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

Abstract

Abstract 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 nitrile into α-imino nitrile, are much improved as regards efficiency by the development of a Cu-catalyzed insertion of α-diazo ketone into N-protected α-amino acid, and as regards yields by the use of ozone as the oxidant. With these methods, various types of α,α-disubstituted α-amino acids have been synthesized including cyclic analogs, which can be viewed as a conformational variant of serine. Their incorporations into Leu-enkephalin have revealed that these amino acids play an important role not only to constrain the peptide conformation but also for high affinity bindings to the opioid receptors. Applications to the synthesis of biologically active natural products have been exemplified by the syntheses of the Corey intermediate of lactacystin and of marine natural products, manzacidin A and C.