Enantioselective Synthesis of Inherently Chiral Quinoline‐Fused Calix[4]arenes via Palladium‐Catalyzed C−H Cycloimidoylation ^†

Comprehensive Summary Owing to their unique architectures, calix[4]arenes exhibit considerable potential in molecular recognition, catalysis, sensing, nanotechnology, and biotechnology. However, the exploration of their structure–function relationships has been constrained by the challenge of synthesizing these molecules in optically pure form. Existing asymmetric strategies include: (1) direct asymmetric macrocyclization; (2) asymmetric post‐assembly modification; and (3) asymmetric substitution to increase the conformational inversion barrier. Although significant progress has been achieved in the enantioselective synthesis of inherently chiral calix[4]arenes, there remains an urgent need for the asymmetric divergent synthesis of inherently chiral calix[4]arenes fused with bicyclic heteroaromatic rings. Palladium‐catalyzed cycloimidoylation of functionalized isocyanides represents a powerful strategy for constructing N ‐heterocyclic frameworks. This approach has proven effective for enantioselective desymmetrization of symmetric isocyanides via C(sp 2 )–H activation, affording N ‐heterocycles with central, planar, axial, and helical chirality. Inspired by our ongoing interest in inherently chiral molecules, we envisioned that Pd‐catalyzed cycloimidoylation could be strategically applied to construct inherently chiral calix[4]arenes with extended aromatic systems. Herein, we report an efficient approach for the enantioselective synthesis of inherently chiral quinoline‐fused calix[4]arenes via palladium‐catalyzed asymmetric C−H cycloimidoylation. The cyclization strategy of forming a six‐membered heterocyclic ring employs readily available calix[4]arene derived isocyanides and aryl iodides as coupling partners under mild conditions with low catalyst loading, and a wide range of calix[4]arenes with extended aromatic systems were obtained with high yields and excellent enantioselectivities (up to >99% ee). Notably, the double C(sp 2 )–H imidoylative annulation of calix[4]arene‐derived bisisocyanides affords unique inherently chiral calix[4]arenes embedded with bis‐phenanthridine units. Density functional theory (DFT) calculations reveal the origin of the enantioselectivity during the C(sp 2 )−H imidoylative cyclization process. This methodology offers versatile access to structurally intriguing inherently chiral calix[4]arenes for further functionalization.