Catalytic enantioselective synthesis of inherently chiral calix[4]arenes via organocatalyzed aromatic amination enabled desymmetrization

Abstract

Inherently chiral calix[4]arenes represent a distinct class of chiral frameworks whose chirality arises from the dissymmetry of the entire molecule. Although these chiral scaffolds have been widely applied in various research fields, their catalytic enantioselective synthesis remains largely underexplored. Herein, we report the enantioselective synthesis of inherently chiral calix[4]arenes using an organocatalyzed desymmetrization method. By using chiral phosphoric acid catalysis, the asymmetric electrophilic amination reactions of the phenol-containing prochiral calix[4]arenes led to a range of inherently chiral calix[4]arenes with high yields and enantioselectivities. Significantly, the practicability of this method is underscored by its successful implementation using as little as 0.05 mol% of chiral catalyst, without compromising reaction efficiency and enantioselectivity. Moreover, the aminophenol moiety in the products could be easily modified to produce unique calix[4]arenes with diverse N,O-heterocycles, as well as the simple meta-amino-substituted chiral calix[4]arene, which have shown promising potential in the development of new chiral catalysts.