亚胺引发四肽环化反应机理的理论研究

doi:10.6023/A14050392

摘要/Abstract

运用密度泛函的理论方法（M06//B3LYP）对亚胺引发的关环肽环化的反应机理进行了研究. 计算结果表明，由亚胺到环肽的转化过程存在两种不同的反应机理. 一种是羰基转移-合环机理：先经历羰基转移，然后H转移与C-O合环同时进行. 另一种是H转移-合环-羰基转移-H转移机理：H原子先从O原子转移到N原子然后再进行C-O合环，随后再进行羰基转移与H原子转移. 计算结果显示，羰基转移-合环反应历程为有利路径，该反应路径中的H原子转移及C-O成环过程为整个反应的决速步骤.

关键词: 环肽, 协同反应, 分步反应, 反应机理, 密度泛函理论

The small-sized cyclic peptides have attracted much research interest in the organic and bioorganic chemistry. In the present study, the mechanism of cyclization of tetrapeptides by an imine-induced ring-closing strategy has been studied in detail using the density functional theory method. The geometries of all the species were fully optimized at the B3LYP/6-31G(d) level. The M06/6-311++G(2df,2p) method is employed to calculate the single point energies. The solvent effect [Trifluoroacetic Acid (TFA) was used as a solvent] was calculated by using SMD (solvation model based on the quantum mechanical charge density of a solute molecule interacting with a continuum description of the solvent) model. Both the carbonyl transfer-cyclization and the H transfer-cyclization-carbonyl transfer-H transfer mechanism might be responsible for the transformation of the imine reagent to the cyclic peptide product. According to the calculation results, the carbonyl transfer-cyclization mechanism occurs via the carbonyl transfer from O(Ph-) atom to N atom, corresponding to three possible transition states with the barrier height of 20.2, 16.4 and 62.7 kcal/mol, respectively (the second one is the most feasible among different ones). Then the concerted H transfer & C-O cyclization step occurs via a six-membered ring transition state. The second step (the concerted H transfer & C-O cyclization step) is the rate-determining step, and the overall activation barrier is 28.3 kcal/mol. In contrast, the H transfer-cyclization-carbonyl transfer-H transfer mechanism includes four steps: the hydrogen atom first transferred from oxygen atom to N atom with the breaking of C—C to form the intermediate M3 and a CH₃COH molecule, cyclization via the C—O and C—C bond formation, the carbonyl transfer from O(Ph-) atom to N atom accompanied with the breaking of C—N, and the transfer of hydrogen atom with the cyclization of C—N then occurred subsequently. In this context, the second step (i.e. cyclization via the C—O and C—C bond formation) is the rate-determining step, and the overall activation barrier is 40.1 kcal/mol. Accordingly, the carbonyl transfer-cyclization mechanism is relatively more feasible than the H transfer-cyclization-carbonyl transfer-H transfer mechanism, and the rate-limiting step is the concerted H transfer & C-O cyclization step with a barrier of 28.3 kcal/mol.

Key words: cyclic peptide, concerted reaction, stepwise reaction, reaction mechanism, density functional theory

引用此文

田燕, 傅尧, 张琪, 于海珠, 石景. 亚胺引发四肽环化反应机理的理论研究[J]. 化学学报, 2014, 72(8): 935-941.

Tian Yana, Fu Yao, Zhang Qi, Yu Haizhu, Shi Jing. Theoretical Study on the Mechanism of the Imine-induced Tetrapeptides Cyclization[J]. Acta Chimica Sinica, 2014, 72(8): 935-941.

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