A modular synthesis of tetracyclic meroterpenoid antibiotics

作者：Wildermuth Raphael; Speck Klaus; Haut Franz Lucas; Mayer Peter; Karge Bianka; Broenstrup Mark; Magauer Thomas

来源：Nature Communications, 2017, 8(1): 2083.

DOI：10.1038/s41467-017-02061-7

<jats:title>Abstract</jats:title><jats:p>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 sp<jats:sup>2</jats:sup>–sp<jats:sup>3</jats:sup> cross-coupling reactions. The selective installation of either the <jats:italic>cis</jats:italic>- or <jats:italic>trans</jats:italic>-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 <jats:italic>Staphylococcus aureus</jats:italic>.</jats:p>

• 出版日期2017-12-12