Advanced strategies and methods for the total synthesis of natural endoperoxides

Natural endoperoxides present a challenge in total synthesis. Over the past decade, we have focused our research on developing new methods to synthesize these heterocycles. These strategies involve the insertion of molecular oxygen into strained cycloalcohols, followed by the addition of silylated nucleophiles to peroxycarbenium species. This approach has been successful in the total synthesis of marine endoperoxides, such as mycaperoxides and ethyl plakortide Z, as well as in the synthesis of analogs of mycangimycin, a natural antifungal and antimalarial agent isolated from an insect–bacteria mutualism. Despite the effectiveness of our strategy, controlling chirality remains a formidable challenge in peroxide synthesis. Silylium-based asymmetric counteranion-directed catalysis enabled the synthesis of chiral endoperoxides and significantly improved previous results in terms of diastereoselectivity.