Diversity-oriented synthesis (DOS) strategies are attractive approaches to generate collections of natural product-like small molecules with a high degree of complexity and diversity in a few steps. While some DOS strategies have exploited natural products as starting points for creating such collections, these approaches can be limited by the functional groups present in the natural product. In this work, our group explored a new strategy for chemoenzymatic DOS in which P450-catalyzed oxyfunctionalization is leveraged as a key step for enabling the diversification of a natural product scaffold into a library of skeletally diverse natural product-like molecules. Starting from a plant-derived sesquiterpene lactone, this approach was applied to generate a diverse collection of over 40 natural product-like scaffolds by combining late-stage P450-mediated oxidation with various ring formation, expansion, and rearrangement strategies. These novel natural product-like scaffolds were tested against a panel of human cancer cell lines, resulting in the discovery of compounds with highly diverse anti-cancer activity profiles.

Chemoenzymatic diversification of natural products enabled by P450 oxyfunctionalization

ACS Spring 2022

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