Asymmetric Synthesis of Anti‐tuberculosis‐specific Drug TBAJ‐876 through Synergistic Li/Li Catalysis

Abstract

Comprehensive Summary TBAJ‐876, developed by TB Alliance, a novel anti‐tuberculosis‐specific drug, has entered Phase II clinical trials. Herein, the first asymmetric synthesis of TBAJ‐876 has been realized using synergistic Li/Li catalysis with excellent yield of 95% and 88 : 12 er (99.6 : 0.4 er, 10 : 1 dr after simple recrystallization). Furthermore, DFT calculations and 7Li‐NMR analysis illustrated the mechanism of the synergistic reaction: a chiral Li‐complex activates the nucleophile to control the stereoselectivity, while the other achiral Li‐complex activates the electrophile to catalyze the carbonyl addition reaction. Additionally, this protocol has been successfully carried out at 5 gram‐scale, showing its industrial potential.

Active Components of Pueraria lobata through the MAPK/ERK Signaling Pathway Alleviate Iron Overload in Alcoholic Liver Disease

“…The “degree” value is the number of connections a node has to other nodes in the network. Targets with high “degree” values can be regarded as key targets in the network [38–39] . We screened the top 10 key core therapeutic targets utilizing cytoHubba functionality and visualized the results using Cytoscape [40–41] …”

Development of a Continuous Flow Process for the Efficient Preparation of Anti-Tuberculosis-Specific Drug TBAJ-876

“…Generally, the stereocontrolled construction of contiguous tertiary and tetrasubstituted carbons is one of the greatest challenges in synthetic chemistry . Very recently, we have developed a synergistic Li/Li bimetallic system to address the problems concerning nucleophilic addition reactions to aryl ketones. − The bimetallic strategy combined with noncovalent interactions in this system has been shown to be a compelling strategy for the asymmetric synthesis of the anti-tuberculosis drugs BDQ and TBAJ-876 bearing contiguous chiral centers. As shown in Scheme a, based on synergistic Li/Li bimetallic catalysis, starting materials 1 and 2 undergo a lithiation/addition sequence at −78 °C, with the target product being prepared on a 5 g scale (95% yield and 88:12 er) using traditional batch methods.…”

Synergistic Li/Li Bimetallic System for the Asymmetric Synthesis of Antituberculosis Drug TBAJ-587

“…In the past few years, our group has started a research program studying synergistic bimetallic catalysis, , which is one of the most powerful tools for constructing C­(sp 3 )–C­(sp 3 ) bonds and has also been evidenced by many other elegant pieces of work. , Very recently, we have developed a synergistic Li/Li bimetallic system to address the problems concerning the nucleophilic addition reaction of aryl ketones. The bimetallic system combined with noncovalent interactions has been shown to be a compelling strategy for the asymmetric synthesis of antituberculosis drugs BDQ and TBAJ-876 bearing contiguous chiral centers (Scheme b and c) . Furthermore, we have established a library of known ligands for the synthesis of these types of compounds.…”

“…In order to improve the result, another chiral ligand L7 for complex 7 was also examined, and a better selectivity was obtained (entry 7, 86:14 er) but with a poor yield. Based on our previous studies, we knew that a simple combination of a chiral ligand and an achiral ligand could enhance both catalytic efficiency and selectivity in the synergistic Li/Li bimetallic system (see the Supporting Information for the comprehensive optimization of the chiral ligands) . Thus, we employed L8 as the achiral ligand to match L4 , which formed a triple-coordinated Li complex for the electrophile and provided the best result for the synthesis of TBAJ-876.…”

“…In the past few years, our group has started a research program studying synergistic bimetallic catalysis, 10 , 11 which is one of the most powerful tools for constructing C(sp 3 )–C(sp 3 ) bonds and has also been evidenced by many other elegant pieces of work. 12 , 13 Very recently, we have developed a synergistic Li/Li bimetallic system to address the problems concerning the nucleophilic addition reaction of aryl ketones.…”