Wang Yue, Zhang Suping, Zeng Ke, Zhang Pengli, Song Xiaorong, Chen Tie-Gen, Xia Guoqin
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China.
Nat Commun. 2024 Aug 8;15(1):6745. doi: 10.1038/s41467-024-50897-7.
Building C(sp)-rich architectures using simple and readily available starting materials will greatly advance modern drug discovery. C(sp)-H and C(sp)-O bonds are commonly used to strategically disassemble and construct bioactive compounds, respectively. However, the direct cross coupling of these two chemical bonds to form C(sp)-C(sp) bonds is rarely explored in existing literature. Conventional methods for forming C(sp)-C(sp) bonds via radical-radical coupling pathways often suffer from poor selectivity, severely limiting their practicality in synthetic applications. In this study, we present a single electron transfer (SET) strategy that enables the cleavage of amine α-C - H bonds and heterobenzylic C - O bonds to form C(sp)-C(sp) bonds. Preliminary mechanistic studies reveal a hydrogen bond interaction between substrates and phosphoric acid facilitates the cross-coupling of two radicals with high chemoselectivity. This methodology provides an effective approach to a variety of aza-heterocyclic unnatural amino acids and bioactive molecules.
使用简单且易于获得的起始原料构建富含C(sp)的结构将极大地推动现代药物发现。C(sp)-H键和C(sp)-O键通常分别用于策略性地拆解和构建生物活性化合物。然而，现有文献中很少探索这两种化学键直接交叉偶联形成C(sp)-C(sp)键的方法。通过自由基-自由基偶联途径形成C(sp)-C(sp)键的传统方法往往选择性较差，严重限制了它们在合成应用中的实用性。在本研究中，我们提出了一种单电子转移（SET）策略，该策略能够裂解胺α-C-H键和杂苄基C-O键以形成C(sp)-C(sp)键。初步机理研究表明，底物与磷酸之间的氢键相互作用促进了两个自由基的交叉偶联，具有高化学选择性。该方法为各种氮杂环非天然氨基酸和生物活性分子提供了一种有效途径。
