Zerong GUO, Yunlong Qin, Qingling Wu, Jianing Zhang, Huabing Yin, Cuihuan Geng, Yang Zhao, Lijuan Chen, Junwei Zhao, Qilin Wang
We report a dearomative multifunctionalization strategy that converts planar isoquinoliniums into three-dimensional, sp 3 -rich bridged bis-tetrahydroisoquinolines. Nucleophiles serve dual roles as reaction switches and stereodefined bridging linkers, enabling precise regio-, chemo-, and stereocontrol. This streamlined approach unlocks the full reactive potential of isoquinolines for constructing architecturally complex polycyclic frameworks with broad applicability to carbon-, nitrogen-, and sulfur-centered nucleophiles. PMI analysis and physicochemical evaluation confirm their pronounced three-dimensionality and drug-like profiles.