Asymmetric synthesis of planar-chiral metacyclophanes via aromatic amination enabled enantioselective desymmetrization

Abstract

Metacyclophanes are a type of macrocyclic cyclophanes with the ansa chain linked to the aryl rings at the two meta positions, which have been widely found in natural products and bioactive small molecules. However, due to the stringent requirements for maintaining planar chirality and a crowded environment for macrocyclization, the catalytic enantioselective synthesis of planar-chiral metacyclophanes has received significantly less attention compared to their paracyclophane counterparts. Herein, we present an efficient method for enantioselective synthesis of planar-chiral metacyclophanes through an organocatalyzed desymmetrization strategy. By utilizing the chiral phosphoric acid (CPA)-catalyzed asymmetric aromatic amination reaction between arylamines and azodicarboxylates, we successfully broke the mirror symmetry of prochiral m-phenylenediamine-derived metacyclophanes, which yielded various planar-chiral metacyclophanes with good to high enantioselectivities. Notably, when the prochiral metacyclophane substrates feature additional meta-substituents, chiral cyclophanes with both planar chirality and C–N axial chirality could be generated in a single step. The planar-chiral metacyclophane products have demonstrated good configurational stability and the potential for diverse derivatizations, which underscored the value of this method.