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.