Isopropyl chloroformate as a superior reagent for mixed anhydride generation and couplings in peptide synthesis

Abstract

Mixed anhydrides of N‐tert. ‐butoxycarbonyl‐, N ‐benzyloxycarbonyl‐ and N ‐9‐fluorenylmethoxycarbonylamino acids were prepared using isopropyl chloroformate, and purified by edulcoration. They were more stable than the corresponding anhydrides obtained using ethyl and isobutyl chloroformates. Aminolysis of the anhydrides by an amino acid ester proceeded efficiently, the amount of urethane generated by reaction at the carbonate moiety being the same as that generated from the other anhydrides. Racemization attending the coupling of N ‐benzyloxycarbonylglycylamino acids by the mixed anhydride method using isopropyl chloroformate was one third to one quarter of that observed for the same couplings using ethyl and isobutyl chloroformate.