Programmable late-stage functionalization of bridge-substituted bicyclo[1.1.1]pentane bis-boronates

Modular functionalization enables versatile exploration of chemical space and has been broadly applied in structure-activity relationship (SAR) studies of aromatic scaffolds during drug discovery. Recently, the bicyclo[1.1.1]pentane (BCP) motif has increasingly received attention as a bioisosteric replacement of benzene rings due to its ability to improve the physicochemical properties of prospective drug candidates, but studying the SARs of C₂-substituted BCPs has been heavily restricted by the need for multistep de novo synthesis of each analogue of interest. Here we report a programmable bis-functionalization strategy to enable late-stage sequential derivatization of BCP bis-boronates, opening up opportunities to explore the SARs of drug candidates possessing multisubstituted BCP motifs. Our approach capitalizes on the inherent chemoselectivity exhibited by BCP bis-boronates, enabling highly selective activation and functionalization of bridgehead (C₃)-boronic pinacol esters (Bpin), leaving the C₂-Bpin intact and primed for subsequent derivatization. These selective transformations of both BCP bridgehead (C₃) and bridge (C₂) positions enable access to C₁,C₂-disubstituted and C₁,C₂,C₃-trisubstituted BCPs that encompass previously unexplored chemical space.