Remote desymmetrization of tetraoxacalix[2]arene[2]triazines enables the asymmetric synthesis of inherently chiral heteracalix[4]aromatics.

The catalytic enantioselective synthesis of inherently chiral macrocycles remains a major challenge, particularly through non-cyclization strategies. Herein, we report a chiral phosphoric acid (CPA)-catalyzed remote desymmetrization of tetraoxacalix[2]arene[2]triazines, enabling access to inherently chiral heteracalix[4]aromatics. The strategy relies on sequential SNAr aminations, in which the first amination installs an aniline N-H unit as a "control handle" that both creates a hydrogen-bonding recognition site for the catalyst and suppresses macrocyclic ring inversion. In the subsequent CPA-catalyzed step, the monoaminated intermediate undergoes kinetic resolution, allowing asymmetric differentiation of two remote enantiotopic sites within a flexible macrocyclic scaffold. The method affords a broad range of inherently chiral heteracalix[4]aromatics in good yields and high to excellent enantioselectivities (up to 99% ee), and is further applicable to disubstituted products and diverse derivatizations. Mechanistic studies indicate that hydrogen-bond-assisted catalyst recognition and steric inhibition of conformational inversion are both crucial for enantiocontrol. This work establishes a practical asymmetric strategy for inherently chiral macrocycles and expands the scope of remote desymmetrization in flexible supramolecular scaffolds.