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Total Synthesis of (±)-Merochlorin A
Biomimetic Total Synthesis of (±)-Merochlorin A.
Angew. Chem. Int. Ed. 2013;
18 November 2013 (online)
Key wordsmerochlorin A - antibiotics - oxidative dearomatization - [5+2] cycloaddition - domino reaction
The first total synthesis of (±)-merochlorin A, an unusual chlorinated meroterpenoid isolated from the marine bacterium Streptomyces sp. strain CNH-189, is reported together with an alternative proposal for its biosynthesis. The natural product, which harbors four contiguous stereogenic centers within a compact bicycle[3.2.1]octanone, exhibits antibiotic activity against several multi-drug resistant Staphylococcus aureus strains (MIC = 2-4 μg·mL–1) as well as Clostridium difficile (MIC = 0.15 μg·mL–1) and is thus considered an interesting new lead candidate.
The very concise and potentially biomimetic route towards this natural product as reported by Pepper and George delivers the desired target in a longest linear sequence of only six steps starting from commercially available geranyl bromide and could thus be used to prepare over one gram of this novel antibiotic to date. Thereby, the key element of the synthesis is an oxidative dearomatization–[5+2]-cycloaddition domino reaction that forges the required bicyclic core scaffold as well as all of the four contiguous stereogenic centers in a single step.