Asymmetric Synthesis of α, α-Disubstituted α-Amino Acids via an Intramolecular Strecker Synthesis

Abstract

A series of optically active α, α-disubstituted α-amino acids have been synthesized starting with an achiral or a racemic 2-hydroxy ketone. The key transformation to the present synthesis is an intramolecular version of Strecker synthesis. An α-keto ester having a chiral amino acid as the ester group afforded cyclic amino nitrile, in a highly stereoselective manner, in which the amino group and the chirality were diastereoselectively transplanted into the internal ketone group via an imine-enamine equilibrium of the cyclic ketimine intermediate. Oxidation of the amino group followed by removal of the resulting imino group and hydrolysis of the nitrile group afforded α-hydroxymethyl α-amino acid. The use of L-amino acid as the chirality transferring group gave R enantiomer, and its S enantiomer was obtained when D-amino acid was employed. The syntheses of optically active α-substituted serines, α-methylthreonines, and 1-amino-2-hydroxycycloalkanecarboxylic acids are described.