Total synthesis of 25 picrotoxanes by virtual library selection

• 成果类型: Article
• 署名作者: Li, Chunyu; Shenvi, Ryan A.
• 署名单位: Scripps Research Institute; Scripps Research Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2292
• DOI: 10.1038/s41586-024-08538-y
• 发表日期: 2025-02-27
• 关键词: stereocontrolled total-synthesis; hydrogen abstraction; organic-chemistry; alkoxyl radicals; transition-state; 2nd-generation; corianin; cleavage; complex; MODEL

摘要

The synthesis of a complex molecule begins from an initial design stage1, 2, 3-4 in which possible routes are triaged by strategy and feasibility, on the basis of analogy to similar reactions2,3. However, as molecular complexity increases, predictability decreases5; inevitably, even experienced chemists resort to trial and error to identify viable intermediates en route to the target molecule. We encountered such a problem in the synthesis of picrotoxane sesquiterpenes in which pattern-recognition methods anticipated success, but small variations in structure led to failure. Here, to solve this problem but avoid tedious guess-and-check experimentation, we built a virtual library of elusive late-stage intermediate analogues that were triaged by reactivity and altered the synthesis pathway. The efficiency of this method led to concise routes to 25 naturally occurring picrotoxanes. Costly density-functional-theory transition-state calculations were replaced with faster reactant parameterizations to increase scalability and, in this case, inform the mechanism. This approach can serve as an add-on search to human or computer-assisted synthesis planning applicable to high-complexity targets and/or steps with little representation in the literature or reaction databases.