Proline-Catalyzed Direct Asymmetric Aldol Reactions

著者: Benjamin List, Richard A. Lerner, Carlos F. Barbas - Journal of the American Chemical Society 2000 被引用: 2,833

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.