We report practical methodology for the catalytic, asymmetric synthesis of beta-lactams resulting from the development of a catalyzed reaction of ketenes (or their derived zwitterionic enolates) and imines. The products of these asymmetric reactions can serve as precursors to a number of enzyme inhibitors and drug candidates as well as valuable synthetic intermediates. We present a detailed study of the mechanism of the beta-lactam forming reaction with proton sponge as the stoichiometric base, including kinetics and isotopic labeling studies. Stereochemical models based on molecular mechanics (MM) calculations are also presented to account for the observed stereoregular sense of induction in our reactions and to provide a guidepost for the design of other catalyst systems.

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We report a mechanistically based study of bifunctional catalyst systems in which chiral nucleophiles work in conjunction with Lewis acids to produce beta-lactams in high chemical yield, diastereoselectivity, and enantioselectivity. Chiral cinchona alkaloid derivatives work best when paired with Lewis acids based on Al(III), Zn(II), Sc(III), and, most notably, In(III). Homogeneous bifunctional catalysts, in which the catalyst contains both Lewis acidic and Lewis basic sites, were also studied in detail. Mechanistic evidence allows us to conclude that the chiral nucleophiles form zwitterionic enolates that react with metal-coordinated imines. Alternative scenarios, which postulated metal-bound enolates, were disfavored on the basis of our observations.

The central importance of halogenation reactions, in which organic molecules are formally oxidized, is a widely accepted fact in synthetic organic chemistry. Halocarbon products are useful chemical intermediates, serving as branch points in the synthesis of numerous functionalized molecules. 1 Within this context, R-halogenations of carbonyl compounds have played a particularly notable role. 2 For over 100 years, the most commonly used halogenation reagents for this purpose have been diatomic halides, which are known to be highly reactive and in some cases very nonselective. For this reason R-halogenation reactions are not often deliberately catalyzed, and the chemical control and selectivity derived from a finely tuned catalytic process is not brought to bear. Similarly, the full utility of chiral, optically active R-carbonyl halides 3 could be extended by suitable catalytic, asymmetric halogenation reactions. 4 The products would serve as useful precursors for optically active amines, ethers, and sulfides. We report herein a tandem asymmetric halogenation/ esterification process of inexpensive acyl halides that successfully addresses the twin problems of catalysis and enantioselectivity to yield highly optically enriched R-haloesters as versatile products (eq 1).

[reaction: see text]. We describe a superior procedure for the catalytic, asymmetric synthesis of beta-lactams using a bifunctional catalyst system consisting of a chiral nucleophile and an achiral Lewis acid.