α-氨基酸-N-硫代羧酸酐可控聚合的催化剂与机理研究

Poly(ɑ-amino acid)s are polymerized by N-carboxyanhydrides (NCAs) which are difficult to prepare and store due to the instability and the use of phosgene. In the previous studies, we have discovered that the ring-opening polymerization of ɑ-amino acid-N-thiocarboxyanhydride (NTA) can synthesize poly(ɑ-amino acid) without using phosgene or its derivatives. With high stability, NTA can be prepared and purified under ambient environment, which is superior to NCA. However, the low activities of NTAs set obstacles to polymerization and the mechanism is not known. The key is to find suitable catalysts to increase their reactivities. The project aims to develop highly active and controllable rare-earth catalysts and organic catalysts for the polymerization of various amino acid-NTAs to prepare poly(ɑ-amino acid)s with precise structures, high molecular weights and narrow molecular weight distributions. With density functional theory calculations and experimental characterizations, the reaction mechanism of NTA polymerization is to be revealed and compared with that of NCA. Systematic approaches to quantitatively attach reactive groups and bio-active molecules onto both ends of poly(amino acid) chains are also to be introduced. NTA polymerization route develops a new way to synthesize poly(amino acid)s safely and easily after solving the problems of low activity of NTA monomers and the bad controllability of their polymerizations.

聚-α-氨基酸的N-羧酸酐(NCA)合成路线存在单体制备繁琐又难以提纯保存等缺点。申请人前期研究发现α-氨基酸-N-硫代羧酸酐(NTA)开环聚合是合成聚-α-氨基酸的新途径，无需使用光气或其衍生物。NTA稳定性好，制备和提纯均无需除水除氧操作，显著优于NCA合成路线。但是NTA单体聚合活性低、副反应多、聚合机理不明。本项目针对这些问题，探索高活性且高可控性的稀土催化剂和有机催化剂，催化各种氨基酸-NTA可控开环聚合，合成具有明确结构、高分子量和窄分子量分布的聚氨基酸。结合实验表征和密度泛函理论(DFT)计算，揭示NTA聚合反应机理，与NCA聚合对比异同。运用催化剂结构设计和聚合后官能化方法，实现聚氨基酸两端定量键接反应性官能团和生物活性分子。本项目研究成果将解决NTA单体活性低和聚合控制性差的难题，为聚氨基酸的功能研究奠定基础。

本项目开拓了新的聚氨基酸合成方法学，系统研究了alpha-氨基酸-N-硫代羧酸酐(NTA)单体的合成方法与可控聚合，结合实验表征与密度泛函理论(DFT)揭示了新的单体合成与聚合反应的机理，证明了NTA单体聚合对水、引发剂中的羟基和巯基、氨基酸单体侧基中的羟基和羧基等亲核试剂的高耐受性，提出了无需保护亲核功能基团的NTA可控聚合方法，实现了在含水达1.4%的溶剂和高极性有机溶剂中NTA单体的可控聚合，合成了带有羟基和羧基侧基的聚氨基酸，合成了alpha,omiga-不对称双功能端基的聚氨基酸。由NTA聚合合成的聚氨基酸产物种类丰富、结构明确、分子量可控、分子量分布窄、性质独特，可作为新一代生物医学材料获得广泛研究和应用。本项目超计划完成了研究任务，在Prog Polym Sci、Macromolecules、高分子学报中英文版等国内外著名期刊发表SCI收录论文共计24篇，获得4项中国发明专利授权，申请国际专利1项，远超10篇论文和2篇专利的预期目标。项目负责人参加5次国际学术会议，完成了2次邀请报告和3次口头报告。培养毕业博士和硕士共6名，其中1人获得浙江省优秀硕士论文奖，2名博士在读期间分赴法国和德国合作交流2年和半年。