General Access to Cubanes as Benzene Bioisosteres.

The replacement of benzene rings with sp 3 -hybridized bioisosteres in drug candidates generally improves pharmacokinetic properties while retaining biological activity 1-5 . Rigid, strained frameworks such as bicyclo[1.1.1]pentane and cubane are particularly well-suited since the ring strain imparts high bond strength and thus metabolic stability on its C-H bonds. Cubane is the ideal bioisostere since it provides the closest geometric match to benzene 6,7 . At present, however, all cubanes in drug design, like almost all benzene bioisosteres, act solely as substitutes for mono- or para-substituted benzene rings 1-7 . This is due to the difficulty of accessing 1,3- and 1,2-disubstituted cubane precursors. The adoption of cubane in drug design has been further hindered by the poor compatibility of cross-coupling reactions with the cubane scaffold, owing to a competing metal-catalyzed valence isomerization 8-11 . Herein, we disclose expedient routes to 1,3- and 1,2-disubstituted cubane building blocks using a convenient cyclobutadiene precursor and a photolytic C-H carboxylation reaction, respectively. Moreover, we leverage the slow oxidative addition and rapid reductive elimination of copper to develop C-N, C-C(sp 3 ), C-C(sp 2 ), and C-CF 3 cross-coupling protocols 12,13 . Our research enables facile elaboration of all cubane isomers into drug candidates thus enabling ideal bioisosteric replacement of ortho-, meta-, and para-substituted benzenes.