MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China.
Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
Phys Chem Chem Phys. 2020 Jul 8;22(26):14868-14874. doi: 10.1039/d0cp01174f.
Polypeptides and polypeptoids are promising materials in biomedical applications bearing α-amino acid repeating units, which are prepared from ring-opening polymerizations of α-amino acid N-carboxyanhydride (NCA) or N-thiocarboxyanydride (NTA) monomers. Detailed studies on monomer synthetic routes are essential to explore new α-amino acid NCA and NTA monomers as well as the corresponding poly(α-amino acid) materials. In this contribution, density functional theory (DFT) is applied to investigate the mechanism of the Leuchs approach including two possible pathways, precursor structure and racemization in the ring-closing reaction. According to DFT calculations, pathway 2 is preferred with lower ΔG than pathway 1, and the rate-determining step is recognized as an SN2 substitution with releasing equivalent halogenated hydrocarbon, which explains our experimental observations. Racemization results from the reaction between the NTA monomer and a strong protonic acid, which can be suppressed by low temperature and short reaction time. Racemization is inhibited by steric hindrance in those NTAs of α-amino acids containing high bulkiness at the β-carbon, such as leucine-NTA.
多肽和类多肽是在生物医学应用中很有前途的材料，它们具有重复的α-氨基酸单元，是通过α-氨基酸的 N-羧酸酐（NCA）或 N-硫代羧酸酐（NTA）单体的开环聚合制备的。详细研究单体的合成路线对于探索新的α-氨基酸 NCA 和 NTA 单体以及相应的聚（α-氨基酸）材料至关重要。在本研究中，应用密度泛函理论（DFT）研究了 Leuchs 方法的反应机理，包括两种可能的途径：前体结构和环化反应中的外消旋化。根据 DFT 计算，路径 2 比路径 1 更有利，ΔG 更低，速率决定步骤被认为是释放等效卤代烃的 SN2 取代，这解释了我们的实验观察结果。外消旋化是由 NTA 单体与强酸之间的反应引起的，可以通过低温和短反应时间来抑制。在外消旋化中，β-碳上含有大体积侧基的α-氨基酸的 NTAs 会受到空间位阻的抑制，例如亮氨酸-NTA。
