Diastereoselective synthesis of alpha,beta'-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, NH 2XaaPsi[P(O)OHCH 2]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 alpha-aminoalkyl- H-phosphinates to acrylates and subsequent diastereoselective alkylation at the beta'-position of the resulting Michael adducts.