美国普林斯顿大学MacMillan, David W. C.团队报道了双基多环的耦合-闭合构造。相关研究成果发表在2024年3月13日出版的国际学术期刊《自然》。

杂芳烃是普遍存在于生物活性分子中的基序，与芳烃对映体相比，具有良好的物理性质。特别是，半饱和杂芳烃具有吸引人的溶解性和更高比例的sp3碳，这可以提高结合亲和力和特异性。然而，由于目前合成方法的局限性，这些理想的结构仍然很少。事实上，半饱和杂环是通过非模块化的适合用途的合成方法费力地制备的，这降低了产量，限制了化学多样性，并阻止了它们被包括在许多直接生产活动中。

该文中，研究人员描述了一种更直观和模块化的耦合闭合方法，从对偶自由基前体构建半饱和环系统。该平台将金属光氧化还原C（sp2）–C（sp3）交叉偶联与分子内Minisci型自由基环化相结合，将丰富的杂芳基卤化物与作为双自由基合成子的简单双功能原料融合，以快速组装各种传统方法极难制备的螺环、桥环和取代饱和环类。由于所需原料的广泛供应，可以对勘探不足的化学空间区域进行采样。试剂控制的自由基生成导致高度区域选择性和立体特异性的环化，可用于药物支架的后期功能化，取代漫长的从头合成。

附：英文原文

Title: Couple-close construction of polycyclic rings from diradicals

Author: Long, Alice, Oswood, Christian J., Kelly, Christopher B., Bryan, Marian C., MacMillan, David W. C.

Issue&Volume: 2024-03-13

Abstract: Heteroarenes are ubiquitous motifs in bioactive molecules, conferring favourable physical properties when compared to their arene counterparts1,2,3. In particular, semisaturated heteroarenes possess attractive solubility properties and a higher fraction of sp3 carbons, which can improve binding affinity and specificity. However, these desirable structures remain rare owing to limitations in current synthetic methods4,5,6. Indeed, semisaturated heterocycles are laboriously prepared by means of non-modular fit-for-purpose syntheses, which decrease throughput, limit chemical diversity and preclude their inclusion in many hit-to-lead campaigns7,8,9,10. Herein, we describe a more intuitive and modular couple-close approach to build semisaturated ring systems from dual radical precursors. This platform merges metallaphotoredox C(sp2)–C(sp3) cross-coupling with intramolecular Minisci-type radical cyclization to fuse abundant heteroaryl halides with simple bifunctional feedstocks, which serve as the diradical synthons, to rapidly assemble a variety of spirocyclic, bridged and substituted saturated ring types that would be extremely difficult to make by conventional methods. The broad availability of the requisite feedstock materials allows sampling of regions of underexplored chemical space. Reagent-controlled radical generation leads to a highly regioselective and stereospecific annulation that can be used for the late-stage functionalization of pharmaceutical scaffolds, replacing lengthy de novo syntheses.

DOI: 10.1038/s41586-024-07181-x

Source: https://www.nature.com/articles/s41586-024-07181-x