Amino Acid Catalyzed Direct Asymmetric Mannich Type Reactions Employing Unmodified Donors: Structure Based Catalyst Screening for Anti/syn Selectivity

Abstract

Amino acid catalyzed direct Mannich-type additions to   N-Tos protected α-imino ethyl glyoxylate employing unmodified   carbonyl donors is described. The reaction was performed   in DMSO using a catalytic amount (30 mol %) of L-proline   and its derivatives providing a facile route to functionalized   β-keto substituted α-amino acid derivatives with excellent   diastereo- and enantioselectivities. Unmodified 3-pentanone   and cyclohexanone were used as donors for the one pot generation   of two quaternary stereocenter. Organocatalysis using   L-proline and 5,5-dimethyl thiazolidinium-4-carboxylate   were typically syn-diastereoselective. Anti-diastereoselectivity   was achieved using (S)-2-methoxymethyl-pyrrolidine and   L-proline benzyl ester. Stereochemical outcomes are explained   on the basis of previously proposed transition state and the   reasons governing syn- and anti-selectivity are described. Poor   selectivity of (S)-2-methoxy-methylpyrrolidine compared to   L-proline benzyl ester in contrast to earlier reports are explained   in terms of a fast cis-trans event and possible sterics.