Synthesis of N-Fmoc 3-(4-(di-(tert-butyl)phosphonomethyl)phenyl)pipecolic acid as a conformationally constrained phosphotyrosyl mimetic suitably protected for peptide synthesis

Phosphonomethylphenylalanine (Pmp, ) has shown wide utility as a hydrolytically stable phosphtyrosyl (pTyr, ) mimetic, particularly in Src homology 2 (SH2) domain-binding peptides. (2S,3R)-3-(4-(phosphonomethyl)phenyl)pipecolic acid () represents a variant of Pmp having φ and χ1 torsion angles constrained through incorporation into the piperidinyl ring structure contained within pipecolic acid. Reported herein is the enantioselective preparation of , in an orthogonally protected form () suitable for use in peptide synthesis. Stereochemistries at both the 2- and 3-positions are derived inductively from a single chiral center provided by the commercially available Evans chiral auxiliary, (4S)-4-benzyl-1,3-oxazolidin-2-one. Incorporation of into a Grb2 SH2 domain-directed tripeptide () showed that Grb2 SH2 domain-binding affinity was reduced relative to the parent Pmp-containing tripeptide (). Although conformational constraint did not enhance affinity in this case, novel amino acid analogue may serve as a useful tool for the induction of defined phosphotyrosyl geometry in peptides directed at other signal transduction targets.