A Bicyclo[3.2.0]hept-3-en-6-one Approach to Prostaglandin Intermediates Emanuela Marotta, Paolo Righi, and Goffredo Rosini* Dipartimento di Chimica Organica “A. Mangini” dell’UniVersita ` di Bologna, Viale Risorgimento no. 4, 40136 Bologna, Italy rosini@ms.fci.unibo.it Received September 27, 2000 ABSTRACT The substituted cyclopentanic structures, 6-benzyloxymethyl-7-hydroxy-2-oxabicyclo[3.3.0]octan-3-one (1), a Corey lactone derivative, and 6-exo- benzyloxymethyl-2-oxabicyclo[3.3.0]oct-7-en-3-one (2), have been obtained stereoselectively through the bicyclo[3.2.0]hept-3-en-6-one approach via 5-benzyloxymethyl-3-hydroxy-6-heptenoic acid, easily accessible from the inexpensive monoprotected cis-2-butene-1,4-diol. Prostaglandins (PGs) constitute a part of a large class of natural products, the eicosanoids, biosynthesized in mammals mainly from arachidonic acid. Their complex structures play key roles in the process of inflammation, in tissue repair, and in immune response. From their initial isolation and characterization, 1 they have acquired immense biochemical importance 2 and have inspired and challenged synthetic chemists for decades. 3,4 Recently, much attention has been devoted to antineoplastic and antiviral prostaglandins 5 and to isoprostanes, 6 epimeric prostaglandins with cis-dialkyl stereochemistry at the five-membered ring. Access to pros- taglandin analogues (prostanoids) with improved pharma- cological profiles has been and continues to be a main target in organic and medicinal chemistry. In attempting to achieve molecular diversity in this field, Ellman 7 and Janda 8 have reported, respectively, the solid-phase synthesis of a variety of E- and F-prostaglandins and the soluble-polymer supported synthesis of a prostanoid library, of which some components have shown an interesting antiviral activity. 8b To better exploit the potentialities of the “toolbox” (cyclopentenone, R-chain, ω-chain) and with the linear/ multistep Corey-type plan 9 to assembly the prostaglandin (1) von Euler, U. S. Arch. Exp. Pathol. Pharmakol. 1934, 175, 78. (2) Collins, P. W.; Djuric, S. W. Chem. ReV. 1993, 93, 1533. (3) (a) Bindra, J. S.; Bindra, R. Prostaglandin Synthesis; Academic Press: New York, 1977. (b) Mitra, A. The Synthesis of Prostaglandins; Wiley: New York, 1977. (c) New Synthetic Routes to Prostaglandins and Tromboxanes; Roberts, S. M., Scheinmann, F., Eds.; Academic Press: New York, 1982. (d) Newton, R. F.; Roberts, S. M. Prostaglandins and Tromboxanes; Butterworth: London, 1982. (e) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; John Wiley and Sons: New York, 1989. (f) Nicolaou, K. C.; Sorensen, E. J. In Classics in Total Synthesis- Targets, Strategies, Methods; VCH: Weinheim, 1996; p 65. (g) Nicolaou, K. C.; Vourlomis, D.; Wissinger, N.; Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 45. (4) For recent general syntheses of these molecules, see: (a) Sannigrahi, M.; Mayhew, D. L.; Clive, D. L. J. J. Org. Chem. 1999, 64, 2776. (b) Fleming, I.; Winter, B. D. Tetrahedron Lett. 1995, 36, 1733. (c) Lipshutz, B. H.; Wood, M. R. J. Am. Chem. Soc. 1994, 116, 11689. (d) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014. (e) Gooding, O. W. J. Org. Chem. 1990, 55, 4209. (f) Noyori, R.; Suzuki, M. Chemtracts: Org. Chem. 1990, 173. (g) Johnson, C. R.; Penning, T. D. J. Am. Chem. Soc. 1988, 110, 4726. (h) Suzuki, M.; Yangisawa, A.; Noyori, R. J. Am. Chem. Soc. 1988, 110, 4718. (5) Suzuki, M.; Kiho, T.; Tomokiyo, K.; Furuta, K.; Fukushima, S.; Takeuchi, Y.; Nakanishi, M.; Noyori, R. J. Med. Chem. 1998, 41, 3084 and literature cited therein. (6) (a) Lai, S.; Lee, D.; U, J. S.; Cha, J. K. J. Org. Chem. 1999, 64, 7213 and literature cited therein. (b) Taber, D. F.; Green, J. H.; Zhang, W.; Song, R. J. Org. Chem. 2000, 65, 5436 and literature cited therein. (7) Thompson, L. A.; Moore, F. L.; Moon, Y.-C.; Ellman, J. A. J. Org. Chem. 1998, 63, 2066. (8) (a) Chen, S.; Janda, K. D. J. Am. Chem. Soc. 1997, 119, 8724; Tetrahedron Lett. 1998, 39, 3943. (b) Lee, K. J.; Angulo, A.; Ghazal, P.; Janda, K. D. Org. Lett. 1999, 1, 1859. ORGANIC LETTERS 2000 Vol. 2, No. 26 4145-4148 10.1021/ol006664v CCC: $19.00 © 2000 American Chemical Society Published on Web 11/28/2000