Total synthesis of graphislactone G
Graphical abstract
Cytotoxic graphislactone G, a metabolite of the fungus Cephalosporium acremonium was synthesized for the first time starting with orcinol and phloroglucinic acid.
Introduction
The metabolisms of fungi1 and lichens2—a symbiosis of algae and fungi, where the latter supply the lichens with secondary metabolites—are very similar. Graphislactone A was identified as reduction product of the fungal metabolite botrallin in 1968,3 but it was first isolated as a natural product from the lichen Graphis scripta var. pulverulenta4 in the late nineties together with graphislactones B–D.4(a), 4(b), 4(c), 4(d) Graphislactones E and F have been isolated from Graphis scripta and Graphis prunicola4d and graphislactones G and H have been isolated from the endophytic fungus Cephalosporium acremonium IFB-E007.5 The biosynthesis of the graphislactones is strongly related to that of alternaria metabolites,4(d), 6 in fact, 3-desmethylgraphislactone A was identified in the metabolism of alternaria toxins.7
A number of biological activities have been reported for graphislactones. Graphislactone A is an antioxidant and a scavenger of free radicals;8 graphislactones A, G, and H were found to be active against the SW1116 cell line (IC50 8.5, 21, and 12 mg/mL, respectively);5 and graphislactone A is a moderate inhibitor of AChE.4e Total syntheses of graphislactones A–F and H have been published by Abe et al.9 and by our group,10 where we were able to supply revised structures of graphislactones E and F. No total synthesis has been published for graphislactones G up to date. Herein we report the first total synthesis of graphislactone G.
Section snippets
Results and discussion
Retrosynthesis of the target compound suggested a Suzuki coupling11 as key step for the construction of the central biaryl bond. Boronate 4 suitable for this transformation could be prepared according to a published procedure10 starting with commercially available acetal-protected phloroglucinic acid 2 (Scheme 1) or—with one more step necessary—from phloroglucinic acid (1).
The other component required for a Suzuki coupling was prepared essentially according to a known protocol12 starting with
Experimental section
Experimental procedures and detailed spectroscopic data for all compounds are given as Supplementary data.
Acknowledgements
We cordially thank Ren Xiang Tan and Hua Wei Zhang for providing NMR spectra of graphislactone G.
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