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.

模块化功能化使得化学空间的多功能探索成为可能，并已广泛应用于药物发现过程中芳香支架的构效关系（SAR）研究。近年来，双环[1.1.1]戊烷（BCP）基序作为苯环的生物电子等排替代品越来越受到关注，因为它能够改善潜在候选药物的理化性质，但研究 C 2 取代的 BCP_的SAR由于需要对每个感兴趣的类似物进行多步骤从头合成，因此受到严重限制。在此，我们报告了一种可编程双功能化策略，可实现 BCP 双硼酸盐的后期连续衍生化，为探索具有多取代 BCP 基序的候选药物的 SAR 提供了机会。我们的方法利用 BCP 双硼酸酯所表现出的固有化学选择性，实现桥头 (C ₃ )-硼频哪醇酯 (Bpin) 的高度选择性激活和功能化，使 C ₂ -Bpin 保持完整并为后续衍生化做好准备。BCP桥头(C ₃ )和桥(C ₂ )位置的这些选择性转化使得能够获得包含先前未探索的化学空间的C ₁ ,C _{2 -}二取代和C ₁ ,C ₂ ,C _{3 -三}取代的BCP。