Issue 30, 2025

Catalytic enantioselective total synthesis of antitubercular agents (–)-bedaquiline and (–)-sudapyridine enabled by dynamic kinetic resolution-asymmetric transfer hydrogenation

Abstract

(–)-Bedaquiline [(–)-BDQ] is considered to be one of the most promising new therapeutic agents for tuberculosis for over 50 years. However, there are limited general and highly stereocontrolled asymmetric synthetic methods available for (–)-BDQ and its analogues due to the challenge of forging their vicinal stereocenters. Herein, we report a concise and stereocontrolled synthetic route to (–)-BDQ in six steps with an overall yield of 34%, integrating a Rh-catalyzed dynamic kinetic resolution-asymmetric transfer hydrogenation (DKR-ATH) with TADDOL-mediated diastereoselective allylation. The reactivity and stereoselectivity of DKR-ATH were systematically investigated using a range of sterically hindered N-hetero-1,2,2-triarylethanones. This approach offers a robust and reliable method for synthesizing N-hetero-1,2,2-triarylethanols featuring two continuous stereocenters, which serve as crucial chiral building blocks for pharmaceutical applications. Furthermore, the aforementioned two-stage protocol has been successfully applied to the synthesis of (–)-sudapyridine, a tuberculosis drug candidate currently in phase III clinical trials. This study presents a versatile and generalizable strategy for the synthesis of BDQ-type architectures, which hold significant interest for both medicinal and process chemists.

Graphical abstract: Catalytic enantioselective total synthesis of antitubercular agents (–)-bedaquiline and (–)-sudapyridine enabled by dynamic kinetic resolution-asymmetric transfer hydrogenation

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Article information

Article type
Edge Article
Submitted
28 May 2025
Accepted
24 Jun 2025
First published
25 Jun 2025
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2025,16, 13864-13872

Catalytic enantioselective total synthesis of antitubercular agents (–)-bedaquiline and (–)-sudapyridine enabled by dynamic kinetic resolution-asymmetric transfer hydrogenation

J. Han, D. Zhang, Y. Tao, P. Tang and F. Chen, Chem. Sci., 2025, 16, 13864 DOI: 10.1039/D5SC03865K

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