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

A convenient enantioselective synthesis of p-hydroxymethyl-L-phenylala nine was developed which produces a 4/1 ratio of L/D enantiomers resul ting from a chiral phase-transfer-catalyzed alkylation. This amino aci d was coupled into the p56(lck) tyrosine kinase substrate Ac-Leu-Pro-T yr-Ala-NHCH3 as a replacement for Tyr and can subsequently be elaborat ed into a variety of potential tyrosine kinase inhibitor designs of ge neral structure Ac-Leu-Pro-AA-Ala-NHCH3, wherein AA is an unnatural am ino acid. The contaminating D enantiomer was readily removed after cou pling to L-Ala-NHCH3 of this sequence. The utility of the p-hydroxymet hyl 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-p henylalanine. (C) Munksgaard 1994.