Mechanism of N-to-S acyl transfer of N-(2-hydroxybenzyl) cysteine derivatives and origin of phenol acceleration effect

查看全文 作　　者：Siwei [1]Bi;Peng [1]Liu;Baoping [1]Ling;Xiangai [1]Yuan;Yuanye [1]Jiang 机构地区：[1]School of Chemistry and Chemical Engineering, Qufu Normal University 出　　处：《Chinese Chemical Letters》索引2018年第29卷第8期,共5页 基　　金：supported by the National Natural Science Foundation of China (Nos. 21702119, 21473100, 21603116 and 21703118);Natural Science Foundation of Shandong Province (Nos.ZR2017QB001, ZR2017MB038);Special Fund Project for Postdoctoral Innovation of Shandong Province (No. 201602021) 摘　　要：N-(2-Hydroxybenzyl)cysteine derivatives were recently disclosed to be efficient crypto-thioesters for native chemical ligation(NCL). To elucidate the mechanism of the relevant N-to-S acyl transfer process as well as the origin of the acceleration effect of the phenol substitutes, a density functional theory(DFT)study was performed. It was found that the N-to-S acyl transfer of N-(2-hydroxybenzyl)cysteine derivatives involve four major steps: concerted nucleophilic addition of thiolate/proton transfer,inversion of an amine moiety, water-assisted proton transfer and CààN bond cleavage. The phenol substitutes promote the nucleophilic addition of thiolate by protonating the carbonyl oxygen atom synergistically and the proton transfer from hydroxyl to amide nitrogen atom is the rate-determining step of the N-to-S acyl transfer. By contrast, changing the phenolic hydroxyl to methoxyl was found to significantly slow down the nucleophilic addition of thiolate and thus hinders the N-to-S acyl transfer overall. These computational results are consistent with the observation of previously reported control experiments, by which our proposed mechanism is further validated. 关 键 词：半胱氨酸 衍生物 机制 起源 酚 质子转移 转移过程 控制实验