Synthesis of azapeptides by the Fmoc/tert-butyl/polyamide technique

Abstract

A new synthesis of azapeptides for use in the study of a proteolytic enzyme associated with Alzheimer's disease is described. The method utilizes fluoren-9-ylmethoxycarbonyl (Fmoc) amino acid carbazates and hydrazides in the Fmoc/tert-butyl/polyamide technique. The preparation of these compounds is presented. Reaction of Fmoc-amino acid hydrazides with an appropriate aldehyde, followed by reduction, gave fully protected amino acid carbazate dipeptide synthon. These derivatives were used to prepare aza amino acid peptide analogues by reaction with a resin-bound amino group, activated with bis-2,4-dinitrophenyl carbonate in the presence of a base. With this activation of the amino group, hydantoin is formed in a major side-reaction, but the cyclisation could be virtually eliminated by omission of the base from the activation procedure. Upon final trifluoroacetic acid-mediated cleavage of the azapeptide, trifluoroacetylation of the N-terminal serine residue was observed.