Isopropenyl chlorocarbonate (IPCC)1 in amino acid and peptide chemistry: Esterification of N-protected amino acids; Application to the synthesis of the depsipeptide valinomycin

Abstract

Esterification of N-protected α-amino acids was achieved via isopropenyl chlorocarbonate (IPCC) activation. In situ alcoholysis of the unstable mixed anhydride intermediate was catalyzed by 4-(dimethylamino)pyridine (DMAP). Competing isopropenyl ester formation was negligible when using methylene chloride as the solvent. A variety of esters from primary and secondary alcohols were obtained with good yields (60 to 96 %), and even the more hindered tertiobutyl alcohol gave acceptable yields under more drastic conditions. The improvement in depsipeptide synthetic methodology is illustrated by preparation of the antibiotic valinomycin, using IPCC for ester bond formation, and BOP reagent for peptidic coupling and the last-step cyclization.