Diastereoselective Synthesis of α,β′-Disubstituted Aminomethyl(2-carboxyethyl)phosphinates as Phosphinyl Dipeptide Isosteres

A new and efficient method has been developed for the diastereoselective synthesis of unnatural dipeptide analogues containing the metabolically stable phosphinic moiety, NH2XaaΨ[P(O)OHCH2]XaaOH, which mimics the transition state of tetrahedral geometry of a scissile peptide bond in hydrolysis by protease. The method is based upon stereospecific Michael addition of stereodefined α-aminoalkyl-H-phosphinates to acrylates and subsequent diastereoselective alkylation at the β′-position of the resulting Michael adducts.