions are exceptional for the high level of enantioselectivity, and for the fact that in certain cases that have been investigated, the additions can be carried out with as little as 0.5 mol% catalyst without detriment to product selectivities. In a typical reaction, the additions are conducted at 78 with 5 10 mol% complex. A careful study of the copper-bisoxazoline complexes has revealed that for a range of solvents such as THF, Et2O, CH2Cl2, toluene, hexane, and trifluoromethylbenzene, the enantioselectivity of the adducts is maintained at 95% ee. For all but hexane, yields of more than 88% have been noted with reaction times of 1 3 hours. Only in hexane is a slight decrease in product yield observed as well as a dramatic increase in reaction time (3 days), presumably because of partial insolubility of the catalyst in this solvent. Nonetheless, the
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ORGANIC REACTIONS
2+ O
1.
O N N Sn 2 OTf OH O EtO SPh O (90%) 98% ee
O EtO O H +
Bn OTMS SPh
Bn 7 (10 mol%)
(Eq. 38)
1. O EtO O H + OTMS SBu-t
N O SbF6 N Sc N Cl Cl Ph Ph 16 (10 mol%)
OH O EtO SBu-t O (92%) 90% ee
(Eq. 39)
use of THF is optimal, as it routinely provides high yields and selectivities in the shortest amount of time over a broad temperature range. For example, in the addition of tert-butyl thioacetate O-trimethylsilyl ketene acetal in Et2O the enantioselectivity fluctuates between 98 and 85% ee in the temperature range 78 to 20; by contrast, 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 mechanistic insight have revealed the beneficial effects of added TMSOTf, which leads to considerable acceleration of the reaction. Thus the addition reaction of pyruvate and trimethylsilyl tert-butyl thioketene acetal mediated by 2 mol% of copper(bisoxazoline) affords product in 97% ee over the course of 14 hours; interestingly, when the same addition is conducted with one equivalent of TMSOTf and Cu catalyst under otherwise identical conditions, reaction is observed to reach completion in 35 minutes with no diminution in product enantioselectivity. This represents a rare example where the TMSOTf-catalyzed reaction in the absence of Cu complex is considerably slower 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 with concomitant high selectivities also result in some limitations.202 Thus, carbonyl substrates forming chelates greater than five-membered rings (e.g., 3-benzyloxypropionaldehyde) are not good substrates. The process can display significant matching/mismatching with chiral substrates. In particular, when the configuration at C interferes with chelation by the substrate, diminished product diastereoselectivity can be observed (Fig.16).
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TMSO BnO O SBu-t
25
BnO
CHO
OTMS SBu-t
8 (5 mol%), CH2Cl2 78, 12 h
dr = 98.5:1.5 BnO CHO + OTMS SBu-t 8 (5 mol%), CH2Cl2 78, 12 h 2+ O N N Cu N Ph 8 Ph O 2 SbF6 TMSO BnO O SBu-t
dr = 1:1
Figure 16. Matching and mismatching in the copper-catalyzed aldol reaction.
The extensive structural and mechanistic studies to which the process has been subjected has permitted an in-depth understanding of not only the detailed aspects of the aldol process, but also the structural and coordination chemistry of the corresponding metal complexes. Consequently, of particular significance is the fact that a high level of predictability is possible in this process; moreover, the insight afforded by these studies is sure to impact the evolution of metal-based complexes for enantioselective catalysis. Key applications of a tin catalyst and copper complex 8 can be found in the synthesis of phorboxazole A and altohyrtin C, respectively (Figs. 17 and 18).196,203 205
2+ 1. Ph N O CHO + OTMS SBu-t O N Ph N Sn O Ph (10 mol%) 2 OTf OH O Ph N O (91%) 94% ee OH O OMe HO H H O HO MeO Br N O phorboxazole A O H O N H O O H O H H SBu-t
Figure 17. Application of the tin-catalyzed aldol reaction to the synthesis of phorboxaxole A.
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26
OTMS t-BuS O H
ORGANIC REACTIONS
8 (5 mol%) OBn CH2Cl2, 78 OH HO O H O OH
OBn 41 t-BuS (100%) 99% ee
O OH H O
41
OMe
O HO OH O O AcO
HO
O O
O AcO
OH altohyrtin C
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 trialkyl substituted silyl ketene acetals. Indeed, recent studies describe the use of enoxytrichlorosilanes 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
Me N O P 1. N N Ph Me 17 ( 5 mol%), Ph CH2Cl2, 78 2. aq. NaHCO3
O Ph H
OSiCl3
OH O Ph (98%) 87% ee
(Eq. 40)
fact that they are at present rare examples of Lewis base catalyzed asymmetric reactions. Interestingly, the background rate of aldol addition between such enolates and aldehydes in the absence of additives has been shown to be rapid, even at low temperature. Nonetheless, stereoselective additions are possible since the Lewis base catalyzed processes are markedly faster. In this respect, the basic oxygen of chiral phosphoramides interacts with silicon leading to the formation of a hypervalent siliconate species with enhanced Lewis acidity that is subsequently poised to activate an aldehyde. The resulting cyclic arrangement of aldehyde, enoxysilane, and phosphoramide leads to selective addition processes. A key advance in this exciting area is the use of chiral silicon Lewis acids that are generated from SiCl4 and chiral Lewis basic phosphoramides. Such processes that rely on chiral Si-Lewis acids employ the more conventional trialkylenoxysilanes as reacting partners (Eqs. 41 and 42). Studies of the mechanism of activation have led to the design of bisphosphoramides for silicon, resulting in even more highly selective additions.
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1. 9 (5 mol%), SiCl4, CH2Cl2, 78 2. NaHCO3
27
O c-C6H11 H
OTBS OMe
OH O OMe c-C6H11 (86%) 88% ee
(Eq. 41)
Me O N P N N (CH2)5 Me Me
2
(Eq. 42)
OH O Ph OMe (95%) 94% ee
O Ph H
OTBS OMe
9 (5 mol%) SiCl4, CH2Cl2, 78
Despite the numerous documented examples of the catalytic, enantioselective aldol addition reactions to aldehydes, addition reactions to ketones are rare. The difficulty faced by investigators working in this area are manifold, not only because ketones are less reactive than aldehydes, but also because differentiation of the two alkyl groups flanking the ketone C =O on the basis of sterics alone presents a more difficult challenge in comparison to the corresponding differentiation that must occur with aldehyde involving alkyl versus proton. Nonetheless, with Lewis base catalysts 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 remarkable.75,134,154 156,209 211,213
O Ph 1. OSiCl3 OMe Ph , 18 (10 mol%), CH2Cl2 OH O OMe
(96%) 83% ee
2. aq. NaHCO3 O HO O t-Bu N N O O OBu BuO 18 (90%) 80% ee Bu-t OMe
Figure 19. N-oxide-catalyzed aldol reaction of aryl ketones.
An additional departure from the traditional aldol addition reaction of enol silanes catalyzed by Lewis acid activation of the electrophilic aldehyde component is the use of complexes that lead to activation of the enoxysilane component via transient formation of metalloenolates. One of the earliest examples in catalytic asymmetric synthesis is the report that acetophenone-derived trimethylsilyl enol ethers can be
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ORGANIC REACTIONS
activated by BINAP/palladium(II) complexes to afford putative palladium enolates.144,145 These are generated from a mixture of enol silane and a complex formed between palladium(II) and p-Tol-BINAP (5 mol%) in the presence of molecular sieves and have been shown to undergo aldol additions in up to 89% ee (Eq. 43).
O + Ph H Ph OTMS [Pd((R)-Tol-BINAP)(H2O)2](BF4)2 (5 mol%) 4 MS, 1,1,3,3-tetramethylurea, 0 OH O Ph Ph (92%) 89% ee
(Eq. 43)
By comparison to enol silanes, there is a paucity of catalytic, enantioselective aldol 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 a novel silver(I)/BINAP complex. The adducts can be isolated in up to 95% ee and useful yields (Eq. 44).94 Control experiments have led to the conclusion that the systems behave in analogy to the typical reaction of enol silanes with electrophilic activation of the aldehyde component, without proceeding through a silver(I) enolate.
O Ph H + OSn(Bu-n)3 Bu-t (R)-BINAPMAgOTf (10 mol%) THF, 20 OH O Ph Bu-t (78%) 95% ee
(Eq. 44)
Direct Aldol Addition Reactions of Unsubstituted Systems. In parallel with reactions involving the generation of metal enolates from stannylated or silylated precursors, there have been recent developments on the use of ketones that undergo in situ enolization or activation by transient conversion into enamines and participate in aldol addition reactions.214 In the first of these, lanthanum binaphthoxide complexes (LLB) are able to effect deprotonation of ketones and activation of aldehydes to 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 been documented.
O + Ph H O (R)-LLB (20 mol%) THF, 20 Ph (71%) 94% ee OH O
(Eq. 45)
CHO + OTBS
O Ph
(R)-LLB (8 mol%), KHMDS (7.2 mol%) H2O (16 mol%), THF, 20, 48 h
OH O Ph OTBS +
OH O Ph OTBS
(Eq. 46)
I II (85%) I:II = 86:14, I 99% ee, II 93% ee
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(R)-LLB (20 mol%), KHMDS (18 mol%) Ph H2O (40 mol%),THF, 20 O O
1
29
O CHO () +
OH O Ph I +
O
1
OH O Ph II
(59%) I:II = 1:1, I 89% ee, II 88% ee
O N S
HO
1
O O O OH
epothilone A
Figure 20. Application of the hetero-bimetallic-catalyzed aldol reaction to the synthesis of epothilone A.
HO O + BnO H O Ph OH Ph BnO OH O Ph (76%) 91% ee
(Eq. 47)
Ph Ca[N(TMS)2]2(thf)2, KSCN
The easily accessible ligand 11 and its bimetallic zinc complex have also been used in aldol addition reactions of methyl ketones and aldehydes that proceed via in situ enolization (Eq. 48).84,220,213
Ph Ph OH N HO OH N Ph Ph
(Eq. 48)
O + c-C6H11 H O 11 (10 mol%) Et2Zn (20 mol%), 4 MS, THF, 5 OH O c-C6H11 (85%) 93% ee
Another way that ketones can undergo activation and participate in stereoselective aldol additions is through their in situ conversion to the corresponding enamines. Proline is remarkably effective in this process. Indeed, the enantioselective 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 proline-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,
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ORGANIC REACTIONS
a solvent which appears to be critical, utilizing 30 mol% of proline at ambient temperatures giving adducts in up to 99% ee. The proline-catalyzed aldol addition reaction of acetaldehyde can be carried out in a domino process proceeding by a double aldol addition and elimination to give useful building blocks for asymmetric synthesis (Eqs. 51 and 52).
O + i-Pr H OH O i-Pr (97%) 96% ee
L-proline (30 mol%)
DMSO, rt
(Eq. 49)
O O O O
CHO O
L-proline (30 mol%)
O O O
OH O O
DMSO, rt
(Eq. 50)
O dr = 99:1
O H
L-proline (1.7 mol%)
OH CHO (10%) 90% ee
THF, rt, 14 h
(Eq. 51)
O H + O2N O
N N H (3 mol%) 2,4-(O2N)2C6H3SO3HM2H2O (3 mol%), O2N acetone, rt
OH O
(Eq. 52)
(72%) 93% ee
Propionates and Substituted Enolates Enoxysilanes and Stannanes. The addition reactions of propionate-derived silyl ketene acetals and other substituted enolates or their equivalents can be effected with a broader range of catalysts than that of the unsubstituted systems described in the previous section. In principle, two kinds of stereochemical families of reaction processes can be identified: (1) those processes in which each geometrical isomer of the enolate gives divergent, complementary diastereomeric products and (2) those in which both enolates stereoselectively lead to convergent formation of a preferred diastereomer. Examples of both types have been documented. For the first of these in 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
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limitations as to the type of stereochemical relationships in the product that can be accessed. As with the additions of acetates and other unsubstituted enolates, the classics in this area are the enantioselective aldol additions mediated by tin(II) diamine complexes (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 systems and careful scrutiny of these can be rewarding because this system represents one in which the effect of many different variables on reaction selectivity and rate have been carefully examined. Moreover, there is an equally large amount of mechanistically relevant data making the careful study of these reports a fruitful venture. In the typical procedure the reactions employ thioester-derived silyl ketene acetals and are 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 enantioselectivity is maximized. Optimal selectivities are obtained when the aldehyde is added slowly to the reaction mixture, minimizing stereorandom, background reactions while allowing for concomitant catalyst turnover. Both O-trimethylsilyl and O-dimethyl-tert-butylsilyl enol ethers give adducts in equally good selectivities. The propionate additions using these complexes have been conducted with the Zenolates and afford products displaying syn simple diastereoselectivity and high enantiomeric purity (Eq. 53). The use of ester-derived enol silanes has been examined for alkoxyacetate-derived enolates (Eqs. 54 and 55).225,230,232 High anti or syn selectivity was shown to be a function of whether the Z- or E-starting enolate was employed, respectively.227
H N N 1-naphthyl Me ent-12 (22 mol%) Sn(OTf)2 (20 mol%), CH2Cl2, 78, slow addition
O R H
OTMS + SEt
TMSO R
O SEt
(Eq. 53)
dr % ee R n-C7H15 (76%) 99:1 98 Ph (86%) 93:7 91
N Me O H + BnO OTMS OPh
H N
(20 mol%), Sn(OTf)2 (20 mol%) CH2Cl2, 78, slow addition
TMSO
OPh OBn (80%) dr = 98:2, 96% ee
(Eq. 54)
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ORGANIC REACTIONS
H N N 1-naphthyl Me 12 (20 mol%) Sn(OTf)2 (20 mol%) CH2Cl2, 78, slow addition Ph
O Ph H
OTMS + OPr-i OBn E:Z = 71:29
OH O OPr-i OBn (60%) dr = 90:10, 96% ee
(Eq. 55)
Catalysts derived from titanium(IV) or zirconium(IV) and BINOL or its substituted 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 has been studied extensively in the addition of substituted ester137,67 as well as ketonederived77,233 silyl enolates to chelating aldehydes, such as benzyloxyacetaldehyde and ethyl glyoxylates. The addition of the E-enol silanes preferentially affords syn adducts in up to 98% ee (Eq. 56).137 By comparison, addition of the Z-enol silanes furnishes the complementary anti adduct in 90% ee (Eq. 57). A particularly attractive feature of these titanium-catalyzed reactions is the fact that trifluoroacetaldehyde
O BuO O H + SEt
OTMS
(R)-BINOL/TiCl2(OPr-i)2 (5 mol%) PhMe, 0 TMSO BuO O I O SEt + TMSO BuO O (64%) dr = 92:8, 98% ee II O SEt
(Eq. 56)
O BuO O H +
OTMS SEt
(R)-BINOL/TiCl2(OPr-i)2 (5 mol%) PhMe, 0 TMSO BuO O O SEt + TMSO BuO II O SEt
O I (72%) dr = 8:92, 90% ee
(Eq. 57)
can be utilized, albeit the products exhibit poor diastereoselectivity (Eqs. 58 and 59).67 There have been some interesting studies involving the enol silane derived from 3-pentanone (Eq. 60), wherein a highly selective aldehyde addition is observed.77 Although the process is best classified as an ene addition, the products isolated after exposure to acid are -hydroxy ketones. In this process the addition of either the Z- or E-trimethylsilyl enolate of 3-pentanone to glyoxaldehyde gives syn adducts in up to 99% ee.
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1. (R)-BINOL/TiCl2(OPr-i)2 (20 mol%), PhMe, 0 2. H+ OH O CF3 SEt + CF3 OH O SEt
33
O + CF3 H
OTMS SEt
(Eq. 58)
I II (64%) I:II = 48:52, I 55% ee, II 64% ee
O + CF3 H
OTMS SEt
1. (R)-BINOL/TiCl2(OPr-i)2 (20 mol%), PhMe, 0 2. H+ OH O CF3 SEt + CF3 OH O SEt
(Eq. 59)
I II (48%) I:II = 44:56, I 89% ee, II 83% ee
O MeO O
TMSO + H Et
(R)-BINOL/TiCl2(OPr-i)2 (5 mol%) CH2Cl2, 0 MeO2C
OH OTMS
(Eq. 60)
(54%) Z:E = 96:4, dr = 98:2, 99% ee
Catalysts prepared from Zr(OBu-t)4 and 3,3-diiodo-BINOL in the presence of propanol and water are effective at mediating the addition of primarily phenyl propionate-derived E-enolates to aldehydes. Thus 12 mol% of the putative zirconium complex affords products in excellent diastereo- and enantioselectivities (99% ee), favoring the anti product (955 dr) (Eq. 61).179,180,234 In addition to propionates,
(R)-3,3'-I2BINOL (12 mol%), Zr(OBu-t)4 (10 mol%) Ph
O + Ph H
OTMS
OH O OPh
OPh n-PrOH (80 mol%), H O (20 mol%), PhMe, 0 2
(94%) dr = 95.5, 99% ee
(Eq. 61)
isobutyrate-derived silyl ketene acetals have been reported to participate in the addition 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 alcohol mixtures renders the complex unique as a rare example of an early group-(IV) transition-metal catalyst displaying wide tolerance to moisture.
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OTMS + Ph H OMe
ORGANIC REACTIONS
OH O Ph OMe
(R)-3,3'-I2BINOL (12 mol%) Zr(OBu-t)4 (10 mol%), n-PrOH (80 mol%), H2O (20 mol%), PhMe, 0
(95%) 98% ee
(Eq. 62)
Enantioselective aldol addition reactions employing boron catalysts were some of the earliest processes reported for propionate aldol addition reactions. A particularly attractive feature of the reported catalysts is the ease with which the ligands and the corresponding complexes are generally accessible. The optically active ligand on boron is typically derived from either -amino acids or tartrates.181 As such, the process is notable because of the large library of structurally and functionally related boron 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
i-PrO 1. O + Ph H OTMS OPh O CO2H CO2H OH O Ph I OPh + Ph OH O OPh
O OH OPr-i ent-6 (20 mol%)
(Eq. 63)
BH3MTHF (20 mol%), EtCN, 78 2. TBAF/THF
II (73%) I:II = 79:21, I 92% ee, II 3% ee
This versatile catalytic system can also be employed in the aldol addition reaction of ketone-derived silyl enol ethers. Irrespective of the enolate geometry, these systems afford the syn aldol adduct in useful levels of relative and absolute stereocontrol (Eqs. 64 and 65).72,177,182,32 The addition of enol silanes derived from cyclic ketones and aldehydes is also possible, with the formation of the syn aldol adduct
1. 6 (20 mol%), BH3MTHF (20 mol%) EtCN, 78 2. 1 N HCl Ph
O Ph H
OTMS Et
OH O Et + Ph
OH O Et
(Eq. 64)
I II (97%) I:II = 93:7, 94% ee
O Ph H
OTMS + Et
1. 6 (20 mol%), BH3MTHF (20 mol%) EtCN, 78 2. 1 N HCl Ph
OH O Et + Ph I
OH O Et II
(Eq. 65)
(96%) I:II = 94:6, 96% ee
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once again favored in impressive diastereo- and enantioselectivity (Eqs. 66 and 67).181,235 The reaction has been employed in the asymmetric synthesis of cheimonophyllal (Fig. 21).235
O Ph H OTMS 1. 6 (20 mol%), BH3MTHF (20 mol%) EtCN, 78 2. 1 N HCl Ph OH O + Ph I II (57%) I:II >95:5, I >95% ee OH O
(Eq. 66)
O 1. N Ts O BBu
O + Ph H
OTMS
N H 13 (40 mol%) EtCN, 78, 14 h 2. 1M HCl Ph
OH O + H I Ph
OH O H II
(Eq. 67)
(71%) I:II = 94:6, 92% ee
O + H
OTMS
1. 6 (20 mol%), 2-PhOC6H4B(OH)2 (20 mol%), EtCN, 78 2. BzCl, Py HO HO
OBz O
(85%) dr = 10:1, 97% ee H O
O CHO cheimonophyllal H
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
1. O + Ph H SEt OTMS
i-Pr 14 (20 mol%) BH3MTHF (20 mol%), 78, EtCN 2. 1 M n-Bu4NF, THF Ph
NHTs CO2H
OH O SEt + Ph
OH O SEt
(Eq. 68)
I II (84%) I:II = 55:45, I >98% ee
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ORGANIC REACTIONS
Additions of the ethyl thiopropionate-derived E-silyl enolate afford products in good enantioselectivities (98% ee), albeit modest diastereoselection (syn/anti 5545). By contrast, the use of the Z-silyl enolate furnishes a mixture of syn and anti adducts wherein the anti is preferred in up to 946 ratio and in up to 82% ee (Eq. 69). When the E-silyl enolate prepared from phenyl propionate is utilized, the absolute selectivity is improved (87% ee) in comparison to that observed for the same substrate with thioproprionate enoxysilanes. However, for the phenyl ester the simple diastereoselectivity of the addition is somewhat diminished (Eq. 70).140
1. 14 (20 mol%), BH3MTHF (20 mol%) 78, EtCN 2. 1 M n-Bu4NF, THF R I
O + R H
OTMS SBu-t
OH O SBu-t + R
OH O SBu-t
II R I:II % ee I Ph (78%) 94:6 82 2-C4H3O (54%) 88:12 79
(Eq. 69)
O + Ph H
OTMS OPh
1. 14 (20 mol%), BH3MTHF (20 mol%) 78, EtCN 2. 1 M n-Bu4NF, THF Ph
OH O OPh + Ph
OH O OPh
(Eq. 70)
II I (77%) I:II = 77:23, I 87% ee
One particularly interesting aspect of the boron Lewis acid catalysts derived from amino acids like 19 is that dichloro-, difluoro-,236 and dithio-237 substituted enoxysilanes have been employed to give adducts that are otherwise not easily accessed in useful levels of induction (Eqs. 71 73).
O i-Pr O N O (20 mol%) S B Ph O H CH2Cl2, 78, 7 h MeO
O H + Cl MeO Cl
OTMS OMe
OH CO2Me Cl Cl (88%) 77% ee
(Eq. 71)
O t-Bu O + i-Pr H OTMS F F OEt OH (20 mol%), NHNs BH3MTHF (22 mol%), EtNO2, 45 i-Pr
OH O OEt F F (90%) 95% ee
(Eq. 72)
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1. O2N OTMS + H S S OEt
O O S N H
CO2H
O Ph
19 (20 mol%), BH3MTHF (20 mol%), EtNO2 78, 1 h 2. Ni2B/H2 Ph
OH CO2Et (86%) >98% ee
(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 and 75).184,195,236 An unusual catalyst derived from optically active -trimethylsilyl-hydroxyacetic acid functions in such additions (Eq. 76), affording adducts in up to 90% ee.239
O + Ph H
OTMS OPh
1. 19 (20 mol%), BH3MTHF (20 mol%), EtNO2, 78, 1-4 h 2. TBAF Ph
OH O OPh
(Eq. 74)
(92%) 90% ee
1. O + BnO H OTMS OEt
i-Pr 14 (20 mol%) BH3MTHF (20 mol%), 78 2. 1 N HCl/THF BnO
NHTs CO2H
OH O OEt (59%) 96% ee
(Eq. 75)
1. O + Ph H OTMS OEt
CO2H (10 mol%), OH BH3MTHF (10 mol%), Ph
TMS
OH O OEt
(Eq. 76)
EtCN, 78, 3 h 2. pH 7 buffer
(92%) 86% ee
There has been a single report of the use of allenyl enolates in enantioselective aldol 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
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ORGANIC REACTIONS
O Pr O i-Pr + H I OTMS 1. n-C3F7 Bn
N CO2H (20 mol%), H BH3MTHF (20 mol%) OH O Pr I I II (63%) I:II = 1:20, II 97% ee + i-Pr I OH O Pr
EtCN, 78, 7 h 2. aq. HCl i-Pr
(Eq. 77)
As discussed in the section above on acetate-type additions, substrates such as benzyloxyacetaldehyde and glyoxal have unique structural features that allow them to chelate with Lewis acidic metal centers. This has been elegantly capitalized upon in the development of highly stereoselective propionate-type aldol addition reactions catalyzed by copper-, tin-, and scandium- bisoxazoline complexes. The two ligand families that have been reported include either bidentate bisoxazolines derived from malonate or tridentate bis-oxazolines prepared from 2,6-pyridinedicarboxylic acids. For copper(II), for example, the two ligands afford complementary products, giving adducts with opposite face selectivity (Eqs. 78 80).37
2+ O 1. O BnO H OTMS + SBu-t t-Bu N N Cu O 2 OTf OH O BnO SBu-t Bu-t 4 (10 mol%)
(Eq. 78)
(50%) dr = 81:19, 84% ee
This family of catalysts includes a wide selection of complexes that can be used in enantioselective aldol additions, which is the key advantage of these systems. This versatility, when coupled to the range of aldehydes that can be employed, such as glyoxylates and benzyloxyacetaldehyde, provides access to a broad range of substituted aldol adducts possessing the various permutations of complementary, diverse stereochemical patterns. The typical reaction calls for the use of 5 10 mol% catalyst loadings with the reaction conducted at 78. The strict requirement for the substrate to form five-membered chelated adducts with the metal center leads to a system that is impressive in its high selectivity, reaction rate, and yield for a wide range of enoxysilanes. These silanes include those derived from esters,197 thioesters,70 ketones,37,197,199 and lactones.74
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2+ O N O 2 SbF6 N Cu N Ph Ph 8 (10 mol%) OH O BnO SEt
39
1. O BnO + H Z:E 95:5 1:99 OTMS SEt
(Eq. 79)
dr % ee (90%) 97:3 97 (48%) 86:14 85
O BnO + H
OTMS Pr-i Z:E 90:10 10:90
1. 8 (10 mol%), CH2Cl2, 20, 2 d 2. aq. HCl, THF
OH O BnO Pr-i
(Eq. 80)
dr % ee (90%) 95:5 90 (10%) 38:62 28
In additions mediated by copper complexes, the correlation between enolate geometry and product diastereoselectivity has been studied and found to be ligand and substrate dependent. Thus, for example, for the tridentate bisoxazoline copper complexes the E- and Z-silyl thioketene acetals derived from thiopropionate afford syn adducts (Eqs. 79 and 80). The additions of the latter are, however, considerably more selective (Eq. 79).37 In a study involving ketone additions mediated by the tridendate copper-bisoxazoline complexes, the Z-silyl enolates afford exceptional levels of induction, whereas the corresponding E-enol silanes lead to preferential formation 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 bidentate aldehydes. In this regard, the addition of the Z-thioketene acetal derived from thiopropionate gives the anti aldol adduct in high selectivities (Eq. 81).39 Importantly, the adducts can be obtained in equally good selectivites for a wide range of C substituents and are thus not limited to the propionate systems. Scandium(III) catalyst 16 affords the complementary products resulting from addition with opposite facial selectivity (Eq. 82).198
2+ O 1. O EtO O H + OTMS SPh Bn N N Sn O 2 OTf Bn 7 (10 mol%) OH O SPh O (87%) dr = 90:10, 95% ee EtO
(Eq. 81)
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ORGANIC REACTIONS
+
1. O EtO O H + OTMS SBu-t
N O SbF6 N Sc N Cl Cl Ph Ph 16 (10 mol%)
OH O EtO SBu-t O (93%) dr = 92:8, 95% ee
(Eq. 82)
These addition reactions have been examined with alkoxy-substituted silyl enolates as well as cyclic enolates. The former are reported to work particularly well with the scandium catalysts (Eq. 83).198 The use of copper-bisoxazoline complexes in the addition of the butyrolactone-derived enoxysilanes provide access to useful adducts in a 937 syn/anti mixture and 96% ee (Eq. 84).74 In addition to propionate-derived enolates, isobutyrate and related silyl enolates have been examined (Eqs. 85 87).199
O EtO O H + OBn OTMS SEt 1. 16 (10 mol%), CH2Cl2, 78 2. aq. HCl OH O EtO SEt O OBn (92%) dr = 92:8, 95% ee
(Eq. 83)
2+ O N O 2 SbF6 N Cu N Ph O BnO H + TMSO O Ph 8 (10 mol%) OH BnO O O (95%) dr = 96:4, 95% ee
1.
(Eq. 84)
+
1. O EtO O R H + OTMS
N O SbF6 N Sc N Cl Cl Bu-t t-Bu (10 mol%) O
OH O EtO Ar O R R % ee (85%) 95 (85%) 95 (80%) 97 (81%) 98
Ar TMSCl (2 equiv), CH2Cl2, 78 R 2. aq. HCl Ar R Ph Me 4-FC6H4 Me n-C5H11 Ph Ph n-C4H9
(Eq. 85)
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1. 8 (10 mol%), CH2Cl2, 78, 16 h 2. H+
41
O EtO O H +
OTMS SEt
OH O EtO O (61%) 98% ee SEt
(Eq. 86)
O EtO O H +
OTMS SEt
OH O 16 (10-15 mol%) CH2Cl2, 78, 16 h EtO O (90%) 95% ee SEt
(Eq. 87)
In addition to the traditional enoxysilanes derived from ketones and esters, the bisoxazoline catalysts have been shown to mediate an aldol-type addition between aldehydes 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 that can chelate the metal center (Eq. 88). Interestingly, the use of a new class of aluminum complexes permits the use of a wider range of aryl-substituted aldehydes for which chelation is not a prerequisite (Eq. 89),241 affording adducts not only possessing 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 at ambient temperature.
2+ O N O EtO O H + O R N OMe MeO t-Bu N Cu O Bu-t 4 (1 mol%) THF, 40 MeO 2 OTf R CO2Me N O CO2Et
dr % ee R H (99%) 95:5 97 Me (94%) 94:6 99
(Eq. 88)
The bisoxazoline-derived complexes of tin(II) and copper(II) which have proven so 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 such ketones can be effected in 84 96% yield and up to 99% ee. It is worth noting that the tin(II)- and copper(I)-catalyzed additions provide access to products possessing complementary simple stereochemical patterns.
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ORGANIC REACTIONS
t-Bu
Bu-t X N O Al (5 mol%) N O X = SbF6 Bu-t O Y X H + MeO O N OMe t-Bu LiClO4 (20 mol%), 3 MS, PhMe, rt, 20 h CO2Me Y X X F OMe Cl + MeO I:II % ee I 89:11 98 91:9 98 74:26 92 N O II Y Cl (100%) Br (90%) NO2 (99%) Y X
CO2Me N O MeO I
(Eq. 89)
O R1O O R2 + OTMS 1. 4 (10 mol%), THF, 78 X 2. aq. HCl HO R2 O X O (84-96%) 36-99% ee R1O
(Eq. 90)
X = SEt, OEt, Ph, Me
R1, R2 = Me, Me; Bn, Me; t-Bu, Me; Me, Et; Me, t-Bu; Et, i-Pr
2+ O N O 2 TfO N Sn N Ph Ph (10 mol%) HO O
1. O + O OTMS SBu-t
(Eq. 91)
SBu-t O (85%) dr = 99:1, 98% ee
Recent advances in the use of chiral phosphoramides have permitted the use of chiral silicon Lewis acid catalysts, which are generated in situ from SiCl4. The reaction 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 outcome 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 991 enantioselectivity and 991 diastereoselec-
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tivity, with preference for the anti-substituted product. Accompanying mechanistic studies are consistent with an open transition state and rule out isomerization of the starting enolate.
Me O N P N N (CH2)5 Me Me O + Ph H OTBS OBu-t 9 (1 mol%)
2
OH O Ph OBu-t
SiCl4 (1 mol%), 78, CH2Cl2
dr % ee E:Z 95:5 (93%) 99:1 >99 12:88 (73%) 99:1 >99
(Eq. 92)
A significant departure from the use of traditional enoxysilanes involves the chemistry of trichlorosilyl enolates prepared from the corresponding silyl or stannyl enolates.208 The use of trichlorosilyl enolates in aldol addition reactions results in a process 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 employed (Eq. 93).207 The addition of the Z-trichlorosilyl enolate prepared from propiophenone to a wide range of aldehydes yields adducts in high simple induction
O + Ph H Ph OSiCl3 1. 17 (15 mol%), CH2Cl2, 78, 6-8 h 2. aq. NaHCO3 Ph OH O Ph + Ph I II (95%) I:II = 18:1, 95% ee OH O Ph
(Eq. 93)
(syn/anti up to 181) and absolute selectivity (up to 96% ee). Trichlorosilyl enolates prepared 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-substituent for a given enantiomer of a phosphoramide catalyst can lead to generation of the diastereomeric product.
O + Ph H OSiCl3 1. 17 (10 mol%), CH2Cl2, 78, 2 h 2. aq. NaHCO3 OH O Ph + Ph I II (94%) dr = 1:99, 97% ee OH O
(Eq. 94)
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ORGANIC REACTIONS
R N O P N N Ph R (10 mol%) Ph
Ph O Ph H OSiCl3 +
OH O + Ph
OH O
CH2Cl2, 78
I II I:II % ee I R Ph (94%) 97:1 51 Me (95%) 1:61 92
(Eq. 95)
The studies of these systems have included an examination of enolates derived from chiral ketones (Eq. 96).210 For the ketone-derived Z-enolate examined, the syn aldol is formed preferentially. Further studies employing chiral ketones have revealed interesting results.209,210,242 The addition can show excellent catalyst control but having the requisite starting enolate geometry is critical (Eqs. 97 and 98).
O + Ph H
OTMS OTBS
1. Hg(OAc)2, SiCl4, CH2Cl2, rt 2. ent-17 (5 mol%), CH2Cl2, 78, 10 h Ph
OH O + diastereomers OTBS (88%) dr = 95:5
(Eq. 96)
O + Ph H
Cl3SiO
OTIPS catalyst (10 mol%), CH2Cl2, 78, 8 h OH O + Ph III
OH O Ph I OTIPS + Ph
OTIPS +
OH O Ph II OTIPS
OTIPS
OH O
IV (84%) (80%) (86%) I:IV 1:16 10:1 1:1 I+IV:II+III 30:1 26:1 3:1
Z:E 16:1 16:1 1:15
cat ent-17 17 17
(Eq. 97)
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Cl3SiO + H OTIPS + OH O R II R Ph Ph 1-C10H7 1-C10H7 cat ent-17 17 ent-17 17 (84%) (82%) (71%) (79%) I:IV 24:1 1:8 89:1 1:17 OTIPS + OTIPS
45
O R OH O R I
catalyst (10 mol%), Bu4NI (20 mol%), CH2Cl2, 78, 8 h OH O R III I+IV:II+III 53:1 32:1 14:1 14:1 OTIPS + OH O R IV OTIPS
(Eq. 98)
A particularly noteworthy feature of these Lewis base catalyzed additions of trichlorosilyl 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-enolates from an aldehyde, with each showing complementary relative diastereoselectivity.
O Ph H + CH 5 11 1. 9 (5 mol%), CHCl3/CH2Cl2 (4:1), 78, 6 h 2. MeOH OH Ph CHO C5H11 (92%) dr = 99:1, 90% ee
OSiCl3
(Eq. 99)
OSiCl3 1. 9 (5 mol%), CHCl3/CH2Cl2 (4:1), 78, 6 h C5H11 2. MeOH OH Ph CHO C5H11 (91%) dr = 97:3, 82% ee
O + Ph H
(Eq. 100)
Catalysts derived from complexes prepared with metals such as lead,243 silver,244,245 platinum,143 and lanthanides246 mediate catalytic, enantioselective propionate aldol addition reactions. The addition of propiophenone to benzaldehyde mediated by a praseodynium complex prepared with a chiral macrocyclic ether is noteworthy, as it is a rare example of the use of a lanthanide in such aldol addition reactions and constitutes the successful use of a macrocyclic ligand (Eq. 101). The addition of isobutyrate-derived enoxysilanes catalyzed by platinum(II) complexes is also interesting for a number of reasons (Eq. 102).143 Firstly, the additions afford a mixture of both silylated product and free alcohol, with both adducts formed with identical enantioselectivity. Secondly, the enantioselectivity of the process actually
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ORGANIC REACTIONS
benefits from the inclusion of oxygen and water during catalyst preparation. It is also intriguing as it represents one of the few processes in which an isobutyrate addition is proposed to proceed by way of a metalloenolate intermediate. The reaction prescribes the use of 20 mol% catalyst, furnishing adducts in up to 95% ee.
O N O O + Ph H Ph OTMS
O N O (20 mol%) Ph OH O Ph
(Eq. 101)
Pr(OTf)3 (24 mol%), H2O/EtOH (1:9), 0, 18 h
(85%) dr = 91:9, 82% ee
Ph2 P O Pt P Ph2 O O Ph H OTMS + OMe
Bu-t (5 mol%), Bu-t
TfOH (5 mol%), 2,6-lutidine (5 mol%) CH2Cl2, 25 OH O Ph I OMe + Ph II TMSO O OMe
(94%) I:II = 51:49, 95% ee
(Eq. 102)
Simple chiral bisphosphine silver(I) complexes catalyze enantioselective addition reactions of stannyl enolates,244 trimethoxysilyl enolates,245 and diketene247 with aldehydes. Under typical conditions, the addition reaction is catalyzed by 5 10 mol% of silver-BINAP complexes at 20. The additions involving tin(II) enolates prescribe the use of a complex prepared from AgOTf and BINAP. The requisite tin enolates for the aldol addition can be prepared prior to use (Eq. 103) or can be generated in situ from the corresponding enol acetates (Eq. 104) or diketene (Eq. 105) upon treatment with Me3SnOMe. In such addition reactions, adducts are formed in up to
O Ph H OSnBu3 + OH O (R)-BINAPMAgOTf (10 mol%) THF, 20 Ph + Ph I II (90%) I:II = 85:15, I 96% ee OH O
(Eq. 103)
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964 anti:syn diastereoselectivity and up to 96% ee. Alternatively, ketone-derived trimethoxysilyl enol ethers have been employed in MeOH with the complex prepared from BINAP and AgF (Eq. 106). This represents a noteworthy example of a transition metal catalyzed process involving aldol addition that can be carried out successfully in a polar, protic solvent.
OCOCCl3 + H OH O (R)-p-Tol-BINAPMAgOTf (5 mol%) Me3SnOMe (5 mol%), MeOH (2 equiv), THF, 20 Ph + Ph OH O
O Ph
I II (86%) I:II = 94:6, I 96% ee
(Eq. 104)
O Ph H
O + O
(R)-Tol-BINAPMAgOTf (22 mol%) Bu2Sn(OMe)2 (20 mol%), MeOH (2 equiv), THF, 20 Ph
OH O
OMe (59%) 84% ee
(Eq. 105)
O Ph H
OSi(OMe)3 (R)-BINAPMAgF (10 mol%) Bu-t MeOH, 78 Ph
OH O Bu-t + Ph
OH O Bu-t
I II (77%) I:II = 1:99, I 97% ee
(Eq. 106)
There have been some recent exciting advances in asymmetric phase-transfer catalysis that make possible the addition of substituted ketone-derived enol silanes to aldehydes with useful levels of relative and absolute induction (Eq. 107).248
HSO4 Ar N+ CHO + OTMS Ar (2 mol%) KFM2H2O (0.5 equiv), THF, rt Ar = 3,5-(CF3)2C6H3 OH O
(90%) dr = 94:6, 91% ee
(Eq. 107)
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ORGANIC REACTIONS
Direct Aldol Addition Reactions of Substituted Systems. The direct aldol addition reactions of enolizable carbonyl compounds have been of interest for some time 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 addition 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 absolute stereocontrol that can be obtained. Additionally, the process can be conducted with low catalytic loadings. The addition of substituted -isocyanoacetates is possible, with the phenyl-substituted derivative affording products in the highest levels of relative and absolute induction (Eq. 109). Since its original disclosure the enolate precursor can be widely varied to include amides63,249 and other esters.250,251 Additional developments in ligand innovation and design,252,253 as well as the use of other metals (e.g. platinum),254 have also yielded improvements.
Me N
Fe
PPh2 PPh2 O n-C13H27 O (89%) 93% ee OMe N
ent-1 (1.1 mol%) O + n-C13H27 H CN O CH2Cl2, rt, 20-40 h
[Au(c-C6H11CN)2]BF4 (1 mol%) OMe
(Eq. 108)
Me N Fe O + Ph H O CN Ph OMe PPh2 PPh2 (1.1 mol%) [Au(c-C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt, 65-200 h Ph Ph O O OMe N + Ph Ph O N O OMe
N O
I II (97%) I:II = 93:7, I 94% ee, II 53% ee
(Eq. 109)
The first of the more recent advances in the in situ enolization of carbonyl C H acids and the subsequent stereocontrolled addition of the derived enolates to aldehydes was documented with lanthanide binaphthoxide catalysts, a class of bifunctional catalysts notable for their convenient synthesis and ready accessibility. These
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catalysts make possible the direct addition of ketones and hydroxy ketones to aldehydes in useful levels of relative and absolute stereoselectivity (Eqs. 110 and 111).65,83,216
O +
Ph
CHO
(R)-LLB (8 mol%), KHMDS (7.2 mol%) H2O (16 mol%), THF, 20, 99 h OH O Ph + Ph OH O
I II (95%) I:II = 93:7, I 76% ee, II 88% ee
(Eq. 110)
O H + OH OMe OH O Ph OH I + Ph OH II (50%) dr = 81:19, I 98% ee, II 79% ee OMe OMe OH O (S)-LLB (10 mol%), KHMDS (9 mol%) H2O (20 mol%), THF, 40
O Ph
3
(Eq. 111)
There have also been advances in this area involving the use of zinc(II) complexed to chiral alkoxy or phenoxy ligands (Eqs. 112 and 113, and Fig. 22).83,213,214
O O O Zn O O Zn O + C5H9 H OH O OMe 10 (1 mol%) THF, 30, 16-24 h OH O C5H9 OH OMe + C5H9 OH OH O OMe
I II (88%) I:II = 88:12, I 95% ee, II 91% ee
(Eq. 112)
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ORGANIC REACTIONS
Ph Ph
OH N
HO OH N
Ph Ph
(Eq. 113)
O + c-C6H11 H O OH O 11 (5 mol%) Et2Zn (10 mol%), 4 MS, THF, 35, 24 h OH c-C6H11 O OH O (90%) dr = 6:1, 96% ee
Ar Ar
OH N
HO OH N
Ar Ar
(5 mol%) O n-Bu H OH + O O Et2Zn (10 mol%), 4 MS THF, 35, 24 h Ar = 4-PhC6H4 OAc OAc O O OAc boronolide 1 OH n-Bu O OH O (90%) dr = 6:1, 97% ee
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 phenol. The typical addition reactions are conducted at reduced temperature and provide adducts in impressive levels of selectivity. For the BINOL-derived systems catalytic loadings as low as 1 mol% have been documented, while for the prolinol-derived systems slightly higher loadings are prescribed.65,218,222 A zinc(II) catalyst has been used 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 particularly noteworthy that a racemic titanium/BINOL complex is employed, which in the presence of optically active mandelic acid produces the aldol adducts as a 919 mixture of diastereomers with the major syn isomer formed in 91% ee.255
O Ph H + O rac-BINOL2-Ti2(OPr-i)3 (R)-mandelic acid (10 mol%), rt Ph (85%) dr = 91:9, 91% ee OH O
(Eq. 114)
There are reports of in situ enolization and aldol addition reactions mediated by catalytic phase-transfer catalysts.256 The addition of glycinate Schiff bases to alde-
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hydes under basic conditions in the presence of a chiral tetraalkylammonium phase transfer agent furnishes protected amino alcohol products in 21 dr and 95% ee (Eq. 115).
HSO4 Ar N+ O + Ph H Ph N OBu-t Ar (2 mol%) aq. NaOH (1 mol%), PhMe, 0 Ar = 3,5-(CF3)2C6H3 c-C6H11 NH2 (78%) dr = 2:1, 95% ee OH O OBu-t
O c-C6H11
(Eq. 115)
Proline has been investigated in the addition reactions of substituted ketones to aldehydes. These proline-mediated reactions, as well as other amine-catalyzed aldol addition reactions, are remarkable because of the high level of regio- and enantioselectivity they display. Thus, in an early example, the addition of cyclohexanone to isopentanal using 20 mol% of proline affords a 71 mixture of anti/syn adducts in 86 and 89% ee, respectively (Eq. 116).257 Hydroxyacetone has also been demonstrated to undergo facile, regioselective aldol addition reactions.66,258 The addition of excess hydroxyacetone to isobutyraldehyde mediated by 20 30 mol% of L-proline in DMSO at ambient temperature affords the adducts as a 201 mixture favoring the anti diol, itself isolated in 99% ee (Eq. 117). The ability to access 1,2-anti diol products complements the more conventional method involving asymmetric dihydroxylation of unsaturated ketones.259 These reactions have also been carried out in ionic liquids71,260,261 and with polymer-bound 4-hydroxyproline.262,263
O + H
L-proline (20 mol%)
O i-Pr
OH O i-Pr I + i-Pr CHCl3, rt, 60 h
OH O
II
(41%) I:II = 7:1, I 86% ee, II 89% ee
(Eq. 116)
O + H OH OH O i-Pr OH (62%) dr = 20:1, >99% ee
O i-Pr
L-proline (25 mol%)
DMSO, rt, 60 h
(Eq. 117)
Recent studies in this area have subsequently shown that it is possible to effect crossed aldol addition reactions between two aldehydes to give adducts in useful
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ORGANIC REACTIONS
levels of simple diastereoselectivity and high enantioselectivity (Eq. 118).86 For the addition of propionaldehyde to isobutyraldehyde or cyclohexanecarboxaldehyde the simple induction can be as high as 241; however, for additions to aldehydes such as propionaldehyde and isopentanal the selectivity is 3 4:1, with a preference for the anti adduct. The key to the success of this process appears to be the selection of the appropriate reactive components and the reaction conditions; thus, slow addition of the nucleophilic aldehyde component to the electrophilic aldehyde counterpart and 10 mol% of proline in DMSO at 4 constitute the optimal conditions for the cross-aldol addition reaction. The addition reaction of aldehydes to non-enolizable ketones has also been documented, affording adducts in 90% yield and up to 90% ee (Eq. 119)264,265
O H
L-proline (10 mol%)
OH O H (80%) dr = 4:1, 99% ee
DMF, 4
(Eq. 118)
O EtO O O OEt +
O H
L-proline (50 mol%)
CH2Cl2, rt, 3 h
OH O EtO2C H EtO2C (90%) 90% ee
(Eq. 119)
Enoxysilanes of Acetoacetate and Furan. The addition reactions of dienolates are gaining increased attention, as they provide access to densely functionalized building blocks for asymmetric synthesis. These additions offer a unique advantage in molecule assembly as a C4 carbon unit is appended to the aldehyde in the course of aldol addition. Consequently, they offer enhanced efficiency over an iterative aldol process that would otherwise require two sequential aldol addition reactions with concomitant protections and oxidation-state adjustments. One of the earliest examples of the use of a dienolate, namely 1-methoxy-3trimethylsilyloxy-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 mild acid into the corresponding 4H-pyran-4-ones with optical purity of up to 82% ee.
O 1. N Ts O BBu
O Ph H
OTMS OMe
N H 13 (20 mol%) EtCN, 78, 14 h 2. CF3CO2H
(Eq. 120)
O Ph O (100%) 82% ee
Pioneering examples of the use of acetoacetate-derived dienoxysilanes in aldehyde additions were reported using both boron- and titanium(IV)-derived catalysts
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(Eqs. 121 and 122).266,267 In these reactions large loadings of catalyst were necessary along with slow addition of the aldehyde substrate and the products were isolated in 38 69% yield and 67 92% ee.267
MeO CO2H O O B H (50 mol%), OMe O O CH2Cl2, 78, slow addition acidic work up O
O R H
O OTMS
OH O
(Eq. 121)
R O % ee R Ph (69%) 67 n-Bu (52%) 70
O Cl (20 mol%), Ti O Cl O R H + O O OTMS THF, 78, slow addition acidic work up OH O O
(Eq. 122)
R O % ee R Ph (38%) 88 n-Bu (55%) 92
Advances in the enantioselective addition of acetoacetate-derived dienolates has been reported with the titanium(IV) complex 5 and its enantiomer. The adducts are formed 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 aldol adducts that can be subsequently extensively functionalized, providing convenient building blocks for complex molecule assembly. This ability significantly facilitates the assembly of polyacetate-derived natural products, as exemplified in the synthesis of macrolactin A (Fig. 23).35
Bu-t N Br O Ti O O O O t-Bu Bu-t RCHO + O O OTMS ent-5 (2 mol%), Et2O, 0 2. TFA, THF R OH O O O
1.
% ee R (E)-PhCH=CH (88%) 92 Ph (83%) 84
(Eq. 123)
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ORGANIC REACTIONS
5 (2 mol%) O Bu3Sn H + O O OTMS ent-5 (2 mol%)
TMSO Bu3Sn 9
O
3 O
(80%) 92% ee O O 11
9
TMSO
17 SnBu3
(80%) 92% ee OH
3
O
11
HO HO
17
macrolactin A
Figure 23. Use of -stannylpropenal as starting material in the synthesis of macrolactin A.
Bisphosphine copper(I) complexes are also efficient in mediating dienolate additions to aldehydes. Thus, the complex that is generated upon mixing Tol-BINAP, Cu(OTf)2, and (Bu4N)Ph3SiF2 effects the rapid addition reaction of acetoacetatederived dienolates to aldehydes to give adducts in high yield and with high selectivity (Eq. 124).69,190,268,269 The addition of these dienolates to crotonaldehyde and other unsaturated aldehydes serves as an important launching point in a total synthesis of leucascandrolide A (Fig. 24),270 salicylhalamide A (Fig. 25),271 and madumycin 1 (Fig. 26).268
O H S + O O OTMS (S)-Tol-BINAP (2.1 mol%), Cu(OTf)2 (2 mol%) Bu4N+Ph3SiF2 (4 mol%), THF, 78 S (98%) 95% ee OH O O O
(Eq. 124)
O H
O OTMS
1. (R)-Tol-BINAP (2.1 mol%), Cu(OTf)2 (2.0 mol%), Bu4N+Ph3SiF2 (4.0 mol%), THF, 78 2. TFA O O OMe O O O MeO O leucascandrolide A
3
OH O
3
O O
(48%) 91% ee
O H N N O
Figure 24. Application of the copper-catalyzed aldol reaction to the synthesis of leucascandrolide A.
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1. (R)-Tol-BINAP (2.1 mol%), Cu(OTf)2 (2.0 mol%), Bu4N+Ph3SiF2 (4.0 mol%), OTMS THF, 78 2. TFA H N OH O O O
9 OH
55
O H + O O
OH O
9
O O
(64%) dr = 4.2:1
salicylhalamide A
Figure 25. Application of the copper-catalyzed aldol reaction to the synthesis of salicylhalamide A.
O BocHN H
O OTMS
(R)-Tol-BINAP 1. CuF, THF, 78 2. PPTS, MeOH, rt OH O BocHN

14
O O
(80%) 81% ee O O H N O N O
14 OH
O madumycin 1
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 reactions, useful levels of stereoinduction are observed, thus considerably expanding the scope of the acetoacetate aldol addition reactions. In studies aimed at the synthesis of octalactin A, the catalytic system afforded a useful intermediate (Eq. 126). 273
Cu(OTf)2 (10 mol%), (S)-Tol-BINAP (11 mol%) n-Bu4N+Ph3SiF2 (20 mol%), THF, rt
O Ph H
OTMS + OMe
OH Ph *
O OMe
(80%) 70% ee * not defined
(Eq. 125)
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ORGANIC REACTIONS
Cu(OTf)2 (10 mol%), (S)-Tol-BINAP (11 mol%) n-Bu4N+Ph3SiF2 (20 mol%), THF, rt
O
+
OTMS H OEt
OH i-Pr *
O OMe
i-Pr
(90%) 80% ee * not defined
(Eq. 126)
The catalytic systems that have been shown to effectively mediate additions to chelating aldehydes, such as benzyloxyacetaldehyde, have also been examined in the context of dienolate additions.37,74 The additions have been investigated with both acetoacetate-derived enoxysilanes (Eq. 127) as well as the bis-silyldienolate prepared directly from acetoacetate derivatives 20 and 21. The addition has been used in the preparation of the C4-C9 subunit of phorboxazole B (Eq. 128)274 as well as a key fragment in bryostatin 2 (Fig. 27).275,276
2+ O N O 2 SbF6 N Cu N Ph O BnO H + O O OTMS Ph 8 (5 mol%) BnO (94%) 92% ee
1.
OH O
O O
(Eq. 127)
O BnO H 20 + TMSO OTMS 1. 8 (0.5 mol%), CH2Cl2, 78 BnO (98%) 97% ee OH OH O OMe
OMe 2. acidic workup 3. Me4N(OAc)3BH
(Eq. 128)
O BnO H TMSO + 21 OTMS 1. ent-8 (5 mol%), CH2Cl2, 78 BnO (85%) 99% ee HO MeO2C O HO O O CO2Me bryostatin 2 O O H OH O O OH OH OH O O OBu-t
OBu-t 2. acidic workup
Figure 27. Application of the copper-catalyzed aldol reaction of dienolate in the synthesis of bryostatin 2.
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Silyloxyfurans are synthetically useful equivalents of -alkoxysubstituted ,unsaturated ester enolates. Their use in aldehyde additions has been documented using 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 to 90% ee. The use of this system has been documented in a total synthesis of 4-deoxygigantecin (Fig. 28).281 Bisoxazoline copper(II) complexes are effective in mediating these addition reactions as well. Thus, the addition of 1-trimethylsilyloxyfuran to pyruvate (Eq. 130) and benzyloxyacetaldehyde (Eq. 131) employing 10 mol% copper(II) catalyst affords adducts in high diastereoselectivity and 99% ee.197
O Ph (R)-BINOL (40 mol%), Ti(OPr-i)4 (20 mol%) O OTMS Et2O, 20 Ph O OH I O Ph OH O II
+ H
(99%) I:II = 24:76, I 60% ee, II 90% ee
(Eq. 129)
O C11H23 H O O O OH 4-deoxygigantecin
+ O
(R)-BINOL (40 mol%) OTMS Ti(OPr-i)4 (20 mol%), Et2O, 20 OH O
O O OH (80%) dr = 60:40, >96% ee C11H23 C11H23
Figure 28. Use of silyloxyfurans in the synthesis of 4-deoxygigantecin.

2+ O 1. t-Bu O MeO O + O OTMS N N Cu O 2 OTf HO MeO O O
Bu-t 4 (10 mol%) THF, 78 2. aq. HCl
O (99%) dr = 95:5, 99% ee
(Eq. 130)
2+ O N O 2 SbF6 N Cu N Ph O BnO H + O OTMS Ph 8 (10 mol%)
1.
(Eq. 131)
HO O O BnO (93%) dr = 91:9, 92% ee
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ORGANIC REACTIONS
Domino Reactions Involving Aldol Additions. Among the various exciting new developments involving enantioselective aldol addition reactions is their use in the context of domino processes. Although there are only a few examples, these are quite innovative and promising, as a consequence of the ability of such processes to potentially lead to powerful simplifications in synthetic planning and execution. Domino enantioselective processes involving aldol additions can be grouped into two general classifications on the basis of whether the aldol reaction is the first step or the subsequent in a series. There are several reports of domino sequences in which an aldol addition is the leading step. In these, aldolization is followed by either C=O reduction or ring formation. In the first of these, 2 mol% of a chiral yttrium complex effects the crossed aldol addition reaction between non-enolizable aldehydes and isobutyraldehyde.282 In the presence of excess aldehyde, the -hydroxyaldehyde aldol adduct subsequently undergoes Tishchenko reduction to afford a selectively protected 1,3-diol which is isolated in up to 84% ee (Eq. 132).
Ph H (13 mol%), N Ar Ar Y5O(OPr-i)13 (2 mol%), H CH2Cl2, 4 MS Ar = HO adamantyl Ph (70%) 84% ee Ph H N
O OH O Pr-i
O Ph H
+ i-Pr
(Eq. 132)
Another process in which an asymmetric aldol addition leads the sequence is the intramolecular version of the catalytic, enantioselective Wynberg -lactone synthesis, giving rise to bicyclic lactones through a sequence involving intramolecular aldol and lactone formation (Eq. 133).283 Thus, the formylacid initially undergoes conversion into the corresponding formylketene via chemoselective formation of the acid chloride. The ketene is then suggested to undergo reaction with the cinchona alkaloid catalyst to form a chiral enolate, which subsequently participates in aldol addition and ring closure. The products formed from these reactions are isolated enantioselectively in up to 92% ee.
MeO N + Cl Me I (3 equiv) i-Pr2NEt (4 equiv), MeCN, rt, slow addition O H AcO N CHO O OH CHO H N (10 mol%) (54%) 92% ee O O
(Eq. 133)
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A third example of aldehyde addition as the leading step in a domino sequence involves the addition of two equivalents of diethylketene acetal to phenyl pyruvate in the presence of 20 mol% of a copper-bisoxazoline catalyst (Eq. 134).284 Aldol-like addition to the ketone by the electron-rich diethyl ketene acetal leads to the formation 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 newly formed copper alkoxide, leading to the formation of a densely funtionalized pyran in up to 93% ee.
2+ O N EtO + EtO Ph O O OEt t-Bu N Cu O Bu-t 4 (20 mol%) Et2O, 15 2 OTf EtO OEt OEt OEt O Ph
(Eq. 134)
OEt O (80%) 93% ee
There are a number of processes wherein aldol addition follows a different initial reaction whose outcome is the generation of an enolate intermediate. Such processes have been documented in the context of conjugate additions. The reduction of enones and enoates generally proceeds through the intermediacy of metal enolates. When the conjugate additions are carried out with chiral metal complexes, they provide chiral metal enolates which can subsequently participate in enantioselective aldol addition reactions. In this respect, the reaction of methyl acrylate with benzyloxyacetaldehyde, in the presence of a chiral tridentate bisoxazoline ligand 22, and Ir(COD)Cl dimer, and a silane reductant leads to formation of propionate aldol adducts (Eq. 135).285,286 The adduct is formed diastereoselectively with a preference for the syn diastereomer (up to 101) in up to 96% ee. With certain chiral substrates the reaction process can display a significant amount of matching/mismatching. Thus, the addition of the acrylate-derived propionate enolate to both enantiomers of 3-benzyloxybutyraldehyde using the same catalyst affords complementary products
O 1. O BnO H O OMe N
N N
22 (3 mol%) [(COD)IrCl]2 (1 mol%), Et2MeSiH, rt, 24 h 2. aq. HCl
OH O BnO OMe
(84%) dr = 8:1, 96% ee
(Eq. 135)
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ORGANIC REACTIONS
in equally good selectivities (Eq. 136). However, for a given catalyst enantiomer only one enantiomer of the chiral 2-benzyloxypropionaldehyde undergoes addition. The reaction process has been applied in the synthesis of borrelidin 1 (Fig. 29), a complex natural product macrolide isolated from Streptomyces.287
O + H OMe 1. 22 (7.5 mol%), [(COD)IrCl]2 (2.5 mol%) Et2MeSiH, rt, 24 h 2. aq. HCl R syna OH O R synb R (R)-MeCH(OBn) (S)-MeCH(OBn) (R)-MeCH(OBn)CH2 (S)-MeCH(OBn)CH2 (50%) (<5%) (65%) (57%) syna:synb syn:anti >95:5 >95:5 n.d. n.d. 2.7:1 89:11 3.0:1 88:12 OMe + R anti OH O OMe OH O OMe +
O R
(Eq. 136)
O + H OMe 1. ent-2 (3 mol%), [(COD)IrCl]2 (1 mol%) Et2MeSiH, rt, 24 h 2. aq. HCl OH OH NC O CO2H borrelidin 1 O OH O PMBO OMe
O PMBO
(84%), dr = 6:1, >90% ee
Figure 29. Conjugate reduction/aldol sequence in the synthesis of borrelidin 1.
Enone acceptors can also lead to the formation of enolates through asymmetric metal-mediated conjugate addition reactions of carbon nucleophiles. The rhodiumcatalyzed addition reaction of phenylboronic acid to aryl enones affords an intermediate rhodium enolate which participates in a subsequent intramolecular aldol addition reaction, giving cyclic adducts in high yield and up to 95% ee (Eq. 137).288
O Ph(BOH)2 + Ph O [Rh(COD)Cl]2 (2.5 mol%), (R)-BINAP (7.5 mol%) H2O (5 equiv), dioxane, 95 Ph (88%) 94% ee O Et Ph OH
(Eq. 137)
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In another domino process involving conjugate addition followed by aldol addition, the enolate formed upon asymmetric 1,4-addition of diethyl methylmalonate carbanion to cyclopentanone participates in an intermolecular aldol addition, affording adducts in up to 89% ee and good yields (Eq. 138).68,289 The catalyst used in this process is the multifunctional complex 23 conveniently formed from LiAlH4 and BINOL. This cascade process has been elegantly employed in a synthesis of 11deoxy-PGF1 (Fig. 30).
CO2Bn CO2Bn Li O O Al O O 23 (10 mol%), NaOBu-t, THF, rt 2. OHC TBDMSO CO2Me
5
1.
OH CO2Me
TBDMSO
CO2Bn CO2Bn
(75%) dr = 12:1, 97% ee
(Eq. 138)
1. 23 (10 mol%)/ O THF, rt, 72 h
CO2Bn CO2Bn
O CO2Me CO2Bn CO2Bn (73%) 92% ee CO2H
2. OHC(CH2)5CO2Me 3. MsCl, DMAP, toluene 4. Al2O3 HO
OH 11-deoxy-PGF1
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 that there are typically numerous approaches available for the synthesis of any given building 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 develop reactions that display broad substrate scope, in reality no method can provide access
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ORGANIC REACTIONS
to the endless structural space of chiral building blocks. In this respect, even when a method displays the broadest scope, access to subclasses of starting materials may be sufficiently laborious that the use of the method may be precluded. In considering the preparation of aldol fragments, one cannot escape considering the use of diastereoselective chiral auxiliary-based methods. The development of asymmetric aldol addition processes has been most thoroughly and successfully studied in the context 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 this respect, addition reactions in which the stereochemical outcome of the reaction is derived from a chiral enolate component are most common. In particular, chiral carboxylic acid derivatives have proven most versatile and general. Hydrolysis of the aldol product affords the -hydroxy carboxylic acid (or ester) and the conjugate acid of 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 have permitted 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
O N Bn O n-Bu2BOTf, i-Pr2NEt, Et2O Ph O N O
O O Ph H +
OH O
(Eq. 139)
Bn (84%) dr >97%
O N Bn
S O 1. TiCl4, (i-Pr)2NEt, CH2Cl2, 0 2. i-Pr O H i-Pr
OH O N
S O
(Eq. 140)
Bn (87%) dr >95%
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 fact that the products are diastereomeric allows for ease of isomer purification by simple chromatographic means.
O O H + O MesSO2 N Bn Ph (c-C6H11)2BOTf, Et3N CH2Cl2, 78, 2 h MesSO2 OH O O N Bn Ph
(Eq. 141)
(90%) dr >96:4
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O + H O OH O Ph I O NHTs + Ph NHTs
63
O Ph
TiCl4, (i-Pr)2NEt CH2Cl2, rt OH O O II NHTs
(63%) I:II = 99:1
(Eq. 142)
In parallel with the developments in imide-derived chiral auxiliaries, there have been exciting advances in the use of chiral boron reagents which allow for the formation of chiral enolates (Eqs. 143 and 144).312 314 These permit efficient stereoselective coupling of ketone enolate and aldehyde fragments and are particularly noteworthy in the context of complex fragment couplings, imparting a great degree of convergency in the assembly of polyketides.
O H + O ()-Ipc2BCl (i-Pr)2NEt, Et2O (68%) 78% ee OH O
(Eq. 143)
Ph O MeO TBSO H + O SPh
Ph OH O MeO TBSO SPh (85%) 96% ds
Ar N B N Ar Br (i-Pr)2NEt Ar = 4-O2NC6H4O2S
(Eq. 144)
There has been a dramatic increase in the understanding of the various factors in the aldol addition reaction involving chiral enolate and chiral aldehyde coupling reactions. The nature of these processes makes them particularly amenable to mechanistic studies and analysis, and consequently it is possible to carry out numerous fragment coupling reactions that lead to stereochemically dense polyketide fragments (Eqs. 145 147).292,314 However, it should be noted that periodically one finds unexpected results even in chiral auxiliary-mediated aldol addition reactions, which require reevaluation of the accepted models in this area (Eq. 148).315,316
O Ph H O + OPMB n-Bu2BOTf (i-Pr)2NEt, Et2O, 78 Ph (89%) anti:syn = 95:5 OH O OPMB
(Eq. 145)
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O H +
ORGANIC REACTIONS
O OBz OH O
(c-C6H11)2BCl Me2NEt, Et2O
(Eq. 146)
OBz (97%) dr = 98:2
TBSO
O H + O
TBSO
OTBS (c-C6H11)2BCl Et3N, Et2O TBSO OH O
TBSO
OTBS
(84%) syn:anti = 82:18
(Eq. 147)
O H + TES O OBu-t OH O TES O O + OBu-t I (68%) I:II = 5:1 II OH O O TES O OBu-t
OLi O
THF, 120
(Eq. 148)
An overview of the aldol reaction in its various incarnations reveals an interesting dichotomy in the development of the two general class types for stereocontrol with respect to the family of ketides they provide access to. Thus, although chiralauxiliary controlled diastereoselective aldol processes that afford syn or anti substituted -hydroxy carbonyl compounds allow the ready synthesis of propionate fragments, they in general do not work well, with some exceptions (Eqs. 149 and 150),317 320 in furnishing acetate adducts. Yet, this latter case of aldol processes can be 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 synthetic chemist.
O Ph H O + O Ph Ph LDA, 100 Ph OH O O Ph Ph
Ph
Ph
OH
OH (89%) dr = 50:1
(Eq. 149)
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O O
Li Pr-i LDA/THF
O O
Pr-i
O Ph H Ph
OH O O
Pr-i
Pr-i
Pr-i
Pr-i (62%) dr >99:1
(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 preparation of both acetate and propionate fragments can be effected by catalytic, asymmetric hydrogenation of -diketones and -keto esters (Eq. 151).321,322 Applications of these highly effective processes are numerous. A particularly innovative application involves the asymmetric reduction of 1,5-dichloro-2,4-pentanone to an optically active diol and conversion of the diol product to the corresponding diepoxide, which serves as a useful starting material (Eq. 152).323 Optically active monosubstituted epoxides can be directly converted into -hydroxycarbonyl compounds (Eq 153).324 These serve as entry points for the preparation of anti-propionate subunits via the alkylation of -alkoxyenolate dianions.325 328
O
BnO
O OMe
(S)-BINAP-Ru 50 atm H2, rt

BnO
OH O OMe (94%) 99% ee
(Eq. 151)
Cl OH OH
Cl
KOH O
Br 1. Li2NiBr4 O 2. acetone, CSA
Br O O
(79%) overall from diol
(Eq. 152)
O Co2(CO)8 (5%), 3-HO-pyr (10%) CO, MeOH, THF, 60 OH O OMe
(92%)
(Eq. 153)
The allylation reaction of aldehydes leading to the formation of homoallylic alcohols has long been recognized as a useful, practical alternative for the generation of aldol fragments.329,330 Convenient access to -hydroxycarbonyl compounds is available from optically active homoallylic alcohols by oxidative olefin functionalization. These alcohols are readily accessed through asymmetric allylation reactions of aldehydes.331 340 The use of chiral allylboron reagents is most common
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ORGANIC REACTIONS
(Eqs. 154 and 155).341 343 Chiral allyllithium reagents generated in the presence of sparteine have also been documented (Eq. 156).344 Optically active allylsilanes have been cleverly utilized in the synthesis of complex polyketides (Eqs. 157 and 158).345,337 A particularly attractive feature of these processes is that alteration of the reaction conditions can lead to divergent stereochemical patterns in the products. Related methods commencing with chiral propargyl mesylates (Eq. 159) and allenylstannanes (Eq. 160) have been described and elegantly employed in complex molecule assembly.346
O H
+
2
Et2O, 100 B
OH
(82%) >99% ee
(Eq. 154)
O TESO TBDPSO O H + O B O O TESO TBDPSO I OH N N
CF3 PhMe, sieves, 78
CF3 TESO + TBDPSO II OH
I:II = 9:1
(Eq. 155)
O O O ()-sparteine N(Pr-i)2 s-BuLi Li O O i-Pr N(Pr-i)2 H i-Pr
OH O O (95%) 83% ee N(Pr-i)2
(Eq. 156)
OH BnO CO2Me (68%) syn:anti = 6.5:1
O BnO H
CO2Me SiPhMe2
BF3MOEt2 CH2Cl2, 78
(Eq. 157)
O BnO + H CO2Me SiPhMe2
MgBr2 CH2Cl2, 78
OH BnO CO2Me (59%) syn:anti = 1:12.2
(Eq. 158)
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TBSO O H + OMs TBSO OH
67
Pd(OAc)2, Ph3P Et2Zn, THF
(Eq. 159)
(76%)
BnO
O H
H + n-Bu3Sn
1. BF3MOEt2, CH2Cl2, 78 2. TESOTf, Et3N
BnO
OTES
(Eq. 160)
(88%) syn:anti = 94:6
The catalytic, enantioselective allylation of aldehydes has been examined and documented. The use of allyl stannanes in combination with a catalyst system derived from BINOL and Ti(IV) has proven highly effective for the synthesis of homoallylic alcohols (Eq. 161).338,347 The catalytic, enantioselective addition of allyltrimethylsilane has been effected with a catalyst derived from TiF4 BINOL.348,349
O Ph H + SnBu3 (+)-1,1'-BINOL (10 mol%) Ti(OPr-i)4, (10 mol%), CH2Cl2, 20 OH Ph (88%) 95% ee
(Eq. 161)
O + H
TMS
1. (S)-1,1'-BINOL (10 mol%), TiF4 (5 mol%), CH2Cl2, MeCN, 0 2. Bu4NF, THF, 0
OH
(90%) 94% ee
(Eq. 162)
There are new developments in the use of homoallylic alcohols for the synthesis of polyketide fragments. Treatment of a homoallylic alcohol with acetone in the presence of mercury leads to the formation of an alkyl mercurial intermediate that can subsequently undergo carbonylation to afford an aldehyde (Eq. 163).350 352 The silyl
PMBO i-Pr OH
Yb(OTf)3 (20 mol%) HgCl(OAc), acetone
PMBO i-Pr
O (75%)
O HgCl
Rh(acac)(CO)2 (3 mol%), P(OC6H4Bu-t-2)3 (6 mol%), 800 psi H2/CO, DABCO, EtOAc
PMBO i-Pr
O ()
O H
(Eq. 163)
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ORGANIC REACTIONS
ethers derived from homoallylic alcohols and diallylchlorosilane participate in a domino sequence of reactions involving directed hydrocarbonylation and intramolecular allylation of the aldehyde product, providing rapid entry into polyketides subunits (Eq. 164).353
Si 1. Rh(acac)(CO)2 (3 mol%), 1000 psi CO, C6H6 2. H2O2, NaHCO3 (55%) dr >10:1 OH OH OH
(Eq. 164)
The ability to prepare optically active epoxy alcohols as well as glycidate derivatives provides additional access to ketide fragments (Eqs. 165 167).354 358 Chiral epoxy alcohols have been shown to undergo pinacol rearrangements to furnish hydroxy aldehydes.359 362 Regioselective nucleophilic opening by carbon nucleophiles (or hydride) subsequently affords useful ketides.363 366
C3H7 OH t-BuOOH, Ti(OPr-i)4
D-()-diisopropyl tartrate
C3H7 OH (94%) 95% ee O
TBSOTf, i-Pr2NEt
C3H7 O TBSO (78%)
(Eq. 165)
H8-BINOL (5 mol%), Sm(OPr-i)3 (5 mol%) N cumene hydroperoxide THF/toluene, rt, 7 h O O BnO
O O BnO
O O BnO
O N
(80%) dr >99:1
(Eq. 166)
OH O N
S TBS
t-BuLi, HMPA THF
S TBS
S Li
O BnO (2.5 equiv) BnO
HO
OTBS OBn
(Eq. 167)
(86%)
A number of alternative approaches provide access to polyketide fragments and subunits. The recent development of highly diastereoselective dipolar cycloaddition reactions of nitrile oxides and chiral allylic alcohols furnishes a wide range of substituted isoxazolines that can be easily reductively opened to the corresponding hydroxy ketones (Eq. 168).367 369 The cycloaddition reaction of aldehydes with ketenes derived from acid bromides is catalyzed by a chiral aluminum complex,
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which furnishes -lactones in high selectivity and yield (Eq. 169).370 These lactones have been converted into the corresponding aldol fragments.371 Propargylic alcohols have also been converted into hydroxy carbonyl compounds in high optical purity.372 The alkylation of acetonides has been effectively employed in the synthesis of skipped polyols and can be relied upon to provide polyol stretches efficiently with high levels of induction (Eq. 170).373 In a unique approach to -hydroxy ketone and ester fragments, oxabicyclooctanes have been functionalized and cleverly manipulated to furnish long stretches of polyketide subunits (Eq. 171).374 376 The
+ O N TBSO N O TBSO (83%) OH
i-PrOH OMgBr CH2Cl2
(Eq. 168)
Bn N i-Pr Al N Tf Tf Me (10 mol%) C6H11-c (i-Pr)2NEt, CH2Cl2 N Pr-i O O H C6H11-c (85%) 94% ee
O Br
O + H
(Eq. 169)
Cl O O
CN
LiNEt2
Cl O O
NLi
I O O
CN CN Cl O O O O H CN
(45%)
(Eq. 170)
OH Pd(NCMe)2Cl2 (5 mol%), ligand (5 mol%) O Zn(OTf)2 (10 mol%), Me2Zn, (CH2Cl)2, reflux OTBS 1. TBSCl 2. PMBBr PMBO 1. O3, NaBH4 2. DDQ O HO
OH (90%) 88% ee
PMP O OTBS OH
(Eq. 171)
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ORGANIC REACTIONS
tandem sequence of reactions involving the diastereoselective conjugate addition reaction of cuprates to -alkoxy-,-unsaturated enoates followed by stereoselective oxidation of the ensuing enolate is also a powerful approach to polyketides (Eq. 172).376,377
BOMO TBSO O 1. Me2CuLi, TMSCl, THF, 78 2. KHMDS, THF, Davis oxaziridine, 78 BOMO TBSO OH OMe O (86%) ds >50:1
OMe
(Eq. 172)
Advances in bioorganic chemistry and biochemistry have resulted in the identification and engineering of novel enzymatic (Eq. 173 and 174)42 44,378 and antibody45 47 catalysts that provide access to aldolate fragments. The processes are notable by the fact that they are carried out under aqueous conditions and that they furnish polar products rich in functionality free of protecting groups.
N3 HO OH O H + N3 O H HO (70%) 2-deoxyribose-5-phosphate aldolase HO H
OH
(Eq. 173)
O H O H2N OH OH O
L-threonine aldolase
OH NH2 (35%) dr >99:1
(Eq. 174)
A number of the aldol addition reactions presented in this chapter are unique in that other direct routes to hydroxycarbonyl compounds are not easily envisioned because they would require laborious, multi-step synthetic sequences. In this category are found the acetoacetate and furan aldol addition reactions, additions affording isoxazolines, 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 enoxytrialkylsilanes. 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 dioxolinone.266 The preparation of the corresponding trialkoxyenoxysilanes has been described.246 Trichlorosilyl enolates of aldehydes, ketones, and esters are accessed
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from the corresponding enoxysilane or stannyl derivates and have been carefully documented.75,207,208,381 The stannane-derived enolates are prepared from the corresponding 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 prior to 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 the transition-metal-catalyzed processes can be sensitive to moisture, it is difficult to generalize, as some are tolerant of moisture and benefit from the addition of small amounts of water. The amine-catalyzed aldol addition reactions can provide useful alternatives to the transition-metal-catalyzed processes that form the majority of processes that have been documented. They offer a particular advantage in that the additional 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 other well-studied processes in catalytic asymmetric synthesis, catalytic, enantioselective aldol 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 efficiency require additional improvement. Advances in this respect will necessitate mechanistic insight and reaction innovation.
EXPERIMENTAL PROCEDURES
H N 1. N 1-tetrahydronaphthyl (25 mol%), Me Sn(OTf)2 (20 mol%), OH O SnO (20 mol%) TBSO OPh EtCN, 78, slow addition OBn 2. THF/HCl, 0 (70%) dr = 95:5, >96% ee
TBSO
+ BnO H
OTMS OPh
Phenyl (2R,3S)-2-(Benzyloxy)-5-(tert-butyldimethylsiloxy)-3-hydroxypentanoate (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-methyl2-(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 added to the catalyst over 4 hours. The reaction mixture was further stirred for 2 hours at the same temperature and then quenched with saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and evaporated. The crude product was treated with THF/1N HCl (201) at 0. After the usual workup, the crude aldol was purified by chromatography on silica gel to afford the title com-
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ORGANIC REACTIONS
pound in 70% yield. The diastereomer ratio was determined by 1H NMR analysis (syn/anti 955). The enantiomeric excess of the syn adduct was determined to be 96% ee by HPLC analysis using Daicel Chiralcel AD [hexane/i-PrOH (91), flow rate 1.0 mLminutes, tR 8.2 minutes (2S,3R), 15.6 minutes (2R,3S)]. syn: []25D 58.0 (c 2.0, CHCl3); IR (neat) 3478, 2928, 1771, 1594, 1493, 1093 cm1; 1H NMR (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.
O H MeO + OTMS OPh (R)-3,3'-I2BINOL (12 mol%), Zr(OBu-t)4 (10 mol%) n-PrOH (80 mol%), H2O (20 mol%), PhMe, 0 OH O OPh MeO (94%), dr = 95.5, 99% ee
Phenyl (2S,3S)-3-Hydroxy-2-methyl-3-(4-methoxyphenyl)propanoate (Zirconium-catalyzed Aldol Reaction).180 To a suspension of (R)-3,3-diiodo-1,1-binaphthalene-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 stirred for 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 temperature. After cooling at 0, benzaldehyde (0.40 mmol) in toluene (0.75 mL) and silyl enol ether (0.48 mmol) in toluene (0.75 mL) were added successively. The mixture was stirred for 18 hours and saturated aqueous NaHCO3 solution (10 mL) was added to quench the reaction. After CH2Cl2 (10 mL) was added the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2 10 mL). The organic layers were combined and dried over Na2SO4. After filtration and concentration under reduced pressure, the residue was treated with THF/1 N HCl (201) for 1 hour at 0. The solution was then made alkaline with saturated NaHCO3 and extracted 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 (201)] to afford the title compound. The optical purity was determined by HPLC analysis using a chiral column. HPLC (after acetylation), Daicel Chiralcel OD, hexane/i-PrOH (301), flow rate 0.5 mLminute: 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 cm1; 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); detectable peaks of syn isomer 1.34 (d, J 7.1 Hz, 3H), 5.07 (d, J 5.6 Hz, 1H); 13C NMR (CDCl ) anti isomer 14.3, 47.5, 55.2, 76.0, 113.8, 121.5, 125.8, 127.9, 3 129.3, 133.5, 150.5, 159.4, 174.4; detectable peaks of syn isomer 11.9, 47.1, 55.2,
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74.0, 113.7, 121.3, 127.4, 129.3, 129.4, 133.6, 150.3, 159.1, 173.8. HRMS (mz): [M] calcd for C17H18O4, 286.1205; found, 286.1202.
O N Ts O BBu (20 mol%), OH O Bu-n Ph (100%) 90% ee
1.
O Ph H
OTMS Bu-n
N H EtCN, 78, 14 h 2. 1 M HCl
(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-mL round-bottom flask was added benzaldehyde (0.028 mL, 0.28 mmol) followed by 2trimethylsiloxy-1-hexene (0.080 mL, 0.41 mmol). The reaction mixture was stirred for 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 combined organic phases were dried (MgSO4) and concentrated. The residue was dissolved in THF (4 mL) and aqueous 1 M HCl (2 mL), and the resulting solution left standing for 30 minutes. Saturated aqueous NaHCO3 solution (20 mL) was added and the mixture was extracted with Et2O (4 25 mL). The combined organic phases were 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 enantiomeric excess of 90% (tr major 11.5 minutes; minor 13.8 minutes).
Bu-t N Br O Ti O O O O t-Bu O H Ph(CH2)3 + OTMS OMe Bu-t (3 mol%) 2,6-lutidine (40 mol%), Et2O, 0 2. TBAF, THF Ph(CH2)3 (84%) 96% ee OH O OMe
1.
Methyl (R)-3-Hydroxy-8-phenyloct-4-ynoate (Titanium-catalyzed Aldol Reaction).188 To a solution of the chiral Schiff base ligand (5.0 mM, 0.066 equiv) in toluene 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 in toluene) was added. Stirring was continued for an additional hour at room tempera-
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ORGANIC REACTIONS
ture. The solvent was removed in vacuo and the orange solid was dissolved in Et2O to 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-phenylhex-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 hours before it was poured into water. The organic phase was dried over Na2SO4 and concentrated 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. The organic layer was washed with 5% aqueous NaHCO3 solution and then brine, dried (Na2SO4), and concentrated in vacuo. Purification by chromatography on silica gel using CH2Cl2/hexanes (101) to elute the ligand, followed by CH2Cl2 /Et2O (101) 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 cm1; 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.
2+ O 1. O BnO H + OTMS O N N 2 OTf Cu Bu-t t-Bu 4 (10 mol%) BnO
OH O SBu-t (100%) 96% ee
CH2Cl2, 78 SBu-t 2. aq. HCl, THF
(R)-S-tert-Butyl 4-Benzyloxy-3-hydroxybutanethioate (Copper-catalyzed Aldol Reaction).74 To a 5-mL round-bottom flask equipped with a magnetic stirring bar and fitted with a septum was added 200 L (2.5 mol, 0.5 mol%) of a 0.0125 M solution of the catalyst in CH2Cl2. After cooling to 78, benzyloxyacetaldehyde (74.8 mg, 0.50 mmol, 70.0 L) was added followed by (1-tert-butylsulfanylvinyloxy)-trimethylsilane (122 mg, 0.60 mmol, 153 L). The resulting solution was stirred at 78 until the aldehyde was completely consumed, as determined by TLC (30% EtOAc/hexanes). The reaction mixture was then filtered through silica gel (1.5 8 cm plug) with Et2O (50 mL). Concentration of the ether solution gave a clear oil which was dissolved in THF solution (10 mL) and 1 N HCl (2 mL). After standing at room temperature for 15 minutes, the solution was poured into a separatory funnel and diluted with Et2O (10 mL) and H2O (10 mL). After mixing, the aqueous layer was discarded and the ether layer was washed with saturated aqueous NaHCO3 solution (10 mL) and brine (10 mL). The resulting ether layer was dried over MgSO4, filtered, and concentrated to provide pure title compound in 100% yield (141 mg, 0.50 mmol). []rtD 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 Chiralcel OD-H column [hexanes:i-PrOH:EtOAc (94.20.85.0), 1.0 mLminute] R
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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.
Me
Ph O Ph H + OSiCl3 1. Ph
N O P N N
Me
(5 mol%)
OH O Ph (98%) 87% ee
CH2Cl2 2. aq. NaHCO3
(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 a cold (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 stirred at 75 for 2 hours, then was quickly poured into cold (0) saturated aqueous NaHCO3 solution and the resulting slurry was stirred for 15 minutes. The two-phase mixture was filtered through Celite, the phases were separated, and the aqueous phase was extracted with CH2Cl2 (3 50 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated, and the residue was purified by column chromatography [SiO2, pentane/Et2O (11)] to give 321.6 mg (98%) of the title compound as a clear, colorless oil. TLC: Rf 0.16 [hexane/EtOAc (31)]; []24D 51.4 (c 1.47, CHCl3); IR (neat) 3466, 3424, 2910, 1710, 1417, 1361, 1062, 756, 701 cm1; 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.
O Ph H + O Bu3Sn Bu-t (R)-BINAP (11 mol%)/Ag(OTf) (11 mol%) THF, 20, 8 h OH O Ph Bu-t (78%) 95% ee
(R)-4,4-Dimethyl-1-hydroxy-1-phenyl-3-pentanone (Silver-catalyzed Aldol Reaction).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 direct light excluded, and stirred at 20 for 10 minutes. To the resulting solution was added dropwise a THF solution (3 mL) of benzaldehyde (100 L, 0.98 mmol), and then 3,3-dimethyl-1-tributylstannyl-2-butanone (428.1 mg, 1.10 mmol) was added over 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 room temperature, the mixture was treated with brine (2 mL) and solid KF (ca. 1 g). The resulting precipitate was removed by filtration and the filtrate was dried over Na2SO4
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and concentrated in vacuo. The crude product was purified by column chromatography on silica gel to afford the title compound (161.7 mg, 78% yield) as a colorless oil: TLC Rf 0.22 [EtOAc/hexane (15)]; []30D 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 cm1; 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 HPLC analysis using a chiral column (Chiralcel OD-H, hexane/i-PrOH (201), flow rate 0.5 mLminute) tminor 17.7 minutes, tmajor 20.2 minutes. The absolute configuration of the product was unknown and assigned to be R by analogy.
Li O O Li O La O O O Li O + Ph H O NO2 (R)-LLB (8 mol%) KHMDS (7.2 mol%) H2O (16 mol%), THF, 20 Ph (85%) 89% ee OH O NO2
(S)-3-Hydroxy-4-methyl-1-(3-nitrophenyl)-1-pentanone (Heterobimetalliccatalyzed Aldol Reaction).216 To a stirred solution of potassium bis(trimethylsilyl)amide (KHMDS, 43 L, 0.0216 mmol, 0.5 M in toluene) at 0, was added a solution of water (48.0 L, 0.048 mmol, 1.0 M in THF). The solution was stirred for 20 minutes at 0 and then catalyst (400 L, 0.024 mmol, 0.06 M in THF) was added and the mixture was stirred at 0 for 30 minutes. The resulting pale yellow solution was 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-dimethyl3-phenylpropanal (49.9 L, 0.3 mmol) was added and the reaction mixture was stirred 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 combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography [SiO2, Et2O/hexane (112)] to give the title compound (72 mg, 85%, 89% ee); []28D 40.8 (c 0.56, CHCl3) (70% ee); IR (neat) 3541, 1688, 1535, 1351 cm1; 1H NMR (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); 13C NMR (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 mz 237 (MCH3), 165 (Mi-PrCHO), 150 (ArC O, base peak); HPLC [Chiralpak AS, 2-PrOH/hexane (19), flow 1.0 mLminute] tR 16.1 and 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.
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Ph Ph HO OH N Ph Ph
77
OH N
, Ph3P=S O + c-C6H11 H O Ph 11 (5 mol%) Et2Zn (10 mol%), 4 MS, THF, 5 OH O Ph c-C6H11 (60%) 98% ee
(R)-3-Cyclohexyl-3-hydroxy-1-phenylpropan-1-one (Zinc-catalyzed Aldol Reaction).220 Under an argon atmosphere, a solution of diethylzinc (1 M in hexane, 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 of ethane gas), the resulting solution was used as catalyst for the aldol reaction (ca 0.09 M solution). To a suspension of cyclohexylcarboxaldehyde (0.5 mmol), triphenylphosphine sulfide (22.1 mg, 0.075 mol), powdered 4 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 was stirred at 5 for 2 days. The resulting mixture was poured onto 1 N HCl and extracted with Et2O. After normal workup, the crude product was purified by silica gel column chromatography using a mixture of petroleum ether and Et2O. The title compound was obtained in 60% yield and 98% ee.
O i-Pr H + O
L-proline (25 mol%)
OH O i-Pr (97%) 96% ee
DMSO, rt
(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 (41) for 15 minutes. Isobutyraldehyde (0.1 mmol) was added and the mixture was stirred for 4 24 hours. The mixture was treated with saturated aqueous NH4Cl solution and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and concentrated to give the title compound after column chromatography [hexanes/EtOAc (31)].
2+ O 1. O MeO O + OTMS SBu-t O N N 2 OTf Cu Bu-t t-Bu 4 (10 mol%) MeO O (88%) dr = 97:3, 99% ee
OH O SBu-t
THF, 78 2. aq. HCl
S-tert-Butyl (3S)-3-Hydroxy-3-methoxycarbonyl-2-butanethioate (Coppercatalyzed Aldol).197 To a 10-mL round-bottom flask were added, in an inert
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ORGANIC REACTIONS
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 was cooled to 78 and methyl pyruvate (45 L, 0.50 mmol) was added, followed by the 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 by TLC (2.5% Et2O/CH2Cl2). The reaction mixture was then filtered through a 2 4 cm plug of silica gel with Et2O (60 mL). Concentration of the solution gave the crude silyl 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 into a 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 aqueous NaHCO3 solution (10 mL) and brine (10 mL). The resulting ether layer was dried over Na2SO4, filtered, and concentrated to provide the title compound as a clear oil in 88% yield (112 mg, 0.48 mmol) after flash chromatography (10 20% EtOAc/hexanes). Enantiomeric excess was determined by HPLC [Chiralcel OD-H column (hexanes/2-propanol (991), flow 0.5 mLminute]: 2S,3S enantiomer tr 13.4 minutes, 2R,3R enantiomer tr 12.7 minutes, 99% ee; []rtD 25.1 (c 5.2, CHCl3); IR (CH2Cl2) 3534, 2967, 1738, 1678 cm1; 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) (mz): 235 (MH), 252 (M NH4); HRMS (CI/NH3) (mz): calcd for (C10H18O4S NH4), 252.1270; found, 252.1268.
CCl3 O Ph H + O O (R)-p-Tol-BINAP/Ag(OTf) (5 mol%), Me3SnOMe (5 mol%), MeOH THF, 20-rt, 8 h Ph OH O + Ph OH O
I II (86%) I:II = 94:6, I 96% ee, II 18% ee
(2S,1R)-2-(Hydroxyphenylmethyl)cyclohexanone (Silver-catalyzed Aldol Reaction).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 atmosphere and 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 trimethyltin methoxide (0.52 M in THF, 100 L, 0.052 mmol) successively at 20. After being stirred for 4 hours at this temperature and then for 12 hours at room temperature, 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 precipitate was removed by filtration using a glass filter funnel filled with Celite and silica 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 to afford 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 946 by 1H NMR analysis. The enantioselectivities of the anti and syn isomers were determined to be 96% ee and 18% ee, respectively, by HPLC [Chiralcel OD-H, hexane/i-PrOH (91), flow rate 0.5 mL
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minutes]: 2S,1S enantiomer tsyn-minor 14.2 minutes, 2R,1R enantiomer tsyn-major 15.7 minutes, 2S,1R enantiomer tanti-major 17.4 minutes, 2R,1S enantiomer tanti-minor 24.2 minutes. Spectral data of the anti isomer (oil, 96% ee): TLC Rf 0.11 [EtOAc/hexane (15)]; []32D 19.7 (c 1.0, CHCl3). IR (neat) 3700 3140, 2940, 2863, 1700, 1605, 1497, 1453, 1401, 1312, 1296, 1227, 1204, 1130, 1042, 702 cm1; 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,); 13C NMR (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): TLC Rf 0.13 [EtOAc/hexane (15)]; []33D 37.6 (c 1.0, CHCl3); IR (KBr) 3600 3125, 2940, 2855, 1701, 1603, 1495, 1449, 1406, 1320, 1132, 1063, 986, 696 cm1; 1H NMR (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.
N O Fe PPh2 PPh2 (1.1 mol%) OMe [Au(C6H11CN)2]BF4 (1.0 mol%), CH2Cl2 (1 mol%), rt, 18 h Me N
O Ph H
O + CN
O Ph O N Ph OMe + O N
O OMe
I II (99%) I:II = 90:10, I 91% ee, II 7% ee
(4S,5R)-4-(Methoxycarbonyl)-5-phenyl-2-oxazoline (Gold-catalyzed Aldol Reaction).253 To a solution of ligand (37.5 mg, 0.055 mmol) in CH2Cl2 (6 mL) was added the gold complex (25.1 mg, 0.05 mmol). The reaction mixture was stirred for 10 minutes, and then to the resultant solution were added sequentially methyl isocyanoacetate (0.45 mL, 5 mmol) and benzaldehyde (0.56 mL, 5.5 mmol). The reaction mixture was stirred for 18 hours at room temperature. The solvent was removed in vacuo, 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 was bulb-to-bulb distilled (Kugelrohr), to give a 9010 cis/trans mixture of the title compound in 99% combined yield, which was analyzed by GLC using a Chirasil-L-Val column and by 1H NMR with the chiral shift reagent ()-2,2,2-trifluoro-1-(9-anthryl)ethyl alcohol.
O O O Zn O O Zn O Ph H O + OH OMe 10 (1 mol%) THF, 20, 18 h; then acetone, H+ Ph O MeO (83%) dr = 89:11, 96% ee
O O
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(2 R ,3 S )-2,3-Dihydroxy-2,3- O -isopropylidene-1-(2-methoxyphenyl)-5phenyl-1-pentanone (Zinc-catalyzed Aldol Reaction of a Hydroxyketone).83 Molecular sieves (3 , 200 mg, powder) in a test tube were activated prior to use under 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. The mixture 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) was added. 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 mixture was extracted with EtOAc and the combined organic layers were washed with saturated aqueous NaHCO3 solution and brine, and dried over MgSO4. Evaporation of solvent gave a crude mixture of the title compound. The diastereomeric ratio of the aldol product was determined by 1H NMR of the crude product. After purification by silica gel flash column chromatography [hexanes/acetone (81-41)], the title compound was obtained (269.6 mg, 0.898 mmol, 90%, dr syn/anti 8911, 96% ee syn). Spectral data were collected after conversion into the acetonide. colorless oil; []21D 39.4 (c 0.52, CH2Cl2) (92% ee). HPLC (for diol) [Daicel Chiralcel OD, i-PrOH/hexane (2080), flow 1.0 mLminute, detection at 254 nm]: tR 13.6 minutes (minor) and 15.9 minutes (major); IR (neat) 2936, 1685, 1598, 1247 cm1; 1H NMR (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 (mz): 340 [M], 135 [ArCO]; HRMS-FAB (mz): [M H] calcd for C21H25O4, 341.1753; found, 341.1743.
O + OH H O C6H11-c
L-proline (25 mol%)
OH
DMSO, rt, 60 h
C6H11-c OH (62%) dr = 20:1, >99% ee
(3S,4S)-4-Cyclohexyl-3,4-dihydroxybutan-2-one (L-Proline-catalyzed Aldol Reaction of a Hydroxyketone).257 To a mixture of anhydrous DMSO (4 mL) and hydroxyacetone (1 mL) was added cyclohexanecarboxaldehyde (0.5 mmol) followed by L-proline (25 mol%), and the resulting homogeneous reaction mixture was stirred at room temperature for 60 hours. Then half-saturated NH4Cl solution and EtOAc were added with vigorous stirring, the layers were separated, and the aqueous 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 (8515), flow rate 1.0 mLminute, 285 nm]: tR 6.22 minute; []D 83 (c 1, CHCl3); IR (NaBr): 3445, 2922, 2351, 1730, 1640, 1456, 1373, 1253, 1045, 736 cm1; 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:
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25.8, 26.1, 26.2, 72.4, 29.7, 39.7, 77.5, 78.3, 209.9; HRMS (mz): [M Na] calcd for C10H18O3, 209.1148; found, 209.1157.
Bu-t N Br O Ti O O O O t-Bu O Ph H + O O (2 mol%) Bu-t Ph (88%) 92% ee OH O O O
1.
2,6-lutidine (40 mol%), Et2O, 0 OTMS 2. TFA, THF
( 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 chiral Schiff base ligand (5.5 mM, 0.022 equiv) in toluene was added Ti(OPr-i)4 (0.010 equiv). The orange solution was stirred for 1 hour at room temperature and a solution 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 was removed 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 cinnamaldehyde (1.0 equiv) and the dienolate (1.5 equiv). After the reaction mixture was stirred for 4 hours at 0, it was poured into water. The mixture was extracted with 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 the solution was partitioned between Et2O and water. The organic layer was washed twice with a 5% aqueous NaHCO3 solution and then with brine. The solution was dried over Na2SO4 and concentrated in vacuo. Purification by chromatography on silica gel [hexane/EtOAc (21)] afforded the aldol adduct. A portion of the aldol adduct was converted into the corresponding (S)-MTPA ester as follows. To a solution of the alcohol (0.010 mmol, 1 equiv) and DMAP (10 mg) in CH2Cl2 (1 mL) was added (R)-MTPA-Cl (0.011 mmol, 1.1 equiv). The MTPA ester was purified by chromatography on silica gel [hexane/EtOAc (21)]. The enantiomeric excess of the product was determined by integration of the 1H NMR (300 MHz, CDCl3). The title compound was isolated (88%) as a white crystalline solid, mp 85 86; []6.2 (c 1.0, CHCl3). IR (thin film) 3420, 1728 cm1; 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 (mz): [M H] calcd for 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 24.41 (92% ee). After crystallizing 90 mg of the title product from hexane/EtOAc (61), 55 mg (61% yield) of white needle crystals (mp 88 89) were obtained which were found to be 99% ee by integration of the 1H NMR of the (S)-MTPA ester.
c01_tex
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12:31 PM
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82
ORGANIC REACTIONS
O 1. O MeO O H OBn N
N N
(7.5 mol%) [(cod)IrCl]2 (2.5 mol%), Et2MeSiH 2. H3O+ MeO
OH OBn
(49%) 94% ee
(2S,3S)-Methyl-4-benzyloxy-3-hydroxy-2-methylbutanoate (Iridium-catalyzed 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/methyl acrylate solution (1.7 mL, 0.7 M in aldehyde and 0.84 M in acrylate, 1.19 mmol aldehyde, 1.43 mmol acrylate) was added dropwise. The vessel was then sealed and the contents stirred for 24 hours. The solvent was then evaporated from the reaction mixture and 1 mL each of THF, MeOH, and 4 N HCl were added. The solution was stirred at room temperature for an additional 30 minutes. The product was extracted with EtOAc (3 7 mL), and the combined organic layers were washed with saturated NaHCO3 solution (2 20 mL), dried over MgSO4, and filtered. The solvent was removed by rotary evaporation to give the crude product, which was purified via flash chromatography (101 then 81 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 cm1; 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 catalytic asymmetric aldol addition reactionsmeaning catalytic in the enantioinducing chiral speciesuntil January 2003 and was effected using Beilstein and SciFinder. Given the complexity of the subject, different organizations of this tabular survey were conceivable. The finally adopted structure is based on the differentiation between direct aldol reactions and Mukaiyama-type additions. Each section is further subdivided 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 the nucleophilic component (not taking into consideration protective groups), followed by 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 given in the original report.
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12:31 PM
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83
The following abbreviations were used in the tabular survey. Ac acetyl acac acetylacetonyl atm atmosphere BBN borabicyclo[3.3.1]nonyl BINAP 2,2-bis(diphenylphosphino)-1,1-binaphthyl BINOL 1,1-bi-2-naphthol Bn benzyl Boc tert-butyoxycarbonyl Bu butyl Bz benzoyl cod cyclooctadiene de diastereomeric excess DMF N,N-dimethylformamide DMSO dimethyl sulfoxide dr diastereomeric ratio ee enantiomeric excess KHMDS potassium hexamethyldisilazide LLB lithium lanthanum binaphthoxide complex MOM methoxymethyl Ms methanesulfonyl MS molecular sieves Ns 4-nitrophenylsulfonyl PCC pyridinium chlorochromate Ph phenyl Piv pivaloyl PMB p-methoxybenzyl PMP p-methoxyphenyl Py pyridine rac racemic rt room temperature sc supercritical ,,,-tetraaryl-1,3-dioxolan-4,5-dimethanol Taddol TBAF tetra-n-butylammonium fluoride TBAI tetra-n-butylammonium iodide TBDPS tert-butyldiphenylsilyl TBS tert-butyldimethylsilyl TES triethylsilyl Tf trifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran TIPS triisopropylsilyl TMEDA N,N,N,N-tetramethylethylenediamine TMS trimethylsilyl Tol 4-methylphenyl Tr trityl Ts 4-methylbenzenesulfonyl
c01_tex
TABLE 1A. SILVER-CATALYZED MUKAIYAMA-TYPE ALDOL ADDITIONS

Electrophile O (R)-BINAPMAgOTf (10 mol%), 94 R1 R2 % ee (73) (83) (61) (78) (69) (75) (57) (33) (40) 50 41 71 94 86 95 59 53 77 Ph (E)-PhCH=CH Ph(CH2)2 Ph (E)-PhCH=CH Ph(CH2)2 Ph (E)-PhCH=CH Ph(CH2)2 R2 THF, 20, 8 h OH Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C38
OSn(Bu-n)3
R2CHO
R1
R1
12:31 PM
Me
Me
Me
t-Bu
t-Bu
Page 84
t-Bu
Ph
Ph
Ph
84
(R)-Tol-BINAPMAgOTf (22 mol%), O Ph O OH Bu2Sn(OMe)2 (20 mol%), MeOH (2 equiv), THF, 20, 72 h O (R)-BINAPMAgOTf (10 mol%), THF, 20, 8 h I OH Ph + O OH MeO II (R)-Tol-BINAPMAgOTf (5 mol%), Me3SnOMe (5 mol%), MeOH (2 equiv), THF, 20 I II O OH R + O
C4
PhCHO
(59) 84% eea
247
C5
OSn(Bu-n)3
PhCHO
Ph
(92) I:II = 89:11, 92% ee I
94
C6
OCOCCl3
OH R 244
RCHO
c01_tex
R I:II (61) 76:24 94:6 94:6 80:20 78:22 84:16 96:4 92 79 90 77 95 96 83 (86) (66) (49) (76) (29) (74) % ee I (E)-n-PrCH=CH Ph 4-MeOC6H4 O O (E)-PhCH=CH Ph(CH2)2 1-C10H7
4/18/06 12:31 PM Page 85
OSi(OMe)3 O R Ph 4-BrC6H4 (87) 4-MeOC6H4 (86) (78) (R)-Tol-BINAPMAgF (10 mol%), R MeOH, 78
OH
syn:anti % ee syna 84:16 76:24 75:25 87 90 92 245
RCHO
85
O (R)-BINAPMAgOTf (10 mol%), THF, 20, 8 h I II Ph + OH O OH O (R)-Tol-BINAPMAgF (10 mol%), MeOH, 78 t-Bu OH R R Ph 4-BrC6H4 4-MeOC6H4 1-C10H7
OSn(Bu-n)3
PhCHO
Ph
(94) I:II = 92:8, 93% ee I
94
C7
OSi(OMe)3
syn:anti % ee syna (84) (64) (76) (E)-PhCH=CH (56) (63) > 99:1 > 99:1 > 99:1 > 99:1 94:6 97 87 96 85 95 245
RCHO
t-Bu
c01_tex
TABLE 1A. SILVER-CATALYZED MUKAIYAMA-TYPE ALDOL ADDITIONS (Continued)

Electrophile
Product(s), Yield(s) (%) and Stereoselectivity
4/18/06
Nucleophile O O Ph + Ph (90) I:II = 85:15, 96% ee I 94 (R)-BINAPMAgOTf (10 mol%), THF, 20, 8 h I II OH OH
Conditions
Refs.
C7
OSn(Bu-n)3
12:31 PM
PhCHO
C78 (R)-BINAPMAgOTf (10 mol%), t-Bu R I R2 I:II (81) > 99:1 (98) > 99:1 R Ph R Ph Ph c-C6H11 1-C10H7 2-C10H7 OH AgOAc (2 mol%), (S)-BINAP (2 mol%), DMF, rt R Ph O R Ph Ph c-C6H11 1-C10H7 2-C10H7 (100) (100) (100) (100) (100) (100) (36) (83) (82) (100) 95 95 91 % ee 69 80b 47a 54a 58a % ee 11 11b 6a 17a 15a Ph Ph(CH2)2 (77) > 99:1 Ph OH AgPF6 (2 mol%), (S)-BINAP (2 mol%), DMF, rt O % ee I
1
OSn(Bu-n)3 R2 t-Bu R II
1
O + R2
OH
O OH
Page 86
t-Bu THF, 20, 8h
R1
R2CHO
94
R1
Me
86
Me
Et
C8
OTMS
RCHO
385
Ph
RCHO
385
c01_tex 4/18/06 12:31 PM
C9 OH AgOAc (2 mol%), (S)-BINAP (2 mol%), DMF, rt (98) syn:anti = 84:16, 23% ee Ia Ph Ph O
Page 87
OTMS
PhCHO
385
Ph
87
The absolute configuration was not determined.
The reaction was carried out at 30.
c01_tex
TABLE 1B. BORON-CATALYZED MUKAIYAMA-TYPE ALDOL ADDITIONS

Electrophile Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C2 CHO 2-O2NC6H4 S Cl MeO Cl N B H O O CH2Cl2, 78, 7 h O (20 mol%), OMe (88) 77% ee 386 i-Pr O OH O
OTMS
Cl
OMe
12:31 PM
Cl
MeO
Page 88
OTMS O (20 mol%), R OEt Br I R BnOCH2 n-Pr i-Bu Et2CH Ph c-C6H11 Ph(CH2)2 OH (20 mol%), R Br F I O OEt + R F Br II (96) (70) (90) (74) (89) (90) (81) I:II 57:43 46:54 48:52 54:46 69:31 52:48 57:43 (E)-PhCH=CH (96) 46:54 II % ee I % ee II 97 97 98 99 98 94 83 98 97a 98a 98a 98a 90 89a 83a 98a F F Br R OEt + OH O OH O
F Pr-i BH3MTHF (22 mol%), EtNO2, 78 OH NHTs
OEt
RCHO
387
Br
(E/Z = 62:38)
88
O OH NHTs Pr-i EtNO2, 20 BH3MTHF (22 mol%),
OH
O OEt 387
RCHO
c01_tex
R % ee II 72a 93a 88a 74a 13b 81a 92a BnOCH2 n-Pr i-Bu Et2CH Ph c-C6H11 Ph(CH2)2 OH (20 mol%), R F n-Pr i-Bu Et2CH Ph c-C6H11 Ph(CH2)2 n-C9H19 O OH (20 mol%), R F F OEt O R BnOCH2 n-Pr i-Bu Et2CH Ph c-C6H11 Ph(CH2)2 n-C9H19 (60) (90) (85) (90) (96) (97) (E)-PhCH=CH (65) (99) (90) % eea 54 94 96 95 65c 94 26d 70 63 236 t-Bu OH NHNs (85) (81) (99) (87) (98) (93) (91) F BnOCH2 (94) 98 97 82 64 97c 76 96 76 92 OEt R Pr-i BH3MTHF (22 mol%), EtNO2, 78 OH NHTs % eea O 236 (85) 13:87 48 (90) 20:80 18 (89) 49:51 13 (85) 23:77 21 (83) 14:86 21 (87) 11:89 49 (80) 26:74 29
4/18/06
I:II
% ee I
12:32 PM
OTMS O
OEt
RCHO
Page 89
89
BH3MTHF (22 mol%), EtNO2, 45
(E)-PhCH=CH (99)
RCHO
c01_tex
TABLE 1B. BORON-CATALYZED MUKAIYAMA-TYPE ALDOL ADDITIONS (Continued)

Electrophile 1. O Ph 140 Pr-i BH3MTHF (20 mol%), EtCN, 78 2. 1 N HCl/THF O (20 mol%), Ph Br I F F OPr-i Ph Br OH NHTs + OH O OH O OPr-i II 387 OH (20 mol%), NHTs R SEt Ph(CH2)2 (82) 89 (89) 89 OH O R % ee Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C2
OTMS
RCHO
12:32 PM
SEt
OTMS CHO
Page 90
OPr-i Pr-i BH3MTHF (22 mol%), EtNO2, 78 1. CHO NsHN Ph CO2Et BH3MTHF (20 mol%), EtNO2, 78, 1 h 2. Ni2B/H2 1. OTBS NsHN CHO BH3MTHF (20 mol%), EtNO2, 78, 1 h 2. Ni2B/H2 1. OTBS TBSO Ph OH CO2Et (20 mol%), CO2H CHO NsHN BH3MTHF (20 mol%), EtNO2, 78, 1 h 2. Ni2B/H2 Ph CO2H (20 mol%), TBSO OH CO2Et (> 77) 100% de CO2H (20 mol%), OH (86) > 98% ee
Ph
Br
(E/Z = 62:38)
(89) I:II = 39:61, 95% ee I, 95% ee II
OTMS
90
OEt
Ph
237
Ph
237
Ph
(> 77) 100% de
237
c01_tex
1.TsHN O HO n-BuS N H (12 mol%), 3,5-(CF3)2C6H3BCl2 (10 mol%), EtCN, 20 2. 2 N HCl 1. O (20 mol%), (99) 0% ee Ph NsHN n-BuS PhB(OH)2 (20 mol%), EtCN, 78 2. 2 N HCl 1. (20 mol%), NsHN BH3MTHF (20 mol%), EtCN, 78 2. 2 N HCl 1. O OH NHTs SBu-t (20 mol%), R OH O R n-Pr 2-C4H3O Ph c-C6H11 Ph(CH2)2 1. O OH (20 mol%), NHTs R OH O OPh Pr-i BH3MTHF (20 mol%), EtCN, 78 2. 1 N HCl/THF (91) (98) (E)-i-PrCH=CH (91) (86) (75) (77) % ee 92 85 82 87 81 91 140 n-BuS Ph CO2H (90) 66% ee O OH 183 CO2H OH 183 O Ph (99) 37% ee 183 OH
OTMS
PhCHO
4/18/06
SBu-n
12:32 PM
PhCHO
Page 91
PhCHO
91
R Ph Pr-i BH3MTHF (20 mol%), EtCN, 78 2. 1 N HCl/THF
OTMS
RCHO
SBu-t
OTMS
% ee (77) c-C6H11 (87) Ph(CH2)2 (78) 93 84 85 140
RCHO
OPh
c01_tex

Electrophile Conditions 1. OPr-i O OH O n-Pr (49) R Ph (63) 84 OPh 76 73 R % ee O OPr-i BH3MTHF (20 mol%), EtCN, 78 2. TBAF/THF 1. (20 mol%), NsHN BH3MTHF (20 mol%), EtNO2, 78, 13 h 2. TBAF 1. O OH NHTs I (20 mol%), Ph SEt + OH O Ph OH O SEt II (84) I:II = 55:45, > 98% ee I 140 R OPh Ph (66) 80 CO2H i-Pr (60) 70a OH O R % ee 184 OH (20 mol%), CO2H CO2H Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C2
OTMS
RCHO
12:32 PM
OPh
Page 92
RCHO
92
Pr-i BH3MTHF (20 mol%), EtCN, 78 2. 1 M TBAF, THF 1. O OH NHTs (20 mol%), R I R 2-C4H3O (E)-Me(CH2)2CH=CH Ph 4-MeOC6H4 OH O SEt + R Pr-i BH3MTHF (20 mol%), EtCN, 78 2. 1 M TBAF, THF
C3
OTMS
PhCHO
SEt
OTMS
OH
O SEt II I:II (94) 66:33 (80) 80:20 (89) 87:13 (78) 89:11 % ee I 89 60 80 75 140
SEt
RCHO
c01_tex
1.MeO OH R I R n-Pr Ph(CH2)2 (85) 91:9 82 (81) 88:12 70 I:II % ee I II SEt + R SEt 140 O OH O MeO BH3MTHF (20 mol%), EtCN, 78 2. 1 M TBAF, THF NHTs (20 mol%),
CO2H
4/18/06
RCHO
12:32 PM
OTMS O OR1 I II I:II (51) (83) (57) (45) (86) (97) (72) 79:21 65:35 64:36 > 95:5 96:4 50:50 50:50 % ee I % ee II 61 92 88 79 94 97 68 47 6 71 29 10 57 R2 Ph Ph n-Pr i-Pr (E)-MeCH=CMe (E)-n-PrCH=CH Ph + R2 OR1 R2 OH OPr-i (20 mol%), BH3MTHF (20 mol%), EtCN, 78 2. TBAF/THF O
1. OPr-i O OH OH O
Page 93
OR1
R2CHO
CO2H CO2H
73
R1
Et
93
1. O (20 mol%), R I R Ph I:II 2-C4H3O (54) 88:12 (78) 94:6 % ee I 79 82 SBu-t OH NHTs OH O + R OH Pr-i BH3MTHF (20 mol%), EtCN, 78 2. 1 M TBAF, THF
Ph
Ph
Ph
Ph
Ph
Bn
OTMS
O SBu-t II 140
SBu-t
RCHO
c01_tex

Electrophile 1. O (20 mol%), Ph I (77) I:II = 77:23, 87% ee I II OPh + Ph OPh 140 OH NHTs OH O OH O Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C3
OTMS
OPh Pr-i BH3MTHF (20 mol%), EtCN, 78 2. 1 M TBAF, THF 1. OPr-i O O OH I II (73) I:II = 79:21, 92% ee I, 3% ee II Ph OPh + Ph OPh OPr-i (20 mol%), BH3MTHF (20 mol%), EtCN, 78 2. TBAF/THF CO2H CO2H OH O OH O 73
PhCHO
12:32 PM
Page 94
PhCHO
94
1. MeO CO2H OH Ph I (72) I:II = 90:10, > 75% ee I OPh + O Ph II NHTs (20 mol%), CHO MeO BH3MTHF (20 mol%), EtCN, 78 2. 1 M TBAF, THF OH O OPh 140 1. (20 mol%), NsHN BH3MTHF (20 mol%), EtNO2, 78, 1-3 h 2. TBAF R n-Pr i-Pr Ph (60) (64) (91) I I:II 60:40 65:35 76:24 % ee I 60 90 66 II % ee II 91 97 90 CO2H R OH O OPh + R OH O OPh 184
Ph
RCHO
c01_tex
C4 O BBu-n c-C3H5 (87) 181 (83) (100) (80) (57) 69 76 82 67 73 R Ph c-C6H11 Ph(CH2)2 2-C4H3O O (20 mol%), O N Ts N H EtCN, 78, 14 h 2. CF3CO2H O (20 mol%), Pr-i BH3MTHF (22 mol%), EtNO2 1. TsHN OH O SEt I (99) 65% ee 183 O Ph HO N H (12 mol%), 3,5-(CF3)2C6H3BCl2 (10 mol%), EtCN, 20 2. 2 N HCl 1. (20 mol%), NsHN CO2H PhB(OH)2 (20 mol%), CH2Cl2, 78 2. 2 N HCl 1. (20 mol%), NsHN 3,5-(CF3)2C6H3BCl2 CH2Cl2, 78 2. 2 N HCl CO2H (20 mol%), I (29) 50% ee 183 I (87) 24% ee 183 0 (70) 35 OH NHTs 45 30 (70) 53 (88) 52 OMe BnO 78 (97) 83 OH O Temp % eea 236
1. R % ee
OTMS
RCHO
4/18/06
OMe
12:32 PM
OTMS CHO
OMe
BnO
Page 95
OTMS
SEt
PhCHO
95
PhCHO
PhCHO
c01_tex

Electrophile 1. O (20 mol%), R OEt i-Bu (89) (83) (59) 96 > 98a (83) 91 Ph c-C6H11 Ph(CH2)2 > 98a n-Pr (82) > 98a 238 OH NHTs OH R % ee O Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C4
OTMS
12:32 PM
OEt Pr-i BH3MTHF (20 mol%), EtCN, 78 2. 1 N HCl/THF
RCHO
Page 96
1. MeO CO2H OH R n-Pr i-Bu Ph c-C6H11 Ph(CH2)2 1. TMS (+) OH Ph OEt O (92) 86% ee CO2H (10 mol%), OH BH3MTHF (10 mol%), EtCN, OEt BnO(CH2)2 (86) (81) (87) (80) (68) (83) O R NHTs (20 mol%), MeO BH3MTHF (20 mol%), EtCN, 78 2. 1 N HCl/THF
% ee 99a > 98a 97a 84 91 > 98a 238
RCHO
96
78, 3 h 2. pH 7 buffer 1. (20 mol%), NsHN CO2H BH3MTHF (20 mol%), EtNO2, 78, 14 h 2. TBAF R1O O OH R2 R
2
PhCHO
239
OTMS
OR
R2CHO
184 % ee Ph Ph Ph(CH2)2 (92) (65) (97) (E)-PhCH=CH (63) 90 96 95 81
Et
Ph
Et
Ph
c01_tex 4/18/06
1. OMe O R OH n-Bu (52) (44) (69) 73e 67 73e 266 O Ph (E)-PhCH=CH (56) n-C5H11 70 O O % eea O (50 mol%), R BH3MTHF (50 mol%), CH2Cl2, 78 2. HCl OMe OH
RCHO
CO2H CO2H
12:32 PM
OTMS
Page 97
1. O OH O O O Ph (79) 46% eea Ph O
PhCHO
266
97
CH2Cl2, 78 2. HCl 1. OPr-i O O OH OPr-i (50 mol%), R BH3MTHF (50 mol%), CH2Cl2, 78 2. HCl OH O CO2H CO2H R O O n-Bu Ph
CO2H CO2H (50 mol%), OH BH3MTHF (50 mol%),
% eea (45) (74) (E)-PhCH=CH (63) 64 52 38 266
RCHO
c01_tex

4/18/06
Nucleophile
C410 1. O n-C3F7 BH3MTHF (20 mol%), EtCN, 78, 7 h 2. aq HCl R2 I:II (71) 85 98 94 81 98 1:5 < 1:20 (61) < 1:20 97 66 69 72 97 61 88 73 98 97 70 (68) (67) < 1:20 < 1:20 1:6.3 1:2.5 (63) (65) (63) (62) (60) 1:1.8 1:1.9 1:2 Ph 4-MeC6H4 4-MeOC6H4 (E)-PhCH=CH (75) i-Bu Ph Et n-Pr i-Bu i-Bu % ee Ia % ee IIa I II I I N H CO2H (20 mol%), R
2
TMSO Bn R
1
R1 OH + R
2
O R1 240
OH
12:32 PM
2CHO
Page 98
R1
Me
Me
Me
Me
n-Pr
98
1. N Ts N H EtCN, 78, 14 h 2. 1 M HCl O BBu-n (40 mol%), O Ph I OH O + Ph II OH O
n-Pr
Ph
Ph
Ph
4-MeC6H4
C5
OTMS
PhCHO
(71) I:II = 94:6, 92% ee I
181
c01_tex
1. TsHN HO O N H (10 mol%), I + II (74) I:II = 88:12, 33% ee I, 12% ee II 388
4/18/06
PhCHO
3,5-(CF3)2C6H3BCl2 (10 mol%), EtCN, 78, 12 h 2. 1 N HCl/THF, rt 1. OPr-i O OH Et I R n-Pr (E)-MeCH=CH (79) (96) Ph 1. OPr-i O O Et I Ph II CO2H CO2H OH + O Ph OH (20 mol%), OPr-i BH3MTHF (20 mol%), EtCN, 78 2. 1 N HCl 1. OPr-i O O CO2H CO2H OH O Et I R (E)-MeCH=CH (95) Ph (81) + R II I:II 94:6 91:9 % ee I 93 95 OH O Et 182 OH O Et (99) I:II = 94:6, 96% ee I 72 (61) 80:20 > 94:6 94:6 I:II II % ee I 88 93 96 + R Et O OH O 72 R OH (20 mol%), OPr-i BH3MTHF (20 mol%), EtCN, 78 2. 1 N HCl O
12:32 PM
OTMS
Page 99
Et
RCHO
CO2H CO2H
99
R OH (20 mol%), OPr-i 3,5-(CF3)2C6H3B(OH)2 (20 mol%), EtCN, 78 2. 1 N HCl
PhCHO
RCHO
c01_tex

Electrophile 1. TsHN CHO HO O N H (10 mol%), I (99) syn:anti = 48:52, 95% ee I, 93% ee II II i-Pr Et i-Pr Et + 388 OH O O OH Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C5
OTMS
Et
12:32 PM
3,5-(CF3)2C6H3BCl2 (10 mol%), EtCN, 78, 12 h 2. 1 N HCl/THF, rt 1. OMe O O + O I II Ph OMe BH3MTHF (50 mol%), CH2Cl2, 78 2. HCl 1. OPr-i O O OPr-i 3,5-(CF3)2C6H3B(OH)2 (50 mol%), EtCN, 78 2. H+ 1. OPr-i O O OPr-i 2. 1 N HCl OH (20 mol%), OH R2 I R2 Ph n-Pr Ph (97) (62) (86) I:II 93:7 88:12 95:5 % ee I 94 80 95 O R1 + R2 II OH O R1 OH (50 mol%), Ph CO2H CO2H OH O OTBS OBn (29) > 95% de OH (50 mol%), Ph CO2H CO2H OH O O OH O O O
Page 100
PhCHO
267
OTMS
(100) I:II = 25:75, 80% ee I, 63% ee II
100
CO2H CO2H BH3MTHF (20 mol%), EtCN, 78
TMSO
OTBS
OBn
PhCHO
177
C59
OTMS
R2CHO
72
R1
R1
Et
Ph
Ph
c01_tex
1. TsHN OH O I R2 n-Pr i-Pr (94) (> 99) > 99:1 > 99 (> 99) 97:3 95:5 89:11 OH R 388 90 58 97 (92) O + 98 n-Pr i-Pr (E)-MeCH=CH (85) PhC C 1. TsHN O OH R O I R i-Pr (36) Ph 1. OPr-i O O Ph OPr-i BH3MTHF (20 mol%), EtCN, 78 I 2. 1 N HCl 1. OPr-i O O CO2H CO2H OH (20 mol%), OPr-i 3,5-(CF3)2C6H3B(OH)2 (20 mol%), EtCN, 78 2. HCl O OH Ph + O OH Ph (83) I:II > 95:5, 97% ee I 182 OH (20 mol%), II + CO2H CO2H O OH O 77:23 (> 99) 78:22 OH Ph (57) I:II > 95:5, > 95% ee I 72 I:II 96 89 HO N (10 mol%), H 3,5-(CF3)2C6H3BCl2 (10 mol%), EtCN, 78, 12 h 2. 1 N HCl/THF, rt 83:17 92 91 (> 99) 62:38 92 77 II I:II % ee I % ee I R2 R1 + R2 R1 388 O OH O HO N (510 mol%), H 3,5-(CF3)2C6H3BCl2 (510 mol%), EtCN, 78, 12 h 2. 1 N HCl/THF, rt
OTMS
R2CHO
4/18/06
R1
R1
Et
Et
12:32 PM
Ph
Ph
Ph
Ph
C6
Page 101
OTMS
RCHO
II % ee I % ee I 96 5
101
I II
PhCHO
PhCHO
c01_tex

Electrophile 1. O Ph (100) 181 86 90 n-Bu c-C6H11 (56) R OH R % ee N Ts (20 mol%), N H EtCN, 78, 14 h 2. 1 M HCl 1. OPr-i O O
1 OH (20 mol%), R
4/18/06
Nucleophile O O BBu-n
Conditions
Refs.
C6
OTMS
RCHO
12:32 PM
n-Bu
C68 CO2H CO2H O n-Bu R2 I Ph Ph (96) (99) (70) OH R2 % ee 77 83 88 91
Page 102
OTMS
R1 OPr-i 3,5-(CF3)2C6H3B(OH)2 (20 mol%), EtCN, 78 2. 1 N HCl
R CHO
182
R1
n-Bu
n-Bu
102
1. OPr-i O O I Ph Ph OH (20 mol%), OPr-i BH3MTHF (20 mol%), EtCN, 78 2. 1 N HCl CO2H CO2H R2 n-Bu (70) (81) (98) (E)-PhCH=CH (88) 1. OPr-i O O OPr-i EtCN, 78 2. HCl CO2H CO2H OH (20 mol%), R2 I Ph Ph (91) (93) (E)-PhCH=CH (93) 2-PhOC6H4B(OH)2 (20 mol%),
Ph
(E)-PhCH=CH (88)
Ph
R1
% ee 80 85 85 83 72
n-Bu
R2CHO
n-Bu
Ph
Ph
R1
% ee 88 91 94 182
n-Bu
R2CHO
Ph
Ph
c01_tex
C7 1. OPr-i O CHO OH OPr-i (20 mol%), 2-PhOC6H4B(OH)2 (20 mol%), EtCN, 78 2. BzCl, Py O (85) syn:anti = 10:1, 99% ee 235 CO2H CO2H O OBz
4/18/06
OTMS
12:32 PM
OTMS 1. TsHN HO O I (85) I:II = 66:34, 29% ee I, 14% ee II II N (10 mol%), H 3,5-(CF3)2C6H3BCl2 (10 mol%), EtCN, 78, 12 h 2. 1 N HCl/THF, rt OBn CHO HO (90) 91% ee O O O OEt (40 mol%), CO2H NsHN BH3MTHF (45 mol%), EtCN, 78, slow addition 2. TBAF/THF 1. Ph + Ph O OH OH
Page 103
PhCHO
388
103
1. TsHN O HO O N (20 mol%), H BuB(OH)2 (20 mol%), EtCN, 78 2. 1 N HCl/THF, rt Ph OH (82) 89% ee Ph
OTMS
OEt
389
BnO
C8
OTMS
PhCHO
185
Ph
c01_tex

Electrophile TsHN O OTMS (88) 79% ee O Ph (10 mol%), I N H Ph 185 HO Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C8
OTMS
PhCHO
12:32 PM
Ph PhBCl2 (10 mol%), EtCN, 78 TsHN HO N (10 mol%), H 3,5-(CF3)2C6H3BCl2 (10 mol%), EtCN, 78 O I (91) 93% ee 185
Page 104
PhCHO
104
1. O O Ph R OH R n-Pr Ph c-C6H11 (94) 2-C4H3O (100) (82) (67) O BBu-n (20 mol%), % ee 89 92 89 93 181 N Ts N H EtCN, 78, 14 h 2. 1 M HCl 1.TsHN O HO O N (12 mol%), H 3,5-(CF3)2C6H3BCl2 (10 mol%), EtCN, 78 2. 2 N HCl Ph OH (99) 93% ee Ph 183
RCHO
OTES
PhCHO
Ph
c01_tex
C9 1. OPr-i O O OPr-i 3,5-(CF3)2C6H3B(OH)2 (20 mol%), EtCN, 78 2. TBAF, THF n-Pr Ph 1.TsHN HO O N H (12 mol%), O Ph (74) 94% ee OH O 183 (92) 99:1 96 (55) 94:6 80 R I:II % ee I I II OH (20 mol%), Ph R Ph R + 182 CO2H CO2H O OH O OH
4/18/06
OTMS
RCHO
Ph
12:32 PM
C10
Page 105
OTES
PhCHO (1 equiv) 3,5-(CF3)2C6H3BCl2 (10 mol%), EtCN, 78, 3 h 2. 2 N HCl OH Ph HO O N H (12 mol%), Ph O OH O
OTES
105
1.TsHN 3,5-(CF3)2C6H3BCl2 (10 mol%), EtCN, 78, 3 h 2. 2 N HCl
PhCHO (2 equiv)
(93)
183
The configuration of the syn product is 2S,3R.
The product has the R configuration.
The protocol involves slow addition of the reagents.
c01_tex
4/18/06
TABLE 1C. COPPER-CATALYZED MUKAIYAMA-TYPE ALDOL ADDITIONS

Electrophile 2+ OH CHO O (0.5 mol%), X (95) (99) 99 98 BnO N Cu N 2 SbF6 Ph Ph CH2Cl2, 78 2+ 1. O (10 mol%), OH RO SBu-t TBS n-Bu () PMB () () O CHO N O R % ee 88 99 56 37 O N (99) 98 37 O % ee Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
Nucleophile
C2
OTMS
OEt
BnO
12:32 PM
SEt
SBu-t
Page 106
OTMS N Cu N 2 SbF6 Ph Ph CH2Cl2, 78 2. aq HCl, THF 2+ CHO O N Cu N 2 SbF6 Ph Ph CH2Cl2, 78, 12 h 2+ CHO O TMSO BnO O SBu-t BnO O N (5 mol%), TMSO O SBu-t
RO
SBu-t
106
N O (5 mol%), N Cu N 2 SbF6 Ph Ph CH2Cl2, 78, 12 h
BnO
() dr = 1:1
37
BnO
() dr = 98.5:1.5
37
c01_tex
O 1. R2 O O Me Et t-Bu Bn O
3
2+ HO R2 O R1 % ee (96) (84) 94 36 99 99 O SBu-t II 195 94 99 70 SBu-t Me i-Bu (94) i-Pr (84) Me Me (95) (91) Et Me Me R2 R1O (10 mol%), O N N O
4/18/06
R1O
Cu 2 OTf Bu-t THF, 78 t-Bu 2. aq HCl BnO HO MeO O (7.7 mol%), O I Bu-t (100) 92% ee I O N N t-Bu Cu(OTf)2 (7 mol%), 3 MS, THF, 0 SBu-t + O TMSO MeO O
12:32 PM
MeO O
Page 107
107
O (12.4 mol%),
3
O HO O N N O I Bu-t 2+ 1. O CHO N O (10 mol%), BnO OBn dr (21) 74:26 (11) 86:14 % ee 76 63 OH O SEt t-Bu Cu(OTf)2 (7 mol%), 3 MS, THF, 0 MeO O O
O SBu-t +
O TMSO MeO O II SBu-t 195
MeO
(97) 93% ee I
OTMS
SEt
BnO
37
OBn 2. aq HCl, THF
Z/E
N Cu N 2 SbF6 Ph Ph CH2Cl2, 78
90:10
25:75
c01_tex
TABLE 1C. COPPER-CATALYZED MUKAIYAMA-TYPE ALDOL ADDITIONS (Continued)

Electrophile 1. OH BnO X % ee Bu-t () () () () O 1. % ee X O (97) (83) (77) (80) 2+ O O t-Bu 2 OTf CH2Cl2, 78 2+ O N t-Bu Cu 2 OTf CH2Cl2, 78 N O (10 mol%), Bu-t BnO Cu Bu-t N O N (10 mol%), O MeO OH O OEt () dr = 86:14, 39% ee 197 (81) 94b 97 86b 99 92b (76) 93 197 O O t-Bu 2 OTf THF, 78 2. aq HCl O 1. Cu Bu-t N N (10 mol%), O MeO HO 2+ O 51a 91 50 38a 37 O CHO N t-Bu 2 OTf CH2Cl2, 78 2. aq HCl, THF Cu N (10 mol%), O O 2+ Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C28
OTMS
BnO
12:32 PM
Me
OEt
SBu-t
Ph
Page 108
Me
MeO
Me
SEt
108
2. aq HCl 1. CHO OH O SBu-t 2. aq HCl
SEt
Ph
Ph
C3
OTMS
MeO
OEt
OTMS
SBu-t
BnO
(50) dr = 81:19, 84% ee
37
c01_tex
4/18/06
O O Et (10 mol%), O Bu-t SBu-t (85) dr = 93:7, 97% ee 70 O 2 OTf CH2Cl2, 78 2. aq HCl t-Bu Cu N N O
1. OH O
2+
Et
12:32 PM
Page 109
C36 O 1. O O 2 OTf CH2Cl2, 78 2. aq HCl CH2Cl2 THF CH2Cl2 THF CH2Cl2 THF CH2Cl2 THF CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 Solvent (96) (93) (90) (88) (95) (90) (78) (91) (80) (71) (88) (58) t-Bu Cu Bu-t dr 94:6 90:10 95:5 97:3 90:10 94:6 98:2 98:2 90:10 66:34 90:10 93:7 % ee 96 93 98c 99c 95 93 98d 98 99e 97f 93g 97 N O R
1
OTMS OH O MeO (10 mol%), SR2 O N
2+
SR2
MeO
197
109
R1
R2
Geometry
Me
t-Bu
Me
t-Bu
Me
t-Bu
Me
t-Bu
Me
Et
Me
Et
Me
Et
Me
Et
i-Pr
Et
i-Pr
t-Bu
i-Bu
Et
i-Bu
t-Bu
c01_tex

Electrophile 2+ CHO 1. O (10 mol%), R (60) () (90) (48) (85) (86) 1. O N Bu-t HO O O CO2Me (10 mol%), (99) dr = 95:5, 99% eeh 197 O O 2+ (14) 85:15 97 85:15 99 95:5 95 86:14 85 97:3 97 50:50 9 84:16 87 N O dr % ee X 37 BnO OH O Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C38
OTMS
X X
BnO
Z/E
OEt
Me 15:85
12:32 PM
OEt 2. aq HCl, THF
Ph 30:70
SEt
Me 95:5
N Cu N 2 SbF6 Ph Ph CH2Cl2, 78
SEt
Me 1:99
SEt
i-Bu 90:10
Page 110
SBu-t Me 95:5
SBu-t Me 4:96
C4
MeO O 2. aq HCl 2+ 1. CHO O (10 mol%), O OH N Cu N 2 SbF6 Ph Ph CH2Cl2, 78 2. aq HCl, THF 2+ 1. CHO O N Cu N 2 SbF6 Ph Ph CH2Cl2, 78 2. aq HCl, THF N O (10 mol%), O O BnO OH O N O OBn
TMSO
110
N Cu t-Bu 2 OTf THF, 78
BnO
(93) dr = 91:9, 92% ee
37
TMSO
BnO
(95) dr = 96:4, 95% ee
74
c01_tex
OTMS O O N N Pr-i i-Pr Cu(OTf)2 (20 mol%), Triton X-100 (3 mol%), H2O, 0 O O (60) 94% ee (10-15 mol%), Bn OH 199 (20 mol%), Ph OMe (86) 53% eei 193 OH O
4/18/06
OMe
PhCHO
12:32 PM
OTMS CHO O O N Bn 2 TfO CH2Cl2, 78, 16 h 2. Raney Ni Sn N O 1.
EtO
2+
Page 111
SEt
111
(S)-Tol-BINAP (2.1 mol%), Cu(OTf)2 (2 mol%), n-Bu4N+Ph3SiF (4 mol%), R O THF, 78 OH O O R 2-C4H3S Ph 2-C10H7 CHO " BocHN OH O
% ee (91) (98) 94 95 69
RCHO
2-C4H3O (E)-MeCH=CH Me2C=CH 4-MeOC6H4 (E)-PhCH=CH (E)-PhCH=CMe
OTMS
(48) (81) (92) (93) (83) (74) (E)-2-MeOC6H4CH=CH (82) (86)
91 83 94 94 85 65 90 93
O O
BocHN
(80) 81% ee
268
c01_tex

Electrophile (S)-Tol-BINAP (2.1 mol%), OH (64) 72% de 269 O O O Cu(OTf)2 (2 mol%), n-Bu4N+Ph3SiF (4 mol%), THF, 78 2+ 1. CHO N Cu N 2 SbF6 Ph Ph CH2Cl2, 78 BnO O 2. aq HCl, THF 2+ 1. CHO (0.5 mol%), BnO % ee (96) (85) 2+ 1. O CHO N Cu N 2 SbF6 Ph Ph CH2Cl2, 78 2. aq HCl, THF N O (10 mol%), BnO OH O (95) dr = 95:5, 95% ee 37 97 99 O N O OH O O 37 OR O (5 mol%), (94) 92% ee N O OH O O 74 Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C4 CHO
12:32 PM
OTMS
Page 112
BnO
112
N Cu N 2 SbF6 Ph Ph CH2Cl2, 78 2. Acidic workup
TMSO
OTMS
BnO
OR
Me
t-Bu
C5
OTMS
BnO
c01_tex
OTMS O N i-Pr Cu[O2S(OC12H25-n)2] (20 mol%), n-C11H23CO2H (10 mol%), H2O, rt O N i-Pr Pr-i Cu(OTf)2 (x mol%), R Ph Ph Ph 4-ClC6H4 2-MeOC6H4 2-C10H7 2-C10H7 2-C4H3O 2-C4H3O (E)-PhCH=CH Ph(CH2)2 O Cu(OTf)2 (10 mol%), (S)-Tol-BINAP (11 mol%), n-Bu4N+Ph3SiF2 (20 mol%), THF, rt R O R i-Bu 2-C4H3O Ph (E)-PhCH=CH 2-C10H7 (61) (30) (73) (42) 2,3-(MeO)2C6H3 (71) (76) dr > 98:2 > 98:2 > 98:2 > 98:2 > 98:2 > 98:2 % ee 91 86 87 82 91 85 271 20 10 20 10 20 20 10 10 10 10 10 10 10 10 10 5 5 15 20 15 (81) (34) (88) (87) (91) (87) (86) (78) (94) (37) 10 15 (64) x Temp H2O/EtOH (1:9), 20 h 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 N (x mol%), R Et syn:anti % eei 80 81 76 76 75 79 76 76 75 57 59 O OH O 192 Pr-i N (24 mol%), Ph Et (76) syn:anti = 2.8:1, 69% eei 194 O OH O
4/18/06
Et
PhCHO
12:32 PM
OTMS
RCHO
Page 113
Et
113
OTMS
RCHO
OMe
c01_tex

Electrophile O CHO (S)-Tol-BINAP (11 mol%), n-Bu4N+Ph3SiF2 (20 mol%), TBDPSO I CHO (R)-Tol-BINAP (11 mol%), I (50) dr = 9:1 n-Bu4N+Ph3SiF2 (20 mol%), THF, rt Cu(OTf)2 (10 mol%), R OEt Ph 2-C10H7 CHO (S)-Tol-BINAP (11 mol%), n-Bu4N+Ph3SiF2 (20 mol%), THF, 0, 24 h 2+ 1. O CHO N Cu N H2O OH2 Ph Ph 2 SbF6 CH2Cl2, 78 2. aq HCl, EtOAc, rt N O (2.5 mol%), PMBO OH O (93) 95% ee OEt 390 Cu(OTf)2 (10 mol%), OH O OEt (90) 80% eei 273 i-Pr (68) (80) (E)-PhCH=CH (35) (70) (S)-Tol-BINAP (11 mol%), n-Bu4N+Ph3SiF2 (20 mol%), THF, rt R OH O % eei 77 70 56 48 272 Cu(OTf)2 (10 mol%), 271 THF, rt O (60) dr > 95:5 271 Cu(OTf)2 (10 mol%), Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C5
OTMS
TBDPSO
12:32 PM
OMe
Page 114
TBDPSO
OTMS
OEt
RCHO
114
OTMS
PMBO
OEt
c01_tex
C6 1. CHO O (10 mol%), Pr-i O N BnO 37 OH O
2+
4/18/06
OTMS
Pr-i
BnO
Z/E dr (90) (10) OH O R syn:anti (95) 4.0:1 4.0:1 Pr-i 2-C10H7 (97) Ph (20 mol%), R Pr-i % eei 77 81 38:62 28 95:5 90 % ee 2. aq HCl, THF
12:32 PM
90:10
N Cu N 2 SbF6 Ph Ph CH2Cl2, 20, 2 d
10:90
OTMS O N i-Pr Cu(OTf)2 (20 mol%), H2O/EtOH (1:9), 20 h 2+ CHO N O t-Bu 2 TfO CH2Cl2, 78, 16 h
O N
Page 115
Pr-i
RCHO
192
115
O Cu Bu-t O N (1015 mol%), EtO SEt O OH O
+
OTMS
EtO
SEt
(61) 98% ee
199
C9 TfOCO2Me (1 mol%), Ar N O CO2Et (> 99) dr = 95:5, 97% ee 241 O N O t-Bu O
N CHO
EtO
Ar
OMe
Ar = 4-MeOC6H4
N Cu OTf Bu-t 2 H2O
3 MS, THF, 20, 24 h
c01_tex

Electrophile OH O R Ph 4-ClC6H4 (56) 1.6:1 4.6:1 42i c-C6H11 (77) 67i Ph (98) 2.6:1 192 61 syn:anti % ee (20 mol%), R Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C9 O O N N Bn Bn Cu(OTf)2 (20 mol%), H2O/EtOH (1:9), 0, 20 h

+
OTMS
RCHO
12:32 PM
Ph
C10 CHO O t-Bu THF, 40, 17 h 2+ CHO N O t-Bu 2 TfO CH2Cl2, 78, 16 h O Bu-t Cu N (1015 mol%), EtO Ph O O OH O (< 5) 95% ee Ar O CO2Et N (1 mol%), N (94) dr = 94:6, 99% ee N Cu 2 TfO Bu-t O O CO2Me
Page 116
EtO
241
Ar
OMe
Ar = 4-MeOC6H4
116
OTMS
EtO
Ph
199
The reaction was carried out in dichloromethane.
The amount of TMSOTf added was 0.9 equivalents.
The amount of catalyst used was 2.5 mol%.
The reaction was carried out at room temperature.
The amount of TMSOTf added was 0.5 equivalents.
The same result was obtained with dichloromethane as solvent.
c01_tex
TABLE 1D. TIN-CATALYZED MUKAIYAMA-TYPE ALDOL ADDITIONS

Electrophile H N OH (20 mol%), R SEt OTBS I Sn(OTf)2 (20 mol%), EtCN, 78, slow addition Ph CHO R (20 mol%), OTBS I Sn(OTf)2 (20 mol%), EtCN, 78, slow addition Ph OH R (20 mol%), OTBS I Sn(OTf)2 (20 mol%), EtCN, 78, slow addition OH (20 mol%), R OTBS I Sn(OTf)2 (20 mol%), EtCN, 78, slow addition R Me Ph (85) (90) I:II 6:94 5:95 O SEt + R OTBS II R Ph I:II Me (85) 4:96 (86) 5:95 OH O SEt 141 SEt + O R OTBS II (85) 96:4 OH O SEt 141 Me (86) 96:4 R I:II II OTBS SEt + SEt R OTBS N Me H N OH O OH O 141 (85) 94:6 Me (84) 94:6 R I:II II OTBS + SEt 141 R O OH O Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C2 CHO N Me OTBS
OTMS
12:32 PM
SEt
Page 117
117
CHO OTBS N Me H N CHO OTBS N Me H N
c01_tex
TABLE 1D. TIN-CATALYZED MUKAIYAMA-TYPE ALDOL ADDITIONS (Continued)

Electrophile Conditions NH (20 mol%), R i-Pr n-Bu Sn(OTf)2 (20 mol%), EtCN, 78 n-BuC C c-C6H11 n-C7H15 PhC C R (E)-n-PrCH=CH (65) R C6F5 SEt (90) % ee 72 68 153 (71) 79b (79) 93b (81) 92 (68) slow addition 88b (79) 91 (48) 90 SEt TMSC C (75) 77a,b 153 TMSO O R % ee Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C2 N Me
TMSO
RCHO
12:32 PM
SEt
Page 118
NH (20 mol%),
TMSO
RCHO
N Me
118
Sn(OTf)2 (20 mol%), EtCN, 78, slow addition H N OH (20 mol%), n-C6H13 O SEt N Me Sn(OTf)2 (20 mol%), SnO (20 mol%), EtCN, 78, slow addition N O N N O (10 mol%), O Ph Sn Ph 2 OTf CH2Cl2, 78 CHO 1. 2+ Ph N O OH O 2. aq HCl
n-C6H13CHO
(87) 94% ee
391
TMSO
Ph
SBu-t
(91) 94% ee
196
SBu-t
c01_tex
TMSO N Me (20 mol%), OBn (E)-n-PrCH=CH (68) 97:3 > 98:2 90:10 89 95 93 Sn(OTf)2 (20 mol%), n-C5H11 Ph (81) (85) SnO (20 mol%), EtCN, 78, slow addition CHO N Me (20 mol%), OBn Sn(OTf)2 (20 mol%), SnO (20 mol%), EtCN, 78, slow addition TMSO CHO " OPh TMS H N (24 mol%), TMS Sn(OTf)2 (20 mol%), SnO (20 mol%), EtCN, 78, slow addition H N (20 mol%), TBSO OBn Sn(OTf)2 (20 mol%), EtCN, 78, SnO (20 mol%), slow addition TMSO O OPh (70) syn:anti = 95:5, 96% ee 227 OBn TMSO O OPh (87) syn:anti = 97:3, 91% ee 31 OBn O (87) syn:anti = 97:3, 91% ee 224 OPh (70) syn:anti > 98:2, 80% ee H N TMSO O 225 (E)-MeCH=CH (87) 97:3 92 R OPh CH2=CH > 98:2 225 96 (80)
H N R syn:anti % ee
TMSO
4/18/06
BnO
RCHO
OPh
12:32 PM Page 119
119
CHO N Me CHO N Me
TMS
TMS
TBSO
c01_tex

Electrophile H N (20 mol%), R1 n-Bu 92 84 94 95 94 93 100:0 > 98 Sn(OTf)2 (20 mol%), SnO (40 mol%), EtCN, 78, slow addition (E)-n-PrCH=CH (81) 100:0 95:5 Ph n-C7H15 H N (20 mol%), R1 Sn(OTf)2 (20 mol%), CH2Cl2, 78, slow addition R2 n-BuC C TMSC C MeC C n-BuC C PhC C CHO O O N R3 CH2Cl2,78 2. aq HCl Sn R3 2 OTf N (10 mol%), O O EtO R1 1. 2+ OH O SR2 R3 Bn Ph Bn Bn Bn i-Pr i-Pr Bn (90) (97) (97) (90) (72) (83) (83) (88) dr 96:4 94:6 92:8 93:7 92:8 94:6 92:8 % ee 98 94 95c 95 95 92 96 98 39 392 393 39 39 39 39 39 (63) (73) (77) (67) (82) R
2
4/18/06
Nucleophile TMSO R i-Pr 92 (71) 99:1 (78) (85) (78) (81) (E)-n-PrCH=CH (83) c-C6H11 (E)-MeCH=CH (50)
2
Conditions O SEt R2 syn:anti % ee 226
Refs.
C23 TMSO N Me
SEt
R1
R2CHO
R1
12:32 PM
Me
Me
Me
Page 120
Me TMSO SEt O
R2CHO
R1
N Me
228 syn:anti % ee 95:5 86:14 93:7 90:10 88 91 88 91 86
120
Me
Me
Me
Me
C26
TMSO
EtO
SR2
R1
R1
R2
Ph
Me
Ph
Me
Ph
Et
Ph
i-Pr
Ph
i-Bu Et
i-Bu t-Bu
i-Bu Ph
c01_tex
C3 R SEt TMSO I SnO (1 equiv), R n-C7H15 (65) 98:2 II TMSO O R SEt (E)-n-PrCH=CH (73) 93:7 93:7 87:13 100:0 89:11 100:0 Ph Sn(OTf)2 (20 mol%), EtCN, 78, slow addition 4-MeC6H4 n-C7H15 H N TMSO R SEt Ph Sn(OTf)2 (20 mol%), CH2Cl2, 78, slow addition 4-ClC6H4 c-C6H11 4-MeC6H4 n-C7H15 H N (24 mol%), n-C9H19 OH O SEt (83) syn:anti = 97:3, 94% ee 231 (E)-MeCH=CH (51) (86) (80) (31) (82) (75) (E)-n-PrCH=CH (62) (20 mol%), R O (75) (80) c-C6H11 (71) 4-ClC6H4 (83) (77) (E)-MeCH=CH 93 90 90 > 98 91 > 98 syn:anti % ee 84:16 81:19 93:7 93:7 99:1 78:22 100:0 77 74 91 93 74 80 > 98 160 (76) 96:4 93 (20 mol%), R syn:anti % eed 160 85 SEt c-C6H11 (58) 91:9 68 TMSOTf (65 mol%), CH2Cl2, 78, slow addition H N Ph (82) 94:6 91 O i-Bu (70) 98:2 94 + Et (65) 94:6 165 67 I:II % ee N Me (50 mol%), R
TMSO
H N TMSO O
4/18/06
SEt
RCHO
12:32 PM
RCHO
N Me
Page 121
121
N Me N Me Sn(OTf)2 (20 mol%), SnO (20 mol%), CH2Cl2, 78, slow addition
RCHO
n-C9H19CHO
c01_tex

Electrophile O 1. Et O O N Sn N 2 TfO Ph Ph CH2Cl2, 78 2. aq HCl 2+ 1. O HO MeO SBu-t O O O (94) dr = 99:1, 99% ee 39 N O (10 mol%), O N O (10 mol%), SBu-t () dr = 99:1, 98% ee 39 HO 2+ O Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C3
TMSO
Et
12:32 PM
SBu-t
Page 122
MeO O 2. aq HCl H N TMSO (22 mol%), R SEt O R Ph 4-ClC6H4 c-C6H11 Sn(OTf)2 (20 mol%), CH2Cl2, 78, slow addition n-C7H15 (86) (80) (64) (76)
N Sn N 2 TfO Ph Ph CH2Cl2, 78
122
N Me H N (20 mol%), Ph I Sn(OTf)2 (20 mol%), EtCN, 78, slow addition OH O OPr-i OBn + N Me
TMSO
syn:anti 93:7 93:7 > 99:1 100:0
% eed 91 93 92a > 98 229
SEt
RCHO
TMSO
OH Ph
O OPr-i OBn II (60) I:II = 90:10, 96% ee I 230
OPr-i
PhCHO
OBn
E:Z = 71:29
c01_tex
C36 O 1. O X O dr (91) (84) (94) (94) (84) (76) (81) 1. O O (60) 94% ee (10-15 mol%), Bn O N Bn 2 TfO CH2Cl2, 78, 16 h 2. Raney Ni 2+ O 1. EtO O O O N Sn N 2 TfO Ph Ph THF 78, 48 h 2. aq HCl N O (10 mol%), OH O SEt (85) 91% ee 394 Sn N O OH 2+ O 199 99:1 99 99:1 97 98:2 97 99:1 97 99:1 99 99:1 96 95:5 92 % ee R O N O (10 mol%),MeO 39 OH O
2+
TMSO
4/18/06
MeO
R 2. aq HCl
Geometry
Me
SEt
N Sn N 2 TfO Ph Ph CH2Cl2, 78
12:32 PM
Me
SBu-t
Me
SBu-t
Et
SEt
Et
SBu-t
i-Bu
SEt
Page 123
i-Bu
SBu-t
C4 CHO
TMSO
EtO
SEt
123
C6
TMSO
SEt
EtO
The amount of catalyst used was 30 mol%.
Dichloromethane was used as the solvent.
c The
R,R-catalyst was used.
c01_tex
TABLE 1E. TITANIUM-CATALYZED MUKAIYAMA-TYPE ALDOL ADDITIONS

Electrophile 1. Bu-t OH TIPSC C 188 395 395 191 188 191 395 94a 98 (98) (89) (84) (84) Bu-t OH Br Cl MOMO t-Bu (2 mol%), Et2O, 10 2. TBAF, THF O (61) SR (87) (38) (35) % eeb 31 44 37 42 397 Bu-t N O O OMe (90) 94% ee 22 OBn OTBS 93 97 96a 188 191 191 191 188 32 OMe n-Pr TBSOCH2C C TBSOCMe2C C Ph Bu-t PhC C (E)-PhCH=CH Ph(CH2)2 (E)-PhCH=CMe Ph(CH2)3C C (95) (96) c-C6H11 (81) 95 (94) 96 (88) 96a (91) 99 (76) 95 (E)-MeCH=CH (82) 97 (88) 97a R Br O O R % ee Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C2
TMSO N O Ti O O O t-Bu (2 mol%), Et2O, 10 2. TBAF, THF
RCHO
12:32 PM
OMe
Page 124
124
1. Cl N CHO N O Ti O O O TMSO O Ti O (20 mol%), Ph O PhMe, 23
MOMO
TMSO
Et
PhCHO
SR
t-Bu
Ph
Ph3C
c01_tex
OTMS (R)-BINOL/TiCl2(OPr-i)2 (5 mol%), 0 Solvent R2 % ee (47) (64) (81) (84) (60) (61) (67) (61) (60) OH X OBn I I:II (71) (45) (61) CHO (20 mol%), PhMe, 0 OBn 2. H+ OBn I I:II (73) (68) (66) (65) 98:2 98:2 97:3 97:3 % ee 1. (S)-BINOL/TiCl2(OPr-i)2 OH O X + OBn II 17:83 18:82 18:82 % ee OH O X 396 + OBn II O X 396 91 91 86 85 81 95 94 88c 80c CH2Cl2 ClCH2 CH2Cl2 BocNHCH2 PhMe BnOCH2 n-BuO2C (E)-MeCH=CH i-Pr n-C8H17 ClCH2 n-C8H17 O PhMe PhMe PhMe PhMe PhMe PhMe 1. (R)-BINOL/TiCl2(OPr-i)2 (20 mol%), PhMe, 0 OBn 2. H+ OH R2 SR1 137
OTMSO
R2CHO
4/18/06
SR1
R1
Et
Et
Et
12:32 PM
Et
Et
Et
Et
t-Bu
Page 125
t-Bu
OR1 CHO
125
R1
TMS OEt
TMS OPh
TMS SBu-t
R1
TMS
OEt
TMS
SBu-t
TES
SBu-t
TMS
OPh
c01_tex
TABLE 1E. TITANIUM-CATALYZED MUKAIYAMA-TYPE ALDOL ADDITIONS (Continued)

Electrophile (S)-BINOL (20 mol%), OH BnOCH2 171 R 2-C4H3O Ph c-C6H11 (E)-PhCH=CH (76) Ph(CH2)2 n-C8H17 (74) 98 (80) 97 89 (70) 89 (90) 97 (88) > 98 SBu-t (82) > 98 O Ti(OPr-i)4 (20 mol%), 4 MS, Et2O, 20, 12 h R % ee Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C2
OTMS
RCHO
12:32 PM
SBu-t
Page 126
OBn 1. (R)-BINOL/Ti(OPr-i)4 OH MeO2C(CH2)4 O (10 mol%), PhOH (10 mol%), Et2O, 0; then 0 to rt 2. 2 N HCl SBu-t
CHO (R)-BINOL, Ti(OPr-i)4 4 MS, Et2O, 20 OBn OH O
SBu-t
(47) dr = 2:1
177
126
1. (R)-BINOL/Ti(OPr-i)4 (10 mol%), PhOH (50 mol%), 4 MS, Et2O; 0, then 0 to rt 2. 2 N HCl n-PrO2C(CH2)4 I SBu-t OH O 1. (R)-BINOL/Ti(OEt)4 (10 mol%), Et2O, 0, 5 h; then 0 to rt, 16 h 2. 2 N HCl I (66) > 97% ee
MeO2C(CH2)4CHO
(65) 96% ee
176
n-PrO2C(CH2)4CHO
(76) > 97% ee
176
n-PrO2C(CH2)4CHO
176
c01_tex
1. (R)-BINOL/Ti(OPr-i)4 OH i-Bu (58) (71) (76) (73) (85) 92 96 93 96 R Ph n-C6H13 Bn Ph(CH2)2 1. (R)-BINOL/Ti(OPr-i)4 (10 mol%), PhOH (50 mol%), NO2 Et2O, 0; then 0 to rt NO2 2. 2 N HCl 1. (R)-BINOL/Ti(OPr-i)4 OH EtO2C R SBu-t O R (65) TBSO(CH2)5 (22) (10 mol%), PhOH (20 mol%), Et2O, 0; then 0 to rt 2. 2 N HCl 1. (R)-BINOL/Ti(OPr-i)4 O CHO then 0 to rt 2. 2 N HCl CHO N (10 mol%), Et2O, 0; O 2. 2 N HCl then 0 to rt Ph 1. (R)-BINOL/Ti(OPr-i)4 N O O SBu-t (76) 95% ee 176 OH SBu-t (10 mol%), Et2O, 0; O O OH O % ee 63 95 176 SBu-t (31) OH O 176 SBu-t 53 176 O (10 mol%), PhOH (50 mol%), Et2O, 0; then 0 to rt 2. 2 N HCl
% ee
4/18/06
RCHO
12:32 PM
CHO
Page 127
RCHO
127
CHO (10 mol%), Et2O, 0; then 0 to rt 2. 2 N HCl 1. (R)-BINOL/Ti(OPr-i)4 MeO2C OH O SBu-t
(23) 62% ee
176
Ph
MeO2C
(40)
176
c01_tex

Electrophile 1. (R)-BINOL/Ti(OPr-i)4 (5 mol%), O PhOH (61) 97 96 168 t-BuS C6F5OH (62) C8H17-n OH additive (1 equiv), 4 MS, PhMe, 0 2. H+ TMSO CHO (S)-BINOL/TiCl2(OPr-i)2 BnO SBu-t (5 mol%), PhMe, 0 1. (R)-BINOL/TiCl2(OPr-i)2 OH (47) 96% ee F2HC SBu-t O 67 (20 mol%), 5 MS, PhMe, 0, CHF2 2h 2. H+ 1. (R)-BINOL/TiCl2(OPr-i)2 OH n-C8H17 SBu-t O (46) 88% ee 169 (5 mol%), 4 MS, scCHF3, 100 atm, 34 2. H+ 1. (R)-BINOL/TiCl2(OPr-i)2 OH CF3 O 67 SR % ee (56) 90 (38) 96 (20 mol%), PhMe, 0 2. H+ (80) 96% ee O 137 additive % ee Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C2
OTMS
n-C8H17CHO
12:32 PM
SBu-t
BnO
Page 128
OH
EtO
128
R (R)-BINOL/TiCl2(OPr-i)2 (5 mol%), PhMe, 0, 2 h R SBu-t Si O Me O
n-C8H13CHO
OTMS
CF3CHO
SR
t-Bu
Ph
% ee BnOCH2 n-C8H17 (95) (83) 98 97 168
Si
Me
RCHO
SBu-t
c01_tex
TBSO TMSO 397 Ph % eeb (92) 35 60d 40 45 PhMe, 78 (91) (89) (60)
x y
O SR
PhCHO
4/18/06
SR
O Ti O (20 mol%), O
Et
t-Bu
Bn
12:32 PM
Ph2CH
Page 129
TMSO (2 mol%), () 26% ee Ph OBn x = 5, y = 60 Br Ti(OPr-i)4 (2 mol%), PhMe, 0, 36 h 1. OH R Bu-t O =X Bu-t OBn O Bu-t R TBSOCH2C C Ph (E)-PhCH=CH Ph(CH2)2 (99) (94) (98) (95) 3,4-(MeO)2C6H3 (81) (E)-PhCH=CMe (91) N OH HO
S
n
OH
O 398
PhCHO
OBn
129
N O Ti O O O t-Bu (2 mol%), Et2O, 10 2. TBAF, THF OH TrS O CHO 1. ent-X (2 mol%), Et2O, 10 2. TBAF, THF OBn
% ee 99 96 96 91 95 97 191
RCHO
TrS
(99) > 98% ee
33
c01_tex

Electrophile CHO 1. N (84) > 98% ee 189 O Br OPMB O =X Bu-t R OH 1. X (2 mol%), Et2O, 0 to rt 2. 2 .N HCl, Et2O PhC C Ph(CH2)2 Ph(CH2)3C C TMSO (R)-BINOL/TiCl2(OPr-i)2 (5 mol%), PhMe, 0 I R2 SR1 + O TMSO R2 II O SR1 R2 I:II % ee I BnOCH2 (85) 72:28 90 n-BuO2C (64) 92:8 TMSO (R)-BINOL/TiCl2(OPr-i)2 (5 mol%), PhMe, 0 R2 I O SR1 + TMSO R2 II O 98 n-BuO2C (57) 57:43 88 SR1 R2 I:II % ee II BnOCH2 (80) 48:52 BnOCH2 (72) 8:92 n-BuO2C (81) 20:80 86 90 86 137 137 R c-C6H11 Ph (83) (79) (99) (98) (99) O TBSOCH2C C (85) % ee 93 66 75 91 90 98 178 O N O Ti O O O t-Bu (2 mol%), Et2O, 10 2. TBAF, THF OBn Bu-t N OH O Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C2
TMSO
OBn
12:32 PM
OPMB
Page 130
C3
TMSO
RCHO
130
TMSO
R2CHO
SR1
R1
Et
Et
t-Bu
TMSO
SR1
R2CHO
R1
Et
t-Bu
t-Bu
c01_tex
TMSO (20 mol%), PhMe, 0 2. H+ I (48) I:II = 44:56, 89% ee I, 83% ee II 1. (R)-BINOL/TiCl2(OPr-i)2 (20 mol%), PhMe, 0 2. H+ I II (64) I:II = 48:52, 55% ee I, 64% ee II CHO (R)-BINOL/TiCl2(OPr-i)2 O (5 mol%), CH2Cl2, 0 n-Bu RO2C (73) > 99 Me (71) > 99 OH OTBS R % ee 77 CF3 SEt CF3 SEt + 67 OH O OH O II CF3 SEt CF3 SEt + 67
1. (R)-BINOL/TiCl2(OPr-i)2
OH
OH
CF3CHO
4/18/06
SEt
TMSO
12:32 PM
SEt
CF3CHO
Page 131
OTBS
RO
131
CHO (10 mol%), CH2Cl2, 0, 3 h O 2. HCl, MeOH MeO2C CO2Me 1. (R)-BINOL/TiCl2(OPr-i)2 OH O OH () > 99% de, > 99% ee 138 (R)-BINOL (40 mol%), Ti(OPr-i)4 (20 mol%), CH2Cl2, 20 OH I R Ph n-C7H15 n-C7H15 n-C12H25 n-C12H25 (70) (95) (50) (80) (20) I:II 70:30 70:30 53:47 60:40 70:30 % ee I 54b 57 87e 80 90e R O O + R O OH II O 277
MeO
C4
OTMS
RCHO
c01_tex

Electrophile (R)-BINOL (40 mol%), Ti(OPr-i)4 (20 mol%), additive, O OH I II I:II (20) (72) (80) 60:40 > 96g 70:30 93f 60:40 90 % ee I OH additive none (+)-Taddol (20 mol%) none 1. Ti(OPr-i)4 (20 mol%),
5 CHO
4/18/06
Nucleophile
Conditions
Refs.
C4 n-C12H25 O O 278 + O n-C12H25
12:32 PM
O Et2O, 20
OTMS
n-C12H25CHO
Page 132
ligand (40 mol%), Et2O, 20

5
O + OTBS OH III O +
5
279
OTBS 2. HF, THF OTBS OH I
132
5
O II
O OTBS OH IV
OTBS OH Ligand (S)-BINOL (50) I:II:III:IV 26:9:55:10
(R)-BINOL (50) 15:35:10:40 (R)-BINOL (40 mol%), Ti(OPr-i)4 (20 mol%), Et2O, 20 R Ph c-C6H11 (E)-n-C6H13CH=CH n-C12H25 (99) (70) (70) (E)-n-C5H11CH=CH(CH2)2 (99) (80) R O OH II O + R O OH I dr 24:76 65:35 30:70 53:47 60:40 % ee I % ee II 60 71 52 94 > 96 90b 79 24 90 90 O 280
RCHO
c01_tex
1. (R)-BINOL/Ti(OPr-i)4 R OH n-Bu O (E)-PhCH=CH (32) 33 Ph (38) 88 (55) 92 267 R O O % ee (20 mol%), 4 MS, THF, 78 to rt 2. NaHCO3
4/18/06
RCHO
OTMS
12:32 PM
Ti(OPr-i)4 (50 mol%), R OH 3-C4H3O O Ph 4-O2NC6H4 n-C9H19 1. Bu-t (72) (39) 4-MeOC6H4 (59) (63) 3-C4H3O (42) 80h 92 75 98 89 (65) 89 R O O % ee (R)-BINOL (50 mol%), 4 MS, THF, 78
RCHO
399 399 400 400 400 400
Page 133
133
N O Ti O O O Br OH R O O O O t-Bu (2 mol%), Bu-t Et2O, 0 2. TFA, THF R TIPSC C (Z)-TBSOCH2CH=CH n-Bu3SnCH=CH Ph (E)-PhCH=CH Ph(CH2)2
RCHO
139
% ee (86) (97) (79) (E,E)-MeCH=CH-CH=CH (95) (83) (88) (97) 91 94 92 92 96 99 80
c01_tex 4/18/06

Electrophile
Nucleophile 1. CHO N O Ti O O O Br O O t-Bu (2 mol%), Bu-t Et2O, 0, 5.5 h 2. TFA, THF OH (79) 97.5% ee O O 401 Bu-t
Conditions
Refs.
C4
12:32 PM
OTMS
Page 134
134
1. Ti(OPr-i)4 (8 mol%), OH R I OMe O O (R)-BINOL (8 mol%), THF, 78 2. TFA R 3-C4H3O Ph 4-O2NC6H4 4-MeOC6H4 n-C7H15 (67) (65) (86) (68) (31) (E)-PhCH=CH (92) 1. Ti(OPr-i)4 (2 mol%), (R)-BINOL (2 mol%), THF, 78 2. TFA I R 3-C4H3O Ph n-C9H19 (82) (94) (E)-PhCH=CH (84) (70) % ee 99 92 99 98 402 % ee 99 88 90 91 92 99 402
TMSO
OTMS
RCHO
OMe
RCHO
c01_tex 4/18/06
Ti(OPr-i)4 (17 mol%), (R)-BINOL (17 mol%), THF, 78 R Ph 4-O2NC6H4 4-MeOC6H4 95 90 36 (E)-PhCH=CH (30) n-C9H19 1. (R)-BINOL/Ti(OPr-i)4 R % ee (37) (93) 79 92 76 267 I Ph (E)-PhCH=CH (58) n-Bu (20 mol%), 4 MS, THF, 78 to rt 2. NaHCO3 (37) (55) (76) 90 (69) 92 I O OH 3-C4H3O (89) 94i 399 400 400 400 400 400 O O 3-C4H3O (59) 87 399
R % ee
RCHO
12:32 PM
OTMS
Page 135
RCHO
135
CHO (R)-BINOL/TiCl2(OPr-i)2 O (5 mol%), CH2Cl2, 0 n-BuO2C OH OTMS Et CHO (R)-BINOL/TiCl2(OPr-i)2 O (5 mol%), CH2Cl2, 0 MeO2C OH OTMS
C5 (67) Z:E = 95:5, > 99% ee 77
OTMS
n-BuO
Pr-n
OTMS
MeO
Et
(54) Z:E = 96:4, dr = 98:2, 99% ee
77
c01_tex

Electrophile CHO (R)-BINOL/TiCl2(OPr-i)2 O (5 mol%), CH2Cl2, 0 R2 Z:E (58) 94:6 99:1 99 77 84:16 73:27 99:1 98:2 99 (63) (73) R OEt Ph 2-C10H7 i-Pr (18) (45) (25) dr % ee Me n-Bu Me Ti(Oi-Pr)4 (20 mol%), (R)-BINOL (40 mol%), CH2Cl2, rt R OH O R O2C
2
4/18/06
Nucleophile OH Me 77 OR1
Conditions
Refs.
C5
OR1
R 2O
Et
12:32 PM
R1
TMS
TMS
TBS
Page 136
OTMS
% eeb 70 75 75 60 272
OEt
RCHO
136
Ti(Oi-Pr)4 (50 mol%), (R)-BINOL (50 mol%), THF, 78 R OH O O O R Ph 1. (R)-BINOL/Ti(OPr-i)4 (20 mol%), 4 MS, THF, 78 to rt 2. NaHCO3 I Ph OH O O O +
(E)-PhCH=CH (45)
% ee 3-C4H3O 3-C4H3O 4-O2NC6H4 (40) (41) (45) (73) 67h 72 73 62 400
RCHO
OTMS
PhCHO
OH Ph
O O II (62) I:II = 51:11, 100% ee I, 26% ee II
267
OTMS
c01_tex
OTBS OH CHO (10 mol%), CH2Cl2, 0 + MeO2C I OH MeO2C I:II (47) 98.4:1.6 99.6 5.9:94.1 (44) % ee I II CO2Me O OH CO2Me 138 O 2. HCl/MeOH OH
MeO
1. (R)-BINOL/TiCl2(OPr-i)2 O OH
4/18/06
CO2Me
% ee
Configuration
12:32 PM
98.5
95.9
C6 Cl Ti (10 mol%), OMe MeOH (1 equiv), THF, rt Ph (55) syn:anti = 79:21, 58% eeb
OCOCCl3
OH 403
Page 137
PhCHO
137
OH (R)-BINOL/TiCl2(OPr-i)2 (x mol%), CH2Cl2, 0, 15 min R2 I CF3 R1 + OR3 CF3 x 5 1 20 20 20 20 I (67) (90) (0) (77) (68) (72) II (14) (4) (27)j (10) (22) (18) E:Z I 1:5 1:5 1:6 1:5 1:6
C810
OR3
OH
O R1 R2 II 233
R2
CF3CHO
R1
R1
R2
R3
syn:anti II 1:1 5:3 2:1
% ee (Z)-I 98 96 94 95 95
Ph
TBS
Ph
TIPS
4-MeC6H4
Me
TMS
4-MeC6H4
Me
TBS
4-MeOC6H4 Me
TBS
4-MeSC6H4
Me
TBS
c01_tex 4/18/06 12:32 PM

Page 138
Nucleophile
138
e Diethyl
ether was used as the solvent.
The amount of (R)-BINOL used was 20 mol%.
The aldehyde and the silyl acetal were added in four portions.
For this reaction, 17 mol% of Ti(OPr-i)4 and 17 mol% of (R)-BINOL were used.
For this reaction, 50 mol% of Ti(OPr-i)4 and 50 mol% of (R)-BINOL were used.
Product II was obtained as its silyl ether.
c01_tex
TABLE 1F. OTHER METAL-CATALYZED MUKAIYAMA-TYPE ALDOL ADDITIONS

Electrophile (R)-3,3'-I2BINOL (12 mol%), OH (E)-MeCH=CH (76) 97 95 96 95 81a 180 180 179 180 180 SEt Ph 4-MeOC6H4 (E)-PhCH=CH Ph(CH2)2 2+ OH O (10 mol%), BnO SBu-t t-Bu Ph Bn OTBS O R2 OR1 R2 CO2Bn Ph CCl3 CBr3 c-C6H11 (84) (79) (70) (63) 2-C4H3O (95) (76) () () () 18 78 40 % eeb 49 60 72c 80c 47 23 186 i-Pr () 36 O R % ee 38 CHO O R 2 SbF6 R CH2Cl2, 78 NHTf
4/18/06
Nucleophile O (91) (92) (94) (69) R % ee
Conditions
Refs.
C2 Zr(OBu-t)4 (10 mol%), n-PrOH (80 mol%), H2O (20 mol%), R PhMe, 0
OTMS
RCHO
12:32 PM
SEt
OTMS N N Zn N
BnO
Page 139
SBu-t
139
Ph (40 mol%), CO2TBS ZnEt2 (20 mol%), PhMe, 78
+
OTBS
OR1
R1
R2CHO
Et
Et
Bn
Bn
Bn
Bn 1. CHO O O EtO O OBn OH O SEt (92) d.r. = 92:8, 95% ee 198
OTMS
EtO
SEt
OBn
N O (10 mol%), N Sc N Cl Cl Ph SbF Ph 6 CH2Cl2, 78 2. aq HCl
c01_tex
TABLE 1F. OTHER METAL-CATALYZED MUKAIYAMA-TYPE ALDOL ADDITIONS (Continued)

Electrophile NHTf (40 mol%), 186 R2 R2 CCl3 CBr3
+
4/18/06
Nucleophile OH OR1 % eeb (61) (66) 93 88 O
Conditions
Refs.
C2 CO2TBS ZnEt2 (20 mol%), PhMe, 78
OTBS
R2CHO
OR1
R1
12:32 PM
Bn
Bn 1. CHO O EtO SR2 O dr (92) (93) (90) (90) (94) (90) 92:8 95:5 93:7 92:8 92:8 90 95 93d 99 93 95 % ee R1 O OH O
C26
OTMS
EtO
Page 140
SR2
198
R1
R1 2. aq HCl
R2
t-Bu
N O (10 mol%), N Sc N Cl Cl Ph SbF Ph 6 CH2Cl2, 78
140
(R)-3,3'-I2BINOL (12 mol%), Zr(OBu-t)4 (10 mol%), n-PrOH (80 mol%), H2O (20 mol%), PhMe, 0 R2 OH O OR1 R2 Ph Ph 4-ClC6H4 Ph(CH2)2
Me
t-Bu
Me
t-Bu
i-Pr
t-Bu
i-Bu t-Bu
Et
Ph
C3 180 syn:anti % ee (79) (E)-MeCH=CH (65) (94) (96) 4-MeOC6H4 (E)-PhCH=CH (89) (92) (61) 7:93 11:89 5:95 9:91 7:93 15:85 14:86 96 92 99 96 98 98 89
OTMS
OR1
R2CHO
R1
Me
Ph
Ph
Ph
Ph
Ph
Ph
c01_tex
OTMS (R)-3,3'-I2BINOL (24 mol%), Zr(OBu-t)4 (20 mol%), n-PrOH (160 mol%), H2O (20 mol%), PhMe, 0 R n-Pr 81 28 85 89 31 82 78 i-Bu n-C5H11 i-BuCH2 c-C6H11CH2 Ph(CH2)2 C6H11(CH2)2 (52) 14:86 (71) 10:90 (14) 21:79 (56) 12:88 (64) 12:88 (16) 17:83 (71) 15:85 syn:anti % ee R OPh 180 O
OH
4/18/06
OPh
RCHO
12:32 PM Page 141
I Zr(OBu-t)4 (10 mol%), n-PrOH (80 mol%), H2O (20 mol%), PhMe, 0 I OPh
CHO
(R)-3,3'-I2BINOL (12 mol%),
OH
O (79) syn:anti = 20:80, 96% ee 234
141
Bu-t R Bu-t I R i-Bu neo-C5H11 Ph c-C6H11 Ph(CH2)2 (92) (96) (99) (7) (E)-PhCH=CH (90) (94) TMSO O OMe + R Ph2 P O Pt P Ph2 O (5 mol%), TfOH (5 mol%), 2,6-lutidine (5 mol%), CH2Cl2, 25
C4 OH O OMe II I:II 55:45 82:18 65:35 65:35 65:35 51:49 % eeb 91 88 59 46 95 143
OTMS
OMe
RCHO
c01_tex 4/18/06

Nucleophile
C4 TMSO R I II I:II (99) (66) (99) 82:18 (5) > 99:1 56 46 91 94:6 80 91:9 90 % eeb (5 mol%), R i-Bu neo-C5H11 Ph c-C6H11 Ph(CH2)2 (E)-PhCH=CH (92) 84:16 (96) 84:16 OMe R + OMe O OH O 143
12:32 PM
TMSO Ph2 P O Pt P Ph2 O TfOH (5 mol%), 2,6-lutidine (5 mol%), CH2Cl2, 25
OMe
RCHO
Page 142
142
(R)-3,3'-I2BINOL (12 mol%), O MeO R (E)-MeCH=CH (74) n-C5H11 Ph 4-MeOC6H4 Ph(CH2)2 (93) (95) (90) (92) Zr(OBu-t)4 (10 mol%), n-PrOH (80 mol%), H2O (20 mol%), PhMe, 0 OH R 90e 84 98 93 80
RCHO
% ee 179 180 180 179 180
c01_tex
TMSO Ph (20 mol%), Ph I R I:II (71) (84) (82) (72) (98) (93) 16:39 29 42 20:16 1 8f 35:58 41 41f 5:93 42 44 36:36 44 32f,g 27:55 44 17g 41:43 51 48f 16:55 41 31 Ph Ph Ph Ph 4-O2NC6H4 4-O2NC6H4 4-MeOC6H4 (55) 4-MeOC6H4 (36) % ee Ib % ee IIb II NNa Tf Yb(OTf)3 (20 mol%), CH2Cl2, 40 R OEt R OEt 404 + OH O TMSO O
Tf NNa
4/18/06
OEt
RCHO
12:32 PM Page 143
C6 [Pd((R)-Tol-BINAP)(H2O)2](BF4)2 (1 mol%), 4 MS, wet DMF, Ph 20, 43 h O OH
143
O PdCl2[(R)-BINAP] (5 mol%), AgOTF, 4 MS, DMF, H2O, rt
+
OTMS
PhCHO
(56) syn:anti = 44:12, 70% eeb
145
OH Ph (58) syn:anti = 43:15, 72% eeb 144
PhCHO
OTMS CHO O O
OH EtO O
O SEt
EtO
R Ph Ph
X t-Bu Cl Cl
Y SbF6 () OTf OTf () SbF6 ()
% ee 62h 6 95 199
SEt
N O (1015 mol%), N Sc N X X R Y R CH2Cl2, 78, 16 h
c01_tex 4/18/06

Nucleophile
C6
+
12:32 PM
TMSO CHO 1. O N O O N Sc N Cl Cl Ph SbF Ph OH

6
O O (80) 95% ee
EtO
199
Page 144
(1015 mol%), CH2Cl2, 78, 16 h 2. Raney Ni O CHO O " O Et Et OH (76) 95% ee 199
OTMS
144
O CHO " O O OH [Pd((R)-Tol-BINAP)(H2O)2](BF4)2 (1 mol%), 4 MS, DMF, H2O, 20, 17 h Ph Ph OH O
Et
EtO
SEt
Et
C7
OTMS
EtO
SEt
(88) 92% ee
199
C8
OTBS
PhCHO
(77) 74% ee
145
Ph
c01_tex
C812 [Pd((R)-Tol-BINAP)(H2O)2](BF4)2 OH 145 R2 R1 R2 % ee (92) 81 87 (89) 89 Ph Ph(CH2)2 (88) Ph O (5 mol%), 4 MS, 1,1,3,3-tetramethylurea, 0
OTMS
R2CHO
4/18/06
R1
R1
Ph
Ph
12:32 PM
2-C10H7 OH [Pd((R)-Tol-BINAP)(H2O)2](BF4)2 (1 mol%), 4 MS, wet DMF, rt R2 % ee 74i 72 R2 Ph R2 R1 (80) Ph(CH2)2 (86) % ee 73 73 (82) Ph(CH2)2 (78) Ph R2 R1 O
R2CHO
145
R1
Page 145
Ph
2-C10H7
145
OH PdCl2[(R)-BINAP] (5 mol%), AgOTf 4 MS, DMF, H2O, rt O
+
R2CHO
144
C818 CHO O EtO O O 1. OH
OTMS
EtO
O Ar 198
Ar
R R % ee (85) (80) (81) (85) (91) (96) 95 97 98 95 91 96
Ar 2. aq HCl
N O (10 mol%), N Sc N Cl Cl t-Bu SbF Bu-t 6 TMSCl (2 equiv), CH2Cl2, 78
Ph
Me
Ph
n-C5H11
Ph
n-C4H9
4-FC6H4
Me
4-BrC6H4
2,5-Cl2C6H3
c01_tex

Electrophile CHO N N O I II I:II (99) (98) (93) (99) (99) (95) (95) (89) (98) (96) (96) (100) CO2Me R2 N Ar O R1 I R1 Cl NO2 Br Me R2 H H H (96) (93) OMe (98) (86) I:II > 99:1 93:7 96:4 > 99:1 + Ar 96:4 96:4 95:5 92:8 83:17 93:7 96:4 N O R1 II % ee I > 99 > 99 95 > 99 93:7 88:12 97 99 > 99 > 99j 98 96 95 > 99 99 CO2Me R2 241 73:27 91 90:10 99 96:4 > 99j 95:5 99 % ee I (5 mol%), =X H 4-F 3-Cl 3-NO2 4-NO2 3-OMe 4-OAc 4-OPh 3-Me 4-Me 4-CN 4-Ph R1 CHO X (5 mol%), LiClO4 (20 mol%), 3 MS, R2 PhMe, rt, 20 h R R R + Ar O 241 Ar Bu-t N N Bu-t t-Bu LiClO4 (20 mol%), 3 MS, PhMe, rt, 20 h O Al SbF 6 O Bu-t CO2Me CO2Me Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C9
Ar
OMe
12:32 PM
Ar = 4-MeOC6H4
Page 146
146
4-CO2Me (98)
c01_tex
CO2Me CO2Me N O O R1 II I:II % ee I 98 98 92 CO2Me N + Ar O I I:II (58) (96) (98) (97) (98) OH Ph I R n-C5H11 Ph 4-ClC6H4 4-O2NC6H4 4-MeOC6H4 4-MeC6H4 1-C10H7 (82) (85) (77) (82) (80) (89) (E)-PhCH=CH (90) (87) Bu-t Ga(OTf)3 (20 mol%), H2O/EtOH (9:1), 05, 36 h I:II 89:11 85:15 82:18 77:23 88:12 90:10 90:10 80:20 + R 77:23 90:10 90:10 96:4 96:4 O 405 Ph II % ee I 30 85 78 62 84 88 86 82 O R 2-C4H3O 2,5-(MeO)2-3-NO2C6H2 (E)-4-NO2C6H4CH=CH 1-C10H7 2-C10H7 Ph Ph OH OH R (20 mol%), O N OH N HO Ph Ph R Ar R II % ee I 96 98 98 > 99 > 99 241 (100) 89:11 (90) (99) 74:26 91:9 R2 R1 I R1 F OMe Br Cl X (5 mol%), LiClO4 (20 mol%), 3 MS, PhMe, rt, 20 h N CO2Me NO2 Cl R2 R2 + 241 Ar N Ar CHO 3 MS, PhMe, rt, 20 h X (5 mol%), LiClO4 (20 mol%),
4/18/06
R2
R1
12:32 PM
Page 147
RCHO
147
C9
OTMS
RCHO
Ph
c01_tex

Electrophile OH O Ph N O Pr(OTf)3 (20 mol%), H2O/EtOH (1:9), 0, 18 h O OH O Ph O O (24 mol%), Pb(OTf)2 (20 mol%), H2O/EtOH (1:9), 0, 24 h O O Ph O O (24 mol%), Pb(OTf)2 (20 mol%), H2O/EtOH (1:9), 0, 24 h
+
4/18/06
Nucleophile O Ph (85) syn:anti = 91:9, 82% ee 246
Conditions
Refs.
C9 O
OTMS
PhCHO N O (24 mol%),
12:32 PM
Ph
Page 148
O Ph (62) syn:anti = 90:10, 55% ee 243
PhCHO O
148
O OH Bu-i O O CHO O Ph O O OH OEt R Ph Ph N O O (1015 mol%), N Sc N X X R Y R CH2Cl2, 78, 16 h
i-BuCHO
(99) syn:anti = 94:6, 87% ee
406
C10
OTMS
EtO
X t-Bu Cl OTf Cl
Y SbF6 OTf SbF6 () () ()
% ee 85h,k 90 70 199
Ph
c01_tex
C1014
+
4/18/06
1. O O O 199 Ar % ee (60) (62) (60) (49) 98 95 95l 95 CHO O 78, 16 h 2. Me4NBH(OAc)3 3. TsOH
OTMS
EtO
Ar
N O (10-15 mol%), N Sc N HO Cl Cl t-Bu SbF Bu-t 6 TMSCl (2 equiv), CH2Cl2,
12:32 PM
Ar
Ph
Ph
4-FC6H4
Page 149
C10H7
C12 CHO " O HO Ph O (65) 98% ee
O 199
OTMS
EtO
149
Ph
The desilylated product was isolated.
n-Butyl alcohol (50 mol%) was added.
The protocol involves slow addition of the nucleophile.
Yb(OPr-i)3 was used instead of Yb(OTf)3.
The product has the S configuration.
TMSCl (2 equivalents) were added and the reaction was carried out at 35.
Reduction was performed using Et2BOMe/NaBH4 to give the trans product.
c01_tex
TABLE 1G. NON-METAL-CATALYZED MUKAIYAMA-TYPE ALDOL ADDITIONS

Electrophile O Et (84) (84) (87) (87) (96) (90) (91) (94) (91) (94) (87) Me Me (97) (89) 81 86b 76c 68 32 35 11 35 56c 83b 49 43e 20 OMe c-C3H5 t-Bu Me Me Me Et HC C (89) Me Me Me Me 2-C4H3O Ph Ph Ph 4-CF3C6H4 4-MeOC6H4 c-C6H11 PhC C Ph(CH2)2 1-C10H7 O HO " O OMe (90) 80% eea 102 Me Me 32 102 R2 N t-Bu O O OBu-n n-BuO CH2Cl2, 20, 12 h 2. aq NaHCO3 N (10 mol%), R1 R2 Bu-t 1. OH O R1 % ee R2
a
4/18/06
Nucleophile
Conditions
Refs.
C2
OSiCl3
12:32 PM
OMe
R1
Page 150
(E)-PhCH=CH Me
150
O HO " O OMe Me OH (10 mol%), R OMe O R N O P N N Me CH2Cl2, 78 Ph
(86) 8% eea
102
% eea t-Bu (76) (88) 26 20 206
RCHO
c01_tex
4/18/06
RCHO R Ph Ph (94) 38d (87) 33 OMe
Ph (10 mol%), t-Bu 206 (78) 40
Me N O P N N Ph Me OH O R % ee
12:32 PM
CH2Cl2, 78
OH t-Bu R t-Bu Ph (91) 23 (78) OMe 50d (75) 49
% ee 206
Page 151
RCHO
Me N O P N N Me (10 mol%), CH2Cl2, 78
151
OH R OMe O R Ph c-C6H11 Me O N P N (CH2)5 N Me Me
2
OTBS
% ee 2-C4H3O (94) (97) (86) 4-MeC6H4 4-CF3C6H4 4-MeOC6H4 (E)-PhCH=CH Ph(CH2)2 1-C10H7 2-C10H7 (97) (97) (97) (95) (72) (E)-PhCH=CMe (98) (98) (98) 87 93e 88e 94 91 97 94 81e 45 80 94 208
RCHO
OMe
(5 mol%), SiCl4, CH2Cl2, 78, 15 min
c01_tex
4/18/06
TABLE 1G. NON-METAL-CATALYZED MUKAIYAMA-TYPE ALDOL ADDITIONS (Continued)

Electrophile 1. R OH (1020 mol%), Ph Ar Ph Ph Ph Ph Ph 2,6-(MeO)2C6H3 Et 4-t-BuC6H4 4-t-BuC6H4 4-t-BuC6H4 Et Et Et Et ClO4 SbCl6 ClO4 PF6 SbCl6 Et ClO4 Et ClO4 3h 4.5 h 6h 4h 3h 3h 4h Me ClO4 6h Me TfO 3h (75) (92) (52) (67) (99) (53) (40) (20) (48) R X Time % ee 3b 12b 24 16 11 22 38 32 6 OEt O 407 R Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
Nucleophile
C2
OTBS + Ar X CH2Cl2, 78 2. aq HF/CH3CN
12:32 PM
PhCHO
OEt
Page 152
152
OH Me O N P N (CH2)5 N Me Me Ph
2
C3 O OR 208
OTBS
OR
PhCHO
R (1 mol%), SiCl4, CH2Cl2, 78, 3 h
E/Z
d.r. (98) (78) (93) (73) (98) 99:1 98:2 99:1 99:1 94:6
% ee 72 76 > 98 > 98 88
Me
82:18
Et
95:5
t-Bu
95:5
t-Bu
12:88
Ph
94:6
c01_tex 4/18/06
OTBS R dr (29) 92:8 208 89:11 93:7 91:9 88f 89 36f,g (49) f OEt c-C6H11 Ph(CH2)2 (55) Ph(CH2)2 (71) c-C6H11 % ee Me O N P N (CH2)5 N Me Me R
2
OH
12:32 PM
OEt
RCHO
(5 mol%), SiCl4, CH2Cl2, 78, 24 h
Page 153
OTBS R OBu-t 4-CF3C6H4 4-MeOC6H4 (E)-PhCH=CH PhC CCH2 1-C10H7 2-C10H7 1. Hg(OAc)2, SiCl4, CH2Cl2 2. Me N O Ph P N N Ph Me CH2Cl2, 78 (10 mol%), R 3. aq NaHCO3 O R OH Ph Me (65) i-Bu (71) % ee 75 57 Ph R
OH
dr (93) (93) (88) (98) (92) 99:1 > 99:1 > 99:1 > 99:1 96:4 > 99:1 (98) (95) 96:4 > 99:1
% ee > 98 92 98 > 98 68 92 94 > 98 208
OBu-t
RCHO
Me O N P N (CH2)5 N Me Me
2
153
(1 mol%), SiCl4, CH2Cl2, 78, 3 h
(E)-PhCH=CMe (90)
C36
OTMS
PhCHO
380
c01_tex

Electrophile Conditions 1. R2 R1 I I:II (85) (95) (42) (98) (86) (47) 97:3 98:2 99:1 99:1 OH CHO R1 I I:II (91) (E)-MeCH=CH Ph C6H11 PhC C (E)-PhCH=CH Ph(CH2)2 1-C10H7 2-C10H7 Ph (97) (69) (99) (88) (79) (E)-PhCH=CMe (89) (97) (99) (91) 98:2 99:1 99:1 98:2 99:1 99:1 99:1 98:2 98:2 97:3 R2 + R2 R1 CHO II % ee I 52 59 19 76 26 66 90 70 53 82 75 68 54 86 90 (97) (99) (92) 95:5 8 99:1 42 98:2 7 97:3 44 98:2 81 99:1 5 % ee I II R2 (E)-MeCH=CH Ph c-C6H11 PhC C (E)-PhCH=CH Ph(CH2)2 (E)-PhCH=CMe (91) 1-C10H7 2-C10H7 Ph OH " R2 R1 Me O N P N (CH2)5 N Me Me CHO + R2 75 CHO (5 mol%), CHCl3/CH2Cl2 (4:1), 78, 6 h 2. MeOH
2
4/18/06
Nucleophile OH OH
Refs.
C37
OSiCl3
R1
R2CHO
R1
12:32 PM
Me
Me
Me
Me
Page 154
Me
Me
Me
Me
Me
154
n-C5H11
OSiCl3
R2CHO
R1
Me
Me
Me
Me
Me
Me
Me
Me
Me
n-C5H11
c01_tex
C38 Ph 408 R % ee (98) (94) (97) 81 85 82 52 49 O + OR I:II (78) 3.4:1 1.3:1 (85) (78) 1.5:1 (85) 73:1h 1:1.1 (77) 11:1h Ph (78) 20:1h
1
1. O Ph 87 86 OH
OSiCl3
PhCHO
4/18/06
Me 2. aq NaHCO3 (98) (95) (95) (93) 1. Hg(OAc)2, SiCl4, CH2Cl2 O R2 (5 mol%), OR I R2 Ph Ph (E)-MeCH=CH (80) Ph Ph Ph
1
Me N O (5 mol%), P N N Ph Me CH2Cl2, 78, 2 h
TBSOCH2
i-Pr
12:32 PM
n-Bu
i-Bu
t-Bu
Ph OH R2 II OH
Page 155
C4 2. Me N O Ph P N N Ph Me CH2Cl2, 78 3. aq NaHCO3
OTMS
R2CHO
212
OR
155
(E)-MeCH=CH (81) 6.2:1h Ph TBSO (10 mol%), Ph I I:II (72) 1:2.5 (75) 1.3:1i O OH + Me N O P N N Ph Me CH2Cl2, 78, 4 h
R1
Piv
Piv
TBS
TBS
TBS
TBS
Bn
Bn
C5
TBSO
OSiCl3
TBSO
OH 210 Ph II
PhCHO
c01_tex

Electrophile Conditions 1. Hg(OAc)2, SiCl4, CH2Cl2, rt R (E)-MeCH=CH (85) 211 2-C4H3O + diastereomers II (E)-PhCH=CH 1-C10H7 2-C10H7 1. Hg(OAc)2, SiCl4, CH2Cl2, rt 2. + (10 mol%), I I:II (61) (58) (89) (86) 1. Hg(OAc)2, SiCl4, CH2Cl2, rt TBSO O 2. (10 mol%), OH R I TBSO + II O OH R 5.5:1 1:4.4i 1.8:1 1:2.3i R (E)-MeCH=CH CH2=CMe t-Bu Ph C6H11 PhC C (E)-PhCH=CH Ph(CH2)2 (E)-PhCH=CMe 1-C10H7 (85) (81) (E)-MeCH=CMe (78) (73) (80) (47) (83) (81) (34) (84) (85) I:II 4.88:1 242 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 Ph II Ph RO O OH RO O (71) (72) (81) PhC C 93:7 98:2 94:6 (79) 95:5 Ph (88) 95:5 (82) 94:6 93:7 2. R (5 mol%), OTBS I Ph Me N O P N N Ph Me O I:II OH Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C5
OTMS
RCHO
12:32 PM
OTBS
CH2Cl2, 78, 10 h
Page 156
OR
OTMS
OH 210
PhCHO
156
CH2Cl2, 78, 4 h Me N O Ph P N N Ph Me CH2Cl2, 78, 4 h
TBS
Me N O Ph P N N Ph Me
TBS
TIPS
TIPS
TBSO
OTMS
RCHO
c01_tex
1. Hg(OAc)2, SiCl4, CH2Cl2 2. TBSO O R I R I:II (83) 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 (83) 1:8.09 (84) (78) (75) (31) (82) (82) (22) (E)-MeCH=CH CH2=CMe (E)-MeCH=CMe (75) t-Bu Ph c-C6H11 PhC C (E)-PhCH=CH Ph(CH2)2 1-C10H7 (E)-PhCH=CMe (80) II + R 242 OH O OH (10 mol%), TBSO Ph Me N O P N N Ph Me CH2Cl2, 78
4/18/06
TBSO
OTMS
RCHO
12:32 PM
3. aq NaHCO3
Page 157
157
1. O OH R + (10 mol%), Ph O Me N O P N N Ph Me I R Ph PhC C (E)-PhCH=CH 1-C10H7 (95) (90) (94) (E)-PhCH=CMe (98) (94) I:II 1:61 1:5.3 < 1:99 < 1:99 < 1:99 CH2Cl2, 78, 2 h 2. aq NaHCO3 II
C6 OH R 207
OSiCl3
RCHO
% ee II 93 82 88 92 97
c01_tex

Electrophile 1. (10 mol%), Ph Ph 134 + O OH O OH Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C6 Ph N O Ph P N N Ph Ph CH2Cl2, 78, 2 h 2. aq NaHCO3 1. Ph (5 mol%), t-Bu n-Bu R C6H11 (79) (94) (92) (95) (E)-PhCH=CH 1-C10H7 4-PhC6H4 1. CHO Ph (10 mol%), n-Bu I OTBS Solvent CH2Cl2 CH2Cl2 Et2O PhMe EtCN 1. CHO O (10 mol%), n-Bu OH OTBS (88) 75% ee 380 Me N O Ph P N N Ph Me CH2Cl2, 78 (47) (50) (45) (40) (43) I:II 2.7:1i 1:15.6 1:9 1:6.7 1:11.5 OTBS O OH + n-Bu II OTBS Me N O P N N Ph Me 78, 6 h O (E)-PhCH=CMe (95) (81) O 92g 89g 84 91 86 85 OH R % ee 408 (94) I:II = 97:1, 53% ee I I II
OSiCl3
PhCHO
12:32 PM
OSiCl3
RCHO
Page 158
n-Bu CH2Cl2, 78, 2 h 2. aq NaHCO3
Me N O P N N Ph Me
158
2. aq NaHCO3 2. aq NaHCO3
OH 380
TBSO
c01_tex
1. Hg(OAc)2, SiCl4, CH2Cl2 2. CHO Ph (5 mol%), n-Bu Ph (89) 92% ee 408 O OH
4/18/06
OTMS
Ph
n-Bu
Me N O P N N Ph Me CH2Cl2, 78
12:32 PM
3. aq NaHCO3
TIPSO Ph (10 mol%), R I TIPSO R III R (E)-MeCH=CH (E)-MeCH=CH (79) (83) (E)-MeCH=CMe (83) (E)-MeCH=CMe (81) Ph Ph (E)-PhCH=CH (E)-PhCH=CH 1-C10H7 1-C10H7 (84) (86) (83) (81) (80) (75) I+II:III+IV 7:1 1:6 3:1 1:3 16:1 1:10 10:1 1:8 30:1 1:10 IV O OH + II TIPSO O +
OSiCl3
TIPSO R
OH
TIPSO
OH 210
Page 159
RCHO
Me N O P N N Ph Me
CH2Cl2, 78, 8 h
159
OH R
I+IV:II+III 28:1 37:1i > 50:1 > 50:1i 30:1 26:1i > 50:1 > 50:1i 17:1 18:1i
c01_tex

Electrophile TIPSO O R I TIPSO O R III R (E)-MeCH=CH (90) (85) (85) (80) (84) (82) (88) (75) (71) 1-C10H7 (79) (E)-MeCH=CH (E)-MeCH=CMe (E)-MeCH=CMe Ph Ph (E)-PhCH=CH (E)-PhCH=CH 1-C10H7 I+II:III+IV 15:1 1:5 13:1 1:5 24:1 1:8 14:1 1:6 89:1 1:17 + OH O TIPSO OH R IV I+IV:II+III > 50:1 > 50:1i 13:1 19:1i 53:1j 32:1i,j 9:1 15:1i 14:1 14:1i II + R + 209 OH O OH (10 mol%), TIPSO Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C6 Ph Me N O P N N Ph Me
TIPSO
OSiCl3
12:32 PM
RCHO
TBAI (20 mol%), CH2Cl2, 78, 8 h
Page 160
160
RO (10 mol%), O OH Ph + Ph Me N O P N N Ph Me CH2Cl2, 78, 8 h I
OR
OSiCl3
RO
OH Ph 210
PhCHO
II
c01_tex
RO + Ph III I+II:III+IV (59) (60) (84) (86) (80) 1. HO F (10 mol%), Ph R Ph N THF, 70, 10 min 2. aq HCl, MeOH (62) (76) (55) (70) (73) 1. HO Ph N+ OH F (10 mol%), Ph O 409 R (55) (46) % ee 39 36 % ee 62 40 42 37 25 N+ OH O 409 1:1 3:1i 1:10 26:1i 16:1 30:1 1:14 12:1i 14:1 6:1 I+IV:II+III IV Ph +
4/18/06
OH
RO
OH
Z:E
12:32 PM
TBS
12:1
TBS
12:1
TIPS
16:1
TIPS
16:1
TIPS
1:15
Page 161
C68
OTMS
PhCHO
161
N THF, 70, 10 min 2. aq HCl, MeOH
t-Bu
Ph
4-ClC6H4
4-MeOC6H4
2,4-(MeO)2C6H3
PhCHO
t-Bu
Ph
c01_tex 4/18/06

Electrophile 1. O Ph I R (E)-MeCH=CH (94) Ph 4-BrC6H4 PhC C (E)-PhCH=CH 1-C10H7 (96) (97) 9.4:1 3:1 (92) 1:3.5 (89) 12:1 96 58 92 84 (95) 18:1 95 7:1 91 I:II % ee I II R + Ph R OH O OH 207 Ph Me N O (15 mol%), P N N Ph Me CH2Cl2, 78, 68 h Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
Nucleophile
C9
OSiCl3
12:32 PM
RCHO
Ph
Page 162
2. aq NaHCO3
162
Ar HSO4 OH R O N+ Ar (2 mol%), Ar = CF3 KFM2H2O (0.5 equiv), THF/PhMe (2:1), 40, 0.51 h CF3 R Ph Ph 1-C10H7
C10 248
OTMS
RCHO
dr (92) 70:30 (90) 83:17 (90) 9-phenanthryl (88) 94:6 95:5
% ee 76k 84 91 90
c01_tex 4/18/06
1. HO F Ph (12 mol%), Ph R I:II (74) (65) (73) 30 21 15 (73) (67) 81:19 66 82:18 66 76:24 68 73:27 44 6l 70:30 70 20 % ee I % ee II I R II Ph N THF, 70, 6 h 2. aq HCl, MeOH
C11 N + 410
+
OTMS
OH O
OH
12:32 PM
PhCHO
Page 163
OMe
Cl
Br
163
The reaction was quenched after 20 hours.
The protocol involves slow addition of the aldehyde.
The reaction was quenched after 32 hours.
TBAI (0.1 equivalents) was added.
The R,R-catalyst was used.
The S,S-catalyst was used.
No TBAI was added.
The reaction was carried out in THF at room temperature.
THF/MeCN (3:7) was used as the solvent.
c01_tex
TABLE 2A. GOLD-CATALYZED ALDOL ADDITIONS OF UNMODIFIED NUCLEOPHILES

Electrophile Me N N + O I:II (94) 94:6 89:11 94:6 94:6 75:25 67:33 47:53 57:43 48 36 O OMe + N I R Ph 4-FC6H4 C6F5 n-C13H27 N O (1.1 mol%), [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt, 25 h O N O OMe (89) 93% ee 59 (93) (92) 2,3,5,6-F4C6H (93) (92) R O I:II 95:5 94:6 38:62 37:63 N OMe 64 II % ee I % ee II 95 94 33 36 12b 25 90 86 73 86 78 82 89 78 96 19 95 20 90 40 95 (99) (97) (96) (98) (96) (90) (99) 49a % ee I % ee II N II 64 O (1.1 mol%), R Ph 2-FC6H4 3-FC6H4 4-FC6H4 2,6-F2C6H3 2,4,6-F3C6H2 2,3,5,6-F4C6H C6F5 Me N N O (1.1 mol%), O R Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, 0, 20100 h PPh2 O N I R OMe R OMe Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, 0, 20100 h PPh2 O O Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C3
12:32 PM
CN
RCHO
OMe
Page 164
164
CHO Fe PPh2 PPh2 Me N
RCHO
n-C13H27
c01_tex 4/18/06
O OMe O PPh2 (0.5 mol%), I (90) I:II= 73:23, 82% ee I, 33% ee II II [Au(C6H11CN)2]BF4 (0.5 mol%), CH2Cl2, rt, 12 h Fe O O N N PPh2 O + 56 N MeO2C CO2Me CO2Me MeO2C
Me N
12:32 PM
Me N N OMe + O II N N I R Me i-Pr i-Bu t-Bu Ph 4-ClC6H4 4-O2NC6H4 2-MeC6H4 2-MeOC6H4 (99) (100) (99) (94) (93) (97) (80) (98) (98) 3,4-(BnO)2C6H3 (88) OMe O O (1.1 mol%), R R Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt, 2070 h PPh2
Page 165
RCHO
165
(E)-n-PrCH=CH (85)
I:II % ee I % ee II 89:11 99:1 96:4 100:0 87:13 95:5 94:6 83:17 96:4 92:8 94:6 89 92 87 97 92 95 94 86 95 92 95 47c 12 17 75 20 73 32 10 0 62 55 55 55 55 55 55 55 55 55 55
c01_tex
TABLE 2A. GOLD-CATALYZED ALDOL ADDITIONS OF UNMODIFIED NUCLEOPHILES (Continued)

Electrophile Me N N OMe + O I R I:II (86) O Fe Me N N O (1.1 mol%), I O II O NEt2 (1 mol%), O R Me i-Pr t-Bu Ph c-C6H11 (99) (E)-n-PrCH=CH (83) (98) (95) R N I I:II (100) 84:16 98:2 (100) 100:0 81:19 89:11 97:3 OMe + R O N II % ee I % ee II 72 90 97 84 93 90 44 52 49 58 58 57 57 58 57 N + O R N OMe H i-Pr Ph R (89) (99) (94) R OMe Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt, 1640 h PPh2 O I:II % ee I % ee II 99:1 94:6 44 Me (100) 85:15 85 94 95 56 49 61 62 55 55 (80) 100:0 89 55 95:5 96 0 O 55 % ee I % ee II II N N OMe O O (1.1 mol%), R R Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt, 2040 h PPh2 O O Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C3
12:32 PM
CN
RCHO
OMe
Page 166
RCHO
166
H N Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt, 1040 h PPh2
O OMe
RCHO
c01_tex
H N NMe2 + O I R I:II (94) 78:22 37 95 81 91 81 O OMe + O N N Ph OMe 253 4 0 31 57 58 58 57 0 (89) 91:9 (91) 90:10 (96) 98:2 58 % ee I % ee II Me (E)-MeCH=CH (E)-n-PrCH=CH (97) 80:20 Ph c-C6H11 O Ph NMe2 (1.1 mol%), [Au(C6H11CN)2]BF4 (1 mol%), ClCH2CH2Cl, 50, 5 h O R2 OR1 + O I:II (28) O Ph 2-MeC6H4 2-CF3C6H4 3-CF3C6H4 4-CF3C6H4 CH2=C(Me) Ph 95:5 (72) 90:10 (72) 93:7 (94) 84:16 (92) 81:19 (89) 85:15 (90) 68:32 (95) 92:8 N II % ee I % ee II 51 90 92 88 84 85 54 93 59d,e 12 21d,f 86d,g 62d 57d 79d 47d 253 253 253 253 253 253 252 252 N I R2 O NMe2 (1.1 mol%), O R2 PPh2 Me N PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt, 1894 h O PPh2 Me N II N (1 mol%), O N R OMe OMe R Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt, 1040 h PPh2
4/18/06
RCHO
12:32 PM
Page 167
O Fe
CN
PhCHO
OMe
167
Fe
II I (85) I:II = 74:26, 21% ee I, 4% ee II O OR1
CN
R2CHO
OR1
R1
Me
Me
Et
Et
Et
Et
t-Bu
t-Bu
c01_tex

Electrophile Me N NMe2 + 252 O N II I:II (56) (99) 90:10 93:7 91:9 93 O OR + O N II I:II % ee I % ee II 13 7 22 43 N I X Ph OR 411 78 6d 17d 95 7d (69) (88) 89:11 O X NMe2 Ph (1.1 mol%), O Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt PPh2 Ph 91 7d 92:8 72 13d % ee I % ee II (1.1 mol%), O N I R2 CH2=CMe Ph 2,5-Me2C6H3 (84) CH2=CMe Ph R2 OR1 OR1 R2 Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt, 1872 h PPh2 O O Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C3
12:32 PM
CN
R2CHO
OR1
R1
Me
Me
Me
Page 168
Et
Et
168
S (> 85) 72:28 O (> 85) 70:30 O X NMe2 (1.1 mol%), Fe PPh2 CH2Cl2, rt PPh2 Ph Ph O N I X S I:II (> 85) 83:17 O (> 85) 77:23 84 80 OR + [Au(C6H11CN)2]BF4 (1 mol%),
CN
PhCHO
OR
Me
Et
O Ph O N II % ee I % ee II 71 61 OR 411
CN
PhCHO
OR
Me
Et
c01_tex
O X NMe2 + O II I:II (> 85) 88:12 89 67 O OR + O N N I X S O (> 85) 67:33 22 Me N NMe2 (1.1 mol%), I R 2-C4H3O 3-C4H3O 2-C4H3S 3-C4H3S 2-C5H4N 3-C5H4N 4-C5H4N (62) (80) (90) (78) (45) (55) (38) 2,4,6-Me3C6H2 (57) I:II 68:32 86:14 95:5 97:3 75:25 88:12 88:12 100:0 O N R OEt + O N II % ee I % ee II 32 87 33 78 6 79 75 91d 83d 7d 17d 1d 84d 62d 78d Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), ClCH2CH2Cl, 50, 2.524 h PPh2 O R (> 85) 74:26 17 18 43 O OEt 252 I:II Ph OR 411 10 16 % ee I % ee II N 411 (1.1 mol%), I X S O (> 85) 81:19 O X NMe2 Ph (1.1 mol%), II % ee I % ee II O Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt PPh2 Ph O N OR OR Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt PPh2 Ph Ph Ph
4/18/06
CN
PhCHO
OR
Me
12:32 PM
Et
Page 169
PhCHO
Me
169
Et
CN
RCHO
OEt
c01_tex

Electrophile Me N NMe2 + 252 O II N (1.1 mol%), O I (88) I:II = 89:11, 93% ee I, 18% ee II O NMe2 + O II N (1.1 mol%), O I (34) I:II = 77:23, 16% ee I, 1% ee IId O Ph OEt + O R3 H R4 1-C10H7 H H Me Bn Bn CHO Fe PPh2 ClCH2CH2Cl, 40 PPh2 (1.1 mol%), O N Me N NMe2 Me H Bn n-C17H35 H O OEt (65) 413 1-C10H7 H H N N I R2 Me Me O R1 Me Me Me Ph O OEt II I:II % ee I % ee II 1-C10H7 (96) 89:11 95 (88) 90:10 95 (84) 90:10 96 n-C17H35 H 1-C10H7 (35) 68:32 15 (44) 64:36 16 (33) 67:33 26 35 34 40 6 8 11 412 N OEt OEt O 253 N Ph OEt OEt Ph Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt, 24 h CHO Fe [Au(C6H11CN)2]BF4 (1 mol%), ClCH2CH2Cl, 50, 20 h R1 N Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), ClCH2CH2Cl, 50, 20 h (1.1 mol%), PPh2 N R1 O O H N R4 3 2R R PPh2 PPh2 O O Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C3
12:32 PM
CN
PhCHO
OEt
Page 170
Me N
170
[Au(C6H11CN)2]BF4 (1 mol%),
PhCHO
c01_tex
O OEt NMe2 (1.1 mol%), O N (69) 413
CHO Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), ClCH2CH2Cl, 40 O N + O II Temp I:II (74) 94:6 83:17 92:8 77:23 85:15 (88) (78) 15 15 rt OH O R O (1.1 mol%), X O NHBz I R Me Me Ph X Me (65) OMe (78) i-Bu OMe (82) OMe (59) I:II 57:43 86:14 87:13 71:29 NMe2 + X O NHBz II % ee I % ee II 75 90 76 42 74 36 84 74 (82) (87) 89:11 84:16 77:23 81:19 R (87) (89) (84) (83) 94 93 94 93 91 77 84 80 68 OH O NMe2 56 rt 22 20 20 10 20 % ee I % ee II 64 48 28 26 20 24 N O I R Ph 2-FC6H4 4-FC6H4 2,6-F2C6H3 2,4,6-F3C6H2 2,3,5,6-F4C6H 2,3,5,6-F4C6H C6F5 C6F5 O X O PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt, 20108 h 2. HCl/MeOH 3. BzCl, NEt3, CHCl3 Fe PPh2 N 1. Me N N R NMe2 NMe2 R O 63 Me N Fe PPh2 (1.1 mol%), [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, 2050 h PPh2
4/18/06
PPh2 Me N
12:32 PM
CN
RCHO
NMe2
Page 171
171
c01_tex

Electrophile O N Me 91:9 95:5 94:6 94:6 > 95:5 94.5 94.1 97.3 96.3 98.6 Et i-Bu Ph 4-BnOC6H4CH2 (84) O N O (1.1 mol%), R Me (E)-MeCH=CH i-Pr Ph O N (0.51 mol%), O N R N (94) (90) (86) () 95:5 97:3 98:2 97:3 96:4 R Me (84) Ph (73) O N trans:cis % ee 97 99 97 96 95 trans:cis % ee 94:6 95:5 96.1 93.9 60 R OMe N Me (74) (92) (84) (85) 60 O N R NMe2 R trans:cis % ee Me N Fe PPh2 (0.51 mol%), [Au(C6H11CN)2]BF4 (0.51 mol%), CH2Cl2, rt, 4080 h PPh2 Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C3
12:32 PM
CN
RCHO
NMe2
O Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt, 2048 h PPh2
Me N
Page 172
CN
N Me
OMe
RCHO
249
172
(E)-BnOCH2CH=CH (82) Me N Fe PPh2 [Au(C6H11CN)2]BF4 (0.51 mol%), CH2Cl2, rt, 2050 h O NMe2 O N O Ph CHO Fe PPh2 Me N PPh2 PPh2 (1.1 mol%), [Au(C6H11CN)2]BF4 (1 mol%), ClCH2CH2Cl, 40, 20 h
CN
RCHO
CN
() anti:syn > 99:1, 80% de
252
Ph
c01_tex
CHO NMe2 O O I () I:II = 98:2, 81% de I, 40% de II II N O N Ph O + Ph 252 (1.1 mol%), Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), ClCH2CH2Cl, 40, 20 h Me N NMe2 + O O O I II N O N (1.1 mol%), O O 252 Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), ClCH2CH2Cl, 50, 20 h PPh2 PPh2
4/18/06
Me N
12:32 PM
O CHO
CN
Page 173
() I:II = 97:3, 88% de I, 15% de II
173
CHO Fe NMe2 O O I N (1.1 mol%), PPh2 [Au(C6H11CN)2]BF4 (1 mol%), ClCH2CH2Cl, 50, 20 h O R O N % ee (99) (100) (89) (99) (75) 52 64 70 71 67d OMe + O Me N NMe2 (1.1 mol%), Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt, 2090 h PPh2
PPh2 Me N
O 252 O O N II
() I:II = 97:3, 89% de I, 33% de II
C3-9
CN
OMe
(CH2O)n
61
Me
Et
i-Pr
Ph
c01_tex

Electrophile Me N N O (1.1 mol%), I I:II (86) 56:44 93:7 54:46 26 88 R2 OMe O I I:II (95) (92) 88:12 (89) (96) H Ph Me (100) 22:78 (86) 54:46 63 44 90 66 81 35 92 23b 28b 6 5 R2 H Me (94) 44:56 Ph H N + O % ee I % ee II 61 62 62 61 61 62 62 N R1 O OMe II 17 51 62:38 87 66h 94 53 86 54 (97) (92) (86)
1
4/18/06
Nucleophile R2 OMe OMe O II % ee I % ee II N O R2 Me Ph Me Me (100) 24:76 Ph Me N

2
Conditions R1 R2 + 62 N O R1 O
Refs.
C4-6 Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt, 41330 h PPh2
CN
OMe
R2CHO
12:32 PM
R1
Me
Me
Et
i-Pr O
Page 174
i-Pr N (1.1 mol%), R2 R
O Fe PPh2 [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, rt, 20290 h PPh2
CN
OMe
R CHO
R1
174
R1
Me
Me
Me
Et
i-Pr
i-Pr
i-Pr
The absolute configuration of II is 4S,5S.
The absolute configuration of II is 4R,5R.
PPh3 was added.
TMEDA was added.
c01_tex
TABLE 2B. NON-GOLD METAL-CATALYZED ALDOL ADDITIONS OF UNMODIFIED NUCLEOPHILES

Electrophile CHO H2O (22 mol%), THF, 50 2. Citric acid, THF/H2O, rt NH2 I I:II (58) 89:11 (56) 78:22 (98) 20:80 1. (S)-LLB (20 mol%), LiOH (18 mol%), H2O (22 mol%), THF, 50 R NH2 I R 2-C4H3O (82) t-Bu n-C5H11 c-C6H11 CHO H2O (22 mol%), THF, 50 2. Citric acid, THF/H2O, rt 1. (S)-LLB (20 mol%), LiOH (18 mol%), OH CO2Bu-t NH2 I I:II (94) (87) (93) (85) (50) (43) 62:38 53:47 59:41 63:37 56:44 44:56 ee % I 47 64 74 42 61 68 3a 8 20 0a 43c 51b + (89) (73) (71) 61:39 86:14 28:72 70:30 I:II 19 76 42 69 OH CO2Bu-t NH2 II ee % II 414 NH2 II ee % I ee % II 2b b 1b 18b R 2. Citric acid, THF/H2O, 40 CO2Bu-t + OH CO2Bu-t OH 414 33 3a 47 42 38 ee % I ee % II II NH2 CO2R + 414 CO2R 1. (S)-LLB (20 mol%), LiOH (18 mol%), OH OH Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
Nucleophile
4/18/06
C2
Ar
CO2R
Ar
Ar = 4-ClC6H4
12:32 PM
Me
CHPh2
N(Me)OMe
Ar
CO2Bu-t
Page 175
RCHO
Ar
Ar = 4-ClC6H4
175
Ar
CO2Bu-t
Ar
Ar
Ph
4-FC6H4
4-ClC6H4
4-MeC6H4
4-CF3C6H4
4-CF3C6H4
c01_tex
TABLE 2B. NON-GOLD METAL-CATALYZED ALDOL ADDITIONS OF UNMODIFIED NUCLEOPHILES (Continued)

Electrophile HO OH R 84 (5 mol%), R n-Pr I i-Pr i-Bu Et2Zn (10 mol%), 4 MS, THF, 5 Ph 4-O2NC6H4 c-C6H11 Ph(CH2)2 Ph2CH Ph2CH (85) (59) (79) (72) (62) 78 93d 89 82 87d (55) 88 t-Bu (76) 86 (24) 76 (80) 87 (56) 84 ee % O OH N Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C3 Ph Ph OH N Ph Ph
12:32 PM
RCHO
Page 176
176
Ph Ph OH N (10 mol%), OH N I HO Ph Ph R n-Pr n-Pr i-Pr Et2Zn (20 mol%), 4 MS, THF, 5 i-Bu t-Bu Ph 4-O2NC6H4 c-C6H11 Ph(CH2)2 Ph2CH
RCHO
ee % (69) (72) (89) (59) (72) (78) (54) (89) (76) (84) 89 84e 91 84 94 83 76 92 82 91
84
c01_tex 4/18/06
O (1 mol%), Ph2P Pt Cl O O II N I N AgOTf (1 mol%), NEt(Pr-i)2 (10 mol%), THF, rt R Et (91) (82) (80) (82) (85) (90) (91) (87) (82) (73) (60) c-C6H11 2-MeC6H4 3-MeC6H4 4-MeC6H4 2,4,6-Me3C6H2 1-C10H7 2-C10H7 (97) (90) (87) (80) (84) (73) (81) 79:21 78:22 67:33 83:17 75:25 45:55 72:28 74:26 4-O2NC6H4 72:28 79:21 80:20 82:18 86:14 88:12 81:19 71:29 74:26 0 16 16 24 19 15 30 1 12 21 11 3 12 11 26 4 23 2-C5H4N 3-C5H4N 4-C5H4N Ph 2-ClC6H4 3-ClC6H4 4-ClC6H4 2-O2NC6H4 3-O2NC6H4 91:9 30 I:II ee % I ee % II 70 53 61 49 67 49 42 65 56 45 57 74 50 60 61 71 53 66 PPh2 R + 254 OMe R OMe
12:32 PM
CN
RCHO
OMe
Page 177
177
c01_tex

Electrophile O O (1.5 mol%), O I R H (91) (93) (92) (94) (96) (90) (91) (89) (96) (95) (96) (95) 2-MeOC6H4 3-MeOC6H4 4-MeOC6H4 2,4,6-Me3C6H2 O O 1-C10H7 2-C10H7 (94) (95) 87:13 69:31 54 52 8 6 (97) (97) (89) (65) (84) 73:27 66:34 56:44 65:31 70:30 93:7 85:15 65:35 4-CF3C6H4 69:31 68:32 72:28 90:10 68:32 90:10 75:25 18 29 62 13 41 20 65 39 61 41 58 49 64 15 54 69:31 14 Me Et i-Pr 2-C4H3O 2-C5H4N 3-C5H4N 4-C5H4N Ph c-C6H11 2-MeC6H4 15 24 32 32 14 29 25 22 3 9 20 31 17 24 22 6 I:II % ee I % ee II II N O N PPh2 Pt Cl NEt(Pr-i)2 (10 mol%), CH2Cl2, 20 Ph2P O O + 415 O R OMe OMe R O Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C3
12:32 PM
CN
RCHO
OMe
Page 178
178
c01_tex
O O OMe N t-Bu 2 OTf N,N-dimethylaniline (5 mol%), Et2O, rt 2. Et3N, TBSCl Cu Bu-t O O MeO N (10 mol%), (48) 96% ee 265 O O O OTBS
1.
2+
4/18/06
OMe
12:32 PM
C34 OH (R)-LLB (20 mol%), THF, 20 R2 R2 % ee (53) 74 (71) 94 73 t-Bu BnCMe2 (82) BnCMe2 R1 O
R2CHO
214
Page 179
R1
Me
Me
179
H O (1.1 mol%), HO CN Temp 30 30 30 30 10 10 10 0 (67) (85) (86) (80) (82) (86) (96) (80) % ee 35 74 78 82 91 93 87 61 Fe PPh2 H [Rh(acac)(CO)2] (1 mol%), Bu2O, 5100 h X Ph2P Fe
Et
C4
HCHO
250
CN
OMe
OEt
OPr-i
OBu-t
OCH(i-Pr)2
OCH(t-Bu)2
OCHPh2
N(OMe)Me
c01_tex

Electrophile H OH O OR CN I R2 I:II (63) 45:55 31 55 86 57 91 63 10 33 50 23 (61) 47:57 (67) 81:19 (76) 75:25 ee % I ee % II Me Me Me Et EtO2C (88) 68:32 II CN
1
4/18/06
Nucleophile OH + R2 OR1 250 O
Conditions
Refs.
C4 Ph2P (1.1 mol%), R2 Fe Fe
OR1
R2CHO
12:32 PM
CN PPh2 H [Rh(acac)(CO)2] (1 mol%), Bu2O, 2488 h
R1
Et
i-Pr
Page 180
CH(Pr-i)2
CH(Pr-i)2
CH(i-Pr)2 O CHO OH OH Ph HO HO R % ee (71) HO OH (20 mol%), La(OPr-i)3 (20 mol%), BuLi (60 mol%), LiI (10 mol%), PhMe, 20 (62) (70) (66) (70) 40 45 52 60f 67f OH O
C48
180
OH CHO (R)-LLB (8 mol%), KHMDS (7.2 mol%), H2O (16 mol%), THF, 20, 99 h Ph O +
Ph
215
Et
i-Pr
Me2C=CH
Me2C=CH
Ph
C5 OH Ph I II (95) I:II = 93:7, 76% ee I, 88% ee II O 216
Ph
c01_tex
O OH O Et I (5) I:II = 60:40, 51% ee I, 9% ee II HO OH (20 mol%), La(OPr-i)3 (20 mol%), BuLi (60 mol%), LiI (60 mol%), PhMe, 20, 141 h OH O R Et i-Pr t-Bu Ph Et (43) 79:21 (71) 88:12 (85) 91:9 (78) 72:28 dr rac-BINOL2-Ti2(OPr-i)3/ (R)-mandelic acid (10 mol%), rt R % ee 74 71 93 91 78 dr Et i-Pr t-Bu Ph (75) 76:24 (39) 71:29 (70) 81:19 (68) 85:15 PhC C (71) 75:25 Ph Ph OH N OH N HO Ph Ph OH (5 mol%), R O OH O R c-C6H11 (90) % ee 76 74 86 88 81 dr % ee 6:1 96 Ph(CH2)2 (97) 3.4:1 95 213 255 255 II + BnO Et 215 O HO HO BnO OH CHO OH OH
4/18/06
BnO
Et
Et
12:32 PM
Page 181
RCHO
181
OH rac-BINOL2-Ti2(OBu-t)3/ (R)-mandelic acid (10 mol%), rt R Et O R Et2Zn (10 mol%), 4 MS, THF, 35, 24 h
PhC C (68) 73:27
RCHO
C6
OH
RCHO
c01_tex

Electrophile Ar Ar OH N O OH I Ar Et2Zn (10 mol%), 4 MS, THF, 35, 12 h 4-PhC6H4 (90) 78:12 97 86 HO OH (5 mol%) R % eeb (66) (48) Et2Zn (10 mol%), Ph3P=S (15 mol%), (36) (40) OH (R)-LLB (8 mol%), KHMDS (7.2 mol%), R H2O (16 mol%), THF, 20 X R i-Pr t-Bu BnOCH2CMe2 BnCMe2 i-Pr n-C5H11 Et2CH Ph(CH2)2 (90) (75) (91) (85) (68) (55) (60) (50) % ee 33f 88 90 89 70g 42h 80i 30a O 216 96 98 4 MS, THF, 5, 2 d 97 97 O 220 OH N Ph Ph OH N 2-C10H7 (92) 77:15 93 83 Ph (94) 78:16 97 84 I:II % ee I % ee II II O OH O O OH N (5 mol%), 416 n-Bu + n-Bu HO Ar Ar OH OH Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C6
OH
n-BuCHO
12:32 PM
C612 CHO
Page 182
Ph Ph
2-C4H3O
182
2-MeOC6H4
4-MeOC6H4
2-C10H7
C8
RCHO
3-NO2
3-NO2
3-NO2
3-NO2
c01_tex
4/18/06
O CHO KHMDS (7.2 mol%), Ph D I OH Ph D II (33) I:II = 66:34, 78% ee I, 95% ee II NO2 O 216 D H2O (16 mol%), THF, 40, 48 h NO2 + (R)-LLB (8 mol%),
OH
NO2
Ph
12:32 PM Page 183
O OMe (12.5 mol%), OH i-Pr R t-Bu Ba(OPr-i)2 (5 mol%), DME, 20, 1848 h BnOCH2CMe2 BnOCH2CMe2 c-C6H11 BnCMe2 Ph BnOCMe2
OH
R (91) (99) (77) (83) (86) (87) (77)
% ee 50 70 67 69 70d,j 54 56 217
RCHO
Ph
183
OH (3 mol%), OH Ca[N{Si(CH3)3}2]2(THF)2, KSCN, EtCN/THF (4:1), 20 R Ph OH O R t-Bu c-C6H11
% ee (87) BnOCH2CMe2 (76) (88) Ph(CH2)2 PhCH2CMe2 (13) (75) 86 91 66 15k 87 219
RCHO
c01_tex
4/18/06

Electrophile Conditions (R)-LLB (8 mol%), KHMDS (7.2 mol%), OTBS H2O (16 mol%), THF, 20, 48 h OTBS I (85) I:II = 73:12, 99% ee I, 93% ee II II OTBS Ph Ph + 216 OH O OH O Refs. Product(s), Yield(s) (%) and Stereoselectivity
Nucleophile
C8 CHO
12:32 PM
Ph
Page 184
O CHO H2O (40 mol%), THF, 20 () I O O KHMDS (18 mol%), Ph
(R)-LLB (20 mol%), O O OH O +
40
184
Ph Ph OH N (5 mol%), R Ph OH N HO Ph Ph OH O R n-Pr n-Pr i-Pr i-Bu Et2Zn (10 mol%), Ph3P=S (15 mol%), 4 M.S., THF, 5, 2 d Ph2CH
OH
O Ph II
(59) I:II = 1:1, 89% ee I, 88% ee II
% ee (33) (24) (62) (49) TBSOCH2CMe2 (61) c-C6H11 PhCHMe (60) (67) (79) 56l 74m 98 68b,l 93b,n 98 94b,o 99b 220
RCHO
c01_tex
4/18/06
O (S)-LLB (10 mol%), KHMDS (9 mol%), R Ph R OH II I:II (86) (84) (89) (84) (78) (90) 72:28 94 78:22 92 84:16 95 69:31 95 87 74 70a,p 83 74:26 94 84 65:35 90 83 % ee I % ee II OH I R i-Bu n-C5H11 Ph(CH2)2 Ph(CH2)3 Ph(CH2)3 Ph H2O (20 mol%), THF, 50 + 65
OH
OH
Ph
RCHO
OH
12:32 PM Page 185
185
O R OH I (10 mol%), THF, 40, 3660 h R i-Pr i-Bu n-C5H11 Et2CH c-C6H11 Ph(CH2)2 (92) (80) (80) (79) (89) (89) (81) Ph + OH O O O Zn O O Zn
OH R
O Ph OH II I:II % ee I % ee II 5:1 2:1 2:1 7:1 6:1 3:1 2:1 86 83 77 79 85 81 79 67 79 73 72 78 81 75 417
RCHO
c01_tex

4/18/06
Nucleophile
C8 Ar Ar OH N OH i-Bu (96) (83) 92 90p 86p 91 3:1 5:1 (74) > 99:1 90p 87 96 (97) (89) (78) (98) 9:1 5:1 5:1 30:1 c-C6H11 Et2Zn (10 mol%), 4 MS, THF, 35, 24 h Ph(CH2)2 Ph(CH2)2 CH2=CH(CH2)8 (91) Ph2CH n-C7H15 c-C6H11 3:1 88p i-Bu (65) 35:1 94 OH N (2.5 mol%), R Ph i-Pr (89) 213 13:1 93 HO R dr % ee I Ar Ar OH O
Ph
RCHO
12:32 PM
OH
Page 186
186
OH O R OH X (1 mol%), THF, 30, 1624 h I R BnOCH2 BnO(CH2)2 i-Pr i-Bu n-C5H11 Et2CH c-C6H11 n-C6H13 Ph(CH2)2 + O O O Zn O O Zn
OH R
O 83 OH X II I:II (84) (81) (83) (84) (88) (92) (95) (84) (94) 72:28 86:14 97:3 84:16 88:12 96:4 97:3 87:13 89:11 % ee I % ee II 96 95 98 93 95 99 98 96 92 93 90 87 91 87 89
RCHO
OH
2-MeO
2-MeO
2-MeO
2-MeO
2-MeO
2-MeO
2-MeO
2-MeO
2-MeO
c01_tex
4/18/06
2-MeO (94) Ph(CH2)2 (85) (73) OH + OH I R Ph(CH2)3 (90) (96) (96) (69) (82) (50) (76) Ph(CH2)3 OH (R)-LLB (20 mol%), THF, 20 R Ar R i-Pr t-Bu c-C6H11 BnCMe2 t-Bu (59) (81) (72) Ph(CH2)2 (28) (90) (55) % ee 54 91f 44 52 69 76f O 214 (42) 75:25 76:24 77:23 81:19 67:33 74:26 82:18 Ph(CH2)3 n-C5H11 Ph(CH2)3 Ph(CH2)3 Ph(CH2)3 77:23 84 96 96 95 95 98 93 80 I:II X II X OH R 65 O 60:40 86 86d,q 70:30 77 Ph(CH2)2 OH (S)-LLB (10 mol%), KHMDS (9 mol%), H2O (20 mol%), THF, 40, 1235 h R O 77d
86:14
87
92
3-MeO
4-MeO
12:32 PM
C89
RCHO
OH
% ee I % ee II 57 83 89 74 83 79 91 41
Page 187
2-Me
4-Me
4-Me
2-MeO
187
3-MeO
4-MeO
4-MeO
2,5-(MeO)2
C812
RCHO
Ar
Ar
Ph
Ph
Ph
Ph
Ph
1-C10H7
c01_tex 4/18/06
12:32 PM

Nucleophile
Page 188
Ph3P=S (0.5 equivalents) was added.
188
For this reaction, 30 mol% of LLB, 27 mol% of KHMDS and 60 mol% of H2O were used, and the reaction was carried out at 50.
For this reaction, 15 mol% of LLB, 13.5 mol% of KHMDS and 30 mol% of H2O were used, and the reaction was carried out at 45.
The reaction was quenched after 4 days.
The diastereomeric ratio of the products for this entry is 2:1.
c01_tex
TABLE 2C. NON-METAL-CATALYZED ALDOL ADDITIONS OF UNMODIFIED NUCLEOPHILES

Electrophile OH CHO THF (10) 90a DMSO (13) 57 223 Solvent % ee Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C2
L-Proline (1.7 mol%), solvent,
MeCHO rt, 14 h OH R OBu-t NH2 I (2 mol%), aq NaOH (1 mol%), PhMe, 0 CF3 Ar = CF3 Ar HSO4 R I n-C6H13 (2 mol%), aq NaOH (1 mol%), PhMe, 0 F3C CF3 Ar Ph(CH2)2 TIPSOCH2 N
+
MeCHO
12:32 PM
O dr (58) 2.3:1 90 95 93b 91 (40) 2.8:1 (78) 1.2:1 (76) 3.3:1 92 % ee N+ CH2=CH(CH2)2 (71) 2.4:1 c-C6H11 c-C6H11 Ph(CH2)2 R Me
Ph
OBu-t RCHO
Ar HSO4 O
256
Ph Ar
Page 189
189
dr CF3 Ar = CF3
% ee (72) 20:1 (65) 10:1 (71) 12:1 98 80 91 96 256
RCHO
CH2=CH(CH2)2 (62) 6.3:1
c01_tex
TABLE 2C. NON-METAL-CATALYZED ALDOL ADDITIONS OF UNMODIFIED NUCLEOPHILES (Continued)

Electrophile Conditions S OH CO2H R I Ph 2-ClC6H4 4-BrC6H4 4-AcHNC6H4 (60) 4-O2NC6H4 c-C6H11 2-C10H7 R
L-Proline (20 mol%), DMSO,
4/18/06
Nucleophile O i-Pr (61) 71 (75) (60) (71) (65) 80 86 83 88 % ee (97) (56) (62) (94) (74) (68) c-C6H11 2-C10H7 R
L-Proline (30 mol%), DMSO, rt
Product(s), Yield(s) (%) and Stereoselectivity R % ee 94 73 89 74 67 n-C4H9
Refs.
C3 N H DMSO, rt, 2448 h (20 mol%),
RCHO
12:32 PM
(60) (45) (60) 96 68 60 69 65 69 76
Page 190
RCHO rt, 2448 h n-C4H9 Ph 2-ClC6H4 4-BrC6H4 4-O2NC6H4
i-Pr
71
190
I i-Pr t-C4H9 Ph 2-ClC6H4 4-BrC6H4 c-C6H11 2-C10H7
4-AcHNC6H4 (62) (60) (54)
85 77 % ee (97) (62) (94) (74) 4-O2NC6H4 (68) (63) (54) 96 (81) > 99 60 69 65 76 84 CH2=CHCH2CMe2 (85) > 99 77 85 257 85 85 85 85 257 257 85
RCHO
c01_tex
OH O n-C4H9 (31) (29) 70d (34) (23) 61d (35) (22) 36d 73 73 67 R n-C4H9 i-Bu i-Bu CH2=CH(CH2)2 (34) 72d n-C5H11 neo-C5H11 O O O
L-Proline (30 mol%), DMSO, rt L-Proline (1020 mol%), acetone, rt
R 66
% ee
4/18/06
RCHO
12:32 PM
O O O OH X H 4-F X 2-Br 2-NO2 3-NO2 4-NO2 2-OMe 4-OMe 4-CF3 4-CN

L-Proline (30 mol%),
OH O O O % ee (55) (90) (61) (93) (94) (68) (69) (69) (91) (74) 76 68 63 82 70 65e 68 50 73f 70 261 () > 99% de 221
OHC O O O
Page 191
CHO
191
MeN + NBu-n 24 h, rt PF6, OH R O R Ph 4-BrC6H4 c-C6H11 2-C10H7 MeN + NBu-n 24 h, rt PF6,
% ee (58) (72) (65) (60) 71 67 89 69 260
RCHO
c01_tex

Electrophile O OH (30 mol%), 262 R NH O Ph (45) (55) 77 (81) > 98g 63 59 CO2H 4-BrC6H4 4-O2NC6H4 (68) c-C6H11 OH O 222 O2N Chiral diamine N (61) % eei 83 DMF, rt R % ee O O O Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C3
RCHO
12:32 PM
Page 192
CHO 2,4-(NO2)2C6H3SO3H2H2O (3 mol%), acetone, rt
Chiral diamine (3 mol%),
O2N
192
N H N H N N H N N H N N H N
(41)
84
(72)
93
(50)
84
(8) OMe
89
c01_tex
4/18/06
N H O N H NH2 (52) 81 N (15) 83
(3) 58
12:32 PM
N H Ph H2N Ph H2N Ph H2N H N N N (71) N (25) 66
Page 193
76
193
N H N H H N N H H N N H NHBu-t
(88)
63
(81)
81
(84)
81
(7)
84
(72)
11
c01_tex

Electrophile Conditions Chiral diamine (10 mol%), 2,4-(NO2)2C6H3SO3HM2H2O (10 mol%), acetone, rt 222 OH O Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C3 CHO
12:32 PM
Chiral diamine
% eei
Page 194
N H (2)
(6)
80
N H
69
194
N H N N H N N H N N H Ph H 2N NH2 N
(13)
91
(7)
76
(1) OMe (3)
74
78
(27)
68
c01_tex
Ph (56) 72 H2N Ph H2N H N (58) 74 N (69) 45 N
4/18/06 12:32 PM
N H H N (16) 54
Page 195
N H H N
N H
(39)
52
195
N H OH O NHBu-t CHO 2,4-(NO2)2C6H3SO3HM2H2O (15 mol%), acetone, rt Chiral diamine Ph H2N Ph H2N N N Chiral diamine (15 mol%),
(12)
15
222
% eei (8) 28
(32)
42h
c01_tex

Electrophile Conditions Chiral diamine (15 mol%), 2,4-(NO2)2C6H3SO3HM2H2O 222 (15 mol%), acetone, rt Chiral diamine Ph H2N H N (64) N (66) 46h % eei OH O Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C3 CHO
12:32 PM
Page 196
N H H N
80
196
N H H N N H N H HO
(40)
83
(60)
80
NHBu-t
(40)
80
R Et i-Pr OH i-Bu (53) (32) (34)
: 1:2.2 1:2 1:2.5
% ee 11c 12 11 418
EtCHO
RCHO
DMF, 4 to rt, 72 h
c01_tex
OH R CHO Et i-Pr i-Bu Ph c-C6H11 (87) 14:1 S N H OH O i-Pr (< 5) (< 5) (26) (36) (45) (< 5) (29) neo-C5H11 Ph 2-ClC6H4 c-C6H11 PhCHMe 2-C10H7 1:1 3:2 > 20:1 1:1 95 92 95 91 O (< 5) DMSO, 37, 2448 h CO2H (20 mol%), R O R dr % ee 71 OH 99 (81) 3:1 99 (88) 3:1 97 (82) 24:1 > 99 (80) 4:1 99 86 dr % ee
L-Proline (10 mol%), DMF, 4
4/18/06
RCHO R
12:32 PM
RCHO
Page 197
OH
197
O
OH R OH
R O O i-Pr neo-C5H11 Ph 2-ClC6H4 c-C6H11 PhCHMe 2-C10H7 (27)
dr 2:1
% ee 71 > 97 (62) > 20:1 > 99 (24) 1.7:1 (42) (57) 1:1 3:2 > 97 80 67 (60) > 20:1 > 99 (51) > 20:1 > 95 (47) 3:1 79
RCHO rt, 2448 h
c01_tex

Electrophile O
4/18/06
Nucleophile OH R OH O i-Pr t-BuCH2 2-ClC6H4 c-C6H11 PhCHMe (95) 1.5:1 (60) > 20:1 (51) > 20:1 (38) 1.7:1 67 > 99 > 95 (62) > 20:1 > 99 > 97 O (40) 2:1 > 97 R 258 dr % ee
Conditions
Refs.
C3
RCHO rt, 2472 h
12:32 PM
OH
Page 198
198
CHO O (30 mol%), O NH O CO2H OH DMF, rt, 48 h O
L-Proline (50 mol%), CH2Cl2,
OH (48) dr > 20:1, > 98% ee 262
C38 OH OHC R CO2Et rt, 3 h CO2Et CO2Et % eei (90) (91) (88) (94) (91) 90 85 85 88 84 264
CHO
EtO2C
Me
Et
i-Pr
CH2=CHCH2
n-C6H13
c01_tex
C4 CHO O + 261 CF3 CF3 I II (53) I:II = 6:1, 10% ee I, 8% ee II R i-Pr R I 4-O2NC6H4 (57) R
L-Proline (20 mol%), DMSO, L-Proline (30 mol%),
OH O
OH
4/18/06
O MeN + NBu-n PF6, 24 h, rt
CF3
O S N H Et n-Bu 74 (< 5) DMSO, rt, 2448 h % ee (60) (65) 77 58 80 71 CO2H (20 mol%), (< 5) 71
OH
% ee
12:32 PM
RCHO
Et
Page 199
RCHO rt, 2448 h 4-O2NC6H4 (65) CHO MeN + NBu-n PF6 , Et CF3 OH N H N (5 mol%), O2N N (5 mol%), O 24 h, rt
I n-Bu
i-Pr
199
OH
O (59) 76% ee 261
CF3
C5 CHO
222
O2N N H
M2 TfOH cyclopentanone, 30 O
L-Proline (20 mol%), CHCl3,
(88) anti:syn = 43:57, 84% ee anti,i 5% ee syni
OH Bu-i +
OH Bu-i I II (77) I:II = 2.5:1, 95% ee I, 20% ee II 66
i-BuCHO rt, 72 h
c01_tex

4/18/06
Nucleophile
C5
O O OH Ph (83) dr = 61:39, 260 MeN + NBu-n rt, 25 h PF6,
12:32 PM
PhCHO
CHO MeN + NBu-n + CF3 CF3 I II (94) I:II = 1:1, 32% ee I, 86% ee II rt, 24 h PF6 ,
OH
O OH
O 261
Page 200
CF3
200
CHO N H O2N (5 mol%), N N H M2 TfOH 3-pentanone, 30 N (5 mol%), Et OH O CHO S (20 mol%),
n
222
Et
Et
O2N
(81) anti:syn = 54:46, 84% ee anti, 16% ee syn
C56 O OH + NO2 I I:II (63) 24:39 (56) 21:35 % ee I % ee II 60 69 63 90

n
OH 71 NO2 II
O2N
CO2H N H DMSO, rt, 2448 h
c01_tex
CHO
O OH + 71
n n
4/18/06
O OH
O2N NO2 I I:II (73) 27:46 (65) 24:41 O OH R + R OH 257

L-Proline (20 mol%), CHCl3,
rt, 2448 h NO2 II % ee I % ee II 63 67 89 69
12:32 PM
2 O
C6
RCHO rt, 72 h I R i-Pr i-Bu Ph CHO MeN + NBu-n PF6 CF3 rt, 24 h
,
Page 201
II I:II (68) > 20:1 (41) (85) OH O + I CF3 (91) I:II 20:1, 93% ee I II 1:1 85 7:1 86 97 89 76 OH O 261 % ee I % ee II
201
CF3
CHO N H N (5 mol%), N (5 mol%),
OH
O 222 O2N (97) anti:syn = 74:26, 96% ee anti,i 61% ee syni
O2N N H
M2TfOH cyclohexanone, 30
c01_tex

Electrophile R MeO O N n-Pr (37) (48) (39) (37) (45) 92 90 87 90 89 I i-BuO Ph PhNH n-C9H19 (42) t-Bu 92 H N (3 equiv), N+ Cl Me I i-Pr2NEt (4 equiv), MeCN, rt, slow addition H MeO AcO I (8) 11% ee N H N (10 mol%), 419 (10 mol%), Me (54) 92 419 O O O R % ee H Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C6
CHO
12:32 PM
OH
Page 202
202
(3 equiv), Cl Me I i-Pr2NEt (4 equiv), MeCN, rt,
+N
slow addition H OAc N H N (3 equiv), I (10 mol%), OMe O O (51) 86% ee 419
Cl N Me I
i-Pr2NEt (4 equiv), MeCN, rt, slow addition
c01_tex
MeO O N H N (10 mol%), I (42) 90% ee 418
4/18/06
12:32 PM
(3 equiv), Cl I Me i-Pr2NEt (4 equiv), MeCN, rt,

+N
slow addition OH
L-Proline (10 mol%), DMF, rt
n-C5H11CHO i-Pr Bu-n O O O (35 mol%), O NH O DMSO, rt, 90 h OH

L-Proline (10 mol%), DMF, rt
Page 203
i-PrCHO (80) dr = 24:1, 98% ee
CHO
86
C7 O (55) 75% ee O
263
203
CO2H i-Pr Bn CHO
C9
Ph(CH2)2CHO
i-PrCHO
(75) dr = 19:1, 91% ee
86
The reaction was carried out at 0 for 5 hours.
Di-n-butyl ether was used as the solvent.
After 10 hours at 4, the enantiomeric excess was 47%.
Trichloromethane was used as the solvent.
The aldehyde was added after premixing proline, acetone, and ionic liquid.
The same result was obtained using 10 mol% of catalyst.
DMSO was used as the solvent.
Twenty mol% of catalyst was used.
c01_tex
TABLE 3. ALDOL TANDEM REACTIONS

Electrophile 1. O R2 N t-Bu 2 OTf Et2O, 15 Me Me BrCH2 Et i-Pr Ph OEt (E)-PhCH=CH OMe 1. R OMe TBSOCH2 BnOCH2 BnO(CH2)2 Ph [(cod)IrCl]2 (2.5 mol%), Et2MeSiH, rt, 24 h 2. aq HCl (47) (59) (65) (68) O N R N N O (7.5 mol%), OH O dr 8.2:1 9.5:1 2.7:1 6.6:1 OEt OMe (70) (58) (80) (80) % ee 96 96 82 94 286 OEt (55) 53 77 80 93a 85a Ph (58) 90 Et (70) 90 Cu Bu-t R1 O R2 Me OMe (74) 83a N (20 mol%), O Me Me (71) 95 284 O O O EtO % ee OEt R1 R2 2+ OEt OEt Conditions Product(s), Yield(s) (%) and Stereoselectivity Refs.
4/18/06
Nucleophile
C2
EtO
OEt
12:32 PM
R1
Page 204
C3
204
1. CHO N N N O O (3 mol%), PMBO OH O OMe [(cod)IrCl]2 (1 mol%), Et2MeSiH, rt, 24 h 2. aq HCl
RCHO
OMe
PMBO
(76) dr = 6:1, > 90% ee
287
c01_tex
4/18/06
1. OH O N R OMe R (R)-MeCH(OBn) [(cod)IrCl]2 (2.5 mol%), Et2MeSiH, (S)-MeCH(OBn) (R)-MeCH(OBn)CH2 (S)-MeCH(OBn)CH2 (57) 88:12 3.0:1 (65) 89:11 2.7:1 (< 5) rt, 24 h 2. aq HCl (50) > 95:5 > 95:5 syna:synbb syn:antic N N (7.5 mol%), 286 O O
RCHO
12:32 PM Page 205
O (R)-BINAP (6.5 mol%), Et2MeSiH, R t-Bu Ph OPh CH2Cl2, rt, 24 h 2. aq HCl Et
1. [(cod)RhCl]2 (2.5 mol%),
OH R
dr (59) 5.1:1 (48) 1.8:1 (72) 3.4:1
% ee 88 45 87 84 80 285
RCHO
OPh
205
O R OH R adamantyl O Pr-i Ph Ph Ph H N OH H N OH (13 mol%), adamantyl Y5O(OPr-i)13 (2 mol%), CH2Cl2, 4 MS, rt, 15 h
c-C6H11 (54) 3.9:1 1-C10H7 (82) 3.8:1
C4
CHO
% ee (70) 4-BrC6H4 4-MeOC6H4 2-C10H7 (55) (21) (E)-PhCH=CH (50) (50) 74 70 72 10 64 282
RCHO
c01_tex
TABLE 3. ALDOL TANDEM REACTIONS (Continued)

Electrophile O H CHO (64) 91% eed 68 O O Al O O CO2Et CO2Et (10 mol%), THF, rt, 36 h O 1. Ph (82) 89% eed CO2Et CO2Et (10 mol%), THF, rt, 72 h 2. PCC O H CHO
5
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Nucleophile OH Ph
Conditions
Refs.
C9 Li
OAl(ligands)
CO2Et
Ph
12:32 PM
CO2Et
H Li O O Al O O
O 68
Page 206
PhCHO
206
OH Li O O Al O O TBSO (10 mol%), NaOBu-t, 4 MS, THF, rt O 1. [Rh(OH)((S)-BINAP)]2 (3 mol%), DMF, 20, 12 h 2. H2O2/NaOH F I t-Bu OH Et
5
OAl(ligands)
MeO2C
CO2Me (75) 97% eee CO2Bn CO2Bn 289
CO2Bn
TBSO
CO2Bn
C13
O t-Bu +
OH Et 420
t-Bu
EtCHO
F II (44) I:II = 0.8:1, 41% ee I, 94% ee IIf
c01_tex 4/18/06
C14-15 O [Rh(COD)Cl]2 (2.5 mol%), (R)-BINAP (7.5 mol%), H2O (5 equiv),

n
O OH 288
O dioxane, 95 Ph % ee (88) (69) O [Rh(COD)Cl]2 (2.5 mol%), (R)-BINAP (7.5 mol%), H2O (5 equiv),
n
12:32 PM
Ph
n 94g 95g OH
Page 207
C19-20 Ph Ph % ee (78) (88) 88g 77g
Ph dioxane, 95
288
207
Ph n
Syna/synb refers to the ratio of the major syn diastereomer (shown) to the minor syn diastereomer.
Syn/anti refers to the collective syn diastereomers/collective anti diastereomers.
The enolate was generated by in-situ conjugate addition to cyclopentenone.
The enolate was generated by in-situ conjugate addition to the substituted cyclopentenone.
The enolate was generated by rhodium-catalyzed in-situ conjugate addition of 4-FC6H4-9-BBN to the corresponding enone.
The enolate was generated by rhodium-catalyzed in-situ conjugate addition of PhB(OH)2 to the corresponding enone.
c01_tex
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12:32 PM
Page 208
208
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Catalytic Enantioselective Aldol Addition Reactions

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R2 = H Acetate Aldol R2 = Me Propionate Aldol

CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS

N Fe PPh2 PPh2 1 (1.1 mol%) OMe [Au(C6H11CN)2]BF4 (1 mol%), CH2Cl2, 0, 20-100 h

I II I:II 94:6, 95% ee

Ar Ph(CH2)3 Ar OH OH (50%) I II I:II = 81:19, I 98% ee, II 79% ee

1. (R)-BINOL/TiCl2(OPr-i)2, (20 mol%), PhMe, 0

(98%) 95% ee R = 2-thienyl

CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS

OH O SBu-t O (85%) dr = 93:7, 97% ee

CH2Cl2, 78 2. aq. HCl

L-proline (30 mol%)

OH O t-Bu (81%) 99% ee

2-PhOC6H4B(OH)2 (20 mol%), EtCN, 78 2. HCl

CH2Cl2, 78 2. aq. HCl

2+ O N O 2 SbF6 N Cu N Ph Ph 8 (10 mol%) BnO

1. OTMS BnO CHO + O

CH2Cl2, 78 2. aq. HCl, THF

(95%) dr = 96:4, 95% ee

9 (5 mol%), CHCl3/CH2Cl2 (4:1), 78, 6 h 2. MeOH Ph

C5H11 C5H11 (92%) dr = 99:1, 90% ee

O XR1 O XR1 R3Si or R3Sn R R1 R2 OH O XR1 O O XR1

Figure 1. Aldol addition reactions as atom transfer reactions.

CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS

L-proline (30 mol%)

OH O i-Pr (97%) 96% ee

L-proline (10 mol%)

(82%) dr = 24:1, >99% ee

MECHANISM AND STEREOCHEMISTRY

Ln R XR4 R4X H R Si Y O M X O Y R2 O R R2 O R 1 SiR 1 3 R R H G R

Figure 2. Proposed transition states for aldol addition reactions.

CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS

XR1 H electrophilic activation + H XR1 R nucleophilic activation Y B

Figure 3. Electrophilic vs. nucleophilic activation of an enolate intermediate.

Figure 4. Possible binding modes of aldehydes to Lewis acid centers.

CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS

Figure 5. Transition states for asymmetric, catalytic aldol addition processes.

Figure 6. Catalytic cycle of the Lewis acid catalyzed aldol reaction.

RCHO + OTMS OMe R

CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS

O N Cu N O Bu-t O X OTf + TMSOTf

O OTf Bu-t O X O kturnover TMSOTf TMS BnO O O

racemic kcat and kturnover >> kSi-cat

Figure 8. Intermolecular silyl group transfer in copper-catalyzed aldol reactions.

initiation LnMF TMSF

Figure 9. Catalytic cycle of the aldol reaction of enoxysilane.

Figure 10. Amine-catalyzed aldol addition processes.

CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS

SCOPE AND LIMITATIONS

(20 mol%) Sn(OTf)2 (20 mol%), CH2Cl2, 78, slow addition

OTBS dr R Me (85%) 94:6 Ph (86%) 94:6

(S)-BINOL/TiCl2(OPr-i)2 (5 mol%) PhMe, 0

SEt (80%) 96% ee

CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS

OH O CF3 SPh (38%) 96% ee

(R)-BINOL/TiCl2(OPr-i)2 (5 mol%) PhMe, 0

(R)-BINOL (20 mol%) Ti(OPr-i)4 (20 mol%), 4 MS, Et2O, 20, 12 h

Figure 11. Application of the titanium-catalyzed aldol to the synthesis of dermostatin A.

1. 2-PhOC6H4B(OH)2 (20 mol%), EtCN, 78 2. HCl

O 1. O + c-C6H11 H OTMS Ph O TsN BBu N H 13 (20 mol%) c-C6H11

EtCN, 78, 14 h 2. 1 M HCl

CATALYTIC ENANTIOSELECTIVE ALDOL ADDITION REACTIONS

i-Pr 14 (20 mol%) BH3MTHF (20 mol%), 78, 2. 1 N HCl/THF Ph