Catalytic, Enantioselective, Vinylogous Aldol Reactions** Scott E

Reviews S. E. Denmark et al.

Asymmetric Catalysis Catalytic, Enantioselective, Vinylogous Aldol Reactions** Scott E. Denmark,* John R. Heemstra, Jr., and Gregory L. Beutner

Keywords: Dedicated to Professor Albert Eschenmoser aldol reactions · asymmetric catalysis · on the occasion of his 80th birthday dienol ethers · regioselectivity · vinylogy

Angewandte Chemie

4682 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/anie.200462338 Angew. Chem. Int. Ed. 2005, 44, 4682 – 4698 Angewandte Asymmetric Catalysis Chemie

In 1935, R. C. Fuson formulated the principle of vinylogy to explain From the Contents how the influence of a functional group may be felt at a distant point in the molecule when this position is connected by conjugated double- 1. Introduction 4683 bond linkages to the group. In polar reactions, this concept allows the 2. Early Developments in the extension of the electrophilic or nucleophilic character of a functional Vinylogous Aldol Reaction 4684 group through the p system of a carbon–carbon double bond. This vinylogous extension has been applied to the aldol reaction by 3. Synthetic Equivalents of employing “extended” dienol ethers derived from g-enolizable a,b- Acetoacetate Ester Dianions 4686 unsaturated carbonylcompounds. Since 1994, severalmethods for the 4. Simple Ester-Derived Silyl catalytic, enantioselective, vinylogous aldol reaction have appeared, Dienol Ethers 4691 with which varying degrees of regio- (site), enantio-, and diastereoselectivity can be attained. In this Review, the current scope and 5. Lactone-Derived Dienol Ethers 4695 limitations of this transformation, as well as its application in natural 6. Ketone-Derived Dienol Ethers 4696 product synthesis, are discussed. 7. Conclusions and Outlook 4696

1. Introduction

The potent biological activity and structural diversity of allylations,[3] alkylations of 4-cyano-1,3-dioxanes,[4] and the polyketide class of natural products has provided nucleophilic epoxide-opening reactions of epoxyalkynols,[5] inspiration and impetus for research in many subfields of have also been developed as viable alternatives to the aldol the chemical sciences. A main characteristic of these natural reaction. products is presence of complex polyol subunits with repeat- Nevertheless, despite some limitations, the aldol addition ing 1,3-diol relationships within their core structure. Through is ideally suited for efficient access to the targeted polyol elegant biosynthetic studies it is now well established that structures. Moreover, the polar nature of the enolate pre- these polyol chains are synthesized in nature by multifunc- cursor in the addition makes a vinylogous extension of this tional enzymes termed polyketide synthetases.[1] By using reaction possible. Defined as the transmission of electronic small carboxylic acid building blocks (primarily acetate, effects through a conjugated p system, the principle of propionate, and butyrate), which are activated as thioesters vinylogy allows the extension of the nucleophilic or electro- bound to a ketosynthase protein and through carboxylation philic character of a functional group through the p system of (e.g. with malonyl-CoA and 2-methylmalonyl-CoA), the a carbon–carbon double bond.[6] Accordingly, a g-enolizable carbon backbone of the polyketide is assembled two carbon a,b-unsaturated carbonyl substrate can be employed as an atoms at a time as the result of enzymatic, decarboxylative “extended dienolate” in a vinylogous aldol addition to an Claisen condensations (Scheme 1). Reduction of the b-keto aldehyde to give d-hydroxy-b-ketoesters 2 (Scheme 2) or a,b- thioester intermediate by NADPH generates a b-hydroxy unsaturated d-hydroxy carbonyl compounds 4 (Scheme 3) in thioester, which can undergo acyl-group transfer to a which up to two stereocenters and one double bond can be subsequent ketosynthase protein. This sequence is repeated created. These functional arrays are common structural until the appropriate polyol chain length is reached. Each motifs that have found application in synthesis. The newly stereogenic center is created with high selectivity owing to the created hydroxy-substituted stereocenter is adjacent to a ability of the enzyme to rigidly fix the orientation of the double bond or carbonyl group, and these versatile inter- reactive components relative to each other and relative to the mediates can therefore be further elaborated by using various enzyme. highly selective substrate-directable reactions (see Schemes 2 A challenge for the modern synthetic chemist is the and 3).[7] Among the most useful of these reactions are development of non-enzymatic asymmetric reactions for the construction of polyol subunits with equally high selectivity [*] Prof. Dr. S. E. Denmark, J. R. Heemstra, Jr., Dr. G. L. Beutner and efficiency as achieved in nature. With regard to many Roger Adams Laboratory criteria, the asymmetric aldol addition reaction, which University of Illinois at Urbana-Champaign provides b-hydroxy carbonyl compounds with up to two 600 South Mathews Avenue new stereocenters from readily available starting materials, Urbana, IL 61801 (USA) has met this challenge.[2] Indeed, the selectivity, scope, and Fax : (+ 1)217-333-3984 predictability associated with current aldol-addition methods E-mail: [email protected] have allowed this reaction to emerge as a strategy-level [**] Seventy years ago, Reynold C. Fuson formulated the concept of vinylogy that constitutes the conceptual underpinning of the reaction in natural product synthesis. Although the aldol vinylogous aldol reactions described in this Review. (Reprinted with addition reaction has found widespread application in the permission from Chem. Rev. 1935, 16, 1–27. Copyright 1935, synthesis of linear acyclic polyol structures, it is certainly not American Chemical Society. Photograph courtesy of the University the only method available. Other transformations, such as of Illinois at Urbana-Champaign Archives (Record Series 39/2/26)).

Angew. Chem. Int. Ed. 2005, 44, 4682 – 4698 DOI: 10.1002/anie.200462338 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4683 Reviews S. E. Denmark et al.

Scheme 1. The biosynthesis of polyol compounds by polyketide synthetases.[1]

conjugate additions to the double bond, oxidations or classic aldol addition reaction, the development of methods reductions of the double bond, or in the case of the b-keto that combine high levels of regio- (site), diastereo-, and carbonyl compounds, directed reductions or cyclizations. enantioselectivity in vinylogous aldol reactions has lagged For all its advantages, the vinylogous aldol reaction is still significantly behind. Since 1994, a number of creative and a challenging transformation because the additional problem practical solutions have been developed for highly selective of site selectivity overlays the issues of diastereo- and catalytic, enantioselective, vinylogous aldol reactions. Their enantioselectivity already present in simple aldol reactions. direct application in the total synthesis of natural products, as Reactions of dienol ethers or ketene acetals can occur at well as their use in the rapid assembly of complex synthetic either the a or the g carbon atom of the extended conjugated intermediates, attests to the utility of these methods. This system (Scheme 4). In comparison to the progress of the Review summarizes the scope and limitations of the catalytic, enantioselective, vinylogous aldol reaction and highlights its potential as a powerful and perhaps underutilized method for Scott E. Denmark completed his SB degree the synthesis of a number of useful structural motifs when with Richard H. Holm and Daniel S. Kemp used in conjunction with substrate-directable reactions. (MIT, 1975), and his DScTech with Albert Eschenmoser (ETH Zürich, 1980). He then moved to the University of Illinois and became full professor in 1987. Since 1991 2. Early Developments in the Vinylogous Aldol he has been Reynold C. Fuson Professor of Reaction Chemistry. His research interests include newsynthetic reactions, exploratory organo- Historically, the development of a successful catalytic element chemistry, and stereocontrol in CÀC asymmetric vinylogous aldol reaction had to provide solutions bond-forming processes. He is on the Board of Editors of Organic Reactions and Organic to two major problems: 1) viable access to the requisite Syntheses, was a founding Associate Editor dienolates and dienol ethers, and 2) methods to control the of Organic Letters, and is Co-Editor of Topics site selectivity of the addition. As the formation of the in Stereochemistry. acetoacetate-derived dienol ether 1 has recently been reviewed,[8] this discussion will focus on the formation of John R. Heemstra, Jr. was born in Oak dienolates and dienol ethers derived from a,b-unsaturated Lawn, IL in 1978. He graduated from North carbonyl compounds. Early studies on the use of metal- Central College (Naperville, IL) in 2000 with lodienolates showed that direct deprotonation of unsaturated a BA degree in chemistry. He is currently a graduate student at the University of Illinois ester 5 with strong amide bases such as lithium diisopropy- in the research group of Scott E. Denmark. lamide (LDA) was not possible owing to competitive His PhD thesis work concerns the develop- conjugate addition of the base [Scheme 5, Eq. (1)].[9] In ment of catalytic, enantioselective vinylogous 1972, Rathke and Sullivan reported the first successful aldol additions of ketone- and amide-derived enolization of an a,b-unsaturated ester, 5, by the combination silyl dienol ethers. of a bulky amide base (lithium N-isopropylcyclohexylamide (LiICA)) and HMPA [Scheme 5, Eq. (2)].[10] Trapping of the Gregory L. Beutner was born in Malden, MA enolate intermediate with MeI led to the deconjugated a- in 1976. He graduated in 1998 with a BS in alkylation product 7 in good yield and selectivity. Subse- chemistry from Tufts University, where he carried out research with Arthur Utz and quently, Schlessinger and co-workers discovered that a 1:1 Marc d’Alarcao. He completed his PhD in mixture of LDA and HMPA generated a non-nucleophilic 2004 at the University of Illinois, Urbana- base that could readily enolize a variety of unsaturated esters. Champaign under the guidance of Scott E. These reactions gave the products of a alkylation in high Denmark. He is currently an NIH postdoc- yields [Scheme 5, Eq. (3)].[9] toral research associate at the California The high a-site selectivity observed in these alkylations Institute of Technology in the research group illustrates an important feature of dienolate chemistry: The of Robert Grubbs. vinylogous transmission of electronic effects does not guar- antee that reaction at the remote position will be favored or

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even observed. However, high g selectivity is possible through the use of latent dienolate equivalents in Mukaiyama-type aldol reactions[2] promoted by Lewis acids. First reported by Mukaiyama and Ishida, a vinylogous alkylation of the crotonaldehyde- derived silyl dienol ether 8 with dimethyl acetal 9 takes place under activation by [11] TiCl4 (Scheme 6). Since this initial report, the vinylogous aldol addition of silyl dienol ethers to aldehydes has also been demonstrated and high regioselectivities for g addition have been observed for a variety of dienolate structures.[12] Scheme 2. Substrate-controlled methods for elaboration of adduct 2. The reason for the different regioselectivities of the metallodienolate and the silyl dienol ether can be understood by consider- ing the electronic structure of the two reagents. Metallodienolates and their silyl congeners are highly electron rich species, and their reactions are therefore governed by electrostatic interactions, that is, by the total electron density at each carbon atom.[13] Whereas HOMO coefficients and partial charges on the constituent atoms have historically been cited to predict site selectivity,[13] a more meaningful and com- putationally more accurate measure is the frontier-orbital density recommended by Scheme 3. Substrate-controlled methods for elaboration of adduct 4. Fukui et al.[14] The frontier-orbital density

Scheme 4. Site selectivity in the vinylogous aldol reaction. Scheme 6. The first reported vinylogous alkylation of a silyl dienol ether.[11]

can be calculated for attack both by electrophiles (electrophilic susceptibility) and nucleophiles (nucleophilic susceptibility). The diagrams in Figure 1 show the HOMO orbital coefficients (O.C.) and electrophilic susceptibility (E.S.) of the lithium enolate (E)-11 of methyl crotonate, the corre- sponding trimethylsilyl ketene acetal (E)-12, and the trimethylsilyl enol ether (E)-13 of methyl 2-propenyl ketone.[15] In the lithium enolate (E)-11, both the HOMO coefficient and the electrophilic susceptibility are greater at C2 than at C4; a preference for the a-addition product is therefore predicted. On the other hand, both silyl ketene acetal (E)-12 and silyl enol ether (E)-13 display larger HOMO coefficients and electrophilic susceptibilities at C4 than at C2, so that Scheme 5. Successful methods for the preparation of metallodieno- selectivity for the formation of the g-addition products is lates derived from a,b-unsaturated esters.[9,10] HMPA=hexamethyl predicted. The smaller difference between the values at C2 phosphoramide. and C4 in (E)-13 relative to that in (E)-12 suggests that the

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3. Synthetic Equivalents of Acetoacetate Ester Dianions

The frequent occurrence of d-hydroxy-b-ketoesters 2 and their syn- and anti-b,d-diol ester derivatives as structural subunits in biologically active natural products has suggested the use of acetoacetate-derived dienolates 14 and 1 in catalytic, asymmetric, vinylogous aldol reactions (Scheme 7).[8] Whereas the addition of dienolate 1 to alde-

Scheme 7. The vinylogous aldol addition of acetoacetate-derived dienol ethers 14 and 1;[8, 16] Bn =benzyl.

Figure 1. The electronic structures of the lithium dienolate (E)-11, silyl ketene acetal (E)-12, and silyl enol ether (E)-13. hydes affords d-hydroxy-b-ketoesters 16 directly, the addition of the 1,3-dioxin-4-one-derived dienolate 14 affords the protected acetoacetate aldol adduct 15. To demonstrate the synthetic versatility of this adduct 15, Singer and Carreira selectivity in ketone dienol ethers may be attenuated showed that compounds with the dioxinone functionality can compared to silyl ketene acetals. be converted not only into a d-hydroxy-b-ketoesters, but also In rationalizing site selectivity, steric effects cannot be into amides 17 or lactones 18.[16] Furthermore, highly diaster- underestimated. In (E)-12 and (E)-13, C2 is the more eoselective reductions of 16 afford both anti- and syn- sterically hindered site owing to its proximity to the silyl dihydroxy esters, which are synthetically useful polyacetate group and the alkyl group of the ester; therefore, the building blocks (Scheme 2). The lactones formed through the approach of the electrophile to the less sterically encumbered cyclization of these adducts are also valuable synthetic C4 position is favored when C4 is not similarly substituted. subunits, and have been used for the synthesis of several For this reason, consideration of both the electrophilic pyran derivatives found in natural products.[8,12a] susceptibilities and the steric environment around C2 and The first asymmetric vinylogous aldol reactions of the C4 is necessary to rationalize the high selectivity for the g- dioxinone-derived dienol ether 19 were reported by Sato addition products. et al. They employed a boron catalyst that had already proven The inherent g selectivity of silyl dienol ethers in Lewis highly selective for Mukaiyama aldol reactions of simple silyl acid promoted vinylogous Mukaiyama aldol additions has ketene acetals.[17] Under the catalysis of the chiral acylox- provided an ideal platform for the development of several yborane (CAB) complex (2R,3R)-20, the vinylogous aldol catalytic enantioselective variants. Furthermore, various reaction of dienol ether 19 with a number of aldehydes dienol ether structures derived from acetoacetates, lactones, proceeds in moderate yields and enantioselectivities esters, and ketones have been used successfully in additions to (Table 1).[18] aldehydes. The following discussion is organized around the Similar problems are encountered in this reaction to those individual dienol ether structural types in catalytic, enantio- observed in the reactions of silyl ketene acetals catalyzed by selective, vinylogous aldol additions. 20, such as a competitive achiral-silyl-cation-catalyzed path-

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Table 1: CAB-catalyzed vinylogous aldol reactions.[18] As part of their ongoing program on the synthesis of dioxanone-containing compounds, Sato et al. sought an improved protocol for these vinylogous aldol reactions. By adopting another well-known Lewis acid catalyst for aldol additions,[21] they found that a titanium(iv)–1,1’-binaphthol (binol) complex generated in situ could be employed (Scheme 9).[22] This complex is also a highly efficient and

Entry R Catalyst [%] T [oC] Yield [%] R/S 1Ph50 À78 69 83.5:16.5 2 Ph 100 À98 91 86.5:13.5 3 PhCH=CH 50 À78 56 86.5:13.5 4 PhCH=CH 100 À98 93 88:12 5 nBu 50 À78 52 15:85 6 nBu 100 À98 39 18:82

way.[17] . Therefore, slow addition of the silyl dienol ether, low temperatures, and high catalyst loadings (50–100 mol%) are required to attain high selectivities. 1,3,2-Oxazaborolidine catalysts, although not commonly used because of their low selectivity, were employed by Kiyooka and co-workers in the synthesis of a key fragment of the polyol portion of filipin III[19] and in a partial synthesis of the macrolide acutiphycin.[20] In the synthesis of filipin III, the direct product of the vinylogous aldol addition of dienolate 21 to aldehyde 22 catalyzed by oxazaborolidine complex 23 was further elaborated through a substrate-controlled syn reduction with

Et2BOMe and NaBH4 to afford polyol 24 (Scheme 8).

Scheme 9. The Ti(OiPr)4/(R)-binol-catalyzed vinylogous aldol reaction of dienolates 25 and 19 developed by Sato et al.[22]

selective catalyst for aldol additions of simple silyl ketene acetals. However, in this case, the high selectivities observed with acetate- and propanoate-derived silyl ketene acetals translate well to the reactions of dioxinone-derived silyl dienol ethers. High, although not exceptional, selectivities are observed for a variety of aldehyde substrates. Interestingly, the structure of the dioxinone-derived silyl dienol ether has a dramatic effect on both the yield and the selectivity. Whereas dienolate 25 is superior for reactions with aliphatic aldehydes, the use of the spirodioxinone-derived silyl dienol ether 19 leads to higher yields and selectivities with aromatic and olefinic aldehydes. The titanium(iv)–binol catalyst has become popular for the vinylogous aldol reaction, and several recent reports from Scettri and co-workers expand the scope of this catalytic method as well as improve upon its selectivity (Scheme 10).[23] Scheme 8. Oxazaborolidinone-promoted vinylogous aldol addition in During their investigation of the catalyst structure, Scettri and the total synthesis of filipin III;[19] TBS =tert-butyldimethylsilyl; co-workers observed that these reactions exhibit a strong, TMS= trimethylsilyl; Ts =toluenesulfonyl. positive nonlinear effect. The magnitude of the effect is not

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Scheme 11. The vinylogous aldol reaction of dienolate 21 catalyzed by [25] the Ti(OiPr)4/(R)-binol complex; MS= molecular sieves.

Scheme 10. The Ti(OiPr) /(R)-binol-catalyzed vinylogous aldol reaction 4 yields can be attained (Scheme 12).[16] The titanium(iv)–Schiff of dienolates 25 and 19 developed by Scettri and coworkers.[23] base complex (R)-39, which had also proven successful for aldol reactions of simple silyl ketene acetals, presents several concentration dependent. This behavior is indicative of an practical and advantages for synthesis over the catalysts

ML2 catalyst system and suggests that two binol units are described above. This catalyst system, unlike most catalysts incorporated in the active catalytic species.[24] Furthermore, for aldol reactions, provides high yields and enantioselectiv- the addition of dienolate 25 to benzaldehyde proceeds ities with alkynyl aldehydes as well as aromatic, olefinic, and through an autoinductive process with an amplification of aliphatic aldehydes. the enantioselectivity when the reaction is performed in the presence of the enantiomerically enriched aldol product as an additive. These observations led to further refinements in the protocol for the in situ generation of the catalyst, so that reproducibly high enantioselectivities could be attained in the addition of dioxinone-derived dienolates 19 and 25 to a wide range of aldehydes. In a reversal of the trend observed when Sato et al. employed the titanium(iv)–binol catalyst system, dienolate 19 is now more effective in reactions with aliphatic aldehydes, whereas dienolate 25 is superior for aromatic and olefinic aldehydes. Scettri and co-workers reported that the protocol developed in their laboratories for the in situ generation of the titanium(iv)–binol catalyst system is also suitable for the addition of the Chan diene (21) to a wide variety of aldehydes (Scheme 11).[25] Dienolates of this type are extremely reactive and require catalyst loadings of only 2 mol% to afford aldol products in high yields and excellent selectivities. To isolate the aldol product in high selectivity, the use of the procedure developed by Carreira and co-workers for cleaving the silyl protecting group in the aldolate intermediate is essential, as racemization of the newly created stereocenter occurs when other methods are employed. Although this titanium-based system provides high levels of enantioselectivity for a wide variety of substrates, it is less than ideal for synthetic planning because of its poorly defined catalyst structure and the fact that the autoamplification observed in the case of some substrates may not be general. In 1995, Singer and Carreira reported a well-defined catalyst Scheme 12. The TiIV/Schiff base catalyzed vinylogous aldol reaction of system with which consistently high enantioselectivities and dienolate 25.[16]

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The high selectivity and wide substrate scope of this method makes it useful in complex-molecule total synthesis, as illustrated by the synthesis of macrolactin A[26] and [27] dihydroxy vitamin D3. In the synthesis of macrolactin A, both enantiomeric forms of the titanium(iv)–Schiff base complex are employed to construct hydroxy-bearing stereocenters present in two key subunits of the molecule (Scheme 13). The protected acetoacetate adducts (R)-43

Scheme 14. The CuII/pybox-catalyzed vinylogous aldol addition of dienolates 25 and 47 to aldehyde 44;[28] PPTS= pyridinium p-toluene- sulfonate.

Scheme 13. Application of the Ti(iv)/Schiff base catalyzed vinylogous aldol reaction in the total synthesis of macrolactin A.[26]

and (S)-43 were then further elaborated into the C11–C17 and C3–C9 fragments, respectively. The 1,3-anti-diol relation- ship between the C13 and C15 stereocenters is created through a highly selective, substrate-controlled reduction. Evans and co-workers have applied the well-defined and versatile copper–bisoxazoline catalyst (S,S)-45 for vinylogous aldol reactions of the dioxinone- and acetoacetate-derived silyl dienol ethers 25 and 47 with the a-heteroatom-substituted aldehyde 44 (Scheme 14).[28] Because this catalyst requires a potentially chelating substrate for high selectivity, the reaction remains somewhat limited in terms of aldehyde Scheme 15. Application of the vinylogous aldol reaction catalyzed by scope. Nevertheless, this method affords the products in high the CuII/pybox complex (R,R)-45 in the total synthesis of yields and selectivities and has been applied in successful phorboxazole B.[29] syntheses of phorboxazole B[29] and bryostatin 2.[30] To demonstrate the versatility of the acetoacetate aldol adduct 48, Evans and co-workers constructed two different pyran rings Katsuki and co-workers showed that the chiral, cationic in phorboxazole B from this product of a vinylogous aldol chromium–salen complex (R,R)-49 is an effective catalyst for addition (Scheme 15). vinylogous aldol reactions of the dioxinone-derived silyl

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dienol ether 25 (Scheme 16).[31] The enantioselectivity of vinylogous aldol reaction. The application of “Lewis base these reactions is highly sensitive to both the rate of addition activation of Lewis acid” catalysis to the aldol reaction of silyl of the silyl dienol ether and the solvent used. The low ketene acetals has also been extended to the vinylogous aldol enantioselectivities can be attributed to a competitive silyl- reaction.[32] In this case, the use of the chiral bisphosphor-

amide catalyst (R,R)-52 in conjunction with SiCl4 leads to the in situ formation of a putative chiral siliconium ion that promotes the addition of the dioxinone-derived dienol ether 51 to a variety of aldehydes in high yields (Scheme 17). Although the aromatic and olefinic aldehydes studied reacted with only moderate enantioselectivity, the addition to the aliphatic aldehyde leads to the aldol adduct with high enantioselectivity.

Scheme 16. The vinylogous aldol reaction of dienolate 25 catalyzed by the cationic chromium–salen complex (R,R)-49.[31]

cation-catalyzed pathway. Slow addition of dienolate 25 with Scheme 17. The vinylogous aldol reaction of dienolate 51 catalyzed by [32] a syringe pump and the presence of protic cosolvents greatly SiCl4 and bisphosphoramide (R,R)-52. increase the rate of catalyst turnover from the chromium aldolate relative to the release of the silyl cation and lead to an increase in enantioselectivity. Although a protic cosolvent, The catalyst systems discussed thus far represent exten- such as an alcohol, is essential for excellent enantioselectiv- sions of asymmetric methods for simple aldol reactions to ities to be attained, it also has the detrimental effect of vinylogous aldol reactions. The active catalyst is a chiral Lewis decreasing the yield of the aldol adduct. However, reactions acid, which binds to the aldehyde and participates in the performed in the presence of both an alcohol and an amine catalytic cycle by providing electrophilic activation. The first base provide the products in improved yields while high catalyst system that was specifically designed for use in the enantioselectivities are maintained. The authors propose that vinylogous aldol reaction is a copper(ii) fluoride/Tol-binap coordination of the alcohol to the chromium ion generates a catalyst reported by Carreira and co-workers in 1998 Brønsted acid, which, if not neutralized by the amine base, (Scheme 18).[33] Reactions with this catalyst proceed by a can effect protodesilylation of dienolate 25. Under optimized different mechanism to that of the reactions discussed conditions that include 2-propanol as a cosolvent and the previously (Scheme 19). Initial studies suggested that the ii addition of Et3N, a catalyst loading of only 2.5 mol% is copper( ) fluoride catalyst reacts with the silyl dienol ether to adequate to attain moderate to good yields and excellent generate a chiral copper dienolate 56, which is the active enantioselectivities with a variety of aldehydes. species in the subsequent carbon–carbon bond-forming step. As is clear from the preceding examples of enantioselec- This hypothesis was confirmed by ReactIR studies, in which tive Lewis acid catalysis, developments in the aldol reactions both the copper dienolate 56 and the copper aldolate 57 were of simple silyl enol ethers are typically echoed in the observed. This reaction system leads to high yields and

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that attack at the Si face of the carbonyl group in (S)-58 is preferred, coupling of aldehyde (S)-58 to dienolate 25 in the

presence of Cu(OTf)2,(S)-Tol-binap, and (Bu4N)Ph3SiF2 affords an 81:19 mixture of diastereomers in favor of the aldol adduct anti-59 formed from Re-face addition (Scheme 20). In contrast, use of the (R)-Tol-binap ligand in an overall matched case of double diastereoselection, produces an 86:14 mixture of diastereomers in favor of the adduct syn-59. Although the catalyst with the (S)-Tol-binap ligand can override the intrinsic facial selectivity of the aldehyde in the mismatched case to afford moderate anti selectivity, the inherent Cram selectivity, which favors the syn aldol adduct, is low for aldehyde (S)-58. Although several highly selective catalyst systems have been developed for enantioselective, vinylogous aldol additions of the 6-methyldioxinone-derived dienolate 25, a general, highly selective catalyst for the 6-ethyldioxinone-derived analogue 60 has not been reported.[38] In 1995, Sato et al. disclosed the only examples of catalytic, enantioselective, vinylogous aldol additions with dienolate 60 (Scheme 21).[22] Under catalysis with the titanium(iv)–binol complex, the addition of dienolate 60 to benzaldehyde proceeds in modest yield and with syn diastereoselectivity. Remarkably, the syn diastereomer is produced in enantiomerically pure form. Scheme 18. The vinylogous aldol reaction of dienolate 25 catalyzed by When the CAB complex 20 is employed for the addition of the (S)-Tol-binap·CuF complex.[33] 2 the same substrates, poor anti diastereoselectivity is observed along with moderate to good enantioselectivity for both diastereomers.

4. Simple Ester-Derived Silyl Dienol Ethers

Dienol ethers 1 and 14 are synthetic equivalents of ketoester dianions that react with exclusive g-site selectivity owing to the high nucleophilicity at C4. However, as exemplified in Figure 1, silyl dienol ethers (E)-12 derived from a,b-unsaturated esters are not as electronically biased, and steric effects also need to be considered. Indeed, both a- and g-addition products have been observed in vinylogous aldol reactions with ester-derived dienol ethers. Although achieving high site selectivity with these dienol ethers is more challenging than with the acetoacetate-derived dienol ethers, Scheme 19. Catalytic cycle for the vinylogous aldol reaction catalyzed it is well worth the effort, as the a,b-unsaturated d-hydroxy by the Tol-binap·CuF2 complex. carbonyl adducts 4 are chiral homoallylic alcohols, which can be further functionalized through conjugate addition to, or oxidation or reduction of, the double bond (Scheme 3). In 1999, Bluet and Campagne expanded the scope of the enantioselectivities for aromatic, heteroaromatic, and olefinic catalytic, enantioselective, vinylogous aldol reaction to simple aldehydes in the addition to the dioxinone-derived dienol ester-derived silyl dienol ethers 3 by employing the titaniu- ether 25; diminished yields are observed with aliphatic m(iv)–binol catalyst system (Scheme 22).[39] In this initial aldehydes, while high selectivity is maintained. This reaction study, only the ethyl tiglate derived silyl dienol ether 62 was is featured as a key step in the syntheses of leucascandroli- investigated. Although g-aldol adducts were obtained exclu- de A,[34] salicylihalamide A,[35] a subunit of the group-A sively, these less nucleophilic species were found to lead to streptogramin antibiotics,[36] and the amphotericin B polyol lower yields and enantioselectivities than more highly oxy- subunit.[37] genated silyl dienol ethers, such as 25. Nevertheless, the In a total synthesis of salicylihalamide A, the ability to vinylogous aldol addition of simple ester-derived silyl dienol override the inherent Cram selectivity of chiral aldehyde ethers has found application in the synthesis of complex (S)-58 in a catalytic, asymmetric vinylogous aldol addition is natural products, such as callipeltoside A (Scheme 23).[40] The illustrated.[35] Although Felkin–Heathcock analysis predicts C13 stereocenter and the E-configured trisubstituted C10–

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Whereas in the preceding system a Lewis acidic copper catalyst was employed to activate the aldehyde prior to the addition, Bluet and Cam- pagne have explored the use of copper as an activator of ester-derived silyl dienol ethers through generation of chiral copper metallodienolates. The use of the Carreira catalyst (S)-Tol-

binap·CuF2 produces a metallodienolate that provides exclusive g-site selectivity along with high yields and moderate enantioselectivities for the vinylogous aldol addition of dienol ether 62 to aromatic and aliphatic aldehydes (Scheme 25).[42] However, in the addition to cinnamaldehyde a 1:1 mixture of the vinylogous aldol adduct and the 1,4- addition product was obtained. Chemical degrada- tion of 63 to a previously described enantiomerically pure compound and comparison of the optical rotation showed that the major enantiomer is the aldol adduct derived from Si-face attack on the aldehyde. Remarkably, the sense of asymmetric induction observed in this reaction with the (S)- Scheme 20. Addition of dienolate 25 to chiral aldehyde (S)-58 catalyzed by the Tol-binap·CuF2 Tol-binap ligand is opposite to that observed by [35] complex. Carreira and co-workers in the addition of the dioxinone-derived silyl dienol ether 25 to alde- [33] hydes under catalysis by (S)-Tol-binap·CuF2. C11 double bond were installed with excellent selectivity by Campagne and co-workers also studied the effect of an asymmetric, vinylogous aldol reaction of the methyl g substitution on the dienolate in the addition to aldehydes in

senecioate derived silyl dienol ether 67 with dienal 68. the presence of the (S)-Tol-binap·CuF2 catalyst However, high catalyst loadings and long reaction times are (Scheme 26).[43] The addition of the methyl pentenoate required to obtain a high yield because of the low reactivity of derived silyl dienol ether 74 to various aldehydes yielded the dienolate. mixtures of lactones 75 and vinylogous aldol products 76. In an earlier approach to callipeltoside A, Evans et al. Whereas lactones 75 were formed with excellent anti selec- developed a catalytic, asymmetric, vinylogous aldol reaction tivity (> 98:2) along with high enantioselectivity in all cases, with ethyl senecioate derived silyl dienol ether 70 to construct the linear products 76 were isolated as a 1:1 mixture of the same hydroxy-substituted stereocenter and trisubstituted racemic syn and anti diastereomers. The lactones are obtained E double bond (Scheme 24).[41] The addition of dienolate 70 with high diastereo- and enantioselectivity from the reaction to 2-(4-methoxybenzyloxy)acetaldehyde (71) afforded the with aromatic, heteroaromatic, olefinic, and aliphatic alde- vinylogous aldol adduct 73 in high yield with complete hydes. However, the ratio of the lactone to the linear product, E selectivity and excellent enantioselectivity under catalysis a measure of the E/Z selectivity in the formation of the with the air-stable complex (R,R)-72. double bond, is highly substrate dependent. Whereas aro-

[22] Scheme 21. Vinylogous aldol additions of dienolate 60 to benzaldehyde catalyzed by CAB and Ti(OiPr)4/(R)-binol.

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Scheme 22. The Ti(OiPr)4/(R)-binol-catalyzed vinylogous aldol reaction of the ester-derived dienolate 62 (absolute configurations were not established by the authors).[39] Scheme 25. The vinylogous aldol reaction of ester-derived dienolate 62 [42] catalyzed by the (S)-Tol-binap·CuF2 complex.

Scheme 23. Application of the Ti(OiPr)4/(R)-binol-catalyzed vinylogous aldol reaction in the total synthesis of callipeltoside A.[40]

Scheme 26. The vinylogous aldol reaction of ester-derived dienolate 74

catalyzed by the Tol-binap·CuF2 complex (a:R= Ph, b:R= 2-furyl, c: R = cinnamyl, d:R=isopropyl).[43]

matic aldehydes afford the highest proportion of the lactone product, aliphatic and olefinic aldehydes are less selective, and 2-furaldehyde affords both the linear product and the lactone in a 1:1 ratio. Scheme 24. Application of the vinylogous aldol reaction catalyzed by In an extension of this method, the addition of dienol the CuII/pybox complex (R,R)-72 in the total synthesis of callipeltosi- ether 74 to the chiral aldehyde (S)-77 was investigated de A;[41] PMB= p-methoxybenzyl. (Scheme 27).[43] Felkin–Heathcock analysis of the S-config-

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further expanded the scope of the vinylogous aldol reaction of ester-derived dienol ethers [32] (Scheme 28). The SiCl4–phosphoramide catalyst system used for the addition of the acetoacetate-derived dienol ether 51 also effectively promotes the addition of the unsubstituted ethyl crotonate derived dienol ether as well as a-, b-, and g-substituted dienol ethers. Remarkably, excellent g-site selectivity and E-double-bond selectivity are maintained for all substitution patterns on the dienolate in the addition to aromatic, olefinic, and aliphatic aldehydes. Fur- thermore, this catalyst system maintains the high Scheme 27. The vinylogous aldol addition of ester-derived dienolate 74 to chiral aldehyde level of anti diastereoselectivity (> 99:1) that is [43] = (S)-77 catalyzed by the Tol-binap·CuF2 complex; TBDPS tert-butyldiphenylsilyl. observed in the additions of propanoate-derived silyl ketene acetals.[44] With aromatic and olefinic ured aldehyde (S)-77 predicts that approach to the Si face of aldehydes, catalyst loadings of 1 mol% are sufficient to the carbonyl group should be preferred, thus leading to the provide vinylogous aldol adducts in high yields and selectiv- syn diastereomer. Additionally, the (S)-Tol-binap ligand has ities with all four dienolates surveyed. However, aliphatic the same facial bias for attack at the Si face of the aldehyde, as aldehydes require higher catalyst loadings and longer reaction

shown above. When the (S)-Tol-binap·CuF2 catalyst system is times for acceptable yields to be attained in the additions of used, syn/anti-78 is formed as the only lactone diastereomer, the unsubstituted crotonate-derived and b-substituted sene- with the linear product reported to account for less than 10% cioate-derived dienol ethers. Dienol ethers with methyl of the crude reaction mixture. However, when the (R)-Tol- groups in the g and a positions were found to be unreactive binap ligand is employed, an 88:12 mixture of lactones is with aliphatic aldehydes. The aldol adducts are produced with formed, with a switch in diastereoselectivity now favoring the excellent E selectivity regardless of the substitution on the anti/anti lactone 78. Again, the amount of linear product dienol ether, including g substitution. This result stands in

formed is reported to be less than 10% of the crude reaction contrast to catalysis with Tol-binap·CuF2. Whereas the mixture. Although the selectivity in both the matched and the addition of the a-substituted methyl tiglate derived dienol mismatched case is high, the yields of the isolated product are ether occurs with exclusive E selectivity in the presence of this low for both addition reactions (60 and 55%, respectively). catalyst, the g-substituted methyl pentenoate derived dienol A systematic study of the effect on the addition to ether affords the aldol adduct with modest Z selectivity. aldehydes of various substitution patterns on the dienol ether

[32] Scheme 28. The vinylogous aldol reaction of various ester-derived dienolates catalyzed by SiCl4 and bisphosphoramide (R,R)-52.

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5. Lactone-Derived Dienol Ethers Table 2: Modification of the Ti(OiPr)4/binol-catalyzed vinylogous aldol reaction.[45] The Lewis acid catalyzed vinylogous aldol addition of lactone-derived dienol ether 87 to aldehydes leads to the formation of a g-substituted butenolide 88, a structural motif that is found in several biologically active natural products (Scheme 29). Furthermore, these adducts are useful chiral building blocks for the preparation of functionalized g- Entry Additive Yield [%] syn:anti e.r. (syn) lactones through manipulation of the double bond. Buteno- 1[a] none 99 70:30 85:15 lide 88 has also been used for the preparation of compounds 25%(4S,5S)-90 99 70:30 > 98:2 containing 1,2-diol functionality, and for the construction of 35%(4R,5R)-90 99 70:30 70:30 4[b] none 90 60:40 > 98:2 optically active pyrans.[12a] [a] Dienolate 89 was added in one portion. [b] Dienolate 89 was added stepwise in four portions. e.r. =enantiomeric ratio.

involving stepwise addition of dienolate 89 was developed (Table 2, entry 4). This method has been applied to vinylogous aldol reactions of silyl dienol ether 89 and affords adducts with modest to excellent enantioselectivities and modest diastereoselectivities (Scheme 30). Interestingly, the substrate determines which product is formed as the major diastereomer in the addition reaction; whereas aliphatic aldehydes lead to the formation of the syn isomer, olefinic and aromatic aldehydes produce the anti isomer. The chromium–salen catalyst (R,R)-49 used by Katsuki and co-workers for the addition of dioxinone-derived dienol ether 25 to aldehydes Scheme 29. The vinylogous aldol addition of lactone-derived dienol ether 87 and elaboration of the butenolide product. also catalyzes the addition of 89 to aldehydes with high enantioselectivity (Scheme 31).[46] As is the case for the reaction with dienol ether 25, the addition of a protic cosolvent to the reaction Figadre and co-workers disclosed the first catalytic, mixture is essential for high and reproducible selectivities to enantioselective addition involving a lactone-derived dienolate in 1998.[45] The titanium-based chiral catalyst system developed by Sato et al. and improved upon by Scettri and co- workers for acetoacetate-derived dienol ethers can also promote highly site-selective additions of the lactone-derived silyl dienol ether 89 to aldehydes. Interestingly, reactions performed in the presence of a 1:1:1 mixture of Ti(OiPr)4, binol, and a second chiral alcohol afforded the aldol addition product in higher yields and enantioselectivities than those carried out in the presence of only Ti(OiPr)4 and binol. The authors suspected that the aldol product becomes incorporated into the catalytic species to generate a new catalyst structure and therefore explored the possibility of an autoinductive aldol reaction (Table 2). The first experiment established that the aldol addition product was produced with higher enantioselectivity in the presence of 5 mol% of the enantiomerically enriched aldolate syn-(4S,5S)-90 than in the reaction performed in the absence of additives (Table 2, entries 1 and 2). Furthermore, the inclusion of the minor enantiomer syn-(4R,5R)-90 under the same reaction conditions causes a decrease in enantioselectivity (Table 2, entry 3). To allow amplification of the enantioselectivity through the incorporation of the major syn butenolide formed during the Scheme 30. The Ti(OiPr)4/(R)-binol-catalyzed vinylogous aldol reaction reaction into the catalyst structure, a general procedure of lactone-derived dienolate 89.[45]

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ketone-derived dienol ethers in catalytic, asymmetric, vinylogous aldol reactions was recently reported from these laboratories.[47] The combination of catalytic amounts of the

chiral bisphosphoramide (R,R)-52 and SiCl4 promotes the addition of silyl dienol ethers derived from simple acyclic a,b- unsaturated ketones to aldehydes. In this initial report, dienol ether 99 reacts with aromatic, heteroaromatic, olefinic, and propargylic aldehydes with exclusive g-site selectivity and high enantioselectivity (Scheme 33). However, the failure of aliphatic aldehydes to undergo this reaction remains a limitation of this method.

Scheme 31. The vinylogous aldol reaction of lactone-derived dienolate 89 catalyzed by the cationic chromium–salen complex (R,R)-49 (absolute configurations were not established by the authors).[46]

be attained. The authors propose that the protic cosolvent is needed to suppress the undesired retroaddition reaction by rapidly converting the aldolate into the hydroxyl lactone product, thereby enabling the isolation of the adduct formed under conditions of kinetic control. Although only modest to good syn diastereoselectivities are observed with aromatic Scheme 33. The vinylogous aldol reaction of acyclic-ketone-derived [47] and aliphatic aldehydes, both the syn and anti isomers are dienolate 99 catalyzed by SiCl4 and bisphosphoramide (R,R)-52. formed with good to excellent enantioselectivities. Whereas the two previously described catalyst systems afford only modest diastereoselectivities, the copper–bisox- The reactivity of the cyclic-ketone-derived dienol ether azoline catalyst (S,S)-45 developed by Evans and co-workers 104 was examined to evaluate the diastereoselectivity in the affords the anti product with high diastereo- and enantiose- addition to form g-substituted ketones (Scheme 34).[47] Aldol lectivity from the vinylogous aldol reaction of 89 with adducts formed from aromatic, olefinic, and heteroaromatic (benzyloxy)acetaldehyde (44; Scheme 32).[28] However, the aldehydes could be obtained with exclusive g-site selectivity addition only to aldehyde 44 was demonstrated. and good to excellent anti diastereoselectivity. However, as in the case of acyclic-ketone-derived dienol ethers, 104 did not react with aliphatic aldehydes.

7. Conclusions and Outlook

Excellent progress has been made in the development of the catalytic, enantioselective, vinylogous aldol reaction since the initial report in 1994. Through the extension of existing Scheme 32. The vinylogous aldol reaction of lactone-derived dienolate 89 to aldehyde 44 in the presence of the Cu(ii)/pybox complex catalyst systems and the invention of novel ones, several (S,S)-45.[28] general and highly selective methods now exist for the addition of acetoacetate-derived silyl dienol ethers 1 and 14 to a wide variety of aldehydes (see 111, Figure 2). Moreover, 6. Ketone-Derived Dienol Ethers recent studies with dienolates derived from esters have shown that crotonate-derived silyl dienol ethers, as well as dienolates Although the catalytic, enantioselective, vinylogous aldol with a and b substituents, react with a wide range of addition of dienol ethers derived from a,b-unsaturated esters aldehydes with high selectivity (120). This method also has been successfully demonstrated, extension of the nucle- allows for high selectivity in the addition of dienolates ophile scope to other acyclic a,b-unsaturated carbonyl com- derived from g-substituted esters to aromatic and olefinic pounds has remained virtually unexplored. The first use of aldehydes to give compounds 123. Furthermore, high enan-

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of the aldol adducts that can be created by using catalytic, asymmetric methods through the combination of dienol derivatives derived either from b-dicarbonyl compounds or a,b-unsaturated carbonyl compounds with simple aldehydes. A number of important conclusions are readily apparent. First, the range of nucleophiles is limited primarily to ester- derived reagents. With only a single report of dienol ethers derived from a,b-unsaturated ketones (see 119 and 122) and no examples of dienol ethers derived from a,b-keto aldehydes (109, 112, and 115), b-diketones (110, 113, and 116), or a,b- unsaturated aldehydes (118, 121, and 124), this is clearly an area for future development. Another serious omission is the lack of methods for the addition of any nucleophile to a wide range of aldehydes with excellent diastereoselectivity. Although progress has been made in the addition of dienol ethers derived from g-substituted esters, ketones, and lactones, the analogous reactions of dienolates derived from g- substituted acetoacetates or 1,3-diketones represent oppor- tunities for future investigation. Scheme 34. The vinylogous aldol reaction of cyclic-ketone-derived The presence of the vinylogous aldol motif in many [47] dienolate 104 catalyzed by SiCl4 and bisphosphoramide (R,R)-52. natural products, and the easily manipulated functionalities contained in the resulting a,b-unsaturated d-hydroxy carbonyl or d-hydroxy-b-ketoester vinylogous aldol adducts, render this reaction an interesting alternative for the synthesis of many natural products. Although the use of complex enzymes for the synthesis of polyketides is highly successful, the unique strengths and weaknesses of small-molecule asymmetric catalysis inspire the synthetic chemist to find different and innovative solutions to this challenge. The combination of well-established, substrate-controlled asymmetric transformations with these highly selective, catalytic, enantioselective vinylogous aldol reactions is destined to generate new strategies for synthesis in the years to come.

We are gratefulto the NationalScience Foundation (NSF CHE-0105205 and NSF CHE-0414440) for generous financial support. We also thank Dr. Martin Eastgate for performing the DFT calculations.

Received: October 18, 2004 Published online: June 7, 2005

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