DMC法合成α-氨基酸-N-羧酸酐及其定向酰基化和靶向关环催化机制研究

α-amino acids-N-carboxy anhydrides (NCAS) ring opening polymerization is one of the most effective and convenient method for the synthesis of polypeptide. The development NCAs synthesis from DMC is an important way to realize the green preparation of polypeptide and amino acid based chemicals. For the synthesis of NCAs from DMC, amino acids have the low carboxymethylation selectivity and efficiency, and the decarboxylation is the main factor to prevent NCAs synthesis from carboxymethylation intermediates. Herein, the metal ions and phosphorus aluminum based hybrid catalyst were prepared which can capture proton, award proton, catalyze selective carboxymethylation and promote precise cyclization. The modes of substrate adsorption, activation and transformation over catalysts were characterized by in situ FT-IR, in situ NMR and XRS, and TG-GC-MS, Py-GC-MS and in situ FT-IR were used to investigate the correlation between the proton award process and decarboxylation reaction during intermediate cyclization. According to the characterized results, the catalytic cyclization mechanism was studied. The influence of catalyst, solvent molecules, and substrates and activation temperature on carbonyl activation modes was studied to explore the catalytic mechanism of directional carboxymethylation and targeting cyclization. In addition, CO2 was used to inhibit the decarboxylation and alkylation during NCAs forming process, which promoted the synthesis of NCAs from DMC in one pot by the low cost and green method.

α-氨基酸-N-羧酸酐（NCAs）开环聚合是合成多肽的一种最有效和最简便的方法，开发碳酸二甲酯（DMC）法合成NCAs是实现绿色制备多肽和氨基酸基化学品的重要途径。针对DMC法合成NCAs中，氨基酸氨基酰化反应选择性差和效率低，以及酰基化中间体在成环过程中易脱羧导致成环受阻等难题，本课题研制具有夺取质子、授予质子、精准酰化和高效成环的金属离子杂化磷铝基酸碱协同催化剂，利用原位FT-IR、原位NMR和XPS等技术研究底物在催化剂表面的吸附、活化和转化模式，利用同步热分析质谱仪、热裂解气质联用仪和原位FT-IR等解析中间体成环反应中质子授予过程与脱羧之间的关联，阐释成环受限机制。研究催化剂组成、溶剂分子、底物结构和温度效应等对底物活化的影响规律，探索定向酰基化和精准成环中的催化机理。利用CO2抑制成环反应中质子授予过程引发的脱羧和烷基化，实现低成本绿色一锅法合成NCAs。

α-氨基酸-N-羧酸酐（NCAs）开环聚合是合成多肽的一种最有效和最简便的方法，开发碳酸二甲酯（DMC）法合成NCAs是实现绿色制备多肽和氨基酸基化学品的重要途径。针对DMC法合成NCAs中，氨基酸氨基酰化反应选择性差和效率低，以及酰基化中间体在成环过程中易脱羧导致成环受阻等难题，本课题研制了酸碱协同催化剂，研究了底物在催化剂表面的吸附、活化和转化模式，解析了中间体成环反应中质子授予过程与脱羧之间的关联，阐释了成环受限机制。研究了催化剂组成、溶剂分子、底物结构和温度效应等对底物活化的影响规律，探索了定向酰基化和精准成环中的催化机理。.首先，以DMC作为环合剂，研究了L-谷氨酸-γ-苄酯羧酸酐的分步合成过程，酰基化中间体收率达到86.43%，目标产物达到68.34%。其次，以Na2CO3和Zn(OAc)2为催化剂，“一锅法”合成了N-羧基丙氨酸酸酐(Ala-NCA)，在DMF溶剂中Ala-NCA收率达到53.2%。然后，制备了酸—碱协同催化剂NaZnPO4，用该催化剂催化DMC和丙氨酸“一锅法”合成了Ala-NCA，在DMF溶剂中，150℃反应8h, Ala-NCA收率为46.84%。研究了NaZnPO4 中Zn2＋和P-O-Na 酸碱协同催化作用、以及去质子化、精准酰基化和高效成环的作用，探索了催化剂表面上原料转化和中间体精准关环途径。最后，利用NCAs改性3-羟基丁酸与3-羟基己酸的共聚酯（PHBHHx），通过NCAs开环聚合改性，导致改性材料的亲水性和可降解性明显提高。.总之，NCAs可广泛用于聚氨基酸的合成、药物制备、组织工程、生物医用工程等领域，对于蛋白质定向技术的演进以及多种功能机制的研究都发挥着极为重要的作用。