This proposal describes a total synthesis of the marine fungal metabolite spiroxin A. In spite of a wide array of promising biological activity, which includes antibiotic and antitumor properties, no syntheses of spiroxins, either partial or total, have been reported. The construction of spiroxin A relies upon two key hypervalent iodine mediated ring closures to form the hexacyclic core structure. Iodine (III) will be used to induce both an oxidative spiroketalization and an intramolecular phenolic oxidative biaryl coupling. The possibility of achieving diasteroselectivity in the latter process and relaying that to an asymmetric synthesis of spiroxin a will also be explored. In addition, methodology for the synthesis of functionalized 1,4,5,8-tetrahydroxynaphthalenes via a sterically controlled, regioselective benzyne-furan cycloaddition will be developed to access intermediates necessary for the key coupling reaction. The proposed route to spiroxin A is concise and should allow for further biological screening and the elucidation of the SAR of this intriguing natural product.
| Stengard, J H; Frikke-Schmidt, R; Tybjaerg-Hansen, A et al. (2007) Variation in 5'promoter region of the APOE gene contributes to predicting ischemic heart disease (IHD) in the population at large: the Copenhagen City Heart Study. Ann Hum Genet 71:762-71 |
| Wipf, Peter; Lynch, Stephen M (2003) Synthesis of highly oxygenated dinaphthyl ethers via SNAr reactions promoted by Barton's base. Org Lett 5:1155-8 |
