Stereoselective Synthesis of the ABC Ring System of Norzoanthamine Subhash Ghosh, Fatima Rivas, Derek Fischer, Miguel A. Gonza ´lez, and Emmanuel A. Theodorakis* Department of Chemistry and Biochemistry, UniVersity of California, San Diego, 9500 Gilman DriVe, La Jolla, California 92093-0358 etheodor@chem.ucsd.edu Received December 23, 2003 ABSTRACT An efficient synthesis of enone 4, representing the ABC ring motif of norzoanthamine, is presented. The crucial C22 quaternary center was introduced via a stereoselective methylation of enone 8. The trans-anti-trans relative configuration of the ABC framework of 4 was installed via a sequence of reactions that included a hydroboration and a modified Robinson annulation. The zoanthamine alkaloids constitute a distinctive family of marine metabolites that have been isolated during the last 20 years from colonial zoanthids of the genus Zoanthus sp. 1 These natural products are characterized by a densely functionalized and stereochemically rich framework, as exemplified by the structures of zoanthamine (1), 2 norzoan- thamine (2), 3 and zoanthamide (3) 4 (Figure 1), as well as by a wide spectrum of interesting biological activities. 5 For example, compounds 1 and 3 were shown to inhibit phorbol myristate acetate (PMA)-induced inflammation in mouse ear, 4,6 while 2 reportedly inhibits the growth of P-388 murine leukemia cells with an IC 50 value of 24 µg/mL. 3b More significantly, norzoanthamine (2) represents a promising candidate for an antiosteoporotic drug due to its IL-6 inhibitory profile. 1,7 The combination of such challenging molecular architec- tures and potent biological profiles has spurred the develop- ment of novel synthetic strategies that rest primarily on Diels-Alder cycloaddition reactions. 8 Nevertheless, despite such an effort none of these natural products has yet (1) For selected reviews on this topic, see: (a) Rahman, A.-U.; Choudhary, M. I. In Alkaloids; Academic Press: New York, 1999; Vol. 52, pp 233-260. (b) Kuramoto, M.; Yamaguchi, K.; Tsuji, T.; Uemura, D. Zoanthamines, Antiosteoporotic Alkaloids. In Drugs from the Sea; Fusetani, N., Ed.; Karger: Basel, 2000; pp 98-106. (c) Yamada, K.; Kuramoto, M.; Uemura, D. Rec. Res. DeVel. Pure Appl. Chem. 1999, 3, 245-254. (d) Ferna ´ndez, J. J.; Souto, M. L.; Daranas, A. H.; Norte, M. Curr. Topics Phytochem. 2000, 4 105-119. (2) Rao, C. B.; Anjaneyula, A. S. R.; Sarma, N. S.; Venkatateswarlu, Y.; Rosser, R. M.; Faulkner, D. J.; Chen, M. H. M.; Clardy, J. J. Am. Chem. Soc. 1984, 106, 7983-7984. (3) (a) Kuramoto, M.; Hayashi, K.; Fujitani, Y.; Yamaguchi, K.; Tsuji, T.; Yamada, K.; Ijuin, Y.; Uemura, D. Tetrahedron Lett. 1997, 38, 5683- 5686. (b) Fukuzawa, S.; Hayashi, Y.; Uemura, D.; Nagatsu, A.; Yamada, K.; Ijuin, Y. Heterocycl. Commun. 1995, 1, 207-214. (4) Rao, C. B.; Anjaneyulu, A. S. R.; Sarma, N. S.; Venkatateswarlu, Y.; Rosser, R. M.; Faulkner, D. J. J. Org. Chem. 1985, 50, 3757-3760. Figure 1. Selected structures of the zoanthamine alkaloids. ORGANIC LETTERS 2004 Vol. 6, No. 6 941-944 10.1021/ol036492c CCC: $27.50 © 2004 American Chemical Society Published on Web 02/12/2004