Brønsted acid-enhanced copper-catalyzed atroposelective cycloisomerization to axially chiral arylquinolizones via dearomatization of pyridine

Abstract

AbstractThe construction of axially chiral N-heterobiaryls is of great interest as a result of their occurrence in organocatalysts, chiral ligands, natural products, and biologically active molecules. Despite remarkable achievements in this area, strategies for the preparation of new classes of axially chiral N-heterobiaryls remain to be further explored. Herein, we report the enantioselective synthesis of axially chiral arylquinolizones through an intramolecular atroposelective cycloisomerization. The reaction proceeds via the Brønsted acid-enhanced dearomatization of pyridine by a copper catalyst that allows for the formation of the desired products in excellent yields and enantioselectivities. The utility of this methodology is illustrated by a synthesis on gram scale production and transformation of the products into chiral thiourea catalysts. Mechanistic studies demonstrate that Brønsted acid plays a significant role in promoting the reactivity of the reaction, while both the steric and electronic effects of aryl substituents in substrate play a role in controlling the stereoselectivity.