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Biocatalytic site- and enantioselective oxidative dearomatization of phenols

Abstract

The biocatalytic transformations used by chemists are often restricted to simple functional-group interconversions. In contrast, nature has developed complexity-generating biocatalytic reactions within natural product pathways. These sophisticated catalysts are rarely employed by chemists, because the substrate scope, selectivity and robustness of these catalysts are unknown. Our strategy to bridge the gap between the biosynthesis and synthetic chemistry communities leverages the diversity of catalysts available within natural product pathways. Here we show that, starting from a suite of biosynthetic enzymes, catalysts with complementary substrate scope as well as selectivity can be identified. This strategy has been applied to the oxidative dearomatization of phenols, a chemical transformation that rapidly builds molecular complexity from simple starting materials and cannot be accomplished with high selectivity using existing catalytic methods. Using enzymes from biosynthetic pathways, we have successfully developed a method to produce ortho-quinol products with controlled site- and stereoselectivity. Furthermore, we have capitalized on the scalability and robustness of this method in gram-scale reactions as well as multi-enzyme and chemoenzymatic cascades.

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Figure 1: Strategies for oxidative dearomatization of phenolic compounds and application in complex molecule synthesis.
Figure 2: Nature's tools for oxidative dearomatization of resorcinol compounds.
Figure 3: One-pot cascades featuring biocatalytic oxidative dearomatization to access natural products.

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Acknowledgements

This work was supported by funds from the University of Michigan Life Sciences Institute and Department of Chemistry. The authors thank Y. Tang from the University of California Los Angeles for providing a plasmid containing azaH. S.A.B.D. acknowledges a National Institutes of Health Chemistry Biology Interface Training Grant (T32 GM008597). A.L.L. acknowledges Graduate Assistance of Areas in National Need (GAANN P200A150164) for funding. The authors thank C. Suh and J. Liu for assistance with the synthesis of substrates.

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S.A.B.D., A.L.L. and A.R.H.N. designed, carried out and analysed all experiments. S.A.B.D. and M.R.B. synthesized all compounds. S.A.B.D. and A.L.L. expressed and purified proteins. S.A.B.D. and A.R.H.N. wrote the manuscript, with input from all of the authors.

Corresponding author

Correspondence to Alison R. H. Narayan.

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The authors declare no competing financial interests.

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Baker Dockrey, S., Lukowski, A., Becker, M. et al. Biocatalytic site- and enantioselective oxidative dearomatization of phenols. Nature Chem 10, 119–125 (2018). https://doi.org/10.1038/nchem.2879

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