Advances in Synthesis of the Chiral Benzo-Fused N-Heterocycles

Abstract

Chiral benzo-fused N-heterocycles are common in natural products, drugs, and materials. Over the last twenty years, their asymmetric synthesis has evolved from stoichiometric chiral-pool methods to advanced catalytic techniques that control central and axial chirality (atropisomerism) via C-N and emerging N-N bonds. This review critically examines these developments, grouped by bond-forming steps, including nucleophilic cyclizations, asymmetric reductions, cycloadditions, C-H functionalizations, dearomatizations, and photoredox radical cascades. It highlights sustainable catalysis, including earth-abundant metals (Co, Cu, Fe), metal-free organocatalysis, and strategies like enantiodivergent and atroposelective approaches for precise stereocontrol. Their applications are demonstrated through total syntheses and pharmaceutical uses, including the enantiomer-specific activity of approved pharmaceutical compounds. The review also discusses unresolved challenges, medium-ring heterocycles, stable N-N atropisomers, and scalable enantiodivergent platforms, and explores emerging areas such as machine learning (ML) and multi-activation catalysis. It aims to be a comprehensive resource for researchers leveraging modern asymmetric methods to synthesize chiral benzo-fused N-heterocycles.