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 C 2 -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 (C 3 )-boronic pinacol esters (Bpin), leaving the C 2 -Bpin intact and primed for subsequent derivatization. These selective transformations of both BCP bridgehead (C 3 ) and bridge (C 2 ) positions enable access to C 1 ,C 2 -disubstituted and C 1 ,C 2 ,C 3 -trisubstituted BCPs that encompass previously unexplored chemical space. The bicyclo[1.1.1]pentane (BCP) motif has drawn increasing attention recently in drug discovery. Now, a programmable bis-functionalization strategy has been developed to modularly access bridge-substituted BCP scaffolds, based on the inherent chemoselectivity of BCP bis-boronates (3° > 2°). This strategy should enable further structure–activity relationship studies of BCP-containing drug candidates and open the door to unexplored chemical space.