A Skeletally Diverse Library of Bioactive Natural Product-Like Compounds Enabled by Late-Stage P450-Catalyzed Oxyfunctionalization

The discovery of small-molecule agents for chemical biology and therapeutic applications depends upon the ability to access and explore new biologically relevant regions of chemical space, a goal often pursued through diversity-oriented synthesis (DOS). In this report, we describe the design and implementation of P450-mediated chemoenzymatic diversity-oriented synthesis (CeDOS), a strategy that leverages chemo- and regiodivergent P450-catalyzed oxyfunctionalizations as key steps for enabling the synthesis of complex molecules that resemble natural products, a major source of bioactive molecules and drugs. Using this strategy, a library of over 50 novel and structurally diverse natural product-like compounds was generated through skeletal rearrangement and diversification of a plant-derived terpene via divergent chemoenzymatic routes enabled by selective C–H hydroxylation and epoxidation reactions catalyzed by engineered P450s. This CeDOS library encompass many unique and unprecedented organic scaffolds, many of which were determined to exhibit notable cytotoxicity against human cancer cells as well as diversified anticancer activity profiles. This work demonstrates the power of the present chemoenzymatic diversity-oriented synthesis strategy for directing the construction and discovery of novel bioactive molecules and it offers a blueprint for the broader application of this approach toward the creation and exploration of natural product-like chemical libraries.