Preparation of L-Nα-Fmoc-4-[di-(tert-butyl)-phosphonomethyl]phenylalanine from L-tyrosine

The unnatural amino acid analogue, 4-(phosphonomethyl)phenylalanine (Pmp, 2), has proven to be a valuable tool for studying protein-tyrosine kinase dependent signal transduction, where it is most often incorporated into peptides or peptide mimetics as a phosphatase-stable phosphotyrosyl mimetic. Although Pmp has been prepared previously bearing a number of protection strategies, the N-alpha-Fmoc 4- [di-(tert-butyl)phosphonomethyl] phenylalanine form [(N alpha-Fmoc-L-Pmp('Bu-2)-OH, 3] is particularly attractive since it can be cleanly introduced into peptides using standard Fmoc protocols. Synthesis of 3 was first reported as its (D/L)-racemate, and subsequently as its L-3 enantiomer, with the latter synthesis having relied on induction of chirality using a camphor sultam auxiliary. Reported herein is an alternate enantioselective synthesis of L-3 in high ensantiomeric purity by procedures which derive the stereochemistry of the final product directly from the starting amino acid, without the need for chiral induction. A key feature of the route is the racemization-free nucleophilic substitution of lithium di-tert-butyl phosphite onto protected 4-bromomethylphenylalanine (17). (C) 1999 Elsevier Science Ltd. All rights reserved.