10910
D. Benito et al. / Tetrahedron 64 (2008) 10906–10911
was added, and the solution was stirred for further 3 h. When TLC
(CH2Cl2/MeOH, 9:1) showed no further evolution the reaction was
quenched with NH4OH (30%, 15 mL) and the mixture was stirred for
15 min. After that time, the solution was poured into a water/ice
bath, and then extracted with CH2Cl2. The organic phase was
washed, dried with MgSO4, and evaporated under vacuum. The
reaction crude was redissolved in methanol and Dowex Hþ was
added (4 g). The suspension was stirred until complete disappear-
ing of the starting material was observed. Then the solution was
filtered, concentrated under vacuum, and the residue redissolved in
CH2Cl2, washed with an aqueous solution of NaHCO3 (ꢂ3), dried
with MgSO4, evaporated and purified by flash chromatography
(CH2Cl2/MeOH, 9:1) affording 15 (3.36 g, 81% yield). 1H NMR
and concentrated under vacuum. Then the crude was diluted and
washed with an aqueous solution of NaHCO3. The organic layer is
dried, filtered and evaporated to dryness. The crude was purified by
column chromatography (elution system CH2Cl2/MeOH, 10:0,
9.5:0.5, 9:1) affording 18 (116 mg, 70% yield). 1H NMR (300 MHz,
CD3OD, 25 ꢀC)
d 8.25 (s, 1H), 7.91 (s, 1H), 7.63–7.33 (m, 10H), 7.06 (d,
1H, J¼8.7 Hz), 6.68 (d, 1H, J¼8.7 Hz), 6.19 (d, 1H, J¼6.3 Hz), 5.85 (br
s, 2H), 5.08 (d, 1H, J¼3.6 Hz), 4.70 (m, 1H), 4.59 (d, 1H, J¼11.7 Hz),
4.51–4.16 (m, 4H), 4.01 (dd, 1H, J¼11.4, 4.5 Hz), 4.00–3.93 (m, 2H),
3.45 (t, 1H, J¼9.2 Hz), 3.80–3.65 (m, 6H), 1.05 (s, 9H); 13C NMR
(75.4 MHz, CD3OD, 25 ꢀC)
d 160.9, 151.8, 149.6, 143.2, 136.9–128.9,
123.4, 114.6, 98.1 (d, J¼20.5 Hz), 91.6 (d, J¼190.3 Hz), 88.9, 86.4,
80.4, 75.2, 74.6, 73.4, 73.0 (d, J¼17.1 Hz), 71.1 (d, J¼7.3 Hz), 65.3,
(400 MHz, DMSO-d6, 25 ꢀC)
d
11.26 (s, 1H), 8.70 (s, 1H), 8.67 (s, 1H),
62.2, 55.9, 27.6, 20.3; 19F NMR (376.4 MHz, CD3OD, 25 ꢀC)
d
ꢁ202.77
8.05–7.56 (m, 5H), 7.09 (d, 2H, J¼8.7 Hz), 6.75 (d, 2H, J¼8.7 Hz), 6.18
(d, 1H, J¼6.0 Hz), 5.41 (d, 1H, J¼5.0 Hz), 5.21 (t, 1H, J¼5.0 Hz), 4.63
(d,1H, J¼11.6 Hz), 4.59 (d,1H, J¼6.0 Hz), 4.44 (d,1H, J¼11.6 Hz), 4.38
(dd, 1H, J¼7.5, 5.0 Hz), 4.04 (dd, 1H, J¼7.5, 3.8 Hz), 3.72–3.59 (m,
(dd, J¼50.4, 13.9 Hz). Anal. Calcd for C40H48FN5O9Si: 60.82, C; 6.12,
20
H; 8.87, N. Found: 60.79, C; 6.11, H; 8.90, N. [
MeOH).
a
]
þ32.3 (c 0.3,
D
2H), 3.68 (s, 3H); 13C NMR (100.6 MHz, DMSO-d6, 25 ꢀC)
d 165.5,
Acknowledgements
158.5, 151.3, 151.3, 150.2, 142.8, 133.1, 132.3, 128.3, 125.6, 129.2,
128.9, 116.0, 113.2, 86.2, 85.8, 79.6, 70.6, 68.6, 60.9, 54.7. The 1H
NMR spectrum of this product was consistent with the literature
data.22 Anal. Calcd for C25H25N5O6: 61.09%, C; 5.13%, H; 14.25%, N.
Found: 61.02%, C; 5.14%, H; 14.02%, N.
Financial support of DGI CTQ2005-03124 (Ministerio de Ciencia y
´
Tecnologıa, Spain) and technical assistance from the Servei de
Recursos Cientifics (URV) are gratefully acknowledged.
4.5. Synthesis of 30-O-(300,400,600-tri-O-acetyl-200-deoxy-200-
References and notes
fluoro-a-D
-glucopyranosyl)-N6-benzoyl-50-O-tert-
butyldiphenylsilyl-20-O-p-methoxybenzyl adenosine (17)
1. (a) Strunecka, A.; Patocka, J.; Connett, P. J. Appl. Biomed. 2004, 2, 141; (b) Ismail,
F. M. D. J. Fluorine Chem. 2002, 118, 27; (c) Schlosser, M. Tetrahedron 1978, 34, 3;
(d) Fluorinated Carbohydrates, Chemical and Biochemical Aspects; Taylor, N. F.,
Ed.; ACS Symposium Series, nꢀ 374; American Chemical Society: Washington,
DC, 1988; pp 176–190.
2. (a) Ma, T.; Chu, C. K.; Lin, J. S.; Newton, M. G.; Chen, Y. C.; Chu, C. K. J. Med. Chem.
1997, 40, 2750; (b) Watanabe, K. A.; Reichman, U.; Hirota, K.; Lopez, C.; Fox, J. J.
J. Med. Chem. 1979, 22, 21; (c) Etzold, G.; Hintsche, R.; Kowollik, G.; Langen, P.
Tetrahedron 1971, 27, 2463; (d) Begue, J. P.; Bonnet-Delpon, D. J. Fluorine Chem.
2006, 127, 992; (e) Hi, J. U.S. Pat. Appl. Publ. 2,007,225,249, 2007; (f) Hertel, L.
W.; Kroin, J. S. PCT Int. Appl. 9842351, 1998; (g) Hertel, L. W.; Grossman, C. S.;
Kroin, J. S. Eur. Pat. Appl. 329348, 1989; (h) Hertel, L. W. U.S. Patent 4526988,
1987; (i) Watanabe, K. A.; Harada, K.; Zeidler, J.; Matulic-Adamic, J.; Takahashi, K.;
Ren, W. Y.; Cheng, L. C.; Fox, J. J.; Chou, T. C.; Zhu, Q.-Y.; Polsky, B.; Gold, J. W. M.;
Armstrong, D. J. Med. Chem. 1990, 33, 2145.
3. (a) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303; (b) Oshida, M.; Uno,
K.; Suzuki, M.; Nagashima, T.; Hashimoto, H.; Yagata, H.; Shishikura, T.; Imazeki,
K.; Nakajima, N. Cancer 1998, 82, 2227; (c) O’Hagan, D.; Naismith, J.; Schaffrath,
C.; Dong, C.; Spencer, J. B.; Huang, F. PCT Int. Appl. 2004078914, 2004.
4. (a) Katayama, S.; Takamatsu, S.; Naito, M.; Tanji, S.; Ineyama, T.; Izawa, K.
J. Fluorine Chem. 2006, 127, 524; (b) Takagi, Y.; Kobayashi, N.; Chang, M. S.; Lim,
G. J.; Tsuchiya, T. Carbohydr. Res. 1998, 307, 217; (c) Bonjouklian, R.; Grindey, G. B.;
Hertel, L. W. Eur. Pat. Appl. 376518, 1990; (d) Koppel, G. A.; Kennedy, G. D.;
Armour, H. K.; Scott, W. L. Eur. Pat. Appl. 272891,1988; (e) Grindey, G. B.; Hertel, L. W.
Eur. Pat. Appl. 184365, 1986.
Glycosyl acceptor (16) (280 mg, 0.38 mmol), Ag2CO3 (116 mg,
0.42 mmol) and AgOTf (30 mg, 0.11 mmol) were placed in a flask,
then 2 mL of dry toluene was added and evaporated to dryness
(three times), finally 4 Å M.S. (200 mg) were put in and the flask
was protected from light. A similar procedure was followed for
glycosyl donor (12, 200 mg). Then both acceptor and donor were
placed in a dryer with P2O5 and left under vacuum for 24 h. After
that time dry Et2O (1.2 mL) was added to acceptor flask. Then gly-
cosyl bromide was dissolved in dry CH2Cl2 (0.4 mL) and transferred
to acceptor flask. The mixture was stirred for 48 h at rt. After 2 days
the solution was filtered through Celite, and the solvents were
evaporated to dryness. The crude reaction was applied to a silica gel
column using a gradient of hexane/ethyl acetate (1:1, 1:2, 1:4) as
elution system. After purification 17 was afforded (224 mg, 58%
´
´
yield). 1H NMR (400 MHz, CDCl3, 25 ꢀC)
d 9.31 (s, 1H), 8.63 (s, 1H),
8.10 (s, 1H), 8.02–7.35 (m, 15H), 7.06 (d, 2H, J¼8.8 Hz), 6.66 (d, 2H,
J¼8.8 Hz), 6.15 (d, 1H, J¼6.0 Hz), 5.63 (dt, 1H, J¼12.0, 9.6 Hz), 5.27
(d, 1H, J¼4.0 Hz), 5.06 (dd, 1H, J¼10.0, 9.6 Hz), 4.91 (dd, 1H, J¼6.0,
5.2 Hz), 4.62 (d, 1H, J¼11.6 Hz), 4.58 (m, 1H), 4.54 (ddd, 1H, J¼48.8,
9.6, 4.0 Hz), 4.42 (m, 1H), 4.40 (d, 1H, J¼11.6 Hz), 4.17 (dd, 1H,
J¼12.4, 4.4 Hz), 4.11 (m, 1H), 4.04 (ddd, 1H, J¼10.0, 4.4, 2.4 Hz), 3.93
(dd, 1H, J¼12.4, 2.4 Hz), 3.85 (dd, 1H, J¼11.6, 3.6 Hz), 3.72 (s, 3H),
2.11 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 1.08 (s, 9H); 13C NMR
5. (a) Hayashi, T.; Murray, B. W.; Wang, R.; Wong, C. H. Bioorg. Med. Chem. 1997, 5,
497; (b) Murray, B. W.; Wittmann, V.; Burkart, M. D.; Hung, S. C.; Wong, C. H.
Biochemistry 1997, 36, 823; (c) Shouming, H.; Withers, S. G. J. Biol. Chem. 1997,
272, 24864; (d) Notenboom, V.; Birsan, C.; Warren, R. A. J.; Whiters, S. G.; Rose,
D. R. Biochemistry 1998, 37, 4751.
6. Tsuchiya, T. Adv. Carbohydr. Chem. Biochem. 1990, 48, 91.
7. Schweizer, E.; Hoffmann-Ro¨der, A.; Scha¨rer, K.; Olsen, J. A.; Fa¨h, C.; Seiler, P.;
Obst-Sander, U.; Wagner, B.; Kansy, M.; Diederich, F. Chem. Med. Chem. 2006,
1, 611.
8. Kirk, K. L. Curr. Top. Med. Chem. 2006, 6, 1447.
9. Takahashi, M.; Kagasaki, T.; Hosoya, T.; Takahashi, S. J. Antibiot. 1993, 46, 1643.
10. Takahashi, M.; Tanzawa, K.; Takahashi, S. J. Biol. Chem. 1994, 269, 369.
(100.6 MHz, CDCl3, 25 ꢀC)
d 170.6, 170.2, 169.8, 164.8, 159.5, 152.6,
149.6, 142.3, 135.7–113.8, 123.4, 96.1 (d, J¼20.5 Hz), 87.2 (d,
J¼196.8 Hz), 87.5, 83.6, 78.0, 74.8, 72.4, 70.6 (d, J¼19.9 Hz), 68.2,
67.9 (d, J¼6.8 Hz), 63.1, 61.6, 55.4, 27.1, 20.9, 20.8, 29.4; 19F NMR
´
11. (a) El-Laghdagh, A.; Echarri, R.; Matheu, M. I.; Barrena, M. I.; Castillon, S.; Garcia,
(376.4 MHz, CDCl3, 25 ꢀC)
d
ꢁ201.25 (dd, J¼48.8, 12.0 Hz).
J. J. Org. Chem. 1991, 56, 4556; (b) El-Laghdach, A.; Matheu, M. I.; Castillo´ n, S.;
Bliard, Ch.; Olesker, A.; Lukacs, G. Carbohydr. Res. 1992, 233, C1; (c) Fernandez,
´
R.; Matheu, M. I.; Echarri, R.; Castillo´n, S. Tetrahedron 1998, 54, 3523; (d) Bar-
rena, M. I.; Matheu, M. I.; Castillo´n, S. J. Org. Chem. 1998, 63, 2184; (e) Ferna´ndez,
R.; Castillo´n, S. Tetrahedron 1999, 55, 8497; (f) Poopeiko, N.; Ferna´ndez, R.;
Barrena, M. I.; Castillo´n, S.; Fornie´s-Ca´mer, J.; Cardin, C. J. Org. Chem. 1999, 64,
4.6. Synthesis of 30-O-(200-deoxy-200-fluoro-
a-D-
glucopiranosyl)-50-O-tert-butyldiphenylsilyl-20-O-p-
methoxybenzyl adenosine (18)
´
´
1375; (g) Aghmiz, M.; Dıaz, Y.; Jana, G. H.; Matheu, M. I.; Echarri, R.; Castillon, S.;
Jimeno, M. L. Tetrahedron 2001, 57, 6733; (h) Molas, P.; Dı´az, Y.; Matheu, M. I.;
´
Castillon, S. Synlett 2003, 207.
A solution of compound 17 (214 mg, 0.21 mmol) was dissolved
in dry methanol (0.2 mL). Then sodium methoxide (62 mg,
1.15 mmol) was added to the solution. The reaction mixture was
stirred at rt for 4 h. The solution was neutralized with acetic acid,
12. Some representative examples are: (a) Behr, J.-B.; Gourlain, T.; Helimi, A.;
Guillerm, G. Bioorg. Med. Chem. Lett. 2003, 13, 1713; (b) Efimtseva, E. V.; Shel-
kunova, A. A.; Mikhailov, S. N.; Nauwelaerts, K.; Rozenski, J.; Lescrinier, E.;
Herdewijn, P. Nucleosides, Nucleotides Nucleic Acids 2003, 22, 1109; (c) Xu, X.-H.;