美国德克萨斯大学Qin, Tian团队报道了桥取代双环[1.1.1]戊烷双硼酸盐的可编程后期功能化。相关研究成果于2023年10月26日发表在国际顶尖学术期刊《自然—化学》。

模块化功能化实现了对化学空间的多用途探索，并在药物发现过程中广泛应用于芳香支架的结构-活性关系（SAR）研究。最近，双环[1.1.1]戊烷（BCP）基序作为苯环的生物同位取代物，由于其能够改善潜在候选药物的物理化学性质，越来越受到关注，但研究C2取代的BCP的SAR受到了对每种感兴趣类似物的多步从头合成需求的严重限制。

该文中，研究人员报道了一种可编程的双功能化策略，以实现BCP双硼酸酯的后期顺序衍生，为探索具有多取代BCP基序的候选药物的SAR开辟了机会。该方法利用了BCP双硼酸酯表现出的固有化学选择性，实现了桥头堡（C3）-硼酸频哪醇酯（Bpin）的高度选择性活化和功能化，使C2 Bpin保持完整并为随后的衍生化做好准备。BCP桥头堡（C3）和桥（C2）位置的这些选择性转化使得能够进入C1，C2二取代和C1，C2，C3三取代的BCP，其包含先前未探索的化学空间。

附：英文原文

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

Author: Yang, Yangyang, Tsien, Jet, Dykstra, Ryan, Chen, Si-Jie, Wang, James B., Merchant, Rohan R., Hughes, Jonathan M. E., Peters, Byron K., Gutierrez, Osvaldo, Qin, Tian

Issue&Volume: 2023-10-26

Abstract: 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.

DOI: 10.1038/s41557-023-01342-7

Source: https://www.nature.com/articles/s41557-023-01342-7