Rapid and Modular Access to All‐Carbon Quaternary Center‐Containing 2,2‐Disubstituted Bicyclo[1.1.1]pentanes via Cyanocarbene Addition to Bicyclo[1.1.0]butanes

While 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs) have garnered considerable interest in medicinal chemistry as bioisosteres of para-substituted benzenes, the utilization of bridge-functionalized BCPs, especially those containing all-carbon quaternary centers at the bridge-positions, in drug design has lagged behind. This is primarily due to the synthetic challenges associated with these scaffolds. Herein, we report the insertion of diazo-free donor-acceptor carbenes into the C─C bond of bicyclo[1.1.0]butanes (BCBs), enabling the rapid and modular synthesis of 1,2,2,3-tetrasubstituted bicyclo[1.1.1]pentanes (BCPs) bearing three all-carbon quaternary centers in up to 83% yield. This transformation is metal-free, one-pot, operationally simple, and accomodates to a wide range of substrates. The decoration of bioactive molecules with 2,2-disubstituted BCP exhibits superior antitumor activity compared to the anticancer drug Sonidegib, rendering this method highly practical and appealing. Density functional theory (DFT) calculations combined with control experiments reveal that the reaction proceeds through a stepwise nucleophilic ring-opening/recyclization pathway, involving the reaction between the singlet carbene species and the BCB skeleton.