Total synthesis of 25 picrotoxanes by virtual library selection

The synthesis of a complex molecule begins from an initial design stage^1-4 in which possible routes are triaged by strategy and feasibility, on the basis of analogy to similar reactions^2,3. 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.