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).D...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 now.Herein,we have successfully developed a cooperative bimetallic system for the asymmetric synthesis of BDQ under the guidance of density functional theory(DFT)computations.Based 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.展开更多
基金supported by the Bill and Melinda Gates Foundation (INV-008413)the National Natural Science Foundation of China (21831005)Shanghai Jiao Tong University
文摘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 now.Herein,we have successfully developed a cooperative bimetallic system for the asymmetric synthesis of BDQ under the guidance of density functional theory(DFT)computations.Based 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.
