Stereoselective and Enantiospecific Synthesis of Trisubstituted 1,3a,4,6a‐Tetrahydropentalene via Cuneane Scaffold Editing

Cage‐type hydrocarbons represented by cubane serve as molecular scaffolds for various useful molecules, such as pharmaceuticals and organocatalysts. However, even for the most readily available cubane, achieving regioselective substitution and controlled induction of chirality remains extremely challenging. A method to access chiral motifs using achiral 1,4‐disubstituted cubanes, highly symmetric cage‐type molecules, as starting materials has been developed. Through asymmetric isomerization of their molecular frameworks, these cubanes are converted into optically active 2,6‐disubstituted cuneanes. Subsequently, treatment with nucleophiles, such as alcohols and 1,3‐diketones, in the presence of a rhodium catalyst enables the stereoselective and enantiospecific synthesis of trisubstituted 1,3a,4,6a‐tetrahydropentalenes via skeletal isomerization accompanied by nucleophilic addition. This cuneane scaffold editing strategy provides an efficient synthetic route to chiral 1,3a,4,6a‐tetrahydropentalenes bearing substituents. These compounds show promise as asymmetric, cage‐derived, bowl‐shaped diene ligands.