Stereoselective Synthesis of Carbocyclic L-4′-Fluoro-2′,3′-dideoxyadenosine Giuseppe Gumina, Youhoon Chong, Yongseok Choi, and Chung K. Chu* Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The UniVersity of Georgia, Athens, Georgia 30602-2352 dchu@rx.uga.edu Received February 14, 2000 ABSTRACT L-(1′S,3′S)-9-[3-Fluoro-3-(hydroxymethyl)cyclopentan-1-yl]adenine 15 has been synthesized from ester 2, which can be conveniently prepared from 2,3-isopropylidene-D-glyceraldehyde 1 in six steps. The key ring closure has been accomplished through an intramolecular nucleophilic substitution reaction. Carbocyclic nucleosides have played an important role in the search for useful antiviral or antitumoral agents in the past 15 years. 1 An outstanding achievement in this field has been the recent approval of abacavir 2 (Figure 1) for the treatment of AIDS. From a chemical point of view, the nonglycosidic nature of carbocyclic nucleosides has made them a challenging target for synthetic chemists. Among “classical” nucleoside analogues bearing a gly- cosidic bond, a variety of substitutions have been made on the sugar moiety in the attempt to improve the biological activity as well as to obtain metabolically stable derivatives. In some cases, an electron-withdrawing substituent such as fluorine has conferred favorable pharmacological properties, and we 3 and others 4 have reported the synthesis and biological evaluation of several 2′- and 3′-fluorinated nucleo- sides. (1) (a) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571. (b) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611. (c) Crimmins, M. T. Tetrahedron 1998, 54, 9229. (2) (a) Daluge, S. M.; Good, S. S.; Faletto, M. B.; Miller, W. H.; StClair, M. H.; Boone, L. R.; Tisdale, M.; Parry, N. R.; Reardon, J. E.; Dornsife, R. E.; Averett, D. R.; Krenitsky, T. A. Antimicrob. Agents Chemother. 1997, 41, 1082. (b) Dobkin, J. F. Infect. Med. 1999, 16, 7. (3) (a) Xiang, Y.; Kotra, L. P.; Chu, C. K.; Schinazi, R. F. Bioorg. Med. Chem. Lett. 1995, 5, 743. (b) Xiang, Y.; Cavalcanti, S.; Chu, C. K.; Schinazi, R. F.; Pai, S. B.; Zhu, Y.-L.; Cheng, Y.-C. Bioorg. Med. Chem. Lett. 1995, 5, 877. (c) Pai, S. B.; Liu, S.-H.; Zhu, Y.-L.; Chu, C. K.; Cheng, Y.-C. Antimicrob. Agents Chemother. 1996, 40, 380. (d) Ma, T.; Pai, S. B.; Zhu, Y. L.; Lin, J.-S.; Shanmuganathan, K.; Du, J.; Wang, C.; Kim, H.; Newton, M. G.; Cheng, Y.-C.; Chu, C. K. J. Med. Chem. 1996, 39, 2835. (e) Ma, T.; Lin, J.-S.; Newton, M. G.; Cheng, Y.-C.; Chu, C. K. J. Med. Chem. 1997, 40, 2750. (f) Kotra, L. P.; Xiang, Y.; Newton, M. G.; Schinazi, R. F.; Cheng, Y.-C.; Chu, C. K. J. Med. Chem. 1997, 40, 3635. (g) Kotra, L. P.; Newton, M. G.; Chu, C. K. Carbohydr. Res. 1998, 306, 69. (h) Choi, Y.; Lee, K.; Hong, J. H.; Schinazi, R. F.; Chu, C. K. Tetrahedron Lett. 1998, 39, 4437. (i) Lee, K.; Choi, Y.; Gullen, E.; Schlueter-Wirtz, S.; Schinazi, R. F.; Cheng, Y.-C.; Chu, C. K. J. Med. Chem. 1964, 7, 1320. Lee, K.; Choi, Y.; Hong, J. H.; Schinazi, R. F.; Chu, C. K. Nucleosides Nucleotides 1999, 18, 537. (4) (a) Owen, G. R.; Verheyden, J. P. H.; Moffatt, J. G. J. Org. Chem. 1976, 41, 3010. (b) Marquez, V. E.; Tseng, C. K.-H.; Mitsuya, H.; Aoki, S.; Kelley, J. A.; Ford, H. Jr.; Driscoll, J. S. J. Med. Chem. 1990, 33, 978. Figure 1. Structures of anti-HIV drug abacavir and natural antibiotic nucleoside nucleocidin. ORGANIC LETTERS 2000 Vol. 2, No. 9 1229-1231 10.1021/ol005665k CCC: $19.00 © 2000 American Chemical Society Published on Web 04/14/2000