Asymmetric synthesis of bedaquiline based on bimetallic activation and non-covalent interaction promotion strategies

作     者：Feng Gao Jing Li Tanveer Ahmad Yicong Luo Zhenfeng Zhang Qianjia Yuan Xiaohong Huo Tao Song Wanbin Zhang 

作者机构：Shanghai Key Laboratory for Molecular Engineering of Chiral DrugsFrontiers Science Center for Transformative MoleculesSchool of Chemistry and Chemical EngineeringShanghai Jiao Tong UniversityShanghai 200240China School of PharmacyShanghai Jiao Tong UniversityShanghai 200240China 

出 版 物：《Science China Chemistry》 (中国科学（化学英文版）)

年 卷 期：2022年第65卷第10期

页      面：1968-1977页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

基　　金：supported by the Bill and Melinda Gates Foundation (INV-008413) the National Natural Science Foundation of China (21831005) Shanghai Jiao Tong University 

主　　题：asymmetric synthesis bedaquiline bimetallic system industrial synthetic process DFT computation 

摘      要：Bedaquiline(BDQ),approved by Food and Drug Administration(FDA)in 2012 as the first anti-tuberculosis-specific drug in the last 40 years,is viewed as one of the world’s most promising treatments for tuberculosis(TB).Due to the stereoselective construction of the Csp^(3)–Csp^(3)bond with vicinal stereocenters of BDQ and its analogues being an unsolved challenge,there have not been any reports concerning its asymmetric synthesis for the current industrial production process until ***,we have successfully developed a cooperative bimetallic system for the asymmetric synthesis of BDQ under the guidance of density functional theory(DFT)*** on the optimized conditions,BDQ could be synthesized with excellent enantioselectivity(99%ee)and diastereoselectivity(16:1 dr).A 5-g scale reaction was also conducted with comparably excellent results,showing its potential for industrial application.