School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
Nat Commun. 2018 Nov 15;9(1):4802. doi: 10.1038/s41467-018-07194-x.
The expedient assembly of complex, natural product-like small molecules can deliver new chemical entities with the potential to interact with biological systems and inspire the development of new drugs and probes for biology. Diversity-oriented synthesis is a particularly attractive strategy for the delivery of complex molecules in which the 3-dimensional architecture varies across the collection. Here we describe a folding cascade approach to complex polycyclic systems bearing multiple stereocentres mediated by reductive single electron transfer (SET) from SmI. Simple, linear substrates undergo three different folding pathways triggered by reductive SET. Two of the radical cascade pathways involve the activation and functionalization of otherwise inert secondary alkyl and benzylic groups by 1,5-hydrogen atom transfer (HAT). Combination of SmI, a privileged reagent for cascade reactions, and 1,5-HAT can lead to complexity-generating radical sequences that unlock access to diverse structures not readily accessible by other means.
复杂的、类似天然产物的小分子的权宜组装可以提供具有与生物系统相互作用的潜力的新化学实体，并激发用于生物学的新药和探针的开发。多样性导向合成是一种特别有吸引力的策略，可用于提供在整个集合中变化的 3 维结构的复杂分子。在这里，我们描述了一种通过 SmI 的还原单电子转移（SET）介导的带有多个立体中心的复杂多环系统的折叠级联方法。简单的线性底物通过还原 SET 经历三种不同的折叠途径。两个自由基级联途径涉及通过 1,5-氢原子转移（HAT）激活和官能化否则惰性的仲烷基和苄基基团。SmI 的组合，用于级联反应的特权试剂，和 1,5-HAT 可以导致生成复杂的自由基序列，这些序列可以解锁通过其他方式不易获得的各种结构。
