Synthesis of (E)-4-methylhexa-3,5-dien-1-ol and its Diels-Alder reaction with thioester dienophiles: a short enantioselective synthesis of bicyclic lactones

The preparation of (E)-4-methylhexa-3,5-dien-1-ol has been achieved in a single step from 3-methylpenta-1,4-diene via deprotonation with BuLi, alkylation with paraformaldehyde, and metal counterion exchange in situ to promote oxy-anion accelerated [1,3]-sigmatropic shift. This alcohol is shown to undergo intermolecular Diels-Alder reaction with 3-isopropyl acrylate thioesters; the so-formed exclusive endo-adduct may then be closed to the bicyclic lactone, the product of formal intramolecular Diels-Alder reaction (a much more difficult process). Use of chiral thioesters results in an enantioselective synthesis of this bicyclic lactone, an intermediate with application to eunicellane (cladiellane) diterpene synthesis.