Asymmetric Strecker Route toward the Synthesis of Biologically Active α,α-Disubstituted α-Amino Acids

A series of optically active α,α-disubstituted α-amino acids have been synthesized starting with an achiral or a racemic α-hydroxy or α-diazo ketone. In the present synthesis, the key transformation is an asymmetric version of the Strecker synthesis. An α-acyloxy ketone having a chiral amino acid as the acyloxy group afforded cyclic α-amino nitrile in a highly stereoselective manner; in this reaction 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 acyloxy group gave R enantiomer, and its S enantiomer was obtained when D-amino acid was employed. Some problematic processes that remained in the Strecker synthesis, i.e., preparation of the starting α-acyloxy ketone and oxidative conversion of α-amino nitr...