Enantioselective C–H functionalization of bicyclo[1.1.1]pentanes

Bicyclo[1.1.1]pentanes (BCPs) are highly strained carbocycles that have fascinated the chemical community for decades because of their unique structure. Despite the immense interest in this scaffold and extensive synthetic efforts, the construction of BCP derivatives still relies substantially on the manipulation of dimethyl bicyclo[1.1.1]pentane-1,3-dicarboxylate. Furthermore, BCPs that contain a proximal stereocentre are underrepresented in the literature and their generation requires stoichiometric chiral auxiliaries. Here we explore enantioselective C–H functionalization of BCPs as a conceptually innovative strategy that provides access to chiral substituted BCPs. For this purpose, enantioselective intermolecular sp3 C–H insertion reactions of donor/acceptor diazo compounds catalysed by the chiral dirhodium complex, Rh2(TCPTAD)4, were employed to forge new C–C bonds at the tertiary position of a variety of BCPs. This work also establishes that highly strained molecules can undergo direct C–H insertion without losing the integrity of their carbocyclic framework. Bicyclo[1.1.1]pentanes are of interest to the pharmaceutical and chemical communities, due largely to their metabolic stability and potential as bioisosteres. Here the enantioselective C–H activation of these carbocycles is reported, giving access to enantioenriched, substituted products while maintaining the carbocyclic framework.