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An eight-step synthesis of epicolactone reveals its biosynthetic origin

Nature Chemistry volume 7, pages 879–882 (2015)Cite this article

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Abstract

Epicolactone is a recently isolated fungal metabolite that is highly complex for its size, and yet racemic. With its array of quaternary stereocentres, high degree of functionalization and intricate polycyclic structure, it poses a considerable challenge to synthesis, a challenge that can be met by understanding its biosynthetic origin. If drawn in a certain way, epicolactone reveals a pattern that resembles purpurogallin, the archetype of ubiquitous natural colourants formed via oxidative dimerization. Based on this insight, we designed a biomimetic synthesis of epicolactone that proceeds in only eight steps from vanillyl alcohol. We have isolated a key intermediate that supports our biosynthetic hypothesis and anticipate that an isomer of epicolactone stemming from our synthetic efforts could also be found as a natural product.

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Figure 1: The structure of epicolactone (1) from several different perspectives.
Figure 2: Biosynthetic analogy between purpurogallin and epicolactone.
Figure 3: Total synthesis of epicolactone after the proposed biosynthesis and formation of isoepicolactone.
Figure 4: Isolation of the carbonyl-bridged intermediate.
Figure 5: Failed approaches to the synthesis of epicolactone and synthesis of dibefurin.

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Change history

  • 21 September 2015

    In the version of this Article originally published online there was an error in Figure 3. The citation for the five-step synthesis of epicoccine should have read 'ref. 20'. This mistake was introduced in house and has been corrected in all versions of the Article.

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Acknowledgements

We thank the Deutsche Forschungsgemeinschaft (SFB 749) and Center for Integrated Protein Science, Munich for financial support. P.E. gratefully acknowledges the Verband der Chemischen Industrie for a Kekulé Mobility Fellowship. We thank K. Sakata and M. Kojima for experimental assistance. We also thank P. Mayer (LMU Munich) for X-ray analyses.

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Author notes

  1. Pascal Ellerbrock and Nicolas Armanino: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Chemistry and Center for Integrated Protein Science, Ludwig Maximilians University Munich, Butenandtstraße 5-13, Munich, 81377, Germany

    Pascal Ellerbrock, Nicolas Armanino, Marina K. Ilg, Robert Webster & Dirk Trauner

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  1. Pascal Ellerbrock
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  2. Nicolas Armanino
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  3. Marina K. Ilg
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  4. Robert Webster
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  5. Dirk Trauner
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Contributions

D.T. conceived, designed and directed the project and wrote the manuscript with assistance from N.A. and P.E. M.K.I. and R.W. designed and performed experiments in the early phase of the project and P.E. and N.A. designed and performed experiments that led to its successful conclusion.

Corresponding author

Correspondence to Dirk Trauner.

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The authors declare no competing financial interests.

Supplementary information

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Supplementary information (PDF 3194 kb)

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Crystallographic data for compound 19 (CIF 903 kb)

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Crystallographic data for compound 20 (CIF 628 kb)

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Crystallographic data for compound 28 (CIF 1488 kb)

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Ellerbrock, P., Armanino, N., Ilg, M. et al. An eight-step synthesis of epicolactone reveals its biosynthetic origin. Nature Chem 7, 879–882 (2015). https://doi.org/10.1038/nchem.2336

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