Catalytic Access to Chiral <i>δ</i>‐Lactams via Nucleophilic Dearomatization of Pyridine Derivatives
Siriphong Somprasong, Marta Castiñeira Reis, Syuzanna R. Harutyunyan
Abstract
Abstract Nitrogen‐bearing rings are common features in the molecular structures of modern drugs, with chiral δ ‐lactams being an important subclass due to their known pharmacological properties. Catalytic dearomatization of preactivated pyridinium ion derivatives emerged as a powerful method for the rapid construction of chiral N ‐heterocycles. However, direct catalytic dearomatization of simple pyridine derivatives are scarce and methodologies yielding chiral δ ‐lactams are yet to be developed. Herein, we describe an enantioselective C4‐dearomatization of methoxypyridine derivatives for the preparation of functionalised enantioenriched δ ‐lactams using chiral copper catalysis. Experimental 13 C kinetic isotope effects and density functional theory calculations shed light on the reaction mechanism and the origin of enantioselectivity.