新加坡国立大学Wu Jie团队报道了芳烃、乙烯和杂芳烃的模块化组装合成1,2-芳基杂芳烃乙烷。相关研究成果发表在2024年6月27日出版的《自然—化学》。

1,2-芳基异芳基乙烷基序是一种特殊的支架，在药物发现中具有重要意义。这些分子的常规从头合成在很大程度上依赖于预功能化的合成子，需要苛刻的条件和多步骤的过程。

该文中，为了解决这些限制，研究人员提出了一种使用原料化学品（包括乙烯、芳烃和杂芳烃）直接合成1,2-芳基异芳基乙烷的模块化方法。研究人员公开了一种光三重态能量转移引发的自由基级联过程，利用芳基锍盐中C–S键的均裂裂解，作为获得具有优异区域选择性的芳基自由基的关键步骤。

该方法使生物活性分子的快速结构多样化，显示出优异的官能团耐受性，并简化了生物活性化合物及其衍生物的合成。此外，该方法可以扩展到丙烯、非气态末端烯烃和各种其他亲电自由基前体，包括杂芳基、羟基、三氟甲基和α-羰基烷基。

该项研究强调了自由基极性匹配在设计选择性多组分联轴器中的重要性。

附：英文原文

Title: Modular assembly of arenes, ethylene and heteroarenes for the synthesis of 1,2-arylheteroaryl ethanes

Author: Liu, Tao, Li, Talin, Tea, Zhi Yuan, Wang, Chu, Shen, Tianruo, Lei, Zhexuan, Chen, Xuebo, Zhang, Weigang, Wu, Jie

Issue&Volume: 2024-06-27

Abstract: The 1,2-arylheteroaryl ethane motif stands as a privileged scaffold with promising implications in drug discovery. Conventional de novo syntheses of these molecules have relied heavily on pre-functionalized synthons, entailing harsh conditions and multi-step processes. Here, to address these limitations, we present a modular approach for the direct synthesis of 1,2-arylheteroaryl ethanes using feedstock chemicals, including ethylene, arenes and heteroarenes. We disclosed a photo triplet-energy-transfer-initiated radical cascade process, leveraging homolytic cleavage of C–S bonds in aryl sulfonium salts as the key step to access aryl radicals with excellent regioselectivity. This method allows for rapid structural diversification of bioactive molecules, showcasing excellent functional group tolerance and streamlining the synthesis of bioactive compounds and their derivatives. Furthermore, our approach can be extended to propylene, non-gaseous terminal alkenes and various other electrophilic radical precursors, including heteroaryl radicals, hydroxyl radicals, trifluoromethyl radicals and α-carbonyl alkyl radicals. This study highlights the significance of radical polarity matching in designing selective multi-component couplings.

DOI: 10.1038/s41557-024-01560-7

Source: https://www.nature.com/articles/s41557-024-01560-7