Silver-Catalyzed Asymmetric Synthesis of 1,3-Substituted Cuneanes: An Application to a Chiral Isostere of meta-Substituted Benzenes

Cubane, a unique cubic hydrocarbon, is known to undergo isomerization into a wedge-shaped hydrocarbon, cuneane, in the presence of certain transition metals. 1,3- and 2,6-substituted cuneanes have potential as isosteres of benzene rings, and their intrinsic chirality is promising for further biological optimizations. Herein, we report an unprecedented asymmetric isomerization of readily available 1,4-substituted cubanes into 1,3-substituted cuneanes catalyzed by a chiral silver phosphate. DFT calculations elucidated the detailed reaction mechanisms and the origin of enantioselectivity. Moreover, physicochemical evaluation of cuneane analogs of drugs bearing meta-substituted benzene moieties revealed the potential applicability of enantiopure cuneanes as chiral benzene bioisosteres.