Tetrapeptide tyrosine kinase inhibitors. Enantioselective synthesis of p-hydroxymethyl-L-phenylalanine, incorporation into a tetrapeptide, and subsequent elaboration into p-(R,S-hydroxyphosphonomethyl)-L-phenylalanine.

Abstract

A convenient enantioselective synthesis of p-hydroxymethyl-L-phenylalanine was developed which produces a 4/1 ratio of L/D enantiomers resulting from a chiral phase-transfer-catalyzed alkylation. This amino acid was coupled into the p56(1)ck tyrosine kinase substrate Ac-Leu-Pro-Tyr-Ala-NHCH3 as a replacement for Tyr and can subsequently be elaborated into a variety of potential tyrosine kinase inhibitor designs of general structure Ac-Leu-Pro-AA-Ala-NHCH3, wherein AA is an unnatural amino acid. The contaminating D enantiomer was readily removed after coupling to L-Ala-NHCH3 of this sequence. The utility of the p-hydroxymethyl functionality in an efficient divergent synthetic strategy leading to various inhibitor designs is illustrated with the synthesis of Ac-Leu-Pro-AA-Ala-NHCH3, wherein AA is p-(R,S-hydroxyphosphonomethyl)-L-phenylalanine.