Efficient Synthesis of N‑Methyl Polypeptides by Organic Acid Promoted Controlled Ring-Opening Polymerization of N‑Methyl-α- Amino Acids N-Carboxyanhydrides
Xinyan Yu1, Yong Wang1, Yutong Dong1, Ning Zhao2,3, Lifeng Zhang2,4, Sunting Xuan,1*（宣孙婷） Zhengbiao Zhang1,5*（张正彪）
1State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, Suzhou Key Laboratory of Macromolecular Design and Precision Synthesis, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China
2Suzhou Gene Pharma Co., Ltd., Suzhou 215123, China; College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
3College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
4Suzhou Dushu Lake Hospital, Suzhou 215123, China
5State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
Macromolecules 2023, 56, 8899−8911
Abstract: N-Methyl peptides, which are widely found in nature, have emerged as an intriguing material in both polymer science and the biomedical field. The inefficient synthesis of Nmethyl peptides, however, has greatly impeded the progress toward their structure−property investigation and applications. Here, we report an efficient, moisture-tolerant, primary amine-initiated, and acetic acid-catalyzed ring-opening polymerization of enantiomerically pure N-methyl-α-amino acids N-carboxyanhydrides, yielding well-defined, stereoregular, and structurally diverse N-methyl polypeptides. The concentration of the acetic acid, polarity of solvents, and stiffness of polymer chains were found to be crucial to the rate of the polymerization. The acetic acid was proposed to activate the monomer through hydrogen bonding interaction, promote the release of CO2, and form an acid−base equilibrium with the secondary amine chain end. The obtained N-methyl polypeptides exhibited stable helix structures, revealing chain stiffness, consistent with the high glass transition temperatures (>250 °C) from DSC measurements. Moreover, preliminary studies indicated that N-methyl polypeptides are nontoxic both in vitro and in vivo and are enzymatically stable toward trypsin treatment. Together, this study provides a mild and efficient method for the preparation of N-methyl polypeptides, opening avenues for their further structure−property investigation and potential applications.
链接：https://pubs.acs.org/doi/10.1021/acs.macromol.3c01102