Catalytic Enantioselective Remote Transannular Desymmetrization of Calix[4]Arenes to Inherently Chiral...

There has been a recent surge in research aimed at synthesizing inherently chiral macrocycles that lack point, axial, planar, or helical chirality. To overcome the structural limitations of existing inherently chiral macrocyclic systems, which often suffer from facile racemization due to conformational flexibility, we report herein an asymmetric synthesis of a new class of inherently chiral double-macrocyclic molecules through an intramolecular macrocyclization strategy, employing calix[4]arenes as the starting platform. Catalyzed by [Pd(allyl)Cl]₂ and a chiral phosphoramidite ligand, calix[4]arene derivatives bearing a monoaryl bromide linker at the upper rim underwent a facile enantioselective remote transannular Suzuki-Miyaura coupling with the adjacent upper-rim position of the neighboring arene unit, furnishing the desired inherently chiral double-calixarene macrocycles in up to 71% yield and 91% ee. The resulting double macrocycles feature stable conformations and unique semi-enveloped chiral cavities, and exhibit promising chiral catalytic and chiroptical properties.