Self-promoted Controlled Ring-opening Polymerization via Side Chain-mediated Proton Transfer for the Synthesis of Tertiary Amine-pendant Polypeptoids
Mingzhen Liao1, Yao Yao3, Kunyu Gan1, Xianghua Su3, Ning Zhao3,4, Ronald N. Zuckermann5, Sunting Xuan1（宣孙婷）*, Zhengbiao Zhang1,2（张正彪）*
1State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, Jiangsu Key Laboratory of Advanced Functional Polymer Materials, Suzhou Key Laboratory of Macromolecular Design and Precision Synthesis, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou215123, China
2State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
3Suzhou Gene Pharma Co., Ltd. Suzhou 215123, China
4College of Pharmaceutical Sciences, Soochow University, Suzhou,215123, China.
5The Molecular Foundry, Lawrence Berkeley National Laboratory, 1Cyclotron Road, Berkeley, California 94720, United States
Angew. Chem. Int. Ed. 2025, 64, e202417990
Abstract: Proton transfer is essential in virtually all biochemical processes, with enzymes facilitating this transfer by optimizing the proximity and orientation of reactants through site-specific hydrogen bonds. Proton transfer is also crucial in the rate-determining step for the ring-opening polymerization of N-carboxyanhydrides (NCAs), widely used to prepare various peptidomimetic materials. This study utilizes side chain-assisted strategy to accelerate the rate of chain propagation by using NCAs with tertiary amine pendants. This moiety enables hydrogen bond formation between the incoming NCA and the polymer amino growing end. The tertiary amine side chain of the NCA forms a proton shuttle, via a less constrained transition state, to facilitate the proton transfer process. Moreover, the tertiary amine side chains enable the precipitation of NCA monomers through in situ protonation during the monomer synthesis. This greatly facilitates the synthesis of these unreported monomers, allowing the direct controlled synthesis of tertiary amine-pendant polypeptoids. This side chain-promoted polymerization has rarely been reported. Additionally, the tertiary amine side chains, as widely used functional groups, endow the polymers with unique properties including pH- and thermo-responsiveness, tunable pKas, and siRNA transfection capability. The self-promoted synthesis, facile monomer preparation, and attractive properties make tertiary amine-pendant polypeptoids promising materials for various applications.
Article information: //doi.org/10.1002/anie.202417990
