Catalytic Access to Chiral δ‐Lactams via Nucleophilic Dearomatization of Pyridine Derivatives

• Published in: Angewandte Chemie International Edition Vol. 62; no. 9; pp. e202217328 - n/a
• Main Authors: Somprasong, Siriphong, Reis, Marta Castiñeira, Harutyunyan, Syuzanna R.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 20.02.2023; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Catalysis; Chemistry; Chemistry, Multidisciplinary; Copper Catalysis; Dearomatization; Density functional theory; Enantiomers; Lactams; Medicinal Chemistry; Molecular structure; Physical Sciences; Pyridines; Pyridinium; Reaction mechanisms; Science & Technology; Pyridines; ACTIVATION; ASYMMETRIC-SYNTHESIS; HYDROGENATION; ANTAGONIST; ENANTIOSELECTIVE SYNTHESIS; ALKYLATION; Lactams; Medicinal Chemistry; 4+2 ANNULATION; Dearomatization; DIHYDROPYRIDINES; Copper Catalysis; GRIGNARD-REAGENTS; IN-SITU
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202217328

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 13C kinetic isotope effects and density functional theory calculations shed light on the reaction mechanism and the origin of enantioselectivity. We describe an enantioselective C4‐dearomatization of methoxypyridine derivatives for the preparation of functionalised enantioenriched δ‐lactams using chiral copper catalysis. Experimental 13C kinetic isotope effects and density functional theory calculations shed light on the reaction mechanism and the origin of enantioselectivity.