Organocatalyzed diastereo- and enantioselective synthesis of N–N atropisomeric isoindolinones bearing central chirality

Abstract

Methods for catalytically constructing of N–N axially chiral scaffolds have garnered significant attention since such compounds are widely present in natural products, bioactive molecules, and organic materials. Herein, we report a highly diastereoselective and enantioselective organocatalyzed [4 + 1] annulation method for synthesizing diverse valuable isoindolinones that possessing N–N axial and central chiralities. This methodology uses a chiral phosphoric acid as a bifunctional catalyst to promote a cascade sequence involving two nucleophilic additions, dehydration, and dearomatization processes. Control experiments and DFT calculations revealed a possible mechanism in which the stereoselectivity-determining step is likely to involve the irreversible formation of a hydroxy biaryl intermediate. Additionally, preliminary biological activity studies showed that some of these N–N axially chiral isoindolinones have potential in suppressing tumor-cell proliferation.