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. 2024 Nov 4;63(45):e202412296. doi: 10.1002/anie.202412296. Epub 2024 Sep 17.
The development of simplified synthetic strategy to create structurally and functionally diverse pseudo-natural macrocyclic molecules is highly appealing but poses a marked challenge. Inspired by natural scaffolds, herein, we describe a practical and concise ligand-enabled Pd(II)-catalyzed sp C-H alkylation, olefination and arylation macrocyclization, which could offer a novel set of pseudo-natural macrocyclic sulfonamides. Interestingly, the potential of ligand acceleration in C-H activation is also demonstrated by an unprecedented enantioselective sp C-H alkylation macrocyclization. Moreover, a combination of in silico screening and biological evaluation led to the identification of a novel spiro-grafted macrocyclic sulfonamide 2 a, which showed a promising efficacy for the treatment of Parkinson's disease (PD) in a mouse model through the activation of silent information regulator sirtuin 3 (SIRT3).
开发具有结构和功能多样性的简化合成策略来创造假自然大环分子非常吸引人，但也带来了显著的挑战。受天然支架的启发，本文描述了一种实用且简洁的配体辅助 Pd(II)催化的 sp C-H 烷基化、烯丙基化和芳基化环化反应，可提供一组新型的假自然大环磺酰胺。有趣的是，配体在 C-H 活化中的加速作用也通过前所未有的对映选择性 sp C-H 烷基化环化反应得到证明。此外，通过计算机筛选和生物评估相结合，鉴定出一种新型的螺环接枝大环磺酰胺 2a，它通过激活沉默信息调节因子 sirtuin 3 (SIRT3)，在帕金森病 (PD) 小鼠模型中显示出有希望的治疗效果。
