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Catalytic, Enantioselective, Vinylogous Aldol Reactions** Scott E

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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 diaster- eoselectivity 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
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