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) that bear three all-carbon quaternary centers, with yields reaching up to 83%. The utilization of easily accessible starting materials, mild reaction conditions, a metal-free one-pot procedure, and a broad substrate scope, along with the discovery that 2,2-disubstituted BCP-decorated bioactive molecules exhibit superior antitumor activity compared to the anticancer drug Sonidegib, render 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 a singlet carbene species and a BCB ring.