Synthesis of Polypeptides with High-Fidelity Terminal Functionalities under NCA Monomer-Starved Conditions

Controlled polypeptide synthesis viaα-amino acid N-carboxylic anhydride(NCA)polymerization using conventional primary amine initiators encounters two major obstacles:(i)normal amine mechanism(NAM)and activated monomer mechanism(AMM)coexist due to amine basicity and nucleophilicity and(ii)NCA is notoriously sensitive towards moisture and heat and unstable upon storage.We serendipitously discover that N-phenoxycarbonyl-functionalizedα-amino acid(NPCA),a latent NCA precursor,could be polymerized solely based on NAM with high initiating efficiency by using primary amine hydrochloride as an initiator.The polymerization affords well-defined polypeptides with narrow polydispersity and highfidelity terminal functionalities,as revealed by the clean set of MALDI-TOF MS patterns.We further demonstrate successful syntheses of random and block copolypeptides,even under open-vessel conditions.Overall,the integration of moistureinsensitive and air-tolerant NPCA precursors with stable primary amine hydrochloride initiators represents a general strategy for controlled synthesis of high-fidelity polypeptides with sophisticated functions.