Hybocarpone

The formal total synthesis of hybocarpone was achieved in eight steps from commercially available 1,2,4-trimethoxybenzene. Key transformations include a visible-light-promoted benzannulation to construct the key α-naphthol intermediate and a modified CAN-mediated dimerization/hydration cascade sequence to generate the vicinal all-carbon quaternary centers in a stereocontrolled manner. The total synthesis of boryquinone was also achieved in seven steps.

The inhibitory effects of selected phenolic lichen substances were tested against a panel of methicillin- and multidrug-resistant Staphylococcus aureus. Depsidones with long alkyl chains on both of the aromatic rings were consistently active against the strains tested, comparable to or better than the level of clinically used antibacterial drugs. A similar level of activity was also observed for rhizocarpic acid. The previously described cytotoxic pentacyclic compound hybocarpone was by far the most active, exhibiting minimum inhibitory concentrations (MICs) of 4-8 microg/mL (8.13-16.3 microM) against a range of multidrug efflux pump expressing strains of S. aureus.

The concise synthesis of the lichen-derived antitumor agent hybocarpone (1) and its analogs is described. A new synthetic approach is based on the direct oxidative dimerization of the available naphthazarin precursors in the formation of the binaphtho[2,3-b; 2,3-d]furantetraone structure. It was shown that the first step to tetrahydrofuran features is the bridging hindered S*,S* and R*,S* carbon-carbon bonds of the molecules, setting the relative configurations of the 5aS*,6aS*,12aS*,12bS* and 5aS*,6aR*,12aR*,12bS* diastereomers.