Yuan Kang-Ning, Zhuang Hongjun, Wei Jie, Shen Yu, Yao Hong-Qing, Li Ming-Hong, Xu Lin-Lin, Shang Ming
Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, 200240, China.
Research Center for Translational Medicine, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, P.R. China.
Nat Commun. 2025 Jan 22;16(1):920. doi: 10.1038/s41467-024-54648-6.
In drug development, the substitution of benzene rings in aniline-based drug candidates with saturated bridged bicyclic ring systems often enhances pharmacokinetic properties while preserving biological activity. However, current efforts predominantly focuses on bicyclo[1.1.1]pentylamines, accessing analogs capable of mimicking ortho- and meta-substituted anilines remains challenging due to the lack of a versatile and modular synthetic methods. Herein, we present a modular approach to access a diverse array of saturated bioisosteres of anilines via photoelectrochemical-induced decarboxylative C(sp)-N Coupling. The success of this reaction hinges on the merging the cooperative ligand-to-metal charge transfer (LMCT) with copper-catalyzed amination. Notably, this net-oxidative C(sp)-N forming reaction operates under mild electrode potentials and proceeds through hydrogen evolution, eliminating the need for external chemical oxidants. Our research enables the facile decarboxylative amination of a set of sp-rich small-ring cage carboxylic acids, thus offering a versatile bioisosteric replacement for ortho-, meta-, and para-substituted anilines and di(hetero)aryl amines.
在药物开发中，用饱和桥联双环体系取代基于苯胺的候选药物中的苯环，通常会增强药代动力学性质，同时保留生物活性。然而，目前的研究主要集中在双环[1.1.1]戊胺上，由于缺乏通用且模块化的合成方法，获得能够模拟邻位和间位取代苯胺的类似物仍然具有挑战性。在此，我们提出了一种模块化方法，通过光电化学诱导的脱羧C(sp)-N偶联来获得各种苯胺的饱和生物电子等排体。该反应的成功取决于将协同配体到金属的电荷转移（LMCT）与铜催化的胺化反应相结合。值得注意的是，这种净氧化C(sp)-N形成反应在温和的电极电位下进行，并通过析氢过程进行，无需外部化学氧化剂。我们的研究实现了一组富含sp的小环笼状羧酸的简便脱羧胺化反应，从而为邻位、间位和对位取代的苯胺以及二（杂）芳基胺提供了一种通用的生物电子等排体替代物。
