Programmable late-stage functionalization of bridge-substituted bicyclo[1.1.1]pentane bis-boronates.
Programmable late-stage functionalization of bridge-substituted bicyclo[1.1.1]pentane bis-boronates.
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桥取代的双环[1.1.1]戊烷双硼酸酯的可编程后期功能化。
DOI：
10.1038/s41557-023-01342-7
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发表时间：
2024
期刊：
影响因子：
21.8
通讯作者：
Qin,Tian
中科院分区：
文献类型：
--
作者：
Yang,Yangyang;Tsien,Jet;Dykstra,Ryan;Chen,Si-Jie;Wang,JamesB;Merchant,RohanR;Hughes,JonathanME;Peters,ByronK;Gutierrez,Osvaldo;Qin,Tian
模块化功能化可以对化学空间进行多方面的探索，并已广泛应用于药物发现过程中芳香族支架的构效关系（SAR）研究。最近，双环[1.1.1]戊烷（BCP）基序越来越受到关注，作为一个生物电子等排取代苯环，由于其能够改善潜在的候选药物的物理化学性质，但研究的SAR的C2-取代的BCP已严重限制，需要多步从头合成的每一个类似物的兴趣。在这里，我们报告了一个可编程的双官能化策略，使后期的顺序衍生BCP双硼酸盐，开辟了机会，探索具有多取代BCP基序的候选药物的SAR。我们的方法利用BCP双硼酸酯所表现出的固有化学选择性，使桥头（C3）-硼酸频哪醇酯（Bpin）的高选择性活化和功能化，使C2-Bpin完整并为后续衍生化做好准备。BCP桥头（C3）和桥（C2）位置的这些选择性转化使得能够获得C1，C2-二取代和C1，C2，C3-三取代的BCP，这些BCP包含以前未探索的化学空间。
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.