Exploring the Chemistry of Octadride Natural Products

Maleidrides, fascinating natural products produced by fungi, are characterized by a central medium- sized carbocycle fused to one or two maleic anhydride moieties. They can be differentiated into nonadrides, octadrides, and heptadrides based on their ring size. Biosynthetically, they emerge from the fusion of two nine-carbon-containing building blocks followed by enzymatic postmodifications. Maleidrides exhibit various biological activities and potential pharmaceutical applications ranging from anti-cancer to selective herbicidal activity. The unique structural features and biological profile of maleidrides have generated great interest in the chemical community. However, only a few chemical syntheses of nonadrides have been reported so far and octadride natural products are still inaccessible. This project aims to fill this gap by developing powerful asymmetric syntheses to access several maleidrides in the chemical laboratory. Our routes were designed to combine state-of-the art transition metal catalysis with robust organic transformations allowing for maximum flexibility, high efficiency and minimum waste. The key step involves a powerful intramolecular alkylation approach previously established in our lab. The developed syntheses will allow us to explore novel chemical space which is currently unavailable via semi-synthesis or enzymatic methods. This will have a fundamental impact on the preparation of analogues with deep-seated structural modifications for biological evaluation. Establishing a synthetic platform to access medium-sized maleidrides will pave the way for detailed structure-activity relationship studies with important implications for the development of new drugs.