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A modular synthesis of tetracyclic meroterpenoid antibiotics

Author

Listed:
  • Raphael Wildermuth

    (Ludwig-Maximilians-University Munich)

  • Klaus Speck

    (Ludwig-Maximilians-University Munich)

  • Franz-Lucas Haut

    (Ludwig-Maximilians-University Munich)

  • Peter Mayer

    (Ludwig-Maximilians-University Munich)

  • Bianka Karge

    (Helmholtz Centre for Infection Research and German Center for Infection Research (DZIF))

  • Mark Brönstrup

    (Helmholtz Centre for Infection Research and German Center for Infection Research (DZIF))

  • Thomas Magauer

    (Ludwig-Maximilians-University Munich
    University of Innsbruck)

Abstract

Stachyflin, aureol, smenoqualone, strongylin A, and cyclosmenospongine belong to a family of tetracyclic meroterpenoids, which, by nature of their unique molecular structures and various biological properties, have attracted synthetic and medicinal chemists alike. Despite their obvious biosynthetic relationship, only scattered reports on the synthesis and biological investigation of individual meroterpenoids have appeared so far. Herein, we report a highly modular synthetic strategy that enabled the synthesis of each of these natural products and 15 non-natural derivatives. The route employs an auxiliary-controlled Diels–Alder reaction to enable the enantioselective construction of the decalin subunit, which is connected to variously substituted arenes by either carbonyl addition chemistry or sterically demanding sp2–sp3 cross-coupling reactions. The selective installation of either the cis- or trans-decalin stereochemistry is accomplished by an acid-mediated cyclization/isomerization reaction. Biological profiling reveals that strongylin A and a simplified derivative thereof have potent antibiotic activity against methicillin-resistant Staphylococcus aureus.

Suggested Citation

  • Raphael Wildermuth & Klaus Speck & Franz-Lucas Haut & Peter Mayer & Bianka Karge & Mark Brönstrup & Thomas Magauer, 2017. "A modular synthesis of tetracyclic meroterpenoid antibiotics," Nature Communications, Nature, vol. 8(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02061-7
    DOI: 10.1038/s41467-017-02061-7
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