Wang Xing, Shen Boming, Liu Meiwen, Wang Ziyang, Liu Chang, Li Pengfei, Yu Peiyuan, Li Wenjun
Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Qingdao, Shandong, 266021, China.
Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, College of Science, Southern University of Science and Technology Guangming Advanced Research Institute, Southern University of Science and Technology (SUSTech), Shenzhen, 518055, China.
Angew Chem Int Ed Engl. 2024 Jul 15;63(29):e202400143. doi: 10.1002/anie.202400143. Epub 2024 Jun 14.
The chemistry of quinone methides formed in situ has been flourishing in recent years. In sharp contrast, the development and utilization of biphenyl quinone methides are rare. In this study, we achieved a remote stereocontrolled 1,12-conjugate addition of biphenyl quinone methides formed in situ for the first time. In the presence of a suitable chiral phosphoric acid, alkynyl biphenyl quinone methides were generated from α-[4-(4-hydroxyphenyl)phenyl]propargyl alcohols, followed by enantioselective 1,12-conjugate addition with indole-2-carboxylates. The strategy enabled the alcohols to serve as efficient allenylation reagents, providing practical access to a broad range of axially chiral allenes bearing a (1,1'-biphenyl)-4-ol unit, which were previously less accessible. Combined with control experiments, density functional theory calculations shed light on the reaction mechanism, indicating that enantioselectivity originates from the nucleophilic addition of alkynyl biphenyl quinone methides. Notably, not only the presence of biphenyl quinone methides as versatile intermediates was confirmed but also organocatalytic enantioselective 1,12-addition was established.
近年来，原位生成的醌甲基化物的化学研究蓬勃发展。与之形成鲜明对比的是，联苯醌甲基化物的开发与利用却很少见。在本研究中，我们首次实现了原位生成的联苯醌甲基化物的远程立体控制1,12-共轭加成反应。在合适的手性磷酸存在下，α-[4-(4-羟基苯基)苯基]炔丙醇生成炔基联苯醌甲基化物，随后与吲哚-2-羧酸盐进行对映选择性1,12-共轭加成反应。该策略使醇类能够作为有效的联烯化试剂，为广泛的带有(1,1'-联苯)-4-醇单元的轴向手性联烯提供了实用的合成方法，而这些联烯以前较难获得。结合对照实验，密度泛函理论计算揭示了反应机理，表明对映选择性源于炔基联苯醌甲基化物的亲核加成。值得注意的是，这不仅证实了联苯醌甲基化物作为通用中间体的存在，还建立了有机催化的对映选择性1,12-加成反应。
