Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Roche, S. P. & Porco, J. A. Dearomatization strategies in the synthesis of complex natural products. Angew. Chem. Int. Ed. 50, 4068–4093 (2011).

    Article  CAS  Google Scholar 

  2. Wu, W. T., Zhang, L. M. & You, S. L. Catalytic asymmetric dearomatization (CADA) reactions of phenol and aniline derivatives. Chem. Soc. Rev. 45, 1570–1580 (2016).

    Article  CAS  Google Scholar 

  3. Volp, K. A. & Harned, A. M. Chiral aryl iodide catalysts for the enantioselective synthesis of para-quinols. Chem. Commun. 49, 3001–3003 (2013).

    Article  CAS  Google Scholar 

  4. Zhu, J. L., Grigoriadis, N. P., Lee, J. P. & Porco, J. A. Synthesis of the azaphilones using copper-mediated enantioselective oxidative dearomatization. J. Am. Chem. Soc. 127, 9342–9343 (2005).

    Article  CAS  Google Scholar 

  5. Bosset, C. et al. Asymmetric hydroxylative phenol dearomatization promoted by chiral binaphthylic and biphenylic iodanes. Angew. Chem. Int. Ed. 53, 9860–9864 (2014).

    Article  CAS  Google Scholar 

  6. Wang, W. X. et al. Antibacterial azaphilones from an endophytic fungus, Colletotrichum sp BS4. J. Nat. Prod. 79, 704–710 (2016).

    Article  CAS  Google Scholar 

  7. Yang, Q. L. et al. Evolution of an oxidative dearomatization enabled total synthesis of vinigrol. Org. Biomol. Chem. 12, 330–344 (2014).

    Article  Google Scholar 

  8. Shiao, H. Y., Hsieh, H. P. & Liao, C. C. First total syntheses of (±)-annuionone B and (±)-tanarifuranonol. Org. Lett. 10, 449–452 (2008).

    Article  CAS  Google Scholar 

  9. Nicolaou, K. C. et al. Biomimetic total synthesis of bisorbicillinol, bisorbibutenolide, trichodimerol, and designed analogues of the bisorbicillinoids. J. Am. Chem. Soc. 122, 3071–3079 (2000).

    Article  CAS  Google Scholar 

  10. Pettus, L. H., Van de Water, R. W. & Pettus, T. R. R. Synthesis of (±)-epoxysorbicillinol using a novel cyclohexa-2,5-dienone with synthetic applications to other sorbicillin derivatives. Org. Lett. 3, 905–908 (2001).

    Article  CAS  Google Scholar 

  11. Morrow, G. W. & Schwind, B. Synthesis of para-terphenyl via reductive deoxygenation of quinol derivatives. Synth. Commun. 25, 269–276 (1995).

    Article  CAS  Google Scholar 

  12. Schultz, A. G. & Antoulinakis, E. G. Photochemical and acid-catalyzed rearrangements of 4-carbomethoxy-4-methyl-3-(trimethylsilyl)-2,5-cyclohexadien-1-one. J. Org. Chem. 61, 4555–4559 (1996).

    Article  CAS  Google Scholar 

  13. Dong, S. W., Zhu, J. L. & Porco, J. A. Enantioselective synthesis of bicyclo 2.2.2 octenones using a copper-mediated oxidative dearomatization/4+2 dimerization cascade. J. Am. Chem. Soc. 130, 2738–2739 (2008).

    Article  CAS  Google Scholar 

  14. Sun, W. S., Li, G. F., Hong, L. & Wang, R. Asymmetric dearomatization of phenols. Org. Biomol. Chem. 14, 2164–2176 (2016).

    Article  CAS  Google Scholar 

  15. Uyanik, M., Yasui, T. & Ishihara, K. Hydrogen bonding and alcohol effects in asymmetric hypervalent iodine catalysis: enantioselective oxidative dearomatization of phenols. Angew. Chem. Int. Ed. 52, 9215–9218 (2013).

    Article  CAS  Google Scholar 

  16. Ullrich, R. & Hofrichter, M. Enzymatic hydroxylation of aromatic compounds. Cell. Mol. Life Sci. 64, 271–293 (2007).

    Article  CAS  Google Scholar 

  17. Davison, J. et al. Genetic, molecular, and biochemical basis of fungal tropolone biosynthesis. Proc. Natl Acad. Sci. USA 109, 7642–7647 (2012).

    Article  CAS  Google Scholar 

  18. van Berkel, W. J. H., Kamerbeek, N. M. & Fraaije, M. W. Flavoprotein monooxygenases, a diverse class of oxidative biocatalysts. J. Biotechnol. 124, 670–689 (2006).

    Article  CAS  Google Scholar 

  19. Khalil, A. S. & Collins, J. J. Synthetic biology: applications come of age. Nat. Rev. Genet. 11, 367–379 (2010).

    Article  CAS  Google Scholar 

  20. Turner, N. J. Directed evolution drives the next generation of biocatalysts. Nat. Chem. Biol. 5, 568–574 (2009).

    Article  Google Scholar 

  21. Abood, A. et al. Kinetic characterisation of the FAD-dependent monooxygenase TropB and investigation of its biotransformation potential. RSC Adv. 5, 49987–49995 (2015).

    Article  CAS  Google Scholar 

  22. Zabala, A. O., Xu, W., Chooi, Y. H. & Tang, Y. Characterization of a silent azaphilone gene cluster from Aspergillus niger ATCC 1015 reveals a hydroxylation-mediated pyran-ring formation. Chem. Biol. 19, 1049–1059 (2012).

    Article  CAS  Google Scholar 

  23. Sato, M. et al. Combinatorial generation of chemical diversity by redox enzymes in chaetoviridin biosynthesis. Org. Lett. 18, 1446–1449 (2016).

    Article  CAS  Google Scholar 

  24. Fahad, A. A. et al. Oxidative dearomatisation: the key step of sorbicillinoid biosynthesis. Chem. Sci. 5, 523–527 (2014).

    Article  Google Scholar 

  25. Chenault, H. K. & Whitesides, G. M. Regeneration of nicotinamide cofactors for use in organic synthesis. Appl. Biochem. Biotechnol. 14, 147–197 (1987).

    Article  CAS  Google Scholar 

  26. Zhu, J. L., Germain, A. R. & Porco, J. A. Synthesis of azaphilones and related molecules by employing cycloisomerization of o-alkynylbenzaldehydes. Angew. Chem. Int. Ed. 43, 1239–1243 (2004).

    Article  CAS  Google Scholar 

  27. Barnes-Seeman, D. & Corey, E. J. A two-step total synthesis of the natural pentacycle trichodimerol, a novel inhibitor of TNF-α production. Org. Lett. 1, 1503–1504 (1999).

    Article  CAS  Google Scholar 

  28. Wessman, P., Hakansson, S., Leifer, K. & Rubino, S. Formulations for freeze-drying of bacteria and their influence on cell survival. J. Vis. Exp. 78, e4058 (2013).

    Google Scholar 

  29. Cabrera, G. M. et al. A sorbicillinoid urea from an intertidal Paecilomyces marquandii. J. Nat. Prod. 69, 1806–1808 (2006).

    Article  CAS  Google Scholar 

  30. Zhang, S. P. et al. Antiviral anthraquinones and azaphilones produced by an endophytic fungus Nigrospora sp from Aconitum carmichaeli. Fitoterapia 112, 85–89 (2016).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Contributions

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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 10685 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.2879

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing