### 亚胺引发四肽环化反应机理的理论研究

1. a 中国科学技术大学化学系 合肥 230026;
b 安徽农业大学应用化学系 合肥 230036
• 投稿日期:2014-05-21 发布日期:2014-06-24
• 通讯作者: 于海珠, 石景 E-mail:shijing@ustc.edu.cn;yuhaizhu@gmail.com
• 基金资助:

项目受国家自然科学基金（Nos. 21325208，21172209，21361140372，21202006）、高等学校博士学科点专项科研基金资助课题（No. 20123402110051）、中国科学院基金（No. KJCX2-EW-J02）、中央高校基本科研业务费专项基金（No. WK2060190008）及教育部中国教育科研网格ChinaGrid及上海超级计算中心资助.

### Theoretical Study on the Mechanism of the Imine-induced Tetrapeptides Cyclization

Tian Yanaa,b, Fu Yaoa, Zhang Qia, Yu Haizhua, Shi Jinga

1. a Department of Chemistry, University of Science and Technology of China, Hefei 230026;
b Department of Applied Chemistry, Anhui Agricultural University, Hefei 230036
• Received:2014-05-21 Published:2014-06-24
• Supported by:

Project supported by the National Natural Science Foundation of China (Nos. 21325208, 21172209, 21361140372, 21202006), the Specialized Research Fund for the Doctoral Program of Higher Education (No. 20123402110051), the Fundamental Research Funds for the Central Universities (No. WK2060190008), Chinese Academy of Sciences (No. KJCX2-EW-J02) and the ChinaGrid project funded by MOE of China, and the super-computer center of Shanghai.

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.