Rhodium-Catalyzed Enantioselective Synthesis of Planar-Chiral Macrocycles via De Novo Isoquinoline Formation

De novo formation of the aromatic ring is an attractive strategy for atroposelective synthesis, but its application to planar-chiral macrocycles remains challenging. Herein, we report a rhodium-catalyzed enantioselective synthesis of planar-chiral macrocycles via de novo isoquinoline construction. This method is characterized by high levels of enantioselectivity (up to 96% ee), regioselectivity (up to >20:1 rr), and functional group tolerance, providing a series of isoquinoline-based macrocyclic atropisomers. Furthermore, the synthetic utility of this protocol is validated via a mmol-scale reaction and post-modification process of the product. Mechanistic studies, including deuterium labeling, kinetic isotope effect, and DFT calculations, support C─H bond cleavage as the rate-determining step and elucidate the origin of the stereoselectivity.