Planar-Chiral Cyclophanes: From Synthetic Strategies to Configurational Stability Control

Conspectus Planar-chiral cyclophanes, which feature rigid aromatic ring conformations locked by flexible ansa chains, are structurally distinctive scaffolds found in bioactive natural products and pharmaceutical agents. They are also widely employed as privileged frameworks in asymmetric catalysis and as functional materials. The intrinsic conformational strain of these macrocycles confers enhanced configurational stability and improved cell permeability, which are properties that are particularly appealing for drug development and chiral material design. Despite their structural significance, precise control over the rotational barrier of the aromatic ring and reliable prediction of the conformational behavior of the ansa chain remain challenging, thereby impeding both methodological advancement and practical applications of planar-chiral cyclophanes. Consequently, the development of efficient asymmetric synthetic routes and systematic investigations of their configurational stability are of paramount importance. This Account reviews the asymmetric catalytic strategies reported by our group, which have enabled the synthesis of over 500 optically active cyclophanes. Type I and Type II cyclophanes, accessed by installing bulky substituents on the aromatic ring and shortening the ansa chain, have been efficiently assembled via Pd-catalyzed C–H activation, N-heterocyclic carbene (NHC)-catalyzed oxidative esterification, and chiral phosphoric acid (CPA)-catalyzed transfer hydrogenation. These methodologies exhibit broad substrate scope and are compatible with the late-stage structural diversification of drug molecules. Importantly, these studies elucidated the intrinsic relationship between the occurrence of planar chirality and two key determinants, namely, the steric hindrance of the aromatic substituents and the length of the ansa bridge. Our previous studies have also revealed that replacing the benzene ring with an indole ring further influences macrocyclic stability. Consequently, indole-based planar-chiral cyclophanes have been constructed via a Rh-catalyzed C–H activation/intramolecular oxidative annulation with high enantioselectivities. This approach enables macrocyclization, indole ring formation, and planar chirality control in a single step and is further applicable to the synthesis of challenging derivatives bearing all-carbon ansa chains. Subsequently, this Account examines the more structurally intricate Type III cyclophanes, revealing that a cooperative NHC/CPA-catalyzed macrolactonization and a CPA-catalyzed asymmetric macrocyclization enabled the formation of Type III cyclophanes bearing either a distal quaternary carbon stereocenter or a benzylic stereocenter on the ansa chain. Relative to their unsubstituted counterparts, these Type III cyclophanes exhibit higher rotational barriers. Notably, the introduction of a naphthyl group at the benzylic position permits a two-atom extension of the ansa chain without compromising the planar chirality. These findings reveal a dual dependence on the macrocyclic ring size and the position of the ansa chain substituents in these strained macrocyclic systems. In summary, this Account describes the precise construction of planar-chiral cyclophane scaffolds, which have been employed for the late-stage functionalization of bioactive molecules and successfully converted into novel chiral ligands and organocatalysts, thereby expanding the molecular repertoire of planar-chiral cyclophanes. More significantly, systematic investigations into configurational stability have revealed the cooperative influence of ring size, substituent steric hindrance, and the position of bulky substituents along the ansa chain on the rotational barrier. Collectively, the findings presented herein provide both a theoretical and practical foundation for the design of configurationally stable functional molecules with potential for future applications in asymmetric catalysis and beyond.