New Telluride-Mediated Elimination for Novel Synthesis of 2′,3′-Didehydro-2′,3′-dideoxynucleosides Jia Sheng, Abdalla E. A. Hassan, and Zhen Huang* Department of Chemistry, Georgia State UniVersity, Atlanta, Georgia 30303 huang@gsu.edu ReceiVed December 4, 2007 Several 2′,3′-dideoxynucleosides (ddNs) and 2′,3′-didehydro-2′,3′-dideoxynucleosides (d4Ns) are FDA- approved anti-HIV drugs. Via conveniently synthesized 2,2′-anhydronucleosides, we have developed a novel synthesis of d4Ns by discovering and applying a new telluride-mediated elimination reaction. Our experiment results show that after substitution of 2,2′-anhydronucleosides with a telluride monoanion, a telluride intermediate is formed, and its elimination leads to formation of the olefin products (d4Ns). Our mechanistic study indicates that this telluride-assisted reaction consists of two steps: substitution (or addition) and elimination. By using dimethyl ditelluride (0.1 equiv) as the reagent, d4Ns can be synthesized with yields up to 90% via this telluride-mediated elimination. Our novel strategy has great potential to simplify synthesis of these drugs and to further reduce cost of AIDS treatment and will also facilitate development of novel d4N and ddN analogues. Introduction 2′,3′-Dideoxynucleosides (ddNs) and 2′,3′-didehydro-2′,3′- dideoxynucleosides (d4Ns) are an important type of antiviral compounds, which terminate viral DNA polymerization after their incorporation by reverse transcriptase. 1 Several of them (Figure 1), including 2′,3′-dideoxycytidine (ddC, 1), 2′,3′- didehydro-3′-deoxythymidine (d4T, Stavudine, 2), 3′-azido-3′- deoxythymidine (AZT, 3), ddI (2′,3′-dideoxyinosine, 4), 3TC (-3′-deoxy-3′-thiocytidine, 5), ABC (Abacavir, 6), and FTC (Emtricitabine, 7), have been approved and permitted for marketing by the FDA as potent anti-HIV therapeutics. 2 Since the finding of the ddNs and d4Ns with high efficacy against HIV, tremendous attention has been directed toward the development of new chemistry for synthesizing these com- pounds as well as exploring novel analogues in order to reduce cost and better treat AIDS, one of the most deadly diseases caused by HIV. 3 Extensive research has been conducted in this area, and the field has been reviewed. 4 In general, the ddNs can be synthesized from hydrogenation of d4Ns, and d4Ns are synthesized from well-developed strategies, including Corey-Winter reaction through the cyclic thionocarbonates, 5 Eastwood olefination through the cyclic orthoformates, 6 Mattocks reaction through the bromoacetates, 7 and olefin metathesis via the ring-closure reaction. 8 In addition, 2′,3′-anhydro-2′-deoxyuridine and -thy- midine can be converted to d4Ns via base-catalyzed elimina- tion. 9 Furthermore, syntheses of d4Ns via oxidative elimination (1) For a review, see: Chu, C. K., Baker, D. C., Eds. Nucleosides and Nucleotides as Antitumor and AntiViral Agents; Plenum Press: New York, 1993. (2) (a) De Clercq, E. J. Med. Chem. 1995, 38, 2491. (b) Doong, S. L.; Tsai, C. H.; Schinazi, R. F.; Liotta, D. C.; Cheng, Y. C. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 8495. (c) Vince, R.; Hua, M. J. Med. Chem. 1990, 33, 17. (3) (a) Ogilvie, K. K.; Iwacha, D. J. Can. J. Chem. 1974, 52, 1787. (b) Saito, Y.; Zevaco, T. A; Agrofoglio, L. A. Tetrahedron 2002, 58, 9593. (c) Wiley, C. A.; Grafe, M.; Kennedy, C.; Nelson, J. A. Acta Neuropathol. (Berlin) 1988, 76, 338. (d) Kikyoya, T. Jpn. Kokai Tokkyo Koho 1988, JP 63241356-A- 19881006. (e) Luzzio, F. A.; Menes, M. E. J. Org. Chem. 1994, 59, 7267. (4) Huryn, D. M.; Okabe, M. Chem. ReV. 1992, 92, 1745. (5) (a) Dudycz, L. W. Nucleosides Nucleotides 1989, 8, 35. (b) Chu, C. K.; Bhadti, V. S.; Doboszewski, B.; Gu, Z. P.; Kosugi, Y.; Pullaiah, K. C.; Van Roey, P. V. J. Org. Chem. 1989, 54, 2217. (6) (a) Josan, J. S.; Eastwood, F. W. Aust. J. Chem. 1968, 21, 2013. (b) Crank, G.; Eastwood, F. W. Aust. J. Chem. 1964, 17, 1392. (7) (a) Robins, M. J.; Wilson, J. S.; Madej, D.; Low, N. H.; Hansske, F.; Wnuk, S. F. J. Org. Chem. 1995, 60, 7902. (b) Mansuri, M. M.; Starrett, J. E.; Wos, J. A.; Tortolani, D. R.; Brodfuehrer, P. R.; Howell, H. G.; Martin, J. C. J. Org. Chem. 1989, 54, 4780. (c) Robins, M. J.; Hansske, F.; Low, N. H.; Park, J. I. Tetrahedron Lett. 1984, 25, 367. (8) (a) Gillaizeau, I.; Lagoja, I. M.; Nolan, S. P.; Aucagne, V.; Rozenski, J.; Herdewijn, P; Agrofoglio, L. A. Eur. J. Org. Chem. 2003, 666. (b) Ewing, D.; Glacon, V.; Mackenzie, G.; Postel, D.; Len, C. Tetrahedron Lett. 2002, 43, 3503. (9) Horwitz, J. P.; Chua, J.; Rooge, M. A. D.; Noel, R.; Klundt, I. L. J. Org. Chem. 1966, 31, 205. 10.1021/jo7025806 CCC: $40.75  2008 American Chemical Society J. Org. Chem. 2008, 73, 3725–3729 3725 Published on Web 04/15/2008