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
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 tetracyclines3 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 B8 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 (IC100 0.5 μg/mL) and Staphylococcus aureus
FDA-209 (IC100 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.
tuberculosis14 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.
r
10.1021/ol2018196
Published on Web 09/13/2011
2011 American Chemical Society