M. Johar et al. / Bioorg. Med. Chem. 13 (2005) 6663–6671
6669
yielded 15 (340 mg, 55%) as a syrup. 1H NMR (DMSO-
5.8. 30,50-Di-O-mesyl-5-iodo-20-deoxyuridine (52)
d6) d: 2.10 and 2.12 (2s, 6H, COCH3), 2.14 and 2.55
(2m, 2H, H-20), 4.24–4.44 (m, 3H, H-40, H-50), 5.20 (m,
1H, H-30), 6.25 (t, 1H, J = 6.0 Hz, H-10), 7.0 (d,
J = 13.0 Hz, 1H, vinylic H), 7.40 (d, J = 13.0 Hz, 1H,
vinylic H), 7.48 (s, 1H, H-6), 9.54 (s, 1H, NH). Anal. Calcd
for C15H17IN2O7: C, 38.79; H, 3.66; N, 6.03. Found: C,
38.51; H, 3.98; N, 6.32.
5-Iodo-20-deoxyuridine (4) (1.06 g, 3.0 mmol) in dry pyr-
idine (10 mL) was added with methanesulfonylchloride
(0.56 mL, 7.0 mmol), left at 0 ꢁC for 12 h, and poured
onto ice-water (50 mL) to give a solid precipitate, which
was filtered. The wet solid was dissolved in chloroform
and dried with sodium sulfate. Evaporation of the solvent
gave a syrup, which was purified by silica gel column chro-
matography, using chloroform/methanol (93:7, v/v), to
yield 52 as a syrup (1.3 g, 83.3%). 1H NMR (DMSO-d6)
d: 2.60 (m, 2H, H-20), 3.34 (s, 3H, SO2CH3), 4.38 (m,
1H, H- 40), 4.50 (m, 2H, H-50), 5.30 (m, 1H, H-30), 6.14
(t, J = 6.0 Hz, 1H, H-10), 8.10 (s, 1H, H-6), 11.80 (s, 1H,
NH). Anal. Calcd for C11H15IN2O9S2: C, 25.88; H,
2.94; N, 5.49. Found: C, 26.10; H, 3.26; N, 5.24.
5.5. 5-Iodo-30-O-mesyl-50-O-trityl-20-deoxyuridine (49)
A
mixture of 5-iodo-20-deoxyuridine (4) (1.3 g,
3.6 mmol) and trityl chloride (1.11 g, 4.0 mmol) in anhy-
drous pyridine (25 mL) was heated at 45 ꢁC for 6 h and
kept overnight at room temperature. The reaction was
cooled to 0 ꢁC, mesyl chloride (0.56 mL, 7.0 mmol)
was added, and the reaction mixture was stirred for
90 min at room temperature. After the addition of
H2O (1 mL), the solvent was evaporated, and the result-
ing oil was diluted with chloroform (100 mL), washed
with cold H2O (2· 25 mL), dried (Na2SO4), and evapo-
rated. The residue was purified by silica gel column
chromatography by chloroform/methanol (97:3, v/v) as
eluent to yield 49 (1.6 g, 66%) as foam. 1H NMR
(CDCl3) d: 2.47 (m, 1H, H-20), 2.80 (m, 1H, H-20),
3.06 (s, 3H, CH3SO2), 3.52 (m, 2H, H-50), 4.38 (m,
1H, H-40), 5.37 (m, 1H, H-30), 6.35 (t, J = 6.0 Hz, 1H,
H-10), 7.28–7.50 (m, 15H, trityls), 8.16 (s, 1H, H-6),
9.23 (s, 1H, NH). Anal. Calcd for C29H27IN2O7S: C,
51.63; H, 4.00; N, 4.15. Found: C, 51.89; H, 4.27; N,
4.09.
5.9. 30,50-Anhydro-5-iodo-20-deoxyuridine (53)
5-Iodo-30,50-di-O-mesyl-20-deoxyuridine 52 (1.02 g,
2.0 mmol) was added in portions to a stirred solution
of sodium hydroxide (0.24 g, 6.0 mmol) in water
(5 mL) whereupon the reaction mixture became yel-
low-orange. The reaction mixture was then heated to re-
flux for 45 min. After cooling the reaction mixture to
25 ꢁC, concd HCl (0.17 mL) was added. The resulting
solution was concentrated under vacuo on a rotary
evaporator and filtered. The white solid obtained was
dissolved in methanol and purified by silica gel column
chromatography using chloroform/methanol (95:5, v/v)
1
as eluent to yield 53 as a syrup (0.2 g, 30%). H NMR
(DMSO-d6) d: 2.54 (m, 2H, H-20), 3.96 (d, J = 8.0 Hz,
1H, H-40), 4.72 (dd, J = 8.0 Hz, 1H, H-50), 4.91 (m,
2H, H-50), 5.50 (m, 1H, H-30), 6.49 (d, J = 6.0 Hz, 1H,
H-10), 8.62 (s, 1H, H-6), 11.78 (s, 1H, NH). Anal. Calcd
for C9H9IN2O4: C, 32.14; H, 2.67; N, 8.33. Found: C,
32.28; H, 3.00; N, 8.51.
5.6. Reaction of 5-iodo-30-O-mesyl-50-O-trityl- 20-deoxyur-
idine (49) with tetra-n-butyl ammonium fluoride in tetra-
hydrofuran (method A)
A solution of 49 (0.21 g, 0.31 mmol) in THF (4 mL) con-
taining 1 M TBAF was stored at room temperature for
24 h. After evaporation of the solvent, the reaction mix-
ture was divided between CHCl3 (25 mL) and H2O
(25 mL). The chloroform layer was separated, dried
(Na2SO4) and evaporated. The residue obtained was
purified by silica gel column chromatography using
chloroform/methanol (98:2, v/v) as eluent to give 2,30-
anhydro-5-iodo-50-O-trityl-20deoxyuridine 51 (0.12 g,
5.10. 20,30-Didehydro-20,30-dideoxy-5-iodouridine (40)
Potassium tert-butoxide (0.27 g, 2.4 mmol) was added to
a solution of oxetane 53 (0.4 g, 1.2 mmol) in dry DMSO
(7.5 mL) at 10–15 ꢁC under nitrogen. After the addition
was complete, the reaction mixture was stirred for 2 h at
25 ꢁC. The reaction mixture was neutralized to pH ꢀ7
by acetic acid and the solvent was removed on rotavapor
in vacuo. The collected yellowish oily residue was tritu-
rated two-three times with hot acetone. The acetone
washings evaporated to dryness on a rotavapor were dis-
solved in ethanol and decolorized by charcoal, filtered
and evaporated on the rotavapor. The obtained residue
was purified by silica gel column chromatography using
chloroform/methanol (95:5,v/v) as eluent to yield 40
(0.3 g, 75%). 1H NMR (DMSO-d6) d: 3.62 (dd,
J = 4.8, 3.6 Hz, 2H, H-50), 4.82 (s, 1H, H- 40), 5.12 (t,
J = 4.0 Hz, 1H, 50-OH), 5.92 (dd, J = 1.2, 5.0 Hz, 1H,
H-20), 6.40 (d, 1H, J = 6.0 Hz, H-30), 6.80 (d,
J = 1.2 Hz, 1H, H-10), 8.32 (s, 1H, H-6), 11.64 (s, 1H,
1
67%). H NMR (DMSO-d6) d: 2.56 (m, 2H, H-20),
3.14 (m, 2H, H-50), 4.46 (m, 1H, H-40), 5.36 (m, 1H,
H-30), 5.98 (t, 1H, H-10), 7.20–7.40 (m, 15H, trityls),
8.36 (s, 1H, H-6). Anal. Calcd for C28H23IN2O4: C,
58.13; H, 3.97; N, 4.84. Found: C, 58.49; H, 4.23; N,
5.13.
5.7. 2,30-Anhydro-5-iodo-50-O-trityl-20deoxyuridine (51)
(method B)
To
a
refluxing ethanolic solution of 49 (1 g,
1.48 mmol) was added a solution of 1 N NaOH
(1.5 mL, 1.5 mmol) dropwise and the solution was re-
fluxed for 30 min. Removal of the solvent and purifi-
cation, as described for method A, provided 51
13
NH); C NMR (DMSO-d6) d: 61.61 (C-50), 68.81 (C-
5), 87.69 (C-40), 89.41 (C-10), 125.88 (C-20), 135.56 (C-
30), 146.13 (C-6), 150.53 (C-2), 160.58 (C-4). Anal. Calcd
for C9H9IN2O4: C, 32.14; H, 2.67; N, 8.33. Found: C,
31.88; H, 2.43; N, 8.16.
1
(0.7 g, 82%) as a syrup. The H NMR and elemental
analysis of 51 were identical to that of 51 reported in
method A.