Total synthesis of twenty-five picrotoxanes by virtual library selection

The synthesis of a complex molecule begins from an initial design stage^1,2,3,4 in which possible routes are triaged by strategy and feasibility, based on analogy to similar reactions.^2,3 However, as molecular complexity increases, predictability decreases;⁵ 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. To solve this problem but avoid tedious guess-and-check experimentation, we built a virtual library of elusive late-stage intermediate analogs that were triaged by reactivity and altered the synthesis pathway. The efficiency of this method led to concise routes to twenty-five naturally-occurring picrotoxanes. Costly DFT transition state calculations were replaced with faster reactant parameterizations to increase scalability and, in this case, inform mechanism. This approach served as an add-on search to human or computer-assisted synthesis planning (CASP) applicable to high complexity targets and/or steps with little representation in the literature or reaction databases.