Diastereoselective phenol para-alkylation: access to a cross-conjugated cyclohexadienone en route to resiniferatoxin

We document a route for the synthesis of a densely functionalized spiro-fused 2,5-cyclohexadienone as an intermediate for the synthesis of resineferatoxin. The strategy is based on an unprecedented diastereoselective, intramolecular phenol para-alkylation to a cross-conjugated cyclohexadienone. In the course of these synthetic studies we developed rapid access to a chiral nitrile possessing a quaternary stereocenter and disclose an unusual acetal rearrangement from a dioxane, which favors the corresponding dioxepane.