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‐phenylalaninc 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 p561ck 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 enan‐tiomer 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.