Asymmetric Reductive Three‐Component Annulation Reaction for Constructing Fused N‐Heterocycles With Contiguous Stereogenic Centers

ABSTRACT The development of efficient methods for the diverse synthesis of optically active fused N‐heterocycles is vital for advancing medicinal chemistry. Hydrodearomative annulation of weakly reactive azaarenes presents a promising yet challenging strategy to fulfil such a synthetic purpose. Herein, we report a reductive three‐component reaction for the construction of fused N‐heterocycles with contiguous quaternary and tertiary carbon stereocenters, enabled by a simple chiral phosphoric acid/PhSiH 3 catalytic system. A wide variety of isoquinolinium salts were transformed in combination with formaldehyde and N ‐alkyl anilines into the target products with good isolated yields (up to 88%), and high diastereoselectivities (>20:1 dr) and enantioselectivities (up to 96.5:3.5 er). The reaction proceeds through sequential hydrodearomatization, C 4 ‐methylation, and asymmetric annulation, in which the chiral phosphoric acid participates in both the formation of intermediates and the stereocontrolling steps. DFT calculations further reveal that the observed enantioselectivity arises from C–H···O interactions between the substrate and catalyst, with steric repulsion effects playing a decisive role.