Efficient Synthesis of N‑Methyl Polypeptides by Organic Acid Promoted Controlled Ring-Opening Polymerization of N‑Methyl-α-Amino Acids N‑Carboxyanhydrides

• Published in: Macromolecules 2023-11, Vol.56 (21), p.8899-8911
• Main Authors: Yu, Xinyan, Wang, Yong, Dong, Yutong, Zhao, Ning, Zhang, Lifeng, Xuan, Sunting, Zhang, Zhengbiao
• Format: Article
• Language: English
• ISSN: 0024-9297; 1520-5835
• DOI: 10.1021/acs.macromol.3c01102

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 N-methyl 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.