Enantioselective Synthesis of 2,4-Disubstituted Homocubanes as meta-Benzene Bioisosteres

Bridged or caged polycyclic hydrocarbons are of interest in medicinal chemistry as bioisosteric replacements for benzene rings because of their greater three-dimensionality and often improved physicochemical properties. Cubanes are regarded as particularly effective benzene bioisosteres but they are challenging to prepare economically on scale. Despite their close structural homology to cubanes, homocubanes have surprisingly been underexplored as benzene bioisosteres. Herein, we describe the straightforward synthesis of chiral 2,4-disubstituted homocubanes as potential meta-benzene bioisosteres. Both enantiomeric series are accessible in 97% ee using asymmetric catalysis and late-stage diversification is achieved through standard cross-coupling reactions. The two enantiomers of a homocubane analogue of the antileukemia drug ponatinib (Iclusig) were also prepared, in which the 1,3,4-trisubstituted benzene ring was replaced with a 2,4-disubstituted homocubane.