Meroterpenoids are natural products of hybrid biosynthetic origins—derived from both terpenoid and polyketide pathways—with a wealth of biological activities. Given their therapeutic potential, a general strategy to access these natural products in a concise and divergent fashion is highly desirable. Here, we report a modular synthesis of a suite of oxidized meroterpenoids using a hybrid synthetic strategy that is designed to harness the power of both biocatalytic and radical-based retrosynthetic logic. This strategy enables direct introduction of key hydroxyl groups and rapid construction of key bonds and stereocentres, facilitating the development of a concise route (7–12 steps from commercial materials) to eight oxidized meroterpenoids from two common molecular scaffolds. This work lays the foundation for rapid access to a wide range of oxidized meroterpenoids through the use of similar hybrid strategy that combines two synthetic approaches.
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This work is supported by the National Institutes of Health grant GM128895. We thank P. S. Baran and K. M. Engle for discussions and assistance with manuscript preparation. We acknowledge F. H. Arnold (California Institute of Technology) and H. Zhao for providing plasmids encoding the P450BM3 variant 1857 and phosphite dehydrogenase variant Opt13, respectively. We thank the Shen and Roush laboratories for generous access to their instrumentations.
The authors declare no competing interests.
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Li, J., Li, F., King-Smith, E. et al. Merging chemoenzymatic and radical-based retrosynthetic logic for rapid and modular synthesis of oxidized meroterpenoids. Nat. Chem. 12, 173–179 (2020). https://doi.org/10.1038/s41557-019-0407-6
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