Stereoselective Acetate Aldol Reactions from Metal Enolates

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Stereoselective Acetate Aldol Reactions from Metal Enolates StereoselectiveXavier Acetate Aldol Reactions from Metal Enolates Ariza, Jordi Garcia, Pedro Romea,* Fèlix Urpí* Departament de Química Orgànica, Universitat de Barcelona, Martí i Franqués 1-11, 08028 Barcelona, Catalonia, Spain Fax +34(93)3397878; E-mail: [email protected]; E-mail: [email protected] Received 27 January 2011; revised 24 February 2011 Dedicated to the memory of recently deceased Professor Rafael Suau

often contests their capacity to install the required stereo- Abstract: This review deals with stereoselective acetate aldol reactions mediated by metal enolates. It summarizes recent advances in centers efficiently. Hence, it has always been seen as aldol additions of unsubstituted metal enolates that either incorpo- highly desirable to achieve parallel transformations from 8 rate chiral auxiliaries, stoichiometric Lewis acids, or catalytic metal enolates. Unfortunately, acetate aldol reactions Lewis acids or bases, or act in substrate-controlled reactions. These mediated by such intermediates can proceed through dif- approaches provide stereocontrolled aldol transformations that al- ferent six-membered cyclic transition states, represented low the efficient synthesis of structurally complex natural products. in Scheme 2, which hampers the proper differentiation of the two faces of the carbon–oxygen double bond by the 1 Introduction 3,9,10 2 Chiral Auxiliaries unsubstituted enolate. Therefore, stereocontrol in 3 Stoichiometric Lewis Acids these reactions relies on the appropriate choice of the met- 4 Catalytic Lewis Acids and Bases al and the chiral elements on the substrate, the aldehyde or 5 Substrate-Controlled Aldol Reactions the ligands (R1, R2, and L, respectively) to provide a single 5.1 a-Methyl Ketones highly organized transition state. 5.2 a-Hydroxy Ketones

5.3 b-Hydroxy Ketones L H

5.4 b-Hydroxy a-Methyl Ketones n M ML

O O O O R

5.5 a,b-Dihydroxy Ketones 2 R CHO

1 1 1

R R 5.6 Remote Stereocontrol R 6 Conclusions metal enolate

Key words: stereoselective acetate aldol reactions, metal enolates, M = Li, B, Ti, Sn,... L

chiral auxiliaries, Lewis acids, substrate-controlled reactions n O OH

1 2

R R

1 2

R R

new carbon–carbon bond

1 Introduction a new stereocenter

The development of highly stereoselective aldol method- transition-state geometries

O 2

1 R

ologies and their successful application to the synthesis of 2

L M

R n

R O

structurally complex natural products have placed the al- O

L MO

O n 1

dol reaction among the most important carbon–carbon R

boat A boat B twist boat bond-forming processes.1,2 In spite of this, aldol reactions chair from unsubstituted chiral enolates are still a matter of con- Downloaded by: University of Illinois. Copyrighted material. cern.3 Indeed, pioneering studies revealed early on that the Scheme 2 stereochemical control in the acetate aldol reaction (R = H in Scheme 1)4 was much more demanding than for The scope of this overview is limited to the most signifi- its propionate counterpart (R = Me in Scheme 1).5 cant methodologies on stereoselective acetate aldol addi- This challenge is usually countered by the use of tions of chiral metal enolates; that is, it describes the Mukaiyama-like6 and, more recently, organocatalytic ap- reactions in which the chiral elements are located on the proaches.7 Nowadays, there are successful examples of substrate or on the ligands bound to the metal of these in- both methodologies, but the synthesis of natural products termediates. It does not intend to be an exhaustive cover- age of the literature and some other important aspects of O OH O O OH these transformations, such as the influence of aldehyde 3 R3CHO R CHO R2 R1 R3 R1 R1 R3 chirality, are not specifically addressed. R2 = Me R2 = H Me propionate aldol reaction acetate aldol reaction

Scheme 1 2 Chiral Auxiliaries

SYNTHESIS 2011, No. 14, pp 2175–2191xx.xx.2011 The poor stereocontrol observed in preliminary studies on Advanced online publication: 10.05.2011 aldol reactions from unsubstituted enolates triggered an DOI: 10.1055/s-0030-1260040; Art ID: E15611SS intense search for an efficient, covalently bound chiral © Georg Thieme Verlag Stuttgart · New York 2176 X. Ariza et al. REVIEW

1) LDA O OH O Ph

auxiliary. Among the large number of reported auxilia- Ph

THF, 0 °C

OH OH

O ries, chiral 1,1,2-triphenylethanediol arising from man- O

i-PrCHO

11 2)

Ph Ph Ph Ph < –106 °C delic esters, quickly achieved a prominent position. T

1 Indeed, the lithium enolate from acetate 1 (Scheme 3) pro- quant., dr 95:5 vides high yields and diastereoselectivities and has been used successfully in the synthesis of b-hydroxy carbonyl Scheme 3 structures present in natural products.11b,12 cations and the quest for a more general approach However, the extremely low temperatures essential for at- remained active.13,14 Thus, considering that boron eno- taining high diastereoselectivities thwarted further appli- lates from N-acetyl oxazolidinone 2 (Scheme 4) afforded

Biographical Sketches

Xavier Ariza was born in 1993) and at Stanford promoted to Associate Pro- Barcelona (Spain) in 1966. University (Professor B. M. fessor in 2001. His current He studied chemistry at the Trost, 1996–1997) in the research area is the develop- University of Barcelona, area of asymmetric synthe- ment of stereoselective pro- where he received his PhD sis and organometallic cesses applied to the in 1995 under the supervi- chemistry. In 1998, he synthesis of biologically ac- sion of Professor J. Vilarra- joined the Department of tive compounds, in particu- sa for studies on nucleoside Organic Chemistry of the lar polyols and amino- chemistry. He also worked at University of Barcelona as polyols. ETH (Professor D. Seebach, Assistant Professor and was Jordi Garcia was born in University of Barcelona un- where he is currently Full Barcelona (Spain) in 1956. der the supervision of Professor. His research ac- He obtained a degree in Professor J. Vilarrasa on tivity includes both academ- chemistry in 1979 and an- synthetic organic chemistry. ic and applied projects in the other in pharmacy in 1992 at After postdoctoral studies area of stereoselective the University of Barcelona. with Professor S. Masamune methodology and synthesis After a short stay at the In- at the Massachusetts Insti- of natural products, espe- stitut de Chimie des Sub- tute of Technology (USA) cially those related to boron stances Naturelles (CNRS, working on boron chemis- and palladium chemistry. Gif-sur-Yvette, France) try, he was appointed to the He is also involved in re- working on carbohydrate post of Associate Professor search projects at the inter- chemistry in Professor G. at the Department of Organ- face of biochemistry and Lukacs’ laboratory, he ob- ic Chemistry of the Univer- inorganic chemistry. tained his PhD in 1986 at the sity of Barcelona in 1988,

Pedro Romea was born in chemistry. Then, he joined Professor in 1993. His re- Barcelona (Spain) in 1961. the group of Professor Ian search interests have fo- Downloaded by: University of Illinois. Copyrighted material. He studied chemistry at the Paterson at the University of cused on the development of University of Barcelona, Cambridge (UK), where he new synthetic methodolo- where he received his PhD participated in the total syn- gies and their application to in 1991 under the guidance thesis of oleandolide. Back the stereoselective synthesis of Professor J. Vilarrasa for to the University of Barcelo- of biologically active natu- studies on synthetic organic na, he became Associate ral products.

Fèlix Urpí was born in Sant worked as a NATO postdoc- 1991. His research interests Sadurní d’Anoia (Spain) in toral research associate in have focused on the devel- 1958. He studied chemistry titanium enolate chemistry opment of new synthetic at the University of Barcelo- with Professor David A. methodologies and their ap- na, where he received his Evans, at Harvard Universi- plication to the stereoselec- PhD in 1988 under the guid- ty (USA). Later, he moved tive synthesis of biologi- ance of Professor J. Vilarrasa back to the University of cally active natural prod- for studies on synthetic or- Barcelona and he became ucts. ganic chemistry. He then Associate Professor in

Synthesis 2011, No. 14, 2175–2191 © Thieme Stuttgart · New York REVIEW Stereoselective Acetate Aldol Reactions from Metal Enolates 2177

5a,15,16 S

O OH 1) TiCl , i-Pr NEt O

2 a nearly 1:1 ratio of diastereomers, the unprecedent- 4

Cl , –78 °C CH 2

ed stereocontrol observed by Nagao, Fujita and co-work- 2

O N O N

2) -PrCHO, –78 °C

ers in tin(II)-mediated aldol reactions from N-acetyl i

oxazolidinethione 317 and thiazolidinethione 418,19 were 86%, dr 94:6

particularly outstanding (Scheme 4). 5

O OH

1) TiCl , i-Pr NEt O

4 2

O O

O O OH

BOTf, i-Pr NEt 1) Bu

Cl , –40 °C CH 2 2 2 2

Cl , –78 °C CH

2 2 S N Ph S N

2) PhCH=CHCHO, –78 °C

N O N O

2) i-PrCHO, –78 °C

70%, dr 90:10

i-Pr i-Pr

86%, dr 52:48

i-Pr i-Pr

S S

O O OH

1) Sn(OTf) , (C H )NEt

5 10 2 Scheme 6

Cl , –40 °C CH 2 2

N N O O

i-PrCHO, –78 °C

2) 25

60%, dr 91:9 pared from natural and unnatural a-amino acids and tita-

Et 26

3 nium(IV) chloride is a readily available Lewis acid.

S S O O OH

1) Sn(OTf) , (C H )NEt

5 10

2 Thus, the stage was set for further developments in this ar-

Cl , –40 °C CH 2 2

N N S Ph S ea. The crucial role of the exocyclic carbon–sulfur double

2) PhCH=CHCHO, –78 °C bond was well established through careful analyses of al-

81%, dr 97:3

i-Pr -Pr

i dol reactions involving N-acetyl oxazolidinones. As for

4 boron enolates, the titanium-mediated aldol reaction Scheme 4 from N-acetyl-4-isopropyl-1,3-oxazolidin-2-one (2; see Scheme 4) gave good yields but poor diastereoselectivi- The rationale for these highly stereoselective transforma- ties,27 whereas the stereochemical outcome from a closely tions placed four ligands on the tin(II) atom in the transi- related 5,5-disubstituted oxazolidinone turned out to be tion state. Hence, the exocyclic sulfur atom was dramatically dependent on the metal of the enolate.28 The responsible for the lasting chelated tin enolate and the co- most striking advances have thus come from sulfur-con- ordination of the incoming aldehyde far from the R1 group taining chiral auxiliaries. For instance, boron and titanium of the chiral auxiliary (Scheme 5). Eventually, a chair-like enolates from N-acetyl oxazolidinethiones 6 and 729,30 and cyclic six-membered transition state accounted for the thiazolidinethiones 8–1030–33 shown in Figure 1 provide configuration of the new stereocenter in the major diaste- high levels of stereocontrol and the chiral auxiliary can be

reomer. removed easily, using very mild conditions.34

S S

O O S S O OH O

1) Sn(OTf) , (C H )NEt 2 5 10

O N

O N X N R X N

2) RCHO

1 Ar

1 Ph R R

X = O, S

7 Ar = 2,4,6-Me C H

3 6 2 6

Sn(OTf) , N-ethylpiperidine

TiCl (2 equiv), i-Pr NEt

4 2

TiCl , sparteine, NMP

29 Crimmins Phillips

OTf ‡ OTf

S Sn

S O O

S Downloaded by: University of Illinois. Copyrighted material.

O S O

RCHO

S N S N S N

X N X N

1 R R

9 Ar = 2,4,6-Me C H

3 6 2

, sparteine

Scheme 5 PhBCl

TiCl , i-Pr NEt

31 4 2

Sammakia

TiCl , sparteine

4 30,32

Crimmins 33

Although this methodology has been largely used in the Olivo synthesis of natural products, tin(II) trifluoromethylsul- Figure 1 fonate is not easy to handle.20,21 Keeping in mind this drawback, it is not surprising that effort has been directed toward the development of similar procedures using other 3 Stoichiometric Lewis Acids Lewis acids. In this context, Yan and co-workers took advantage of titanium(IV)-mediated aldol reactions from Concurrently with the search for a covalently bound chiral camphor-derived thioimide 5,22,23 whereas Urpí, Vilarrasa auxiliary, significant effort was invested in the application and co-workers used N-acetyl thiazolidinethione 4 in of chiral Lewis acids (LA) to this transformation. In such their aldol additions to a,b-unsaturated aldehydes an approach, the coordination of a Lewis acid to the car- (Scheme 6).24 The latter approach is particularly inspiring bonyl oxygen should enhance the acidity of the methyl ke- since both enantiomers of the chiral auxiliary can be pre- tone and allow the formation of the corresponding enolate

Synthesis 2011, No. 14, 2175–2191 © Thieme Stuttgart · New York 2178 X. Ariza et al. REVIEW by simple addition of a tertiary amine (Scheme 7). Alter- 15 provided a highly stereoselective aldol coupling (dr natively, it could also be introduced by transmetallation of 20:1) and furnished pure aldol 19 in 40–45% yield after a a preformed enolate. In any case, chiral ligands on these simple chromatographic purification (Scheme 8).40d

Lewis acids should provide the source for a proper dis-

15, Et N, Et O, 0 °C crimination of the two faces of the carbon–oxygen double 1)

3 2

bond of the aldehyde in such a way that the stereoselective TBDPSO

carbon–carbon bond formation would render the desired 2)

H N 3

aldol adduct without the need for further synthetic steps. 17 18

The introduction and subsequent removal of the chiral O

1 13

9 7 N auxiliary would be avoided, thereby increasing the effi- TBDPSO

ciency of the process. 3

19 40–45%, dr 20:1

7 LA M

O O O

OH LA

LA, R N 3

1 1

1 Sch38516 aglycon R R R

R CHO single synthetic step

13 OH

O Scheme 8

1 2 R R

Scheme 7 4 Catalytic Lewis Acids and Bases The Lewis acids 11–16 represented in Figure 2 fulfill such requirements.35–39 However, most of these have scarcely As in other areas of synthetic chemistry, much effort is be- been used in the synthesis of natural products and only a ing devoted to the search for new catalytic methodolo- few applications can be found in the literature.40 Isopi- gies.1,41 Early applications of metal catalysts in nocampheylborane 14 (Ipc2BCl) is the exception, and has stereoselective aldol reactions involved Lewis acid medi- been used in many double asymmetric aldol reactions ated addition of silyl enol ethers to aldehydes, the so- from chiral ketones (see below, section 5). called Mukaiyama aldol reaction.1,6 These processes take

advantage of the increase in the electrophilic character of

Ph aldehydes upon binding to chiral Lewis acids, which then

] BX

2 triggers the addition of a preformed, nucleophilic silyl N N

ArSO SO Ar

2 2

B enolate through an open transition state. In turn, organo- OTf

Br catalytic methodologies have blossomed in recent years,

12 13 X = OTf 14 X = Cl 11

35 36 37

Corey Paterson Masamune since they allow direct aldol reactions in which the nucleophilic and electrophilic roles are assigned by the cata-

O lytic species.7 O

DAGO ODAG

] BBr

2 Inspired by Nature, researchers also focused their atten- Cl

DAG:

O tion on aldolases. Class II aldolases use zinc cations to ac-

15 tivate the enolate partner (a metal enolate) and other

39 38 OO Duthaler

Gennari centers on the enzyme assist in the activation of the in- Downloaded by: University of Illinois. Copyrighted material. coming aldehyde. With such a mechanism in mind, the re- Figure 2 search groups of Shibasaki42 and Trost43 described the first direct aldol reactions from unmodified methyl ke- The failure of this methodology can be partially attributed tones in the presence of multifunctional catalysts 20 and to the troublesome preparation of some of these Lewis 21 (Figure 3).

acids, but the Achilles heel of the overall strategy lies in the

Ph Et

O Ph

purification of the resulting products. Indeed, for the ap- Ph O

proach to be viable, these Lewis acids must provide highly Zn

N N

stereoselective transformations, because mixtures of O

Li O Li enantiomers cannot be purified easily, and they are carried O

O La

through the whole synthetic sequence. Thus, this strategy O O

becomes synthetically useful only when the aldol reaction O

proceeds in a highly stereoselective manner or is applied 21 43

to chiral substrates, as in the synthesis of Sch38516 agly- Trost

con (Scheme 8). While lithium, sodium or titanium eno- 20

42 lates of chiral ketone 17 and aldehyde 18 delivered almost Shibasaki equimolar mixtures of both diastereomers, boryl bromide Figure 3

Synthesis 2011, No. 14, 2175–2191 © Thieme Stuttgart · New York

REVIEW Stereoselective Acetate Aldol Reactions from Metal Enolates 2179

(3 mol%)

Heralding a new mechanistic paradigm, the central lantha- 33

34 (3 mol%) S O S OH

] [Cu(MeCN)PF

1 num(III) atom of 20 functions as a Lewis acid activating 1

R R

(3 mol%) +

2 2

H R N R

the aldehyde whereas the lithium binaphthoxide moiety N

DMF, –60 °C

1 1

R R

acts as a Bronsted base. Thus, this catalyst mimics the en- 63–98%, 84–94% ee 31 32

1 2

R = Me, allyl = alkyl zyme action and permits efficient stereoselective aldol re- R

LiO

actions from methyl ketones 22 and a-branched aldehydes Ph

23 under mild conditions (Scheme 9).44 Later, Trost and P

O Ph

colleagues described that one of the zinc atoms of bime- Ph

33 (R,R)-PhBPE tallic catalyst 21 can form the metal enolate while the oth- 34 er binds to the aldehyde, acting as a Lewis acid center. Scheme 11 Then, aldol additions of aryl methyl ketones 24 to 23 pro- ceeded in good yields and outstanding enantioselectivities 50 (Scheme 9). Further studies have expanded the scope of Other metal catalysts have been also reported. Regretta- this procedure to other functionalizable ketones, such as bly, most of them can only be used on a reduced range of methyl vinyl ketone, and the simple acetone.45 substrates, or show a low reactivity; thus their synthetic

scope is restricted.

O O OH

O In contrast to the abovementioned methodologies, an al-

20 (20 mol%)

1 1 2 2

R R R R

H ternative approach devised by Denmark and colleagues THF, –20 °C

22 23 53–90%, 44–94% ee uses chiral Lewis bases to catalyze the stereoselective ad-

(5 mol%) 21 dition of trichlorosilyl enolates to aldehydes and ke-

P=S (15 mol%)

Ph 51,52 O O O OH

3 tones. These species act as metal enolates in such a

4 Å MS

2 2

Ar Ar R H

R way that the binding of chiral phosphoramide 35 to the sil- THF, 5 °C

24 23 40–62%, 93–99% ee icon atom promotes aldol reactions proceeding through

cyclic six-membered transition states. Unsaturated alde-

1 2

R = Ph, Me, Et R = t-Bu, i-Pr, Cy Ar = Ph, naphthyl, 2-furyl, MeOC H 4

6 hydes reacted quickly and cleanly with ketone-derived Scheme 9 trichlorosilyl enolates to provide, enantioselectively, the corresponding adducts (Scheme 12, equation 1). Both methodologies have been applied to the synthesis of Branched aliphatic aldehydes required longer reaction fostriecin using methyl ynones 25 and 26 as the active times, but their unbranched counterparts did not afford al- methylene partners (Scheme 10). Aldol addition of 25 to dol products.51,53 The N-oxide 36 was used to catalyze the chiral aldehyde 27 in the presence of catalyst ent-20 gave analogous addition of the silyl enolate of methyl acetate to aldol 28 in 65% yield and 3.6:1 diastereomeric ratio.46 In aryl ketones (Scheme 12, equation 2).52 turn, catalyst 21 promoted the reaction of ynone 26 and a- ketal aldehyde 29 to produce aldol 30 as a single enantio- mer in 58% yield.47,48 5 Substrate-Controlled Aldol Reactions More recently, Shibasaki and co-workers reported a new An important set of transformations employ metal eno- direct catalytic asymmetric aldol process inspired by the lates in substrate-controlled aldol reactions from chiral biosynthesis of 1,3-diols.49 This new procedure takes ad- methyl ketones, and these are especially useful in advantage of the high chemoselectivity of [Cu(MeCN)PF ] 6 vanced steps of some natural product syntheses. Unfortu- 33

and biphosphine (PhBPE) for the nucleophilic activa- Downloaded by: University of Illinois. Copyrighted material. nately, any clear understanding of these reactions is tion of thioamides 31 (Scheme 11). The addition of lithi- frequently obscured by the broad scope of substrates that um salt 34 to aliphatic aldehydes in the presence of such a they can support and the different factors controlling their catalytic system produced aldols 32 in high yields and stereochemical outcome. In light of this, and in order to enantioselectivities. better explore the intricate structural diversity, the litera-

ture examples summarized here have been organized ac-

O O H OH O

O OH O EtO OEt

OMOM

29 27

O O

ent-20 (10 mol%) 21 (3 mol%), 4 Å MS

OMOM

TMS

EtO OEt

THF, –20 °C

THF, r.t. SiR SiBnMe 3 2

65%, dr 3.6:1

= SiMe 25 SiR

28 3 3 58%, 99% ee 30

SiR = SiBnMe 26 3 2

NaHO PO OH 3

O O

fostriecin OH

Scheme 10

Synthesis 2011, No. 14, 2175–2191 © Thieme Stuttgart · New York

2180 X. Ariza et al. REVIEW

SiCl

O OH O tions. For instance, chiral a-methyl ketones derived from O

35 (5–10 mol%) (1)

+ Roche esters have proved to be an excellent platform to

2 1 2

1 R H R R

R CH Cl , –78 °C 2

2 provide highly stereoselective aldol reactions.1b Specifi-

79–98%, 82–92% ee cally, dicyclohexyl borinates from benzyl-protected ke-

SiCl

O O O

OH tones 37 furnish 1,4-syn aldols 38 with remarkable

36 (10 mol%)

(2) 55,56

3 stereocontrol (Scheme 13). Theoretical calculations MeO MeO Ar R Ar

CH Cl , –20 °C 2

2 suggest that these additions proceed through a highly or- 89–96%, 68–86% ee

1 dered transition state in which a hydrogen bond between R = Me, Et, i-Bu, i-Pr = Ar, CH=CHR, i-Pr, t-Bu R

R Ar = Ph, 4-MeOC = Me, Et, alkynyl H , 4-CF C H

4 3 6 4 6 the benzyl ether and the incoming aldehyde

Me Me

Me (ArCH2O···H–C=O) determines the diastereoselective

N 57

O formation of 38. This procedure turns out to be particu-

N N N

N larly valuable in the addition to chiral aldehydes leading Ph

O 58

Me to the 1,4-syn Felkin adducts, as demonstrated in the BuO

OBu conversion of chiral aldehyde 39 into aldol 40 in the total 36

35 synthesis of dolastatin 19 (Scheme 13).58b Scheme 12 In spite of these achievements, the search for better diastereoselectivities and the use of silicon protecting groups cording to the structure of the ketone, namely the type of on the Roche-derived methyl ketones have led to the use substituent (alkyl or hydroxy group) on the chiral cen- of a chiral boron Lewis acid, in the form of chlorodiisopi- ter(s) at the a- or b-positions relative to the carbonyl. Oth- nocampheylborane (14; Figure 2), in matched pairs of er issues, such as those related to the influence of chiral double asymmetric aldol reactions.59 aldehydes involved in double stereodifferentiating trans- 54 Otherwise, 1,4-anti adducts have been prepared using formations, are not specifically discussed. lithium60 and potassium61 enolates. For instance, addition of the lithium enolate of methyl ketone 41 to chiral alde- 5.1 a-Methyl Ketones hyde 42 furnished a single diastereomer of 1,4-anti aldol product 43 in 94% yield. In turn, coupling of methyl ke- There are no systematic studies on acetate aldol reactions tone 44 and aldehyde 45 produced aldol 46 diastereoselec- based on chiral a-methyl ketones; however, the structure tively when potassium hexamethyldisilazide was used as of the ketone and the aldehyde partners seems to play a the base (Scheme 14).61,62

crucial role in the stereochemical outcome of these reac-

‡

BCy

ArCH

O OH

2 O O

H O

Cy BCl, Et N RCHO

2 3

ArCH O R

ArCH O ArCH O O

2 2 2

Cy R 37 38

OH O OSugar Cy B

H ODMB

ODMB

OTES OTES O

H OH Et O, –78 °C to 0 °C

Downloaded by: University of Illinois. Copyrighted material.

MeO OTBS MeO OTBS MeO O O

89%, dr > 95:5

Br Br Br

39 40 dolastatin 19 DMB = 3,4-dimethoxybenzyl

Scheme 13

O OH OTIPS O

1) LDA, THF, –78 °C

94% R

N 3

3 single diastereomer O OTIPS

OTMS

2) R

41 43 H

OTMS

PMB

OTBS O OTBS O OH O OTBS

1) KHMDS, THF, –78 °C

R R 65%

O OPMBOTBS dr 7:1

OMMTr

H 46 44

OMMTr 45

Scheme 14

Synthesis 2011, No. 14, 2175–2191 © Thieme Stuttgart · New York

REVIEW Stereoselective Acetate Aldol Reactions from Metal Enolates 2181

O O OH

1) L BCl, Et N, CH Cl , –78 °C

L BCl dr (anti/syn) yield (%) 2 3 2 2

2 1

25 2) EtCHO BCl 66:34 Cy 2

PMBO PMBO

44 BCl, (+)-14 (+)-Ipc 18:82 2

48 66 BCl, (–)-14 (–)-Ipc 95:5 2

47 anti 1,4-

O O OH

1) (+)-14, i-Pr NEt, CH Cl , –78 °C

2 2 2

41%

6 SiMe Ph

TBDPSO 9

7 TBDPSO

dr 81:19 O

OPMB

SiMe Ph

H 49 51

OH HO

50 6

7 9

O O

O amphidinolide Y (keto form)

Scheme 15

5.2 a-Hydroxy Ketones the corresponding 1,4-anti adducts 53 in up to 93% yield and with an 85:15 diastereomeric ratio (Scheme 16).66,67 The lack of stereocontrol imparted by borinates from In turn, the lithium counterpart from ketone 54 gave aldol mandelic acid derived a-tert-butyldimethylsilyloxy meth- 55 in similar diastereoselectivity.68,69 yl ketone that was observed in early studies on asymmetric aldol reactions suggested that such systems might be Foreseeing the influence of the protecting group of these unsuitable for these transformations.5c However, Trost ketones on the stereochemical outcome of this sort of re- and Urabe showed that the appropriate choice of the actions, researchers began assessing the reactivity of a-si- Lewis acid and the hydroxy protecting group on lactate- lyloxy ketones. As observed for benzyl-protected ketones, derived methyl ketones could allow highly stereoselective addition of the dicyclohexyl borinate of a-triethylsilyloxy processes.63 methyl ketone 56 to isobutyraldehyde gave 1,4-anti aldol 57 in good yield and high diastereomeric ratio Thus, a remarkable 1,4-anti induction can be expected (Scheme 17).68 However, the diastereoselectivity was dra- from a-alkoxy methyl ketones provided that the proper matically eroded in the case of alkaline enolates,68 where- boron Lewis acid is used. Evans et al. reported that the ad- as the enolization of a-tert-butyldimethylsilyloxy ketones dition of the dicyclohexyl borinate from lactate-derived 58 with titanium(IV) chloride and diisopropylethylamine methyl ketone 47 to propanal furnished 1,4-anti aldol 48 and subsequent addition to isobutyraldehyde gave access in a low diastereomeric ratio, whereas it was considerably to 1,4-syn aldols 59.70 The rationale for this result is based improved by using (–)-14 (Scheme 15).64 Fürstner et al. on a six-membered chair-like transition state in which the employed this methodology in one of the key steps of the antiperiplanar distribution of the TBSO–C and C–OTi synthesis of amphidinolide Y.65 As shown in Scheme 15, bonds would act as the key element to determine the syn boron-mediated aldol addition of the p-methoxybenzyl- configuration (Scheme 17).71 protected a-hydroxy methyl ketone 49 to chiral aldehyde Downloaded by: University of Illinois. Copyrighted material. 50 furnished 1,4-anti aldol 51 in moderate yield and good A fine account of the intricacy of these aldol reactions can diastereoselectivity. be found in the synthesis of the spiroketal core of spirangien A. Paterson et al. reported that the stereoselectivity of Parallel trends have been observed in other transforma- the aldol addition of the a-triethylsilyloxy methyl ketone

tions from a-benzyloxy methyl ketones. For instance,

1) Cy BCl, Et N O OH chlorotriisopropoxytitanium(IV)-mediated aldol addi- O 2 3

O, –78 °C Et

tions of methyl ketones 52 to isobutyraldehyde afforded 2

2) i-PrCHO

OTES OTES

63%, dr 84:16

56 57

1) TiCl (i-PrO), i-Pr NEt O O OH 3 2

CH Cl , –78 °C

2 2

R R 1

1) TiCl , i-Pr NEt O O OH

4 4 2

2) i-PrCHO

Cl , –94 °C CH

2 2

R R 1

ArCH O ArCH O

2 2 4 77–93%, dr 85:15

2) i-PrCHO, –78 °C

53 52

TBSO TBSO

1,4- anti R = Me, Bn, i-Bu 71–95%, dr 77:23 to 96:4

58 59

Ar = Ph, 4-MeOC H

6 4

R = Me, Bn, i-Pr 1,4-syn

‡

O O OH 1) LiHMDS

TBSO THF, –78 °C

TiCl

4 i-PrCHO 2) i-Pr O

OPMB OPMB 46%, dr 87:13 O

54 55

Scheme 16 Scheme 17

Synthesis 2011, No. 14, 2175–2191 © Thieme Stuttgart · New York

2182 X. Ariza et al. REVIEW

O OO OO OO O O

A–C

OTES OTES

60 61

OH OO OH OO OO OO O O

4 4

OTES OTES

M = Li: 79%, dr 3.5:1 M = Cy B: 79%, dr 5:1 M = (–)-Ipc B: 53%, dr 2.5:1 2 2

62 1,4-anti 63 1,4-syn

OPG OPG O

OH OPG OPG O OPG OPG

1) LiHMDS, THF, –78 °C or LDA, THF, –78 °C

R R

O OPGOPG

2 OPG

OPG 2)

68,73

66a 60% overall yield, dr 3:1 64a PG = TES Kalesse

74 66b 64% overall yield, dr 3:1 64b PG = TBS Cossy

65a PG = TES 65b PG = TBS

MeO

COOH

spirangien A

MeO

OH HO

Scheme 18 Reagents and conditions: Method A: LDA, THF, –78 °C; Method B: Cy2BCl, Et3N, Et2O, –78 °C; Method C: (–)-14, Et3N, Et2O, 0 °C.

60 to chiral aldehyde 61 was very sensitive to the enoliza- afforded the corresponding aldol adducts 68 with high tion procedure. Preliminary studies using lithium diiso- diastereoselectivity.75 As shown in Scheme 19, the aldol propylamide, or chlorodicyclohexylborane with triethyl- addition proceeds through a chelated six-membered chair- amine, furnished anti aldol 62, but this inherent diastereo- like transition state in which the bulky camphor backbone selectivity in the undesired direction was eventually over- determines the approach of the aldehyde. From a concep- turned by employing chiral isopinocampheyl (Ipc) ligands tual point of view, the camphor acts as a chiral auxiliary to afford 1,4-syn aldol 63 (Scheme 18).72 Therefore, bo- in such a way that removal of the silicon protecting group ron Lewis acid (–)-14 determined the stereochemical out- of 68 and appropriate manipulation of the resultant hy- come of this transformation and prevailed over the droxy ketones yield enantiopure b-hydroxy acids or ke- induction imparted by the ketone 60 and the aldehyde 61. tones (Scheme 19). Moreover, the research groups of Kalesse73 and Cossy74 have established that aldol reactions of lithium enolates 5.3 b-Hydroxy Ketones from a-silyloxy methyl ketones 64 and aldehydes 65 afford the desired 1,4-syn aldols 66 in 3:1 diastereomeric ra- Aldol reactions of b-hydroxy methyl ketones are very sen- tio (Scheme 18), demonstrating proof that subtle changes sitive to the metal of the enolate and the hydroxy protect- on the metal and the structure of the aldehyde partner can ing group. Indeed, enolization of b-alkoxy ketones with Downloaded by: University of Illinois. Copyrighted material. dramatically affect the stereochemical outcome of these boron Lewis acids (X = Cl, OTf in Scheme 20) and tertia- aldol reactions. ry amines (Et3N or i-Pr2NEt) yielded the less substituted Lastly, it is worth mentioning that the lithium enolate of enolborinate that went on to participate in highly diaste- the camphor-based a-trimethylsilyloxy methyl ketone 67 reoselective 1,5-anti aldol reactions, whereas other metals and protecting groups provided remarkably lower diaste-

‡ reoselectivity.76,77 As previously noted for related trans-

TMS formations, a theoretical model that accounts for such

2 2

R O O R O O OH Li R O

1) L BX, R N O 2 3

1 1 3 5

R R R

2) R CHO

R = alkyl 1,5-anti 1) LDA, THF, –78 °C OTMS OTMS

‡

1 R 2) R CHO

O O 67–80%, dr > 92:8

67 68

R O

H O

B O OH O OH

or 3

1 2 1 HO R R R

Scheme 19 Scheme 20

Synthesis 2011, No. 14, 2175–2191 © Thieme Stuttgart · New York REVIEW Stereoselective Acetate Aldol Reactions from Metal Enolates 2183 high stereocontrol is based on a boat-shaped transition (super silyloxy) methyl ketones 71 added to aliphatic, a,b- structure in which a stabilizing hydrogen bond exists be- unsaturated and aromatic aldehydes in N,N-dimethyl- tween the alkoxy oxygen and the aldehyde proton.57 formamide to provide 1,5-syn aldols 72 in outstanding 85 This powerful transformation has been applied to the syn- diastereoselectivities. In this case, a chair-like transition thesis of the natural products leucascandrolide A,78 roxa- state that minimizes unfavorable steric interactions has ticin,79 and spongistatin 180 (Scheme 21, equations 1, 2, been invoked to rationalize the observed syn induction. and 3, respectively) among others.77,81 The dominant 1,5-anti trend observed for these transfor- 5.4 b-Hydroxy a-Methyl Ketones mations has, occasionally, been overridden by the influ- Most of the examples reported in the literature on sub- ence of remote stereocenters, functional groups or chiral strate-controlled aldol additions of b-hydroxy-a-methyl 82 boron Lewis acids. In this context, Dias and co-workers methyl ketones involve boron enolates. Thus, the stereo- established that good levels of substrate-controlled 1,5- chemical outcome of these reactions depends on the 1,5- syn stereoinduction can be obtained in boron-mediated al- anti and 1,4-syn inductions imparted by the b-hydroxy dol reactions of b-trihalomethyl- as well as b-tert-butyl-b- and the a-methyl groups, respectively (see Schemes 20 hydroxy methyl ketones 69 possessing different hydroxy and 13). In this scenario, an anti b-hydroxy-a-methyl ar- 83,84 protecting groups (Scheme 22). Theoretical calcula- ray corresponds to a matched case and the resultant aldol tions on the competing pathways involved in these reac- reactions usually proceed in excellent diastereoselectivi- tions suggest that a boat-like transition state lacking the ties. An exceptional example of this sort of reaction in- formyl hydrogen bond is the most stable and leads to 1,5- volves the aldol addition of the dicyclohexyl borinate of syn aldol adducts 70 (Scheme 22). Moreover, Yamamoto methyl ketone 73 to chiral aldehyde 74 that furnished al-

and Yamaoka recently reported that lithium enolates of b- dol 75, an advanced intermediate in the total synthesis of

PMBO PMBO

1) Cy BCl, Et N, Et O, 0 °C 2 3 2 O O O O OH

(1)

TIPSO TIPSO OTBS

2) –78 to –30 °C

H OTBS

99%, dr 17:1

O O O O O O OH OTBS

1) Bu BOTf, Et N, Et O, –78 °C 2 3 2

(2)

O OTBS BnO BnO

–110 °C

2) R

79%, dr > 95:5 H

O O TBSO OMe TBSO OMe OH OTES

1) (–)-14, Et N, Et O, 0 °C

3 2

(3)

OPMB

O OTES

–78 to –20 °C 2)

OPMB

89%, dr 97:3 H

OH OH OH OH OH O

OMe

O O N

Downloaded by: University of Illinois. Copyrighted material.

H O

OH O

O O OMe O HO O

leucascandrolide A roxaticin O

Scheme 21

‡

1 R

H H

1) Cy BCl, Et N PGO O PGO O OH 2 3

O or CH Cl , –30 °C or r.t. Et H OPG 2 2 2

1 1 2 5

1 O

L R R R

2 B CHO, –78 °C 2) R

69 70

2 L

79–98%, dr > 65:35

1 1,5- syn

R = CCl , CF , t-Bu 3 3

PG = TBS, Bn, PMB

‡ OPG

H H

(TES) SiO O (TES) SiO O OH

3 3

DMF 1

R H

1) LiHMDS, DMF, –60 °C

1 1 2 15

R R R

DMF 2) R CHO

71 72

1 70–84%, dr 85:15 1,5- syn R = n-Hept, i-Pr, t-Bu

Scheme 22

Synthesis 2011, No. 14, 2175–2191 © Thieme Stuttgart · New York

2184 X. Ariza et al. REVIEW

OMe OMe MeO

OMe O OMe O Me MeO

H N

H O OMe

O O 74 73

OMe OMe MeO

1,5-anti

OMe Me MeO O OMe OH

1) Cy BCl, Et N, Et O, 0 °C

2 3 2

H N

O OMe 2) 74, –78 to 0 °C

70% single diastereomer

O O

1,4-syn 75

OMe OMe MeO

OMe Me MeO O OMe

H N

O OMe

O O

reidispongiolide A O

Scheme 23 reidispongiolide A, as a single diastereomer in 70% yield actions, as occurs for ketone 76c.88 However, it is worth (Scheme 23).59e,86 keeping in mind that these transformations are not fully understood and unexpected effects can play a crucial In turn, the configuration of the new stereocenter in the al- 88 dol reactions from syn b-hydroxy-a-methyl mismatched role.

pairs is usually ruled by the b-hydroxy group, although PMP

the diastereoselectivity is very sensitive to the structure of PMP

1) Cy BCl, Et N O O O O O O OH

the methyl ketone. For instance, a systematic study carried 2

O, –30 °C Et

out by Dias and co-workers on the boron-mediated aldol 2 i-PrCHO, –78 °C 2)

1 2 1 2

R R R

reactions of methyl ketones 76 established that the pre- R

1 2 R dr yield (%)

vailing 1,5-anti induction imparted by the b-alkoxy led to R

H 86:14 H 83 77a

the adducts 77 (Scheme 24).87 These studies also showed 76a H 86:14 Me 97 76b 77b

Me >95:5 H 77 77c that even the configuration of the g-stereocenter plays a 76c

significant role on the stereochemical outcome of these re- Scheme 24

TBSO O OH OPMB TBSO O TBSO O OH OPMB

1) enolization conditions

(1)

BzO BzO BzO

O OPMB

2) , –78 °C

78 80 81 H

enolization conditions 80/81 yield (%)

79a

10:1 90 LiHMDS, THF, –78 °C

Downloaded by: University of Illinois. Copyrighted material.

1:1 51 NaHMDS, THF, –78 °C

1.2:1 65 BOTf, Et N, CH Cl , –40 °C Bu 2 3 2 2

1:2 72 BOTf, Et N, CH Cl , –40 °C (–)-Ipc 2 3 2 2

TBSO O TBSO O OH OPMB

1) LiHMDS, THF, –78 °C

dr 3:1 59%

(2)

TBDPSO TBDPSO O OPMB

2) , –78 °C

H 82

79a

TBSO O TBSO O OH OPMB

1) LiHMDS, THF, –78 °C

dr 2:1 85% (3)

O OPMB

2) , –78 °C

83 H

79a

BzO TBSO O BzO TBSO O OH OPG

1) TiCl , i-Pr NEt, CH Cl , –78 °C aldehyde PG dr yield (%) 4 2 2 2

(4)

79a 15:1 81 PMB O OPG

MeO MeO 79b 7:1 MTM

2) , –78 °C 84

79c 3:1 MOM H

79d 2:1 TBS 79

Scheme 25

Synthesis 2011, No. 14, 2175–2191 © Thieme Stuttgart · New York REVIEW Stereoselective Acetate Aldol Reactions from Metal Enolates 2185

Other metal enolates have been also used in these reac- chemical outcome of a particular transformation. For in- tions, but it is rather difficult to predict their stereochemi- stance, it is well documented that silicon protecting cal induction. For instance, a thorough analysis reported groups provide for poorly stereocontrolled additions,93 by Roush et al. on the addition of the syn b-tert-butyldi- but Carter et al. recently reported that N,N,N¢,N¢-tetra- methylsilyloxy-a-methyl ketone 78 to the chiral aldehyde methylethylenediamine (TMEDA) increased the reactivi- 79a established the dependence of the aldol stereoselec- ty of the lithium enolate of a,b-disilyloxy methyl ketone tivity on the metal enolate (Scheme 25, equation 1).89 Fur- 88 and produced a stereochemical reversal on the aldol thermore, the moderate and low diastereoselectivities addition to aldehyde 89; the bias favoring 1,4-syn 90a was observed for related ketones 82 and 83 (Scheme 25, equa- even improved by cooling to –100 °C (Scheme 27, equations 2 and 3) suggest that the presence of a chelating tion 1).94 group at the d-position is crucial for attaining high stereo- Interestingly, Carter and Zhang found that the aldol addi- control and prove that these aldol reactions are governed a p b 89 tion of - -methoxybenzyloxy- -triethylsilyloxy methyl by several subtle structural details. Parallel studies on ketone 91 to aldehyde 92 gave aldol 93 in 69% yield as a the titanium-mediated aldol reactions of ketone 84 un- single diastereomer through a chelated transition state veiled a close diastereoselectivity dependence on the pro- (Scheme 27, equation 2),95 which obviously makes the tecting group of the aldehyde 79 (Scheme 25, equation 4), most of the chelating ability of the benzyl-like protecting thus providing new proof of the sensitivity of these sub- a 96 90 group placed at the -position. Moreover, Fürstner et al. strate-controlled transformations. found that the lithium-mediated aldol addition of a-p- methoxybenzyloxy-b-triethylsilyloxy methyl ketone 94 to 5.5 a,b-Dihydroxy Ketones aldehyde 95 afforded 1,4-anti aldol 96 in 45% yield (Scheme 27, equation 3).93d A review of Scheme 27 re- The diastereoselectivity of substrate-controlled aldol re- veals that ketones 88 and 91 and aldehydes 89, 92 and 95 actions from a,b-dihydroxy methyl ketones depends on are pretty similar, but lithium enolates from 91 and 94 im- the metal enolate, the configuration of the a- and b-stereo- part a much better stereocontrol than the analogous eno- centers and the hydroxy protecting groups. In this context, late from 88, which proves how important protecting the remarkable 1,5-anti induction of boron-mediated aldol groups can be on the diastereoselectivity of these reac- reactions of b-alkoxy methyl ketones (Scheme 20) also tions. operates in these systems and may be assisted by the parallel 1,4-anti bias observed in related a-hydroxy methyl As one could anticipate from these results, a-alkoxy-b-si- ketones (Scheme 15). Therefore, it is not surprising that lyloxy methyl ketones have also been involved in much the addition of the dicyclohexyl borinate of the a,b-di- more stereoselective transformations. In the abovemen- alkoxy methyl ketone 85 to aldehyde 86 led to the isola- tioned analysis on the reactivity of alkaline enolates from tion of a single diastereomeric aldol adduct 87 in 93% syn a,b-dihydroxy methyl ketones, Fürstner et al. also de- yield (Scheme 26).91,92 scribed that the addition of the lithium enolate from a-p- methoxybenzyloxy-b-tert-butyldimethylsilyloxy methyl

ketone 97 to aldehyde 98 afforded aldol 99 as a single dia-

O 93d

BCl, Et N, pentane 1) Cy

3 2 stereomer in 52% yield (Scheme 28, equation 1). The

TESO

OTES

O excellent diastereoselectivity was attributed to the 1,4-

OBn

85 H

OBn anti directing effect imparted by the a-alkoxy group (see 86 Scheme 16). This hypothesis was corroborated by the fact

Downloaded by: University of Illinois. Copyrighted material. O OH OTES O that the related disilyloxy ketone furnished a poor 2:1

mixture of the two possible diastereomers. However, mi- OBn

TESO nor changes on the aldehyde and the ketone were respon-

OBn 87 sible for significant differences in the diastereoselectivity.

93%, dr > 98:2 For instance, the less elaborate aldehyde 100 delivered the Scheme 26 anti aldol 101 in 70% yield and a slightly lower diastereomeric ratio of > 10:1 (compare equations 1 and 2 in Scheme 28). However, the diastereoselectivity was seri- In spite of these accomplishments, most of the literature ously eroded when the reaction was carried out on ketone examples of substrate-controlled aldol reactions from a,b- 94 lacking the remote tert-butyldiphenylsilyloxy group; dihydroxy methyl ketones take advantage of the high nu- this afforded aldol 102 in only a modest diastereomeric ra- cleophilicity of alkaline enolates. In particular, alkaline- tio (compare equations 2 and 3 in Scheme 28).93d The rea- mediated aldol reactions from chiral syn a,b-dihydroxy son why this particular reaction shows a significantly methyl ketones have been thoroughly assessed through lower selectivity is unclear, but it is also instructive to rec- the syntheses of amphidinolides. These studies have ognize the dramatic influence of the aldehyde partner by proved that the protecting groups play a crucial role on the comparing Scheme 27, equation 3 and Scheme 28, equa- stereochemical outcome of such additions. Unfortunately, tion 3. these aldol reactions are very sensitive to the structure of the reactive partners as well as to the reaction conditions Other protecting groups have also been used in these as a whole, which makes it difficult to predict the stereo- transformations.97 For instance, Zhao and colleagues re-

2186 X. Ariza et al. REVIEW

1,4-syn 1,4-anti

1) LDA, TMEDA

1) LDA

TESO O OH O O OH TESO TESO OTES OTES

O–THF, T Et

O–THF, –40 °C Et

1 1

R R R (1)

O O OTES OTES

2) 2)

OTES

OTES OTES

2 2

R R H H

90a

88 90b

89 89

R R T = –78 °C dr (90a/90b) 2:1 dr (90b/90a) 1.2:1 66% yield

T = –100 °C dr (90a/90b) 8:1 65% yield

‡

TESO O OH

O TESO

1) LDA, Et O OTES

Li 2

R''

–78 °C

(2)

O O

OTES H

2) H

TESO OPMB TESO OPMB

R' PMB

92 69%, dr > 20:1

CN 1,4-anti

TESO TESO O O OH OTES

1) LDA, Et O, –78 °C

(3)

O OTES

2) RCOO OPMB RCOO OPMB

94 96 45%

1,4-syn 1,4-anti

O OH O OH OH OH

HO HO

OH OH

O O

O O amphidinolide B2 amphidinolide B1

Scheme 27

1,4-anti

O O OH TBSO TBSO

O, –78 °C 1) LDA, Et

(1)

TBDPSO TBDPSO

RCOO OPMB RCOO OPMB 2)

52%

single diastereomer

TBSO TBSO O O OH

1) LDA, Et O, –78 °C

(2) TBDPSO TBDPSO O

Downloaded by: University of Illinois. Copyrighted material.

RCOO OPMB RCOO OPMB 2)

97 100 101

70%, dr > 10:1

TESO TESO O O OH

O, –78 °C 1) LDA, Et

(3)

RCOO OPMB RCOO OPMB 2)

94 100 102

58%, dr 3.2:1

1,4-anti 1,4-anti

O OH O OH

HO HO

OH OH

O O

amphidinolide H1 amphidinolide B4

Scheme 28

REVIEW Stereoselective Acetate Aldol Reactions from Metal Enolates 2187

MOMO O OH

MOMO O

TBDPSO 1) KHMDS, –78 °C

TBDPSO

RCOO OMOM O 2)

RCOO OMOM

103 104

67%, dr 7:1

O O

Scheme 29 ported that the diastereoselective addition of the potassi- tion disclosed by Paterson and co-workers in the synthesis um enolate from a,b-di(methoxymethyl)-protected of (+)-discodermolide (Scheme 30).98–100 methyl ketone 103 to aldehyde 98 in an advanced step of The initial report on the total synthesis of discodermolide the total synthesis of amphidinolide H1 (see Scheme 28) was based on the application of an aldol reaction to assem- produced 1,4-anti aldol 104 diastereoselectively and in b a 105 97b ble -hydroxy- -methyl ketone (C1–C6 fragment) 67% yield (Scheme 29). and Z-configured enal 106 (C7–C24 fragment).98 As shown in Scheme 30, enolization of methyl ketone 105 5.6 Remote Stereocontrol with chlorodicyclohexylborane and subsequent addition of the resulting boron enolate to 106 furnished the undes- Finally, it is worth recognizing that other unusual arrange- ired 7R aldol 107 in 67% yield and high diastereoselectiv- ments can come into play and provide insightful synthetic ity (dr 88:12). The observed p-facial selectivity was

approaches. This is the case for the 1,6-asymmetric induc- rationalized by considering that the preferred trans con-

6 O O OH O O

5 1

OH NH 2

discodermolide

first generation

L BCl

1 1

MeO C MeO C

2 2

Et N 3

TBSO O TBSO O OTBS O O O

105

OTBS NH 2

106

MeO C MeO C 2 2

TBSO O TBSO O OH OH OTBS O O OTBS O O

Downloaded by: University of Illinois. Copyrighted material.

OTBS NH OTBS NH 2 2 Nu

108 107

‡

L BCl dr (107/108) yield (%) Me 2

7R O

67 Cy 88:12 BCl 2

H H

16:84 R BCl [(+)-14] (+)-Ipc L 2

second generation

1) Cy BCl, Et N

2 3 5S 7

MeO C 2

10 1

TBSO OH O O OTBS O O OTBS O O

MeO C 2

TBSO O

OTBS NH OTBS NH 2 2 110

111

109

64%, dr > 95:5

‡

trans conformation L Me

RCHO

Cy O

O R

Cy B H O 2

R A(1,3) minimization

Scheme 30

Synthesis 2011, No. 14, 2175–2191 © Thieme Stuttgart · New York 2188 X. Ariza et al. REVIEW formation of the enal determines the approach of the eno- Weinheim, 2004. (f) Geary, L. M.; Hultin, P. G. late. Gratifyingly, the dominating selectivity of the Tetrahedron: Asymmetry 2009, 20, 131. aldehyde was overturned in favor of the desired 7S aldol (2) (a) Yeung, K.-S.; Paterson, I. Angew. Chem. Int. Ed. 2002, 41, 4632. (b) Yeung, K.-S.; Paterson, I. Chem. Rev. 2005, 108 by the use of chiral boron Lewis acid (+)-chlorodiiso- 105, 4237. (c) Schetter, B.; Mahrwald, R. Angew. Chem. Int. pinocampheylborane [(+)-14]. Ed. 2006, 45, 7506. (d) Brodmann, T.; Lorenz, M.; In spite of this success, a revised strategy that reduced the Schäckel, R.; Simsek, S.; Kalesse, M. Synlett 2009, 174. number of steps and eliminated the use of all chiral re- (e) Li, J.; Menche, D. Synthesis 2009, 2293. agents and auxiliaries was reported a few years later.99 (3) For an early review, see: Braun, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24. This second-generation approach built the C6–C7 bond (4) The term acetate aldol reaction refers to any aldol through a highly stereoselective boron-mediated aldol transformation involving unsubstituted enolates, which addition of methyl enone 109 to aldehyde 110 encompasses the reactions of acetate esters, other carboxylic (Scheme 30).100 Here, the remote C10 g-stereocenter in derivatives, and methyl ketones. 109 provided an unprecedented 1,6-asymmetric induction (5) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. and the required 5S aldol 111 was obtained in 64% yield 1981, 103, 2127. (b) Heathcock, C. H.; Pirrung, M. C.; Lampe, J.; Buse, C. T.; Young, S. D. J. Org. Chem. 1981, 46, and an outstanding diastereomeric ratio (dr > 95:5). The 2290. (c) Masamune, S.; Lu, L. D.-L.; Jackson, W. P.; rationale for this unparalleled remote stereocontrol in- Kaiho, T.; Toyoda, T. J. Am. Chem. Soc. 1982, 104, 5523. vokes a chair-like transition state in which the dienolate is (6) (a) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357. constrained in the lower-energy trans conformation, (b) Mahrwald, R. Chem. Rev. 1999, 99, 1095. (c) Carreira, allylic strain A(1,3) is minimized, and other steric clashes E. M. In Comprehensive Asymmetric Catalysis III; Jacobsen, are avoided. E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer Verlag: Berlin, 1999, Chap. 29.1, 997. (d) Carreira, E. M.; Fettes, Irrespective of the mechanistic pathway followed in this A.; Marti, C. Org. React. 2006, 67, 1. transformation, it is proof of the power of substrate- (7) (a) Pellissier, H. Tetrahedron 2007, 63, 9267. (b) Guillena, controlled aldol reactions, provided the appropriate struc- C.; Nájera, C.; Ramón, D. J. Tetrahedron: Asymmetry 2007, tural elements are identified and appropriately placed. 18, 2249. (c) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. (d) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600. (8) The term metal enolate is used in a broad sense. It refers to 6 Conclusions enolates from boron, silicon, alkaline, titanium, tin, and other elements that participate in aldol reactions proceeding In spite of early reports to the contrary, metal enolates through cyclic transition states have emerged as highly valuable intermediates for stereo- (9) (a) Li, Y.; Paddon-Row, M. N.; Houk, K. N. J. Org. Chem. selective acetate aldol reactions. Recent advances in this 1990, 55, 481. (b) Goodman, J. M.; Kahn, S. D.; Paterson, I. area have delivered highly stereoselective methodologies J. Org. Chem. 1990, 55, 3295. (c) Bernardi, A.; Capelli, A. M.; Gennari, C.; Goodman, J. M.; Paterson, I. J. Org. Chem. based on metal enolates from chiral auxiliaries, stoichio- 1990, 55, 3576. (d) Bernardi, A.; Gennari, C.; Goodman, J. metric and catalytic Lewis acids and bases, or acting in M.; Paterson, I. Tetrahedron: Asymmetry 1995, 6, 2613. substrate-controlled reactions, which facilitate the synthe- (e) Liu, C. M.; Smith, W. J. III; Gustin, D. J.; Roush, W. R. sis of structurally complex natural products. Unfortunate- J. Am. Chem. Soc. 2005, 127, 5770. ly, the structural and reactive elements that determine the (10) Stereoselective aldol reactions involving multifunctional configuration of the resultant aldol adducts are sometimes catalysts often proceed through highly organized transition unclear and a proper understanding of the transition states states that have more complex molecular arrangements (11) (a) Braun, M.; Gräf, S.; Herzog, S. Org. Synth. 1995, 72, 32. involved in many of these transformations is still lacking. (b) Braun, M.; Gräf, S. Org. Synth. 1995, 72, 38. Downloaded by: University of Illinois. Copyrighted material. Thus, more insightful, simple and reliable methodologies, (12) (a) Schinzer, D.; Bauer, A.; Böhm, O. 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