Synthesis of (-)-Epibatidine David A. Evans,* Karl A. Scheidt, and C. Wade Downey Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138 eVans@chemistry.harVard.edu Received July 10, 2001 ABSTRACT The synthesis of (-)-epibatidine has been accomplished utilizing a highly exo-selective asymmetric hetero Diels-Alder reaction. The key steps employed to transform the resulting bicycle into the natural product include a fluoride-promoted fragmentation and a Hofmann rearrangement. In 1992, Daly and co-workers disclosed the structure of epibatidine (1), an alkaloid isolated from the skin of the Ecuadorian frog Epibatidores tricolor. 1 Because of its scarcity and unprecedented biological activity as a nonopiate analgesic approximately 200 times more potent than mor- phine, 2 widespread efforts have culminated in numerous total and formal syntheses. 3 Surprisingly, while approximately 50 syntheses have been reported, few full syntheses are enantio- selective. 4 In this Letter, we wish to report a highly stereoselective synthesis of (-)-epibatidine by a route that is readily amenable to analogue production. Our approach to 1 relies on a selective hetero Diels-Alder reaction between bis-silyloxy azadiene 4 5 and an unsaturated acyl oxazolidinone (3) appended to the requisite chloro- pyridine ring (Scheme 1). We anticipated that this Diels- Alder reaction promoted by Me 2 AlCl would exhibit high levels of facial selectivity due to the rigid chelate of the activated acyl oxazolidinone. 6 Furthermore, previous con- tributions by Ghosez and co-workers have established that Diels-Alder reactions utilizing 2-azadienes such as 4 are highly exo-selective. 5 The union of these two control elements would afford an appropriately functionalized 2-azabicyclo[2.2.2]octanone 2. (1) (a) Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J. C.; Pannell, L.; Daly, J. W. J. Am. Chem. Soc. 1992, 114, 3475-3478. (b) Daly, J. W.; Garraffo, H. M.; Spande, T. F.; Decker, M. W.; Sullivan, J. P.; Williams, M. Nat. Prod. Rep. 2000, 17, 131-135. (2) (a) Badio, B.; Daly, J. W. Mol. Pharmacol. 1994, 45, 563-568. (b) Ellis, J. L.; Harman, D.; Gonzalez, J.; Spera, M. L.; Liu, R.; Shen, T. Y.; Wypij, D. M.; Zuo, F. J. Pharmacol. Exp. Ther. 1999, 288, 1143-1150. (c) Kesingland, A. C.; Gentry, C. T.; Panesar, M. S.; Bowes, M. A.; Vernier, J. M.; Cube, R.; Walker, K.; Urban, L. Pain 2000, 86, 113-118 and references therein. (3) For early total syntheses of epibatidine, see: (a) Broka, C. A. Tetrahedron Lett. 1993, 34, 3251-3254. (b) Huang, D. F.; Shen, T. Y. Tetrahedron Lett. 1993, 34, 4477-4480. (c) Fletcher, S. R.; Baker, R.; Chambers, M. S.; Hobbs, S. C.; Mitchell, P. J. J. Chem. Soc., Chem. Commun. 1993, 1216-1218. (d) Corey, E. J.; Loh, T. P.; AchyuthaRao, S.; Daley, D. C.; Sarshar, S. J. Org. Chem. 1993, 58, 5600-5602. (e) Clayton, S. C.; Regan, A. C. Tetrahedron Lett. 1993, 34, 7493-7496. For reviews on the total syntheses of epibatidine, see: Chen, Z.; Trudell, M. L. Chem. ReV. 1996, 96, 1179-1193. For a recent synthesis, see: Barros, M. T.; Maycock, C. D.; Ventura, M. R. J. Chem. Soc., Perkin Trans. 1 2001, 166-173. (4) For enantioselective total syntheses of epibatidine, see: (a) Hernandez, A.; Marcos, M.; Rapoport, H. J. Org. Chem. 1995, 60, 2683-2691. (b) Trost, B. M.; Cook, G. R. Tetrahedron Lett. 1996, 37, 7485-7488. (c) Sza ´ntay, C.; Kardos-Balogh, Z.; Moldvai, I.; Sza ´ntay, C., Jr.; Temesve ´ri- Major, E.; Blasko ´, G. Tetrahedron 1996, 52, 11053-11062. (d) Kosugi, H.; Abe, M.; Hatsuda, R.; Uda, H.; Kato, M. Chem. Commun. 1997, 1857- 1858. (e) Aoyagi, S.; Tanaka, R.; Naruse, M.; Kibayashi, C. Tetrahedron Lett. 1998, 39, 4513-4516. (f) Jones, C. D.; Simpkins, N. S.; Giblin, G. M. P. Tetrahedron Lett. 1998, 39, 1023-1024. Scheme 1. Epibatidine Retrosynthesis ORGANIC LETTERS 2001 Vol. 3, No. 19 3009-3012 10.1021/ol016420q CCC: $20.00 © 2001 American Chemical Society Published on Web 08/30/2001