In 1935, R. C. Fuson formulated the principle of vinylogy to explain

Transcription

1 Asymmetric Catalysis Catalytic, Enantioselective, Vinylogous Aldol Reactions** Scott E. Denmark,* John R. Heemstra, Jr., and Gregory L. Beutner Keywords: aldol reactions asymmetric catalysis dienol ethers regioselectivity vinylogy Dedicated to Professor Albert Eschenmoser on the occasion of his 80th birthday Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: /anie Angew. Chem. Int. Ed. 2005, 44,

2 Asymmetric Catalysis In 1935, R. C. Fuson formulated the principle of vinylogy to explain how the influence of a functional group may be felt at a distant point in the molecule when this position is connected by conjugated doublebond linkages to the group. In polar reactions, this concept allows the extension of the electrophilic or nucleophilic character of a functional group through the p system of a carbon carbon double bond. This vinylogous extension has been applied to the aldol reaction by employing extended dienol ethers derived from g-enolizable a,bunsaturated carbonylcompounds. Since 1994, severalmethods for the catalytic, enantioselective, vinylogous aldol reaction have appeared, with which varying degrees of regio- (site), enantio-, and diastereoselectivity can be attained. In this Review, the current scope and limitations of this transformation, as well as its application in natural product synthesis, are discussed. From the Contents 1. Introduction Early Developments in the Vinylogous Aldol Reaction Synthetic Equivalents of Acetoacetate Ester Dianions Simple Ester-Derived Silyl Dienol Ethers Lactone-Derived Dienol Ethers Ketone-Derived Dienol Ethers Conclusions and Outlook Introduction The potent biological activity and structural diversity of the polyketide class of natural products has provided inspiration and impetus for research in many subfields of the chemical sciences. A main characteristic of these natural products is presence of complex polyol subunits with repeating 1,3-diol relationships within their core structure. Through elegant biosynthetic studies it is now well established that these polyol chains are synthesized in nature by multifunctional enzymes termed polyketide synthetases. [1] By using small carboxylic acid building blocks (primarily acetate, propionate, and butyrate), which are activated as thioesters bound to a ketosynthase protein and through carboxylation (e.g. with malonyl-coa and 2-methylmalonyl-CoA), the carbon backbone of the polyketide is assembled two carbon atoms at a time as the result of enzymatic, decarboxylative Claisen condensations (Scheme 1). Reduction of the b-keto thioester intermediate by NADPH generates a b-hydroxy thioester, which can undergo acyl-group transfer to a subsequent ketosynthase protein. This sequence is repeated until the appropriate polyol chain length is reached. Each stereogenic center is created with high selectivity owing to the ability of the enzyme to rigidly fix the orientation of the reactive components relative to each other and relative to the enzyme. A challenge for the modern synthetic chemist is the development of non-enzymatic asymmetric reactions for the construction of polyol subunits with equally high selectivity and efficiency as achieved in nature. With regard to many criteria, the asymmetric aldol addition reaction, which provides b-hydroxy carbonyl compounds with up to two new stereocenters from readily available starting materials, has met this challenge. [2] Indeed, the selectivity, scope, and predictability associated with current aldol-addition methods have allowed this reaction to emerge as a strategy-level reaction in natural product synthesis. Although the aldol addition reaction has found widespread application in the synthesis of linear acyclic polyol structures, it is certainly not the only method available. Other transformations, such as allylations, [3] alkylations of 4-cyano-1,3-dioxanes, [4] and nucleophilic epoxide-opening reactions of epoxyalkynols, [5] have also been developed as viable alternatives to the aldol reaction. Nevertheless, despite some limitations, the aldol addition is ideally suited for efficient access to the targeted polyol structures. Moreover, the polar nature of the enolate precursor in the addition makes a vinylogous extension of this reaction possible. Defined as the transmission of electronic effects through a conjugated p system, the principle of vinylogy allows the extension of the nucleophilic or electrophilic character of a functional group through the p system of a carbon carbon double bond. [6] Accordingly, a g-enolizable a,b-unsaturated carbonyl substrate can be employed as an extended dienolate in a vinylogous aldol addition to an aldehyde to give d-hydroxy-b-ketoesters 2 (Scheme 2) or a,bunsaturated d-hydroxy carbonyl compounds 4 (Scheme 3) in which up to two stereocenters and one double bond can be created. These functional arrays are common structural motifs that have found application in synthesis. The newly created hydroxy-substituted stereocenter is adjacent to a double bond or carbonyl group, and these versatile intermediates can therefore be further elaborated by using various highly selective substrate-directable reactions (see Schemes 2 and 3). [7] Among the most useful of these reactions are [*] Prof. Dr. S. E. Denmark, J. R. Heemstra, Jr., Dr. G. L. Beutner Roger Adams Laboratory University of Illinois at Urbana-Champaign 600 South Mathews Avenue Urbana, IL (USA) Fax: (+ 1) denmark@scs.uiuc.edu [**] Seventy years ago, Reynold C. Fuson formulated the concept of vinylogy that constitutes the conceptual underpinning of the vinylogous aldol reactions described in this Review. (Reprinted with permission from Chem. Rev. 1935, 16, Copyright 1935, American Chemical Society. Photograph courtesy of the University of Illinois at Urbana-Champaign Archives (Record Series 39/2/26)). Angew. Chem. Int. Ed. 2005, 44, DOI: /anie Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4683

3 Scheme 1. The biosynthesis of polyol compounds by polyketide synthetases. [1] conjugate additions to the double bond, oxidations or reductions of the double bond, or in the case of the b-keto carbonyl compounds, directed reductions or cyclizations. For all its advantages, the vinylogous aldol reaction is still a challenging transformation because the additional problem of site selectivity overlays the issues of diastereo- and enantioselectivity already present in simple aldol reactions. Reactions of dienol ethers or ketene acetals can occur at either the a or the g carbon atom of the extended conjugated system (Scheme 4). In comparison to the progress of the Scott E. Denmark completed his SB degree with Richard H. Holm and Daniel S. Kemp (MIT, 1975), and his DScTech with Albert Eschenmoser (ETH Zürich, 1980). He then moved to the University of Illinois and became full professor in Since 1991 he has been Reynold C. Fuson Professor of Chemistry. His research interests include newsynthetic reactions, exploratory organoelement chemistry, and stereocontrol in C C bond-forming processes. He is on the Board of Editors of Organic Reactions and Organic Syntheses, was a founding Associate Editor of Organic Letters, and is Co-Editor of Topics in Stereochemistry. John R. Heemstra, Jr. was born in Oak Lawn, IL in He graduated from North Central College (Naperville, IL) in 2000 with a BA degree in chemistry. He is currently a graduate student at the University of Illinois in the research group of Scott E. Denmark. His PhD thesis work concerns the development of catalytic, enantioselective vinylogous aldol additions of ketone- and amide-derived silyl dienol ethers. Gregory L. Beutner was born in Malden, MA in He graduated in 1998 with a BS in chemistry from Tufts University, where he carried out research with Arthur Utz and Marc d Alarcao. He completed his PhD in 2004 at the University of Illinois, Urbana- Champaign under the guidance of Scott E. Denmark. He is currently an NIH postdoctoral research associate at the California Institute of Technology in the research group of Robert Grubbs. classic aldol addition reaction, the development of methods that combine high levels of regio- (site), diastereo-, and enantioselectivity in vinylogous aldol reactions has lagged significantly behind. Since 1994, a number of creative and practical solutions have been developed for highly selective catalytic, enantioselective, vinylogous aldol reactions. Their direct application in the total synthesis of natural products, as well as their use in the rapid assembly of complex synthetic intermediates, attests to the utility of these methods. This 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 the synthesis of a number of useful structural motifs when used in conjunction with substrate-directable reactions. 2. Early Developments in the Vinylogous Aldol Reaction Historically, the development of a successful catalytic asymmetric vinylogous aldol reaction had to provide solutions to two major problems: 1) viable access to the requisite dienolates and dienol ethers, and 2) methods to control the site selectivity of the addition. As the formation of the acetoacetate-derived dienol ether 1 has recently been reviewed, [8] this discussion will focus on the formation of dienolates and dienol ethers derived from a,b-unsaturated carbonyl compounds. Early studies on the use of metallodienolates showed that direct deprotonation of unsaturated ester 5 with strong amide bases such as lithium diisopropylamide (LDA) was not possible owing to competitive conjugate addition of the base [Scheme 5, Eq. (1)]. [9] In 1972, Rathke and Sullivan reported the first successful enolization of an a,b-unsaturated ester, 5, by the combination of a bulky amide base (lithium N-isopropylcyclohexylamide (LiICA)) and HMPA [Scheme 5, Eq. (2)]. [10] Trapping of the enolate intermediate with MeI led to the deconjugated a- alkylation product 7 in good yield and selectivity. Subsequently, Schlessinger and co-workers discovered that a 1:1 mixture of LDA and HMPA generated a non-nucleophilic base that could readily enolize a variety of unsaturated esters. These reactions gave the products of a alkylation in high yields [Scheme 5, Eq. (3)]. [9] The high a-site selectivity observed in these alkylations illustrates an important feature of dienolate chemistry: The vinylogous transmission of electronic effects does not guarantee that reaction at the remote position will be favored or Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2005, 44,

4 Asymmetric Catalysis Scheme 2. Substrate-controlled methods for elaboration of adduct 2. Scheme 3. Substrate-controlled methods for elaboration of adduct 4. 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 crotonaldehydederived silyl dienol ether 8 with dimethyl acetal 9 takes place under activation by TiCl 4 (Scheme 6). [11] 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] The reason for the different regioselectivities of the metallodienolate and the silyl dienol ether can be understood by considering 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 computationally more accurate measure is the frontier-orbital density recommended by 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] Scheme 5. Successful methods for the preparation of metallodienolates derived from a,b-unsaturated esters. [9, 10] HMPA = hexamethyl phosphoramide. 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 corresponding 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 selectivity for the formation of the g-addition products is predicted. The smaller difference between the values at C2 and C4 in (E)-13 relative to that in (E)-12 suggests that the Angew. Chem. Int. Ed. 2005, 44, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4685

5 3. Synthetic Equivalents of Acetoacetate Ester Dianions 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. selectivity in ketone dienol ethers may be attenuated compared to silyl ketene acetals. In rationalizing site selectivity, steric effects cannot be underestimated. In (E)-12 and (E)-13, C2 is the more sterically hindered site owing to its proximity to the silyl group and the alkyl group of the ester; therefore, the approach of the electrophile to the less sterically encumbered C4 position is favored when C4 is not similarly substituted. For this reason, consideration of both the electrophilic susceptibilities and the steric environment around C2 and C4 is necessary to rationalize the high selectivity for the g- addition products. The inherent g selectivity of silyl dienol ethers in Lewis acid promoted vinylogous Mukaiyama aldol additions has provided an ideal platform for the development of several catalytic enantioselective variants. Furthermore, various dienol ether structures derived from acetoacetates, lactones, esters, and ketones have been used successfully in additions to aldehydes. The following discussion is organized around the individual dienol ether structural types in catalytic, enantioselective, vinylogous aldol additions. 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 aldehydes 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 showed that compounds with the dioxinone functionality can be converted not only into a d-hydroxy-b-ketoesters, but also into amides 17 or lactones 18. [16] Furthermore, highly diastereoselective reductions of 16 afford both anti- and syndihydroxy esters, which are synthetically useful polyacetate building blocks (Scheme 2). The lactones formed through the cyclization of these adducts are also valuable synthetic subunits, and have been used for the synthesis of several pyran derivatives found in natural products. [8,12a] The first asymmetric vinylogous aldol reactions of the dioxinone-derived dienol ether 19 were reported by Sato et al. They employed a boron catalyst that had already proven highly selective for Mukaiyama aldol reactions of simple silyl ketene acetals. [17] Under the catalysis of the chiral acyloxyborane (CAB) complex (2R,3R)-20, the vinylogous aldol reaction of dienol ether 19 with a number of aldehydes proceeds in moderate yields and enantioselectivities (Table 1). [18] Similar problems are encountered in this reaction to those observed in the reactions of silyl ketene acetals catalyzed by 20, such as a competitive achiral-silyl-cation-catalyzed path Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2005, 44,

6 Asymmetric Catalysis 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 [ o C] Yield [%] R/S 1 Ph : Ph : PhCH=CH : PhCH=CH :12 5 nbu :85 6 nbu :82 way. [17]. Therefore, slow addition of the silyl dienol ether, low temperatures, and high catalyst loadings ( 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 Et 2 BOMe and NaBH 4 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] Scheme 8. Oxazaborolidinone-promoted vinylogous aldol addition in the total synthesis of filipin III; [19] TBS = tert-butyldimethylsilyl; TMS = trimethylsilyl; Ts = toluenesulfonyl. 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] During their investigation of the catalyst structure, Scettri and co-workers observed that these reactions exhibit a strong, positive nonlinear effect. The magnitude of the effect is not Angew. Chem. Int. Ed. 2005, 44, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4687

7 Scheme 11. The vinylogous aldol reaction of dienolate 21 catalyzed by the Ti(OiPr) 4 /(R)-binol complex; [25] MS=molecular sieves. Scheme 10. The Ti(OiPr) 4 /(R)-binol-catalyzed vinylogous aldol reaction of dienolates 25 and 19 developed by Scettri and coworkers. [23] concentration dependent. This behavior is indicative of an ML 2 catalyst system and suggests that two binol units are incorporated in the active catalytic species. [24] Furthermore, the addition of dienolate 25 to benzaldehyde proceeds through an autoinductive process with an amplification of 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 system with which consistently high enantioselectivities and yields can be attained (Scheme 12). [16] The titanium(iv) Schiff base complex (R)-39, which had also proven successful for aldol reactions of simple silyl ketene acetals, presents several practical and advantages for synthesis over the catalysts described above. This catalyst system, unlike most catalysts for aldol reactions, provides high yields and enantioselectivities with alkynyl aldehydes as well as aromatic, olefinic, and aliphatic aldehydes. Scheme 12. The Ti IV /Schiff base catalyzed vinylogous aldol reaction of dienolate 25. [16] Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2005, 44,

8 Asymmetric Catalysis 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 dihydroxy vitamin D 3. [27] 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 Cu II /pybox-catalyzed vinylogous aldol addition of dienolates 25 and 47 to aldehyde 44; [28] PPTS = pyridinium p-toluenesulfonate. 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 relationship 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 scope. Nevertheless, this method affords the products in high yields and selectivities and has been applied in successful 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 in phorboxazole B from this product of a vinylogous aldol addition (Scheme 15). Scheme 15. Application of the vinylogous aldol reaction catalyzed by the Cu II /pybox complex (R,R)-45 in the total synthesis of phorboxazole B. [29] Katsuki and co-workers showed that the chiral, cationic chromium salen complex (R,R)-49 is an effective catalyst for vinylogous aldol reactions of the dioxinone-derived silyl Angew. Chem. Int. Ed. 2005, 44, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4689

9 vinylogous aldol reaction. The application of Lewis base activation of Lewis acid catalysis to the aldol reaction of silyl ketene acetals has also been extended to the vinylogous aldol reaction. [32] In this case, the use of the chiral bisphosphoramide catalyst (R,R)-52 in conjunction with SiCl 4 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] dienol ether 25 (Scheme 16). [31] The enantioselectivity of these reactions is highly sensitive to both the rate of addition of the silyl dienol ether and the solvent used. The low enantioselectivities can be attributed to a competitive silylcation-catalyzed pathway. Slow addition of dienolate 25 with a syringe pump and the presence of protic cosolvents greatly 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, such as an alcohol, is essential for excellent enantioselectivities to be attained, it also has the detrimental effect of decreasing the yield of the aldol adduct. However, reactions performed in the presence of both an alcohol and an amine base provide the products in improved yields while high enantioselectivities are maintained. The authors propose that coordination of the alcohol to the chromium ion generates a Brønsted acid, which, if not neutralized by the amine base, can effect protodesilylation of dienolate 25. Under optimized conditions that include 2-propanol as a cosolvent and the addition of Et 3 N, a catalyst loading of only 2.5 mol % is adequate to attain moderate to good yields and excellent enantioselectivities with a variety of aldehydes. As is clear from the preceding examples of enantioselective Lewis acid catalysis, developments in the aldol reactions of simple silyl enol ethers are typically echoed in the Scheme 17. The vinylogous aldol reaction of dienolate 51 catalyzed by SiCl 4 and bisphosphoramide (R,R)-52. [32] The catalyst systems discussed thus far represent extensions of asymmetric methods for simple aldol reactions to vinylogous aldol reactions. The active catalyst is a chiral Lewis acid, which binds to the aldehyde and participates in the catalytic cycle by providing electrophilic activation. The first catalyst system that was specifically designed for use in the vinylogous aldol reaction is a copper(ii) fluoride/tol-binap catalyst reported by Carreira and co-workers in 1998 (Scheme 18). [33] Reactions with this catalyst proceed by a different mechanism to that of the reactions discussed previously (Scheme 19). Initial studies suggested that the copper(ii) fluoride catalyst reacts with the silyl dienol ether to generate a chiral copper dienolate 56, which is the active species in the subsequent carbon carbon bond-forming step. This hypothesis was confirmed by ReactIR studies, in which both the copper dienolate 56 and the copper aldolate 57 were observed. This reaction system leads to high yields and Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2005, 44,

10 Asymmetric Catalysis Scheme 18. The vinylogous aldol reaction of dienolate 25 catalyzed by the (S)-Tol-binap CuF 2 complex. [33] 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 (Bu 4 N)Ph 3 SiF 2 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. When the CAB complex 20 is employed for the addition of the same substrates, poor anti diastereoselectivity is observed along with moderate to good enantioselectivity for both diastereomers. 4. Simple Ester-Derived Silyl Dienol Ethers Scheme 19. Catalytic cycle for the vinylogous aldol reaction catalyzed by the Tol-binap CuF 2 complex. enantioselectivities for aromatic, heteroaromatic, and olefinic aldehydes in the addition to the dioxinone-derived dienol ether 25; diminished yields are observed with aliphatic aldehydes, while high selectivity is maintained. This reaction is featured as a key step in the syntheses of leucascandrolide A, [34] salicylihalamide A, [35] a subunit of the group-a streptogramin antibiotics, [36] and the amphotericin B polyol subunit. [37] In a total synthesis of salicylihalamide A, the ability to override the inherent Cram selectivity of chiral aldehyde (S)-58 in a catalytic, asymmetric vinylogous aldol addition is illustrated. [35] Although Felkin Heathcock analysis predicts 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, it is well worth the effort, as the a,b-unsaturated d-hydroxy 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 catalytic, enantioselective, vinylogous aldol reaction to simple ester-derived silyl dienol ethers 3 by employing the titanium(iv) binol catalyst system (Scheme 22). [39] In this initial study, only the ethyl tiglate derived silyl dienol ether 62 was investigated. Although g-aldol adducts were obtained exclusively, these less nucleophilic species were found to lead to lower yields and enantioselectivities than more highly oxygenated silyl dienol ethers, such as 25. Nevertheless, the vinylogous aldol addition of simple ester-derived silyl dienol ethers has found application in the synthesis of complex natural products, such as callipeltoside A (Scheme 23). [40] The C13 stereocenter and the E-configured trisubstituted C10 Angew. Chem. Int. Ed. 2005, 44, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4691

11 Scheme 20. Addition of dienolate 25 to chiral aldehyde (S)-58 catalyzed by the Tol-binap CuF 2 complex. [35] C11 double bond were installed with excellent selectivity by an asymmetric, vinylogous aldol reaction of the methyl senecioate derived silyl dienol ether 67 with dienal 68. However, high catalyst loadings and long reaction times are required to obtain a high yield because of the low reactivity of the dienolate. In an earlier approach to callipeltoside A, Evans et al. developed a catalytic, asymmetric, vinylogous aldol reaction with ethyl senecioate derived silyl dienol ether 70 to construct the same hydroxy-substituted stereocenter and trisubstituted E double bond (Scheme 24). [41] The addition of dienolate 70 to 2-(4-methoxybenzyloxy)acetaldehyde (71) afforded the vinylogous aldol adduct 73 in high yield with complete E selectivity and excellent enantioselectivity under catalysis with the air-stable complex (R,R)-72. Whereas in the preceding system a Lewis acidic copper catalyst was employed to activate the aldehyde prior to the addition, Bluet and Campagne 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)-Tolbinap CuF 2 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 degradation 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)- Tol-binap ligand is opposite to that observed by Carreira and co-workers in the addition of the dioxinone-derived silyl dienol ether 25 to aldehydes under catalysis by (S)-Tol-binap CuF 2. [33] Campagne and co-workers also studied the effect of g substitution on the dienolate in the addition to aldehydes in the presence of the (S)-Tol-binap CuF 2 catalyst (Scheme 26). [43] The addition of the methyl pentenoate derived silyl dienol ether 74 to various aldehydes yielded mixtures of lactones 75 and vinylogous aldol products 76. Whereas lactones 75 were formed with excellent anti selectivity (> 98:2) along with high enantioselectivity in all cases, the linear products 76 were isolated as a 1:1 mixture of racemic syn and anti diastereomers. The lactones are obtained with high diastereo- and enantioselectivity from the reaction with aromatic, heteroaromatic, olefinic, and aliphatic aldehydes. However, the ratio of the lactone to the linear product, a measure of the E/Z selectivity in the formation of the double bond, is highly substrate dependent. Whereas aro- Scheme 21. Vinylogous aldol additions of dienolate 60 to benzaldehyde catalyzed by CAB and Ti(OiPr) 4 /(R)-binol. [22] Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2005, 44,

12 Asymmetric Catalysis 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 catalyzed by the (S)-Tol-binap CuF 2 complex. [42] 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 CuF 2 complex (a: R= Ph, b: R= 2-furyl, c: R = cinnamyl, d: R= isopropyl). [43] Scheme 24. Application of the vinylogous aldol reaction catalyzed by the Cu II /pybox complex (R,R)-72 in the total synthesis of callipeltoside A; [41] PMB = p-methoxybenzyl. 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. In an extension of this method, the addition of dienol ether 74 to the chiral aldehyde (S)-77 was investigated (Scheme 27). [43] Felkin Heathcock analysis of the S-config- Angew. Chem. Int. Ed. 2005, 44, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4693

13 Scheme 27. The vinylogous aldol addition of ester-derived dienolate 74 to chiral aldehyde (S)-77 catalyzed by the Tol-binap CuF 2 complex; [43] TBDPS = tert-butyldiphenylsilyl. ured aldehyde (S)-77 predicts that approach to the Si face of the carbonyl group should be preferred, thus leading to the syn diastereomer. Additionally, the (S)-Tol-binap ligand has the same facial bias for attack at the Si face of the aldehyde, as shown above. When the (S)-Tol-binap CuF 2 catalyst system is used, syn/anti-78 is formed as the only lactone diastereomer, with the linear product reported to account for less than 10% of the crude reaction mixture. However, when the (R)-Tolbinap ligand is employed, an 88:12 mixture of lactones is formed, with a switch in diastereoselectivity now favoring the anti/anti lactone 78. Again, the amount of linear product formed is reported to be less than 10% of the crude reaction mixture. Although the selectivity in both the matched and the mismatched case is high, the yields of the isolated product are low for both addition reactions (60 and 55 %, respectively). A systematic study of the effect on the addition to aldehydes of various substitution patterns on the dienol ether further expanded the scope of the vinylogous aldol reaction of ester-derived dienol ethers (Scheme 28). [32] The SiCl 4 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. Furthermore, this catalyst system maintains the high level of anti diastereoselectivity (> 99:1) that is observed in the additions of propanoate-derived silyl ketene acetals. [44] With aromatic and olefinic aldehydes, catalyst loadings of 1 mol% are sufficient to provide vinylogous aldol adducts in high yields and selectivities with all four dienolates surveyed. However, aliphatic aldehydes require higher catalyst loadings and longer reaction times for acceptable yields to be attained in the additions of the unsubstituted crotonate-derived and b-substituted senecioate-derived dienol ethers. Dienol ethers with methyl groups in the g and a positions were found to be unreactive with aliphatic aldehydes. The aldol adducts are produced with excellent E selectivity regardless of the substitution on the dienol ether, including g substitution. This result stands in contrast to catalysis with Tol-binap CuF 2. Whereas the addition of the a-substituted methyl tiglate derived dienol ether occurs with exclusive E selectivity in the presence of this catalyst, the g-substituted methyl pentenoate derived dienol ether affords the aldol adduct with modest Z selectivity. Scheme 28. The vinylogous aldol reaction of various ester-derived dienolates catalyzed by SiCl 4 and bisphosphoramide (R,R)-52. [32] Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2005, 44,

14 Asymmetric Catalysis 5. Lactone-Derived Dienol Ethers 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- lactones through manipulation of the double bond. Butenolide 88 has also been used for the preparation of compounds containing 1,2-diol functionality, and for the construction of optically active pyrans. [12a] Table 2: Modification of the Ti(OiPr) 4 /binol-catalyzed vinylogous aldol reaction. [45] Entry Additive Yield [%] syn:anti e.r. (syn) 1 [a] none 99 70:30 85:15 2 5% (4S,5S) :30 > 98:2 3 5% (4R,5R) :30 70:30 4 [b] none 90 60:40 > 98:2 [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 Figad re and co-workers disclosed the first catalytic, mixture is essential for high and reproducible selectivities to enantioselective addition involving a lactone-derived dienolate in [45] The titanium-based chiral catalyst system developed by Sato et al. and improved upon by Scettri and coworkers 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] Angew. Chem. Int. Ed. 2005, 44, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4695

15 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 SiCl 4 promotes the addition of silyl dienol ethers derived from simple acyclic a,bunsaturated 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 and aliphatic aldehydes, both the syn and anti isomers are formed with good to excellent enantioselectivities. Whereas the two previously described catalyst systems afford only modest diastereoselectivities, the copper bisoxazoline catalyst (S,S)-45 developed by Evans and co-workers affords the anti product with high diastereo- and enantioselectivity from the vinylogous aldol reaction of 89 with (benzyloxy)acetaldehyde (44; Scheme 32). [28] However, the addition only to aldehyde 44 was demonstrated. Scheme 33. The vinylogous aldol reaction of acyclic-ketone-derived dienolate 99 catalyzed by SiCl 4 and bisphosphoramide (R,R)-52. [47] The reactivity of the cyclic-ketone-derived dienol ether 104 was examined to evaluate the diastereoselectivity in the addition to form g-substituted ketones (Scheme 34). [47] Aldol adducts formed from aromatic, olefinic, and heteroaromatic aldehydes could be obtained with exclusive g-site selectivity 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 Scheme 32. The vinylogous aldol reaction of lactone-derived dienolate 89 to aldehyde 44 in the presence of the Cu(ii)/pybox complex (S,S)-45. [28] 6. Ketone-Derived Dienol Ethers Although the catalytic, enantioselective, vinylogous aldol addition of dienol ethers derived from a,b-unsaturated esters has been successfully demonstrated, extension of the nucleophile scope to other acyclic a,b-unsaturated carbonyl compounds has remained virtually unexplored. The first use of Excellent progress has been made in the development of the catalytic, enantioselective, vinylogous aldol reaction since the initial report in Through the extension of existing catalyst systems and the invention of novel ones, several 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, recent studies with dienolates derived from esters have shown that crotonate-derived silyl dienol ethers, as well as dienolates with a and b substituents, react with a wide range of aldehydes with high selectivity (120). This method also allows for high selectivity in the addition of dienolates derived from g-substituted esters to aromatic and olefinic aldehydes to give compounds 123. Furthermore, high enan Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2005, 44,

16 Asymmetric Catalysis Scheme 34. The vinylogous aldol reaction of cyclic-ketone-derived dienolate 104 catalyzed by SiCl 4 and bisphosphoramide (R,R)-52. [47] 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 esterderived 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,bunsaturated 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 opportunities for future investigation. The presence of the vinylogous aldol motif in many 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 and NSF CHE ) for generous financial support. We also thank Dr. Martin Eastgate for performing the DFT calculations. Received: October 18, 2004 Published online: June 7, 2005 Figure 2. Vinylogous aldol adducts created from simple aldehydes and dienol derivatives derived from b-dicarbonyl compounds or a,b-unsaturated carbonyl compounds. tioselectivity can be attained in the vinylogous aldol addition of lactone-derived dienol ethers to different aldehyde structures, although a general method that affords high diastereoselectivity is still lacking (126). When one considers the wide range of structural motifs that can be created by employing the vinylogous aldol reaction, the limited number of dienol ethers thus far examined becomes apparent. Figure 2 provides an overview [1] For a recent review, see: J. Staunton, K. J. Weissman, Nat. Prod. Rep. 2001, 18, 380. [2] a) E. M. Carreira in Modern CarbonylChemistry, (Ed.: J. Otera), Wiley-VCH, Weinheim, 2000, chap. 8; b) E. M. Carreira in Comprehensive Asymmetric Catalysis, Vol. III (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Heidelberg, 1999, chap. 29; c) I. Paterson, C. J. Cowden, D. J. Wallace in Modern CarbonylChemistry (Ed.: I. Otera), Wiley-VCH, Weinheim, 2000, chap. 9; d) E. M. Carreira in Catalytic Asymmetric Synthesis, 2nd Ed. (Ed.: I. Ojima), Wiley-VCH, Weinheim, 2000, chap. 8B2; e) M. Braun in Stereoselective Synthesis, Methods of Organic Chemistry (Houben-Weyl), Vol. 3, Edition E21 (Eds.: G. Helmchen, R. Hoffman, J. Mulzer, E. Schaumann), Thieme, Stuttgart, 1996, p. 1603; f) S. G. Nelson, Tetrahedron: Asymmetry 1998, 9, 357; g) R. D. Norcross, I. Paterson, Chem. Rev. 1995, 95, 2041; h) T. Mukaiyama, S. Kobayashi, Org. React. 1994, 46, 1. [3] W. R. Roush, A. D. Palkowitz, K. Ando, J. Am. Chem. Soc. 1990, 112, Angew. Chem. Int. Ed. 2005, 44, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4697