Submonomer Synthesis of A Hybrid Peptoid–Azapeptoid Library

Abstract

We recently reported efficient conditions for the synthesis of N-azapeptoid libraries via the typical submonomer strategy of peptoid synthesis but that substitutes N-acyl hydrazides for primary amines as submonomers. Unfortunately, this approach is not applicable to the synthesis of mixed azapeptoid-peptoid libraries. When an oligomer containing an N-terminal side chain derived from an acyl hydrazide is bromoacetylated and treated with a primary amine, a chain-terminating intramolecular ring-closure to form an oxadiazinone competes with the desired displacement of the bromide by the amine. Here we overcome this limitation and demonstrate that a hybrid peptoid-azapeptoid library derived from primary amines, acyl hydrazides, carbazates, and semicarbazides can be made efficiently using standard peptoid submonomer chemistry. We find that the unwanted, chain-terminating cyclization reaction is competitive with chain extension only when aryl acyl hydrazides are present. Alkyl or heteroaromatic acyl hydrazides do not cyclize under the conditions used for peptoid-azapeptoid synthesis. We also find that carbazates and semicarbazides work well for chain extension. Using primary amines, acyl hydrazides, carbazates, and semicarbazides as submonomers, a high-quality one bead one compound library of tetramers suitable for screening against protein targets was made by split and pool synthesis.