Enantioselective Organocatalysis

324

144

The mechanism of the proline-catalyzed aldol reaction has stimulated considerable debate, and despite limited experimental data, at least five different mechanisms have been proposed. Complementary to recent theoretical studies we have initiated an experimental program with the goal of clarifying some of the basic mechanistic questions concerning the proline-catalyzed aldol reaction. Here we summarize our discoveries in this area and provide further evidence for the involvement of enamine intermediates. D iscovered in the early 1970s, the Hajos-Parrish-EderSauer-Wiechert reaction (1, 2), a proline-catalyzed intramolecular aldol reaction, represents not only the first asymmetric aldol reaction invented by chemists but also the first highly enantioselective organocatalytic transformation [1(4) 3 2(5) 3 3(6)] (Eq. 1 of Scheme 1) (3-6). Inspired by Nature's phenomenal enzymes, which catalyze direct asymmetric aldolizations of unmodified carbonyl compounds (7, 8), we have recently extended the Hajos-Parrish-Eder-Sauer-Wiechert reaction to the first intermolecular variant (7 ϩ 8 3 9) (Eq. 2 of Scheme 1) (9), and to several other reactions including prolinecatalyzed asymmetric Mannich (10), Michael (11), ␣-amination (12), and intramolecular enolexo aldolization reactions (10 3 11) (13) (Eq. 3 of Scheme 1) (14-18).Similar to the aldolase enzymes, proline catalyzes direct asymmetric aldol reactions between two different carbonyl compounds to provide aldol products in excellent yields and enantioselectivities. Early on it has been speculated that in addition to operating on related substrates, both class I aldolases and proline may also share a similar enamine mechanism (19,20). However, there has been some debate over several mechanistic aspects of the reaction, and a number of alternative models have been proposed. For example, Hajos (1) suggested a mechanism that involves the ''activation'' of one of the enantiotopic acceptor carbonyl groups as a carbinol amine (A of Scheme 1). At least the stereochemistry of this model was questioned by Jung (19) soon after its initial proposal. An enamine mechanism was suggested by various groups already in the 1970s and 1980s (19-21). Nonlinearity studies by Agami and colleagues (21) have led to the proposal of a side-chain enamine mechanism that involves two proline molecules in the C-C-bondforming transition state, one engaged in enamine formation and the other as a proton transfer mediator (B of Scheme 1). Swaminathan et al. (22) favor a heterogeneous aldolization mechanism on the surface of crystalline proline (C of Scheme 1), despite the fact that many proline-catalyzed aldolizations are completely homogenous. Agami's widely accepted twoproline mechanism was recently challenged when we proposed a homogenous one-proline enamine mechanism for the intermolecular variant in which the various proton transfers are mediated by proline's carboxylic acid functionality (9). On the basis of density functional theory calculations, subsequently proposed a very similar mechanism for the in...

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confidence: 99%

New mechanistic studies on the proline-catalyzed aldol reaction

List

Hoang

Martin

2004

324

144

“…Numerous Lewis acidic metalbased chiral catalysts have been shown to promote DielsAlder reactions with excellent enantioselectivities (4 -8). In addition to Lewis acid catalysis, two other catalytic methods have emerged for the promotion of enantioselective DielsAlder reactions, both using metal-free, ''organic'' catalysts (9,10). MacMillan and coworkers (11,12) demonstrated a broadly useful and strategically novel approach for the asymmetric catalysis of Diels-Alder reactions.…”

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confidence: 99%

Enantioselective Diels–Alder reactions catalyzed by hydrogen bonding

Thadani

Stankovic²,

Rawal³

2004

209

Like molecules of life (e.g., proteins and DNA), many pharmaceutical drugs are also asymmetric (chiral); they are not superimposable on their mirror images. One mirror image form (enantiomer) of a drug can have desirable activity, the other not. Consequently, the development of methods for the selective synthesis of one enantiomer is of great scientific and economic importance. We report here that a simple, commercially available chiral alcohol, ␣,␣,␣ ,␣ -tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL), catalyzes the all-carbon Diels-Alder reactions of aminosiloxydienes and substituted acroleins to afford the products in good yields and high enantioselectivities (up to 92% enantiomeric excess). It is remarkable that the reactions are promoted by hydrogen bonding, the ubiquitous ''glue'' that helps to keep water molecules together and holds up the 3D structures of proteins. Hydrogen bond catalysis is little used in chemical synthesis, wherein most reactions are promoted by complexes of Lewis acidic metal salts coordinated to chiral ligands. As it does for enzymes, hydrogen bonding not only organizes TADDOL into a well defined conformation, but, functioning as a Brønsted acid catalyst, it also activates the dienophile toward reaction with the diene. The gross structure of the TADDOL has been found to have a profound influence on both the rate and the enantioselectivity of the cycloadditions. These structure-function effects are rationalized by evaluating the conformation adopted by the TADDOLs in the crystal state. It is suggested that , -stacking plays an central role in the overall catalytic cycle, in particular, the enantioselective step.M ost biomolecules are asymmetric (chiral), that is, they are not superimposable on their mirror image. Likewise, small molecules that might be used to modulate the response of the biomolecule are also frequently chiral. One mirrorimage form (enantiomer) of the small molecule may elicit a desirable response, such as stimulation or inhibition of a particular function, whereas the other image might produce no response or a completely different response. It is, in part, for this reason that a tremendous effort has been put into the development of methods for the selective synthesis of one enantiomer. In 2002, single enantiomer drugs comprised 37% ($152 billion) of the total market of Ϸ$400 billion. This number is projected to increase steadily, such that chiral drugs will constitute a market of Ͼ$200 billion by 2008. The growing economic importance of chiral compounds has spurred major research efforts from many laboratories, academic and industrial, directed at the selective preparation of chiral compounds. In this report, we describe our results on the hydrogenbonding-mediated catalysis of the all-carbon Diels-Alder reaction.The premier process for forming functionalized cyclohexenes, with up to four new stereogenic centers (1), the Diels-Alder reaction plays a pivotal strategic role in the synthesis of numerous complex natural products (2). The steady evolution of this reaction...

“…Moreover, as only a few metals other than palladium have been used in catalytic asymmetric reactions to form all-carbon stereocenters, the reactivity of many additional metals remains to be exploited. Also certain to play a role in future developments in this area are organocatalytic reactions in which catalytically generated chiral nonracemic iminium ion and enamine intermediates are used to construct stereogenic quaternary carbons (38,64).…”

Section: Discussionmentioning

confidence: 99%

Catalytic asymmetric synthesis of all-carbon quaternary stereocenters

Douglas

Overman

2004

798

177

Only a few catalytic asymmetric COC bond-forming reactions have been shown to be useful for constructing all-carbon quaternary stereocenters. This Perspective examines the current state of such methods.C arbon atoms bonded to four carbon substituents (all-carbon quaternary centers) pose a particular challenge for synthesis because creation of such centers is complicated by steric repulsion between the carbon substituents. When the four substituents differ, quaternary stereocenters become a singular challenge for achieving efficient asymmetric syntheses of chiral organic molecules (1-4). The invention of catalytic methods for asymmetric synthesis is one of the foremost recent achievements of chemistry (5), with the 2001 Nobel Prize in Chemistry recognizing William S. Knowles, Ryoji Noyori, and K. Barry Sharpless for their pioneering development of catalytic asymmetric hydrogenation and oxidation reactions. At present, many broadly useful methods for catalytic asymmetric oxidation and reduction exist; however, far fewer catalytic asymmetric methods for forming COC bonds have been invented to date (5). As disclosures in this special feature will attest, this latter area of catalytic asymmetric synthesis is a current focus of intense investigation worldwide.At present only a few catalytic asymmetric COC bond-forming reactions have been shown to be useful for constructing quaternary carbons, undoubtedly reflecting the additional steric challenge involved in forming all-carbon quaternary centers. This Perspective will examine the current state of such methods. The focus will be on reactions for which some generality has been documented, and several examples exist of reactions that proceed with enantiomeric selectivities of at least 9:1 [enantiomeric excesses (ees) Ͼ80%]. The discussion is organized by general reaction types that have proven useful, not by the more commonly used organizations that focus on one specific transformation or one family of asymmetric catalysts. It is hoped that this organization will highlight the many opportunities that exist for future discoveries in this area. The less general approach for forming allcarbon quaternary stereocenters in which a group-selective catalytic asymmetric reaction is used to desymmetrize a prochiral intermediate containing a quaternary carbon will be briefly mentioned also. No attempt to summarize this latter field will be made, as any catalytic asymmetric reaction could in principle be used in this approach. In four areas, catalytic methods for directly forming all-carbon stereocenters are most developed: Diels-Alder reactions, the combination of chiral carbon nucleophiles with carbon electrophiles, reactions of allylmetal intermediates with carbon nucleophiles, and intramolecular Heck reactions. Our discussion will begin with these reaction types. Asymmetric Diels-Alder ReactionsThe Diels-Alder reaction provides two approaches for forming quaternary stereocenters contained within the cyclohexene framework (Scheme 1). In reactions of type I, electron-rich dienes c...