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

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 Li-7-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.

Automated summary

TBAJ-876, a new anti-tuberculosis drug developed by TB Alliance, has entered Phase II clinical trials. In this study, the first asymmetric synthesis of TBAJ-876 was achieved using synergistic Li/Li catalysis with a high yield of 95% and a stereoselectivity of 88:12 (99.6:0.4, 10:1 dr after simple recrystallization). Furthermore, the mechanism of the synergistic reaction was elucidated through DFT calculations and Li-7-NMR analysis, showing the activation of nucleophile and electrophile by chiral and achiral Li-complexes, respectively. Additionally, the scalability of this protocol was demonstrated at a 5-gram scale, indicating its potential for industrial application.