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.
Highlights
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
The carbon–oxygen bond disconnection at C10 leads to the 5,6-dehydrodecalin precursor III, which would enable the crucial late-stage assembly of either the cis- or trans-decalin by an acid-promoted isomerization/cyclization sequence
To account for maximum modularity and convergence, we opted to break down III further into the simple building blocks phenol IV, diene V, and tiglic acid-derived dienophile VI using a sp2–sp[3] cross-coupling and an exo-selective, auxiliary-controlled Diels–Alder reaction that was described in seminal work by Danishefsky[34] and Minnaard[35]
Summary
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. Only a preliminary structure–activity relationship (SAR) study of semi-synthetic analogs of stachyflin (1) has been reported, revealing that subtle modifications of the aromatic isoindolinone component have a drastic effect on the observed H1N1 activity[28,29,30,31,32] We address these limitations and describe a highly modular synthetic platform for the construction of six natural products and 15 fully synthetic molecules that were previously inaccessible using semi-synthesis. Biological profiling reveals that this class of meroterpenoids has potent antibiotic activity against methicillinresistant Staphylococcus aureus
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