Multicomponent reactions are relied on in both academic and industrial synthetic organic chemistry owing to their step- and atom-economy advantages over traditional synthetic sequences¹. Recently, bicyclo[1.1.1]pentane (BCP) motifs have become valuable as pharmaceutical bioisosteres of benzene rings, and in particular 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para-phenyl ring replacements². These structures are often generated from [1.1.1]propellane via opening of the internal C–C bond through the addition of either radicals or metal-based nucleophiles^{3,4,5,6,7,8,9,10,11,12,13}. The resulting propellane-addition adducts are then transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. Although this approach has been effective so far, a multicomponent reaction that enables single-step access to complex and diverse polysubstituted drug-like BCP products would be more time efficient compared to current stepwise approaches. Here we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicyclopentanes using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. This copper-mediated reaction operates on short timescales (five minutes to one hour) across multiple (more than ten) nucleophile classes and can accommodate a diverse array of radical precursors, including those that generate alkyl, α-acyl, trifluoromethyl and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which is substantially more metabolically stable than its commercial progenitor.

多组分反应在学术和工业合成有机化学中都受到依赖，因为它们相对于传统合成序列¹具有步骤和原子经济优势。最近，双环[1.1.1]戊烷 (BCP) 基序作为苯环的药物生物等排体已变得有价值，特别是 1,3-二取代的 BCP 基序已在药物化学中广泛用作对苯环替代物²。这些结构通常由 [1.1.1] 丙烷通过添加自由基或金属基亲核试剂打开内部 C-C 键生成^{3,4,5,6,7,8,9,10,11, 12,13}. 然后，通过一系列传统上涉及多个化学步骤的合成序列，将所得的丙烷加成加合物转化为必需的多取代 BCP 化合物。尽管这种方法到目前为止是有效的，但与目前的逐步方法相比，能够单步获得复杂和多样的多取代药物样 BCP 产品的多组分反应将更节省时间。在这里，我们报告了 [1.1.1] 丙烷的一步三组分自由基偶联，通过金属光氧化还原催化方案使用各种自由基前体和杂原子亲核试剂提供多种官能化双环戊烷。这种铜介导的反应在多个（十多个）亲核试剂类别中以短时间尺度（5 分钟到 1 小时）运行，并且可以适应各种自由基前体，包括产生烷基、α-酰基、三氟甲基和磺酰基自由基的那些。该方法已被用于快速制备已知药物的 BCP 类似物，其中一种药物的代谢稳定性明显高于其商业前身。