title: 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.
authors.affiliation: Departments of Chemistry and Cancer Biology, The Scripps Research Institute , Scripps Florida, 130 Scripps Way, #3A2, Jupiter, Florida 33458, United States.
authors.forename: Bani Kanta
authors.initials: BK
authors.lastname: Sarma
authors.forename: Thomas
authors.initials: T
authors.lastname: Kodadek
mesh_terms: D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D015394:Molecular Structure; D034444:Peptoids / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D001372:Aza Compounds; D034444:Peptoids