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

Abstract

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 amine mechanism for the synthesis of various topological polypeptides via polymerization of moisture-insensitive and air-tolerant N-phenoxycarbonyl-functionalized α-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 well-defined 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.