Enantioselective Synthesis of gem -Difluorinated Spirobenzazepinoindoles by Chiral Phosphoric Acid (CPA)-Catalyzed Asymmetric Pictet–Spengler Cyclization

Abstract

7-membered spirobenzazepinoindole frameworks constitute an important family of heterocyclic skeletons with broad utility in pharmaceutical research. Despite their value, the stereoselective synthetic routes toward chiral gem-difluorinated spirobenzazepinoindoles remain unexplored, and a general, efficient construction method has yet to be reported. In this work, we disclose a chiral phosphoric acid (CPA)-catalyzed asymmetric Pictet–Spengler cyclization between 2,2-difluoro-1H-indene-1,3-diones and (2-aminobenzyl)indoles. This protocol enables facile access to a diverse array of enantioenriched 7-membered gem-difluorinated spirobenzazepinoindoles in moderate to excellent yields with outstanding enantiocontrol. Furthermore, the synthetic practicality of this methodology is validated by gram-scale amplification and multiple downstream derivatizations.