Proline-Catalyzed Direct Asymmetric Aldol Reactions

Abstract

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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Highly Enantioselective Cross‐Aldol Reactions of Acetaldehyde Mediated by a Dual Catalytic System Operating under Site Isolation

“…[2] Therefore, important developments have been achieved since the first report on the direct asymmetric intermolecular aldol reaction catalyzed by proline in 2000. [3] The use of acetaldehyde (the simplest enolizable aldehyde), however, has been a great challenge due to its high reactivity and its inherent tendency to oligomerize. [4] In 2008, Hayashi and co-workers reported the first asymmetric aldol reaction of acetaldehyde with good yields and excellent enantioselectivities by using diaryprolinol as the catalyst.…”

“…Taking the cross-aldol reaction of p-nitrobenzaldehyde as an example, we show in Scheme 4 how crude 3 e can be directly converted to amino alcohol 5 e by reductive amination with MeNH 2 in good overall yield (71 %) and excellent ee (99 %). In a further application, the phenoperidine [21] analogue 6 has been prepared (68 % overall yield, 98 % ee) by reductive amination of crude 3 e with ethyl 4-phenylpiperidine-4-carboxylate and NaBH(OAc) 3 . Polymer-supported 1 b, which could act as a competitive aminating reagent, is conveniently removed by filtration (together with 2) before the reductive amination step.…”