Most enzymatic transformations have a synthetic counterpart. Often though, the mechanisms by which natural and synthetic catalysts operate differ markedly. The catalytic asymmetric aldol reaction as a fundamental C-C bond forming reaction in chemistry and biology is an interesting case in this respect. Chemically, this reaction is dominated by approaches that utilize preformed enolate equivalents in combination with a chiral catalyst. 1 Typically, a metal is involved in the reaction mechanism. 1d Most enzymes, however, use a fundamentally different strategy and catalyze the direct aldolization of two unmodified carbonyl compounds. Class I aldolases utilize an enamine based mechanism, 2 while Class II aldolases mediate this process by using a zinc cofactor. 3 The development of aldolase antibodies that use an enamine mechanism and accept hydrophobic organic substrates has demonstrated the potential inherent in amine-catalyzed asymmetric aldol reactions. 4 Recently, the first small-molecule asymmetric class II aldolase mimics have been described in the form of zinc, lanthanum, and barium complexes. 5,6 However, amine-based asymmetric class I aldolase mimics have not been described in the literature. 7 Here we report our finding that the amino acid proline is an effective asymmetric catalyst for the direct aldol reaction between unmodified acetone and a variety of aldehydes.Recently we developed broad scope aldolase antibodies that show very high enantioselectivities, have enzymatic rate accelerations, and use the enamine mechanism of class I aldolases. 4 During the course of these studies, we found that one of our aldolase catalytic antibodies (Aldolase Antibody 38C2, Aldrich) is an efficient catalyst for enantiogroup-differentiating aldol cyclodehydrations of 2,6-heptanediones to give cyclohexenones, including the Wieland-Miescher ketone. 8,9 These intramolecular reactions are also catalyzed by proline (Hajos-Eder-Sauer-Wiechert reaction) 10 and it has been postulated that they proceed via an enamine mechanism. 11 However, the proline-catalyzed direct intermolecular asymmetric aldol reaction has not been described. Further, there are no asymmetric small-molecule aldol catalysts that use an enamine mechanism. 7 Based on our own results and Shibasaki's work on lanthanum-based small-molecule aldol catalysts, 4,6 we realized the great potential of catalysts for the direct asymmetric aldol reaction.We initially studied the reaction of acetone with 4-nitrobenzaldehyde. Reacting proline (30 mol %) in DMSO/acetone (4:1) with 4-nitrobenzaldehyde at room temperature for 4 h furnished aldol product (R)-1 in 68% yield and 76% ee (eq 1). This result is quite remarkable since it is known that proline can undergo a variety of reactions with aldehydes. For example, aliphatic aldehydes react with proline to give either the oxazolidinone and/ or various other compounds, including products of self-aldolization. 12 Aromatic aldehydes (including 4-nitrobenzaldehyde) can condense with proline to form azomethine ylides that undergo ...

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Quantum mechanical calculations were employed to predict the ratio of four stereoisomeric products expected from two complex reactions involving the aldol reactions of cyclohexanone with benzaldehyde or with isobutyraldehyde catalyzed by (S)-proline. Experimental tests of these predictions provide an assessment of the state-of-the-art in quantum mechanical prediction of products of complex organic reactions in solution.

Recently, the use of enantiomerically pure counteranions for the induction of asymmetry in reactions proceeding through cationic intermediates has emerged as an exciting new concept, which has been termed asymmetric counteranion-directed catalysis (ACDC). Despite its success, the concept has not been fully defined and systematically discussed to date. This Review closes this gap by providing a clear definition of ACDC and by examining both clear cases as well as more ambiguous examples to illustrate the differences and overlaps with other catalysis concepts.