Quaternary Carbon as a Locus for Skeletal Disconnection. Total Synthesis of (±)-Tubingensin A Featuring Assembly of the Backbone Stereotriad Using a Halo-Prins/Halo-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 halo-Prins/halo-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 cis-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 halo-Nazarov cyclization revealed fluxional behavior in the Friedel-Crafts termination step.