An efficient synthesis of N-phosphinoylmethylamino acids and some of their derivatives

N-Phosphinoylmethylamino acid derivatives 11-18 are obtained in high yield on N-bromomethylation of hexafluoroacetone protected amino acids 1-5 and subsequent Michaelis-Arbusov reaction. The carboxy activated species 11-18 react with a wide range of nucleophiles to give the unprotected N-phosphinoylmethylamino acids 19-22, amides 23-25, peptides 26-28, azapeptide 29 and the hydroxamic acid 30, respectively. The reaction sequence is suitable for generating libraries of N-phosphinoylmethylamino acid derivatives, which represent phosphonoamidate isosteres.