Enantioselective Total Synthesis of (+)-Dracocephalone A, (+)-Dracocequinone A, and (-)-Dracocequinone B by Oxabridge Construction With Oxygen.

Oxa-bridged 20-norabietane diterpenoids, which are characterized by unique 6-oxabicyclo[3.2.1]octane and 2-oxabicyclo[2.2.2]octane frameworks in compact tetracyclic cores, exhibit high structural complexity and interesting biological activity. We report the enantioselective synthesis of (+)-dracocephalone A, (+)-dracocequinone A, and (-)-dracocequinone B, featuring two strategic oxygen-engaged transformations. The 2-oxabicyclo[2.2.2]octane frameworks are constructed via a late-stage oxygen-mediated oxabridge reorganization of 6-oxabicyclo[3.2.1]octane precursors. In this cascade reaction, a redox-neutral disproportionation reaction generates reduced phenolic and oxidized cyclohexadienone intermediates simultaneously, followed by an oxabridge reorganization through selective C10-O bond cleavage and regiospecific 1,6-conjugate addition. The 6-oxabicyclo[3.2.1]octane framework is formed efficiently through an oxygen-engaged oxabridge cyclization. The oxabridge construction strategy demonstrated in this work will allow streamlined syntheses of oxa-bridged bioactive natural products and their structural analogs.