Synthesis of Atropisomeric Biaryls via Chiral Suzuki-Miyaura/Enzymatic Kinetic Resolution

Axially chiral biaryl fragments are recurrent scaffolds in drugs. These essential synthons are often built via metal catalyzed Csp2-Csp2 bond formation and subsequent separation of the atropisomers, resulting in low yields and excess waste. Asymmetric variants have been reported, unfortunately without reaching the optical purity desired for active pharmaceutical ingredients. Additional enantioenriching steps are therefore required, but even if efficient, these methods generate waste and are often problematic on scale. Herein, we report an unprecedented chiral Suzuki-Miyaura/enzymatic kinetic resolution sequence for the synthesis of JNJ-4355 and other atropisomeric biaryls yielding the targets in high enantiopurity without chiral separation.

Automated summary

Axially chiral biaryl fragments are important scaffolds in drugs, but their synthesis often results in low yields and excess waste. This study presents a novel chiral Suzuki-Miyaura/enzymatic kinetic resolution sequence for the synthesis of atropisomeric biaryls, achieving high enantiopurity without chiral separation.