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

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Abstract

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 Csp3—Csp3 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.

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Acknowledgements

This work was supported by the Bill and Melinda Gates Foundation (INV-008413), the National Natural Science Foundation of China (21831005), and Shanghai Jiao Tong University. We appreciate Dr. George Wang, Dr. Christopher Cooper, Dr. Rajneesh Taneja, Dr. John Dillon, Dr. Trevor Laird and Dr. Jordi Robinson for their helpful discussions. We thank Dr. Niya Bowers (BMGF) for the project management and the Instrumental Analysis Center of SJTU for characterization.

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China

    Feng Gao, Tanveer Ahmad, Yicong Luo, Qianjia Yuan, Xiaohong Huo, Tao Song & Wanbin Zhang

  2. School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China

    Jing Li, Zhenfeng Zhang & Wanbin Zhang

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  1. Feng Gao
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Dedicated to Professor Guoqiang Lin on the occasion of his 80th birthday.

Supporting information The supporting information is available online at http://chem.scichina.com and http://link.springer.com/journal/11426. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.

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Gao, F., Li, J., Ahmad, T. et al. Asymmetric synthesis of bedaquiline based on bimetallic activation and non-covalent interaction promotion strategies. Sci. China Chem. 65, 1968–1977 (2022). https://doi.org/10.1007/s11426-022-1387-7

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