Heteroarenes are ubiquitous motifs in bioactive molecules, conferring favourable physical properties when compared to their arene counterparts^1,2,3. 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 methods^4,5,6. 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 campaigns^7,8,9,10. 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.

杂芳烃是生物活性分子中普遍存在的基序，与芳烃对应物相比，杂芳烃具有良好的物理特性^1,2,3。特别是，半饱和杂芳烃具有有吸引力的溶解度特性和较高比例的sp ³碳，这可以提高结合亲和力和特异性。然而，由于当前合成方法的限制，这些理想的结构仍然很少^4,5,6。事实上，半饱和杂环是通过非模块化的适合目的的合成方法费力地制备的，这降低了通量，限制了化学多样性，并妨碍了它们被纳入许多先导研究活动中^7,8,9,10。在这里，我们描述了一种更直观和模块化的耦合闭合方法，用于从双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( sp ² )–C( sp ³ )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简单的双功能原料融合，作为双自由基合成子，快速组装各种螺环、桥接和取代的饱和环类型通过传统方法极难制备。所需原料的广泛可用性允许对未充分开发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成环，可用于药物支架的后期功能化，取代冗长的从头合成。