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.

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.

A General Strategy toward Synthesis of Well-Defined Polypeptides with Complex Chain Topologies

The precise synthesis of polypeptides with varying chain topologies has attracted significant interest due to their diverse functional applications.However,conventional polymerization of environment-susceptible N-carboxylic anhydride monomers using primary amine initiators suffers from inevitable side reactions,which greatly compromise chain-end fidelity,thereby disabling access to polypeptides with high-order architectures.Herein,we have developed a general and robust strategy based on normal aminemechanism for the synthesis of various topological polypeptides via polymerization of moisture-insensitive and airtolerant N-phenoxycarbonyl-functionalizedα-amino acid precursors using primary amine hydrochloride as initiators.This strategy enabled the synthesis of a block,star,star-block,brush-type,and multiblock(co)polypeptides with desired sequences,predictable molecular weights,low polydispersity,and high-fidelity chain ends even under open-air conditions.Remarkably,the robustness of this approach has been exemplified by the precise synthesis of welldefined photoresponsive decablock copolypeptides,exhibiting a spontaneous morphological evolution from polymersomes to lamellae nanostructures upon light irradiation.This work provides a general and reliable tool for synthesizing polypeptides with varying topologies,shedding light on the development of synthetic polypeptide-based materials.