Synthesis of the Enediol Isofurans, Endogenous Oxidation Products of Arachidonic Acid Douglass F. Taber* and Zhe Zhang Department of Chemistry and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716 taberdf@udel.edu ReceiVed September 8, 2005 Isofurans (IsoF’s) are a new class of human arachidonic acid oxidation products. They are produced in vivo by a free radical mechanism, independent of the cyclooxygenase enzymes. These new compounds are available from natural sources only in microgram quantities as mixtures. The enantioselective preparation of two enediol isofurans, 15-epi-ent-SC-Δ 13 -8-IsoF and ent-SC-Δ 13 -8-IsoF, is described. A key transformation in the synthesis is the selective cascade cyclization of a diol epoxide benzenesulfonate to give the substituted tetrahydrofuran skeleton of the isofurans. This synthesis will make these metabolites available for physiological evaluation. Introduction Isofurans (IsoF’s) are a new class of human arachidonic acid oxidation products. 1,2 They are produced in vivo by a free radical mechanism, independent of the cyclooxygenase enzymes. Because these compounds are tetrahydrofuran derivatives that are related biosynthetically to the isoprostanes, they were termed isofurans. 3 When oxygen tension is increased in vitro or in vivo isofuran formation increases more rapidly than does isoprostane formation. Even though they are nonenzymatic oxidation products, the isoprostanes have been found to have significant physiological activity. 4 It is therefore important to also investigate the physiological role of the IsoF’s. We have previously reported 5 a stereodivergent synthesis of the SC-Δ 13 -9-IsoFs (1a and 1b). We now report a general route to the other class of isofurans, the enediol isofurans, represented by 15-epi-ent-SC-Δ 13 -8-IsoF (2a) and ent-SC-Δ 13 -8-IsoF (2b). Results and Discussion Synthetic Approach. Our interest was to develop a flexible route for the construction of the enediol isofurans. We sought an advanced intermediate from which each of the enantiomeri- cally pure diastereomers could be prepared. One such advanced intermediate would be the substituted tetrahydrofuran 3 (Scheme 1). We envisioned that 3 could be prepared by cascade cycliza- tion 6 of the diol epoxide 4. Although there are four different modes of epoxide opening available to the diol 4, it seemed likely that exo cyclization would dominate over endo cyclization and that five-membered-ring formation would be faster than (1) Fessell, J. P.; Porter, N. A.; Moore, K. P.; Sheller, J. R.; Roberts, L. J., II Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 16713. (2) An IsoF-type compound has been reported as a product from enzymatic oxidation of arachidonic acid: (a) Pace-Asciak, C. Biochemistry 1971, 10, 3664. (b) Bild, G. S.; Bhat, S. G.; Ramadoss, C. S.; Axelrod, B.; Sweeley, C. C. Biochem. Biophys. Res. Commun. 1978, 81, 486. Neither the relative nor the absolute configuration of this product was assigned. (3) For isofuran nomenclature, see: Taber, D. F.; Morrow, J. D.; Roberts, L. J. Prostaglandins Other Lipid Mediators 2004, 73, 47. (4) For leading references to the physiological activity of the isoprostanes, see: Fessel, J. P.; Hulette C.; Powell S.; Roberts, L. J., II; Zhang, J. J. Neurochem. 2003, 85, 645. Nothing is yet known about the physiological activity of the isofurans. (5) Taber, D. F.; Pan, Y.; Zhao, X. J. Org. Chem. 2004, 69, 7234. (6) (a) Taber, D. F.; Bhamidipati, R. S.; Thomas, M. L. J. Org. Chem. 1994, 59, 3442. (b) Sivakumar, M.; Borhan, B. Tetrahedron Lett. 2003, 44, 5547. 926 J. Org. Chem. 2006, 71, 926-933 10.1021/jo051889a CCC: $33.50 © 2006 American Chemical Society Published on Web 12/31/2005