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Asymmetric total syntheses of (+)- and (−)-versicolamide B and biosynthetic implications

Nature Chemistry volume 1, pages 63–68 (2009)Cite this article

A Corrigendum to this article was published on 01 May 2009

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Abstract

The Diels–Alder reaction is one of the most well-studied, synthetically useful organic transformations. Although it has been postulated that a significant number of naturally occurring substances arise by biosynthetic Diels–Alder reactions, rigorous confirmation of a mechanistically distinct natural Diels–Alderase enzyme remains elusive. Within this context, several related fungi within the Aspergillus genus produce a number of metabolites of opposite absolute configuration, including (+)- or (−)-versicolamide B. These alkaloids are hypothesized to arise via biosynthetic Diels–Alder reactions, implying that each Aspergillus species possesses enantiomerically distinct Diels–Alderases. In this paper, experimental validation of these biosynthetic proposals via deployment of the intramolecular hetero-Diels–Alder reaction as a key step in the asymmetric total syntheses of (+)- and (−)-versicolamide B is described. Laboratory validation of the proposed biosynthetic Diels–Alder construction, coupled with the secondary metabolite profile of the producing fungi, reveals that each Aspergillus species has evolved enantiomerically distinct indole oxidases, as well as enantiomerically distinct Diels–Alderases.

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Figure 1: Several representative prenylated indole alkaloids.
Figure 2: Two proposed biosynthetic pathways to (+)-versicolamide B.
Figure 3: Preparation of the dioxopiperazines 19 and 20.
Figure 4: Preparation of the Diels–Alder precursors 23, 25, 27 and 29.
Figure 5: Biomimetic Diels–Alder cycloaddition reactions.
Figure 6: Molecular modelling in support of the observed Diels–Alder stereochemical preference.

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Change history

  • 06 April 2009

    In the version of this Article originally published, the stereochemical descriptors given in the Methods section for compounds 23, 25, 27 and 29 were incorrect, and the graphical abstract on the Table of Contents page was missing a double bond in (+)-versicolamide B. These errors have now been corrected in the HTML and PDF versions.

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Acknowledgements

This paper is dedicated to Tohru Fukuyama on the occasion of his 60th birthday. Financial support from the US National Institutes of Health (CA70375) is gratefully acknowledged. We are indebted to Alan J. Kennan for measurements of CD spectra and Scott Newkirk for HPLC assistance. We thank Frank R. Stermitz for helpful discussions.

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Authors and Affiliations

  1. Department of Chemistry, Colorado State University, Fort Collins, Colorado, 80523-1872, USA

    Kenneth A. Miller & Robert M. Williams

  2. Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba, 263-8522, Japan

    Sachiko Tsukamoto

  3. University of Colorado Cancer Center, Aurora, USA, Colorado, 80045

    Robert M. Williams

Authors
  1. Kenneth A. Miller
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  2. Sachiko Tsukamoto
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Contributions

R.M.W and K.A.M conceived the experiments. K.A.M performed the laboratory experiments and analysed the results. S.T. discovered (−)-versicolamide B as a natural metabolite of a marine-derived Aspergillus species. K.A.M and R.M.W wrote the paper.

Corresponding author

Correspondence to Robert M. Williams.

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Miller, K., Tsukamoto, S. & Williams, R. Asymmetric total syntheses of (+)- and (−)-versicolamide B and biosynthetic implications. Nature Chem 1, 63–68 (2009). https://doi.org/10.1038/nchem.110

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