Total synthesis of twenty-five picrotoxanes by virtual library selection

Strong-bond activation refers to the conversion of typically inert functional groups (FG) into reactive ones: e.g. C–H or C–C into C–X. Its application in retrosynthetic analysis requires evaluation of strategy (is it simplifying?) and feasibility (will it work?). However, the feasibility of strong bond cleavage can be difficult to predict due to competing low barrier pathways (e.g. 5–8 kcal/mol) in complex molecular environments. If strong bond activation can be strategically evaluated, accurately calculated and experimentally validated, it can simplify the synthesis of complex molecules. Here we build a virtual library of strategic late-stage intermediates en route to diverse picrotoxanes, calculate C–H vs. C–C oxidation preference and experimentally interrogate the predictions. Costly transition state calculations are then simplified to faster parameterizations to explain remote effects on strong bond activation and to devise concise routes to the picrotoxanes .