ABSTRACT 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.
Gou et al. (Fri,) studied this question.