Song Bichao, Guo Xueying, Yang Li, Yu Haiyue, Zong Xinlei, Liu Xiujuan, Wang Hao, Xu Zhongliang, Lin Zhenyang, Yang Weibo
State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Angew Chem Int Ed Engl. 2023 Apr 3;62(15):e202218886. doi: 10.1002/anie.202218886. Epub 2023 Mar 2.
The development of environment-friendly, step economic couplings to generate structurally diverse macrocyclic compounds is highly desirable but poses a marked challenge. Inspired by the C-H oxidation mechanism of cytochromes P450, an unprecedented and practical Rh -catalyzed acylmethylation macrocyclization via C-H/O dual activation has been developed by us. The process of macrocyclization is facilitated by a synergic coordination from pyridine and ester group. Interestingly, the reaction mode derives from a three-component coupling which differs from established olefination and alkylation paths. Density functional theory (DFT) calculations and control experiments revealed the mechanism of this unique C-H/O dual activation. The newly achieved acylmethylation macrocyclic products and their derivatives showed a potent anti-H1N1 bioactivity, which may provide an opportunity for the discovery of novel anti-H1N1 macrocyclic leading compounds.
开发环境友好、经济高效的偶联反应以生成结构多样的大环化合物是非常必要的，但也面临着巨大的挑战。受细胞色素P450的C-H氧化机制启发，我们开发了一种前所未有的、实用的通过C-H/O双活化的铑催化酰甲基化大环化反应。吡啶和酯基的协同配位促进了大环化过程。有趣的是，该反应模式源于一种三组分偶联反应，与已有的烯化和烷基化路径不同。密度泛函理论（DFT）计算和对照实验揭示了这种独特的C-H/O双活化机制。新得到的酰甲基化大环产物及其衍生物表现出强大的抗H1N1生物活性，这可能为发现新型抗H1N1大环先导化合物提供机会。
