Department of Chemistry, Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian, 361005, P.R. China.
Nat Commun. 2020 Oct 20;11(1):5314. doi: 10.1038/s41467-020-19163-4.
The powerful insecticidal and multi-drug-resistance-reversing activities displayed by the stemofoline group of alkaloids render them promising lead structures for further development as commercial agents in agriculture and medicine. However, concise, enantioselective total syntheses of stemofoline alkaloids remain a formidable challenge due to their structural complexity. We disclose herein the enantioselective total syntheses of four stemofoline alkaloids, including (+)-stemofoline, (+)-isostemofoline, (+)-stemoburkilline, and (+)-(11S,12R)-dihydrostemofoline, in just 19 steps. Our strategy relies on a biogenetic hypothesis, which postulates that stemoburkilline and dihydrostemofolines are biogenetic precursors of stemofoline and isostemofoline. Other highlights of our approach are the use of Horner-Wadsworth-Emmons reaction to connect the two segments of the molecule, an improved protocol allowing gram-scale access to the tetracyclic cage-type core, and a Cu-catalyzed direct and versatile nucleophilic alkylation reaction on an anti-Bredt iminium ion. The synthetic techniques that we developed could also be extended to the preparation of other Stemona alkaloids.
生物碱类斯特莫宁组具有强大的杀虫和多种耐药性逆转活性，这使它们有望成为农业和医学领域进一步开发的商业制剂的潜在先导结构。然而，由于其结构复杂，简洁的对映选择性全合成斯特莫宁生物碱仍然是一个艰巨的挑战。我们在此公开了四种斯特莫宁生物碱，包括（+）-斯特莫宁、（+）-异斯特莫宁、（+）-斯特莫布尔基林和（+）-（11S，12R）-二氢斯特莫宁的对映选择性全合成，仅需 19 步。我们的策略依赖于生物发生假说，该假说假设斯特莫布尔基林和二氢斯特莫宁是斯特莫宁和异斯特莫宁的生物前体。我们方法的其他亮点包括使用霍纳-沃兹沃思-埃蒙斯反应连接分子的两个片段，一种改进的方案允许克级获得四环笼型核心，以及铜催化的对反-Bredt 亚胺离子的直接和通用亲核烷基化反应。我们开发的合成技术也可以扩展到其他斯氏宁生物碱的制备。
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