Notes and references
1 H. Mitsuya, J. K. Weinhold, P. A. Furman, M. H. St-Clair, S. Nusinoff-
Lehrman, R. C. Gallo, D. Bolognesi, D. W. Barry and S. Broder, Proc.
Natl. Acad. Sci. U.S.A., 1985, 82, 7096.
2 (a) H. Mitsuya and S. Broder, Proc. Natl. Acad. Sci. U.S.A., 1986, 83,
1911; (b) R. Yarchoan, H. Mitsuya, R. V. Thomas, J. M. Pluda, N. R.
Hartman, C.-F. Perno, K. S. Marczyk, J.-P. Allain, D. G. Johns and S.
Broder, Science, 1989, 245, 412; (c) T.-S. Lin, R. F. Schinazi and W. H.
Prusoff, Biochem. Pharmacol., 1987, 36, 2713.
3 (a) For a recent review, see: E. De Clerq, J. Med. Chem., 1995, 38, 2491;
(b) M. L. Peterson and R. Vince, J. Med. Chem., 1991, 34, 2787 and
references cited therein.
4 (a) B. Belleau, L. Brasili, L. Chan, M. DiMarco, B. Zacharie, N.
Nguyen-Ba, H. J. Jenkinson, J. A. V. Coates and J. M. Cameron, Bioorg
Med. Chem. Lett., 1993, 3, 1723; (b) M. J. Bamford, D. C. Humber and
R. Storer, Tetrahedron Lett., 1991, 32, 271 and references cited therein;
(c) J. Branalt, I. Kvarnstrom, B. Classon and B. Samuelsson, J. Org.
Chem., 1996, 61, 3604 and references cited therein.
5 (a) N. Nguyen-Ba, W. L. Brown, L. Chan, N. Lee, L. Brasili, D. Lafleur
and B. Zacharie, Chem. Commun., 1999, 1245; (b) N. Nguyen-Ba, W.
Brown, N. Lee and B. Zacharie, Synthesis, 1998, 759; (c) J. A. V.
Coates, N. Cammack, H. J. Jenkinson, I. M. Mutton, B. A. Pearson, R.
Storer, J. M. Cameron and C. R. Penn, Antimicrob. Agents Chemother.,
1992, 36, 202; (d) M. W. Chun, D. H. Shin,.H. R. Moon, J. Lee, H. Park
and L. S. Jeong, Bioorg. Med. Chem. Lett., 1997, 7, 1475.
6 J. M. Camaron, P. Collis, M. Daniel, R. Storer and P. Wilcox, Drugs of
the Future, 1993, 18, 319 and references cited therin.
7 K. L. Grove, X. Guo, S.-H. Liu, M. Kukhanova, C. K. Chu and Y.-C.
Cheng, Nucleosides Nucleotides, 1997, 16, 1229.
8 (a) M. R. Harnden, EP 0319 228 A3; (b) E. Grochowski, H. Stepowska,
P. Salanski and J. Jurczak, Carbohydr. Res., 1988, 177, 244; (c) S.
Bailey, M. R. Harnden, R. L. Jarvest, A. Parkin and M. R. Boyd, J. Med.
Chem., 1991, 34, 57; (d) M. R. Harnden, P. G. Wyatt, M. R. Boyd and
D. Sutton, J. Med. Chem., 1990, 33, 187.
9 A similar approach for the synthesis of 1-(hydroxyalkoxy)pyrimidines
has been reported by M. R. Harnden, L. J. Jenning and A. Parkin,
Tetrahedron Lett., 1988, 29, 4013.
Scheme
3
Reagents
and
conditions:
(a)
NaH/THF;
(b)
, TMSI or TMSBr, DMF; (c) NH3/MeOH.
thymidine 13 in DMF. This gave the desired nucleoside 16 and
17 or 18 and 19, respectively, as a 1+1 mixture of cis and trans
isomers in 72 and 66% yields, respectively.12 Replacement of
halotrimethylsilane with trimethylsilyl triflate or the base
sodium hydride with triethylamine did not alter the ratio of
isomers but reduced the yield. Separation of the isomers 16–19
by chromatography followed by deprotection with methanolic
ammonia gave the expected nucleosides 20–27 in high
yields.13
Similarly, cytosine derivatives 28–31 were produced in a 1+1
10 (a) W. Klötzer, Monatsh. Chem., 1964, 95, 1729; (b) W. Klötzer and M.
Herberz, Monatsh. Chem., 1965, 96, 1721.
11 E. Grochowski and H. Stepowska, Synthesis, 1988, 795.
12 The relative stereochemistry of the cis and trans products was assigned
by difference NOE spectra.
13 Selected data for 22: mp 190–191 °C; dH (DMSO-d6) 11.58 (br, 1H),
7.92 (d, 1H, J 5.4), 6.07 (d, 1H, J 4.3), 5.63 (t, 1H, J 5), 5.50 (d, 1H, J
7.5), 5.23 (t, 1H), 3.67 (m, 1H), 3.63 (m, 1H), 3.54 (m, 2H); dC (DMSO-
d6) 163.2, 148.5, 145.1, 109.5, 99.7, 86.8, 64.0, 34.7; HRMS (FAB): M+
calcd for C8H11N2O5S 247.038868, found 247.038107. For 23: mp
180-182 °C; dH (DMSO-d6) 11.59 (br, 1H), 7.99 (d, 1H, J 3.9), 5.97 (t,
1H, J 3.4), 5.52 (d, 1H, J 3.6), 5.49 (t, 1H, J 6), 5.44 (t, 1H), 3.74 (m,
1H), 3.71 (m, 1H), 3.18 (m, 1H), 3.34 (m, 1H); dC (DMSO-d6) 163.71,
148.61, 145.05, 110.87, 99.62, 88.74, 64.99, 35.56; HRMS (FAB): M+
calcd for C8H11N2O5S 247.038868, found 247.039700. For 26: mp
188–189 °C; dH (DMSO-d6) 11.55 (s, 1H), 7.86 (s, 1H), 5.93 (dd, 1H,
J 1.2, 5.0), 5.38 (m, 2H), 3.73 (m, 1H), 3.63 (m, 1H), 3.44 (dd, 1H, J 5.2,
12.6), 3.31 (d, 1H, J 12.4), 1.74 (s, 3H); dC (DMSO-d6) 163.35, 148.12,
140.39, 110.53, 107.23, 88.40, 64.90, 35.49, 11.67; LRMS (FAB) m/z =
261 (MH+). For 27: mp 146–147 °C; dH (DMSO-d6) 11.54 (s, 1H), 7.77
(d, 1H, J 1.2), 6.04 (d, 1H, J 4.4), 5.62 (t, 1H, J 5.0), 5.19 (br s, 1H), 3.64
(m, 1H), 3.52 (m, 1H), 3.35 (dd, 1H, J 4.6, 12.3), 3.21 (d, 1H, J 12.4),
1.75 (d, 3H, J 1.0); dC (DMSO-d6) 163.36, 148.14, 140.22, 108.96,
107.53, 86.46, 63.84, 34.67, 11.73; LRMS (FAB) m/z = 261 (MH+).
For 29 mp 210-212 °C; dH (DMSO-d6) 7.83 (d, 1H, J 7.5), 7.27 (br d,
2H), 5.92 (dd, 1H), 5.60 (d, 1H, J 7.5), 5.43 (t, 1H), 5.37 (t, 1H, J 5.0),
3.75 (m, 1H), 3.61 (m, 1H), 3.42 (m, 1H); dC (DMSO-d6) 165.00,
152.07, 144.82, 109.89, 93.07, 88.72, 65.44, 35.81; LRMS (FAB) m/z =
246 (MH+). For 31 mp 183–185 °C; dH (DMSO-d6) 7.78 (d, 1H, J 7.4),
7.47 (br d, 2H), 6.08 (dd, 1H), 5.62 (d, 1H, J 7.6), 5.59 (t, 1H, J 5.0), 5.20
(br s, 1H), 3.67 (m, 1H), 3.55 (m, 1H), 3.48 (m, 2H); LRMS (FAB) m/z
= 246 (MH+).
mixture of cis and trans isomers under the same conditions
starting from N-1-hydroxycytosine 15. Direct conversion of
uracil nucleoside 16 or 17 to the corresponding cytosine using
the triazolo–phosphorus oxychloride–ammonia procedure was
not successful and gave low yield of the expected product
28–31.
The anti HIV, HBV, HSV-1 and HSV-2 activities of
(±)-1,3-dioxolane and 1,3-oxathiolane nucleoside analogues
20–27, 28–31, were evaluated and compared with 3TC®
(Epivir) and AZT. All of them were found to be inactive and
non-toxic, except the cytosine derivative 29 which displayed
weak inhibition of extracellular HBV.
In summary, described herein is a novel class of (±)-1,3-diox-
olane and 1,3-oxathiolane nucleoside analogues. The biological
results demonstrate that linking the sugar to the heterocyclic
base through an oxygen causes dramatic reduction in antiviral
activity in this series of compounds.
We thank Drs R. Storer and T. Bowlin for reading the
manuscript, Mrs L. Bernier and J. Dugas for technical assistance
with HPLC purification, and Mrs L. Marcil for secretarial and
technical assistance.
2312
Chem. Commun., 2000, 2311–2312