(–)-Bedaquiline [(–)-BDQ] is considered to be one of the most promising therapeutic agents for tuberculosis 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 holds significant interest for both medicinal and process chemists.
