Understanding ring-closing and racemization to prepare α-amino acid NCA and NTA monomers: a DFT study
Understanding ring-closing and racemization to prepare α-amino acid NCA and NTA monomers: a DFT study
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了解闭环和外消旋化以制备 α-氨基酸 NCA 和 NTA 单体：DFT 研究
DOI：
10.1039/d0cp01174f
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发表时间：
2020-07-14
影响因子：
3.3
通讯作者：
Sun, Jihong
中科院分区：
文献类型：
--
作者：
Bai, Tianwen;Shen, Bo;Sun, Jihong
多肽和类多肽是具有α-氨基酸重复单元的生物医用材料，它们是由α-氨基酸N-羧酸酐（NCA）或N-硫代羧酸酐（NTA）单体开环聚合而成。对单体合成路线的详细研究对于探索新的α-氨基酸NCA和NTA单体以及相应的聚（α-氨基酸）材料是必不可少的。在这方面的贡献，密度泛函理论（DFT）被应用到研究的Leuchs方法的机制，包括两个可能的途径，前体结构和外消旋的闭环反应。根据密度泛函理论计算，途径2是优选的，具有比途径1更低的Δ G，并且速率控制步骤被认为是释放当量卤代烃的S（N）2取代，这解释了我们的实验观察。NTA单体与强质子酸之间的反应会导致外消旋，低温和短反应时间可以抑制外消旋。在β-碳上含有高体积的α-氨基酸的那些NTA（如亮氨酸-NTA）中，外消旋受到空间位阻的抑制。
Polypeptides and polypeptoids are promising materials in biomedical applications bearing alpha-amino acid repeating units, which are prepared from ring-opening polymerizations of alpha-amino acidN-carboxyanhydride (NCA) orN-thiocarboxyanydride (NTA) monomers. Detailed studies on monomer synthetic routes are essential to explore new alpha-amino acid NCA and NTA monomers as well as the corresponding poly(alpha-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 Delta Gthan pathway 1, and the rate-determining step is recognized as an S(N)2 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 alpha-amino acids containing high bulkiness at the beta-carbon, such as leucine-NTA.