Rhodium‐Catalyzed Atroposelective Synthesis of Axially Chiral 1‐Aryl Isoquinolines via De Novo Isoquinoline Formation

Abstract Axially chiral heterobiaryl moieties serve as core skeletons for bioactive molecules, chiral ligands, and organocatalysts. Enantioselective de novo formation of the heteroaromatic ring is one of the most straightforward approaches to access enantioenriched heterobiaryls. Herein, an enantioselective de novo construction of isoquinolines by rhodium‐catalyzed C─H activation/annulation of aromatic imines with alkynes is disclosed. This approach is operationally simple, allowing for rapid access to a variety of axially chiral 1‐aryl isoquinolines in excellent yields and enantioselectivity (up to 98% yield and 99:1 er). The synthetic application of the current method was demonstrated by functional group transformations and suitability for millimolar‐scale reactions. Detailed experimental and theoretical studies revealed the turnover‐limiting step and provided insight into the origin of the enantioselectivity for this reaction.