Synthesis and epimerization of phenylalanyl 4-aminocyclophosphamides

Abstract Peptide and amino acid conjugates of (4 R )- and (4 S )-4-aminocyclophosphamides (4-NH 2 -CPA, 3) were designed as prodrug forms of phosphoramide mustard. Four diastereomers of Boc-Phe-4-NH-CPA ( 6 ) were synthesized stereospecifically from homoserine ( R or S ) and the protection strategy was optimized for the homoserine hydroxyl group during the construction of the 1,3,2-oxazaphosphorinane ring. The Phe-4-NH-CPA isomers of the trans-configuration ((2 S ,4 R )- and (2 R ,4 S )-) were found to be less stable than the corresponding isomers of the cis-configuration ((2 R ,4 R )- and (2 S ,4 S )-) and to undergo epimerization of the C-4 chiral center in the presence of 25% TFA used during Boc deprotection. The synthetic route developed should be applicable to the synthesis of a variety of peptide and amino acid conjugates of 4-aminocyclophosphamide.