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.