Concise and Enantioselective Synthesis of Fmoc-Pmp(Bu^t)₂-OH and Design of Potent Pmp-Containing Grb2-SH2 Domain Antagonists

l-Phosphonomethylphenylalanine (l-Pmp) is an important phosphatase-resistant pTyr analogue. A most concise and stereoselective approach to the synthesis of the suitably protected Fmoc-Pmp(Bu^t)₂-OH was developed in order to incorporate the functionally significant l-Pmp residue into peptides and peptidomimetics efficiently using standard Fmoc protocol. With this key building block, we are able to efficiently synthesize a series of potent Pmp-containing Grb2-SH2 domain antagonists, which can be used as chemotherapeutic leads for the treatment of erbB2-overexpressed breast cancer.