Total Synthesis of (–)-Picrotoxinin

We report a concise, stereocontrolled synthesis of the neurotoxic sesquiterpenoid, (–)-picrotoxinin (1, PXN). The brevity of the route owes to regio- and stereoselective formation of the [4.3.0] bicyclic core by incorporation of a symmetrizing geminal dimethyl group at C5. A series of strong C–C and C–H bond oxidations convert the C5 gem-dimethyl group to the C15 lactone of PXN. This counterintuitive strategy features the first example of demethylation (C–C bond cleavage) in total synthesis.