10.1021/ol2018196 r 2011 American Chemical Society Published on Web 09/13/2011 ORGANIC LETTERS 2011 Vol. 13, No. 19 5000–5003 Synthesis of Cytimidine through a One-Pot Copper-Mediated Amidation Cascade Catherine M. Serrano and Ryan E. Looper* Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States r.looper@utah.edu Received June 17, 2011 ABSTRACT A concise synthesis of cytimidine was developed utilizing tandem Cu-mediated N-aryl amidations followed by global deprotection. This sequence exploits a regioselective coupling of an iodobenzamide with a halopyrimidine that allows the union of three fragments in a single synthetic manipulation and will permit the efficient and rapid diversification of the cytimidine core. Various classes of antibiotics including aminogly- cosides, 1 macrolides, 2 and tetracyclines 3 have long demon- strated the drugability of the ribosome. These families comprise clinically relevant compounds that inhibit protein synthesis by binding to rRNA. 4 One particular class of ribosomal antibiotics, the aminohexopyranose nucleo- sides, have remained significantly less explored (Figure 1). Members of this family include amicetin, 5 bamicetin, 5 oxamicetin, 6 plicacetin, 7 and cytosaminomysin B 8 among others. Previous studies have suggested that these natural products share a common binding site near the peptidyl transferase center (PTC) of the ribosome. 9,10 Of particular interest to us is the antibiotic amicetin, isolated from Streptomyces plicatus in 1953, for its potent antibacterial activity against Mycobacterium tuberculosis H37Rv (IC 100 0.5 μg/mL) and Staphylococcus aureus FDA-209 (IC 100 0.2 μg/mL). 5 To date, the total synthesis of amicetin and its analogues, bamicetin and oxamicetin, have yet to be reported. Total synthesis of other members of the aminohexopyranose nucleoside family are quite few and far in between. 12,13 With the resurgence of drug resistant pathogens such as multidrug resistant (MDR) and extensively drug resistant (XDR) strains of M. tuberculosis 14 the need for more efficient therapeutics prompted us to develop a convergent approach to the synthesis of amicetin and its close analogues. (1) (a) Thomas, J. R.; Hergenrother, P. J. Chem. Rev. 2008, 108, 1171–1224. (b) Leibovici, L.; Vidal, L.; Paul, M. J. Antimicrob. Chemother. 2009, 63, 246. (2) Zhanel, G. G.; Dueck, M.; Hoban, D. J.; Vercaigne, L. M.; Embil, J. M.; Gin, A. S.; Karlowsky, J. A. Drugs 2001, 61, 443. (3) Griffin, M. O.; Fricovsky, E.; Ceballos, G.; Villeareal, F. Am. J. Physiol. Cell Physiol. 2010, 299, C539. (4) (a) Mankin, A. S. Mol. Biol. 2001, 35, 509. (b) Poehlsgaard, J.; Douthwaite, S. Nat. Rev. Microbiol. 2005, 3, 870. (5) (a) Hinman, J. W.; Caron, E. L.; DeBoer, C. J. Am. Chem. Soc. 1953, 75, 499. (b) Hinman, J. W.; Caron, E. L.; DeBoer, C. J. Am. Chem. Soc. 1953, 75, 5864. (c) Flynn, E. H.; Hinman, J. W.; Caron, E. L.; Woolf, D. O. J. Am. Chem. Soc. 1953, 75, 5867. (d) Smith, J. L.; Sundaralingam, M. Acta Crystallogr. 1981, B37, 1095. (6) Konishi, M.; Kimeda, M.; Tsukiura, H.; Yamamoto, H.; Hoshiya, T.; Miyaki, T.; Fujisawa, K.; Koshiyama, H.; Kawaguchi, H. J. Antibiot. 1973, 26, 752. (7) (a) Haskell, T. H.; Ryder, A.; Frohardt, R. p.; Fusari, S. A.; Jakubowski, Z. L.; Bartz, Q. R. J. Am. Chem. Soc. 1958, 80, 743. (b) Haskell, T. H. J. Am. Chem. Soc. 1958, 80, 747. (8) Haneda, K.; Shinose, M.; Seino, A.; Tabata, N.; Tomoda, H.; Iwai, Y.; Omura, S. J. Antibiot. 1994, 47, 774. (9) Leviev, I. G.; Rodriguez-Fonseca, C.; Phan, H.; Garrett, R. A.; Heilek, G.; Noller, H. F.; Mankin, A. S. EMBO J. 1994, 13, 1862. (10) Barbacid, M.; Vazquez, D. Eur. J. Biochem. 1974, 44, 445. Hansen, J. L.; Moore, P. B.; Steitz, T. A. J. Mol. Biol. 2003, 330, 1061. (11) Haneda, K.; Shinose, M.; Seino, A.; Tabata, N.; Tomoda, H.; J, L.; Moore, P. B.; Steitz, T. A. J. Mol. Biol. 2003, 330, 1061. (12) Sugimura, H.; Watanabe, R. Chem. Lett. 2008, 37, 1038. (13) Stevens, C. L.; Nemec, J.; Ransford, G. H. J. Am. Chem. Soc. 1979, 94, 3280. (14) (a) Fischbach, M. A.; Walsh, C. T. Science 2009, 325, 1089. (b) Koul, A.; Arnoult, E.; Lounis, N.; Guillemot, J.; Andries, K. Nature 2011, 469, 483.