Catalytic Enantioselective Synthesis of Upper-rim-Functionalized Inherently Chiral Calix[4]arenes Through Desymmetrizing Reductive Amination.

Inherently chiral calix[4]arenes (ICCs) are chiral macrocyclic compounds whose chirality arises from the asymmetric distribution of substituents in their rigid cone conformations. Although inherent chirality in these systems has long been recognized, the enantioselective synthesis of these structurally intriguing frameworks, especially non-meta-type ICCs, remains underexplored. In this work, we report a versatile method for the asymmetric synthesis of both ABCD- and ABCC-type ICCs via an enantioselective desymmetrization strategy. Two classes of diamino-substituted prochiral calix[4]arenes were efficiently desymmetrized through chiral phosphoric acid-catalyzed reductive amination with various aldehydes, tolerating a broad range of upper-rim substitutions and affording both ABCD- and ABCC-type ICCs bearing diverse functional groups with high enantioselectivities. Control experiments suggest that the reaction proceeds via sequential enantioselective desymmetrization and kinetic resolution, with reduction of the imine identified as the enantiodetermining step. Various derivatizations of the ICC products were also performed, including three notable examples involving dimerization of ICCs. Moreover, we demonstrate that combining these asymmetric synthetic and derivatization methods could enable the asymmetric synthesis of all six possible stereoisomers of the ABCD-type ICCs. Furthermore, incorporation of fluorophore groups into these inherently chiral frameworks furnished ICC derivatives with promising photophysical and chiroptical properties, further underscoring the potential of this methodology.