Quaternary Carbon as a Locus for Skeletal Disconnection. Total Synthesis of (±)-Tubingensin A Featuring Assembly of the Backbone Stereotriad Using a <i>Halo</i>-Prins/<i>Halo</i>-Nazarov Cascade

The first successful fragment coupling/cationic cascade approach for the synthesis of a complex indoloditerpenoid tubingensin A is described. The synthesis is the first example of a novel disconnection strategy targeting a central quaternary carbon locus. A <i>halo</i>-Prins/<i>halo</i>-Nazarov cationic cascade sequence enabled the rapid preparation of a complex intermediate as a single diastereomer, containing the vicinal quaternary centers found in the backbone stereotriad. This approach installed much of the complex carbon skeleton of tubingensin A in one step from fragment coupling of two simple reactants. To complete the synthesis, the indane ring system is converted to the target <i>cis-</i>decalin, preserving the integrity of the stereotriad. The isopropylidene fragment is appended in the endgame. The target is obtained in 15 fully diastereoselective steps from simple achiral materials. Investigation of the <i>halo</i>-Nazarov cyclization revealed fluxional behavior in the Friedel-Crafts termination step.