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Vol. 51, No. 4
1
7.13 (d, J5,4ꢁ1.2 Hz, 1H, H-4) and 7.97 (d, J4,5ꢁ1.2 Hz, 1H, H-5). 13C-NMR
(CD3OD) d: 61.78 (C-5ꢀ), 75.79 (C-3ꢀ), 77.73 (C-2ꢀ), 85.90 (C-4ꢀ), 90.77
(C-1ꢀ), 125.16 (C-5), 127.87 (C-4), 145.82 (C-2) ppm. MS (ESI) m/z: 268
(MꢄNaꢄ). Anal. Calcd for C8H11N3O6: C, 39.19; H, 4.52; N, 17.14. Found:
C, 39.63; H, 4.73; N, 15.42.
Alternatively, 7 was prepared by deacetylation of 6. A solution of
NH3/methanol (2 M, 30 ml) was added to 6 (30 mg, 0.51 mmol) and the mix-
ture was stirred at 0 °C for 2 h. A TLC check at this time showed complete
deacetylation of 6 and appearance of a new spot at the Rf for 7.
pure 12. mp 105 °C. H-NMR (CD3OD) d: 1.80 and 2.12 (two s, each for
3H, 2ꢂCOCH3), 3.82 (d, J4ꢀ,5ꢃꢁ4.9 Hz of d, Jgemꢁ12.5 Hz, 1H, H-5ꢃ), 3.94
(d, Jgemꢁ12.5 Hz of d, J4ꢀ,5ꢀꢁ3.9 Hz, 1H, H-5ꢀ), 4.20 (m, J3ꢀ,4ꢀꢁ4.9 Hz of d,
J5ꢀ,4ꢀꢁ3.9 Hz of d, J5ꢃ,4ꢀꢁ4.9 Hz, 1H, H-4ꢀ), 5.28 (d, J2ꢀ,3ꢀꢁ3.4 Hz of d,
J4ꢀ,3ꢀꢁ4.9 Hz, 1H, H-3ꢀ), 5.71 (d, J3ꢀ,2ꢀꢁ3.4 Hz of d, J1ꢀ,2ꢀꢁ4.6 Hz, 1H, H-2ꢀ),
6.85 (d, J2ꢀ,1ꢀꢁ4.6 Hz, 1H, H-1ꢀ), 7.19 (s, 1H, imidazole H-4) and 7.98 (s,
1H, imidazole H-5. 13C-NMR (CDCl3) d: 19.97 (COCH3 at C-2ꢀ), 20.60
(COCH3 at C-3ꢀ), 61.55 (C-5ꢀ), 76.37 (C-3ꢀ), 76.47 (C-2ꢀ), 84.22 (C-4ꢀ),
88.67 (C-1ꢀ), 125.13 (C-5), 128.48 (C-4), 145.31 (C-2), 170.18 and 171.43
(two CꢁO) ppm. Anal. Calcd for C12H15N3O8: C, 43.77; H, 4.59; N, 12.76.
Found: C, 43.69; H, 4.55; N, 12.62.
1-b-D-[5-O-Toluenesulfonyl-2-O-acetyl-arabinofuranosyl]-2-nitroimi-
dazole (8) A solution of 6 (0.23 g, 0.8 mmol) in anhydrous pyridine (10
ml) was cooled to ꢅ5 °C and tosyl chloride (0.3 g, 1.6 mmol), pre-dissolved
in pyridine (5 ml), was added dropwise to this solution. The mixture was
stirred at this temperature for 6 h. Additional tosyl chloride (0.1 g, 0.53
mmol) and DMAP (98 mg, 0.8 mmol) were added to the reaction mixture
and the stirring was continued for 3 d at 22 °C. The reaction was quenched
after tosylation was complete, by adding ice. Pyridine was removed in vacuo
and the impure product was purified by column chromatography using ethyl
acetate/hexanes (40/60, v/v) as eluant to afford 0.18 g (52%) of pure 8. This
compound was subjected to acetylation without any further characterization.
1-b-D-[5-O-Toluenesulfonyl-2,3-di-O-acetylarabinofuranosyl]-2-ni-
troimidazole (9) Acetic anhydride (200 ml) was added to a solution of 8
(0.18 g, 0.4 mmol) in anhydrous pyridine (10 ml) under stirring. The reaction
was continued for 3 h at 22 °C. At that time, a TLC examination of the reac-
tion mixture showed complete conversion of 8 to 9. The solvent was re-
moved in vacuo and the residue was loaded on a silica gel column. Purifica-
tion using ethyl acetate/hexanes (50 : 50, v/v) afforded pure product 9
1-b-D-[5-Deoxy-5-chloro-2,3-di-O-acetyl-arabinofuranosyl]-2-nitroim-
idazole (13) Trifluoromethanesulfonyl chloride (0.34 ml, 3.19 mmol) was
taken in anhydrous dichloromethane (10 ml) and added to a pre-cooled solu-
tion of 12 (0.55 g, 1.67 mmol) and DMAP (0.617 g, 5 mmol) in anhydrous
CH2Cl2 (40 ml) at ꢅ78 °C. The reaction mixture was stirred for 2 h at this
temperature and then quenched by ice. The mixture was allowed to warm to
room temperature (22 °C) to decompose excess triflyl chloride. The organic
layer was dried over anhydrous MgSO4, filtered and the filtrate was evapo-
rated by rotary evaporation. The residue was purified on a silica gel column
using ethyl acetate/hexanes (40/60, v/v) that afforded pure 13 (0.56 g, 96%).
mp 128 °C. 1H-NMR (CDCl3) d: 1.86 and 2.19 (two s, each for 3H, 2ꢂ
COCH3), 3.82 (d, J4ꢀ,5ꢃꢁ5.5 Hz of d, Jgemꢁ12.2 Hz, 1H, H-5ꢃ), 3.94 (d, Jgemꢁ
12.2 Hz of d, J4ꢀ,5ꢀꢁ3.9 Hz, 1H, H-5ꢀ), 4.34 (m, J3ꢀ,4ꢀꢁ3.4 Hz of d, J5ꢀ,4ꢀꢁ3.9
Hz of d, J5 ꢃ,4ꢀꢁ5.5 Hz, 1H, H-4ꢀ), 5.24 (d, J2ꢀ,3ꢀꢁ1.8 Hz of d, J4ꢀ,3ꢀꢁ3.4 Hz,
1H, H-3ꢀ), 5.69 (d, J3ꢀ,2ꢀꢁ1.8 Hz of d, J1ꢀ,2ꢀꢁ4.3 Hz, 1H, H-2’), 6.85 (d,
J2ꢀ,1ꢀꢁ4.3 Hz, 1H, H-1ꢀ), 7.19 (s, 1H, H-4) and 7.98 (s, 1H, H-5). 13C-NMR
(CDCl3) d: 19.97 (COCH3 at C-2ꢀ), 20.64 (COCH3 at C-3ꢀ), 43.16 (C-5ꢀ),
74.74 (C-3ꢀ), 76.82 (C-2ꢀ), 82.26 (C-4ꢀ), 87.80 (C-1ꢀ), 123.18 (C-5), 128.18
(C-4), 145.36 (C-2), 168.10 and 169.50 (two CꢁO) ppm. MS (ESI) m/z: 370
(MꢄNaꢄ). Anal. Calcd for C12H14ClN3O7: C, 41.44; H, 4.03; N, 12.09.
Found: C, 41.53; H, 4.02; N, 11.78.
1
(0.17 g, 88%). mp 117—119 °C. H-NMR (CDCl3) d: 1.90 and 2.18 (two s,
each for 3H, 2ꢂCOCH3), 2.50 (s, 3H, toluyl CH3), 4.26 (d, J3ꢀ,4ꢀꢁ3.4 Hz of
d, J5ꢀ,4ꢀꢁ3.0 Hz of d, J5ꢃ,4ꢀꢁ4.6 Hz, 1H, H-4ꢀ), 4.26 (d, J4ꢀ,5ꢃꢁ4.6 Hz of d,
Jgemꢁ11.3 Hz, 1H, H-5ꢃ), 4.46 (d, Jgemꢁ11.3 Hz of d, J4ꢀ,5ꢀꢁ3.0 Hz, 1H, H-
5ꢀ), 5.14 (dd, J2ꢀ,3ꢀꢁ1.2 Hz, J4ꢀ,3ꢀꢁ3.4 Hz, 1H, H-3ꢀ), 5.66 (d, J3ꢀ,2ꢀꢁ1.2 Hz of
d, J1ꢀ,2ꢀꢁ3.6 Hz, 1H, H-2ꢀ), 6.83 (d, J2ꢀ,1ꢀꢁ3.6, 1H, H-1ꢀ), 7.19 (s, 1H, imida-
zole H-4), 7.42 (d, J2,3ꢁJ6,5ꢁ8.3 Hz, 2H, phenyl H-3 and H-5), 7.78 (s, 1H,
imidazole H-5) and 7.86 (d, J3,2ꢁJ5,6ꢁ8.3 Hz, 2H, phenyl H-2 and H-6).
13C-NMR (CDCl3) d: 19.76 (COCH3 at C-2ꢀ), 19.86 (COCH3 at C-3ꢀ),
20.49 (toluyl CH3), 67.40 (C-5ꢀ), 74.27 (C-3ꢀ), 75.94 (C-2ꢀ), 80.95 (C-4ꢀ),
87.76 (C-1ꢀ), 123.46 (C-5), 127.77 (phenyl C-2, C-6 and C-4), 129.94
(phenyl C-3 and C-5), 128.11 (C-4), 145.31 (C-2), 132.62 (phenyl C-1),
145.31 (imidazole C-2), 168.22 and 169.47 (two CꢁO) ppm. Anal. Calcd
for C19H21SN3O10: C, 47.20; H, 4.38; N, 8.69. Found: C, 47.13; H, 4.21; N,
8.55.
1-b-D-[5-O-tert-Butyldiphenylsilyl-2,3-di-O-acetyl Arabinofuranosyl]-
2-nitroimidazole (11) t-Butyldiphenylchlorosilane (0.95 ml, 3.65 mmol)
was added to a solution of 6 (0.96 g, 3.34 mmol) in anhydrous pyridine
(10 ml) under an inert atmosphere. This mixture was stirred overnight at
30 °C, when analysis by TLC showed complete conversion of 6 to its 5ꢀ-O-
silylated derivative. Acetic anhydride (0.47 ml, 5 mmol) was added in situ to
this reaction mixture and the stirring was continued for an additional 1.5 h.
Afterwards, excess acetic anhydride was decomposed by adding ice to the
reaction vessel and the solvent was removed in vacuo on a rotary evaporator.
Purification of the impure product on a silica gel column, using ethyl ac-
etate/toluene (5 : 95, v/v) as eluant, yielded 1.68 g (88%) of pure 11. mp
145—146 °C. 1H-NMR (CDCl3) d: 1.05 (s, 9H, t-butyl), 1.68 and 2.05 (two
s, each for 3H, 2ꢂCOCH3), 3.81 (d, J4ꢀ,5ꢃꢁ4.2 Hz of d, Jgemꢁ11.6 Hz, 1H,
H-5ꢃ), 3.99 (d, Jgemꢁ11.6 Hz of d, J4ꢀ,5ꢀꢁ3.4 Hz, 1H, H-5ꢀ), 4.09 (m,
J3ꢀ,4ꢀꢁ5.3 Hz of d, J5ꢀ,4ꢀꢁ3.4 Hz of d, J5ꢃ,4ꢀꢁ4.2 Hz, 1H, H-4ꢀ), 5.39 (d,
J2ꢀ,3ꢀꢁ3.4 Hz of d, J4ꢀ,3ꢀꢁ5.3 Hz, 1H, H-3ꢀ), 5.65 (d, J3ꢀ,2ꢀꢁ3.4 Hz of d,
J1ꢀ,2ꢀꢁ3.9 Hz, 1H, H-2ꢀ), 6.74 (d, J2ꢀ,1ꢀꢁ3.9 Hz, 1H, H-1ꢀ), 6.98 (s, 1H, imi-
dazole H-4), 7.30—7.42 (m, 6H, phenyl), 7.52 (s, 1H, imidazole H-5) and
7.60—7.64 (m, 4H, phenyl). 13C-NMR (CDCl3) d: 19.87 (COCH3 at C-2ꢀ),
20.62 (COCH3 at C-3ꢀ), 26.77 (t-butyl CH3), 62.12 (C-5ꢀ), 74.38 (C-3ꢀ),
74.94 (C-2ꢀ), 82.32 (C-4ꢀ), 86.96 (C-1ꢀ), 123.06 (C-5), 127.79 (phenyl C-2,
C-6 and C-4), 127.98 (imidazole C-4), 132.67 and 132.35 (C-1 of two
phenyls), 135.55 and 135.37 (phenyl C-3 and C-5), 145.31 (imidazole C-2),
168.31 and 169.34 (two CꢁO) ppm. Anal. Calcd for C28H33SiN3O8: C,
59.25; H, 5.86; N, 7.40. Found: C, 59.79; H, 6.01; N, 7.16.
1-b-D-[5-Deoxy-5-iodo-2,3-di-O-acetyl-arabinofuranosyl]-2-nitroimi-
dazole (10)
Method A: 9 (5 mg, 0.01 mmol) was dissolved in anhydrous 2-pentanone
(100 ml) in a ReactivialTM (3 ml), and pulverized sodium iodide (3.7 mg,
0.025 mmol) was added to it. The mixture was heated in a 500 W domestic
microwave oven at ‘high’ for 8 min. Co-chromatography with authentic 10
on HPLC confirmed the formation of 10. The chemical yield of 10 by this
method, without any purification (HPLC yield), was 80%.
Method B: Pulverized anhydrous sodium iodide (0.25 g, 1.63 mmol) was
added to a solution of 13 (0.15 g, 0.43 mmol) in anhydrous 2-pentanone
(20 ml) and the mixture was refluxed at 110 °C for 16 h. Afterwards, the sol-
vent was evaporated and the recovered residue was chromatographed on a
silica gel column. Elution with ethyl acetate/toluene (20 : 80, v/v) gave
0.16 g (87%) pure 10. mp 161—163 °C. 1H-NMR (CDCl3) d: 1.85 and 2.18
(two s, each for 3H, 2ꢂCOCH3), 3.52 (d, J4ꢀ,5ꢃꢁ5.7 Hz of d, Jgemꢁ11.0 Hz,
1H, H-5ꢃ), 3.61 (d, Jgemꢁ11.0 Hz of d, J4ꢀ,5ꢀꢁ5.2 Hz, 1H, H-5ꢀ), 4.19 (m,
J3ꢀ,4ꢀꢁ3.4 Hz of d, J5ꢀ,4ꢀꢁ5.2 Hz of d, J5ꢃ,4ꢀꢁ5.7 Hz, 1H, H-4ꢀ), 5.12 (d,
J2ꢀ,3ꢀꢁ1.5 Hz of d, J4ꢀ,3ꢀꢁ3.4 Hz, 1H, H-3ꢀ), 5.69 (dd, J3ꢀ,2ꢀꢁ1.5,
J1ꢀ,2ꢀꢁ3.7 Hz, 1H, H-2ꢀ), 6.83 (d, J2ꢀ,1ꢀꢁ3.7 Hz, 1H, H-1ꢀ), 7.19 (s, 1H, H-4)
and 7.62 (s, 1H, H-5). 13C-NMR (CDCl3) d: 3.43 (C-5ꢀ), 20.01 (COCH3 at
C-2ꢀ), 20.67 (COCH3 at C-3ꢀ), 74.96 (C-3ꢀ), 78.70 (C-2ꢀ), 82.18 (C-4ꢀ),
87.98 (C-1ꢀ), 123.52 (C-5), 128.16 (C-4), 145.42 (C-2), 168.00 and 169.41
(two CꢁO) ppm. Anal. Calcd for C12H14IN3O7: C, 32.82; H, 3.21; N, 9.57.
Found: C, 33.24; H, 3.13; N, 9.24.
1-b-D-[5-Deoxy-5-iodoarabinofuranosyl]-2-nitroimidazole (b-IAZA,
1) Synthesis of 1 (Chart 2) started from b-AZA (7). Triphenylphosphine
(42.9 mg, 0.163 mmol) was added to the solution of 7 (20 mg, 0.08 mmol) in
anhydrous pyridine (5 ml). Iodine (41.4 mg, 0.163 mmol) was introduced in
the reaction mixture after 5 min and the stirring was continued for 16 h at
70 °C. Afterwards, the reaction was stopped by adding methanol (0.5 ml) to
the reaction mixture and the solvent was removed. The residue was chro-
matographed on a silica gel column using ethyl acetate/hexanes (45 : 55, v/v)
that afforded 11 mg (38%) of 1.
Alternatively (Chart 3), diacetate (10, 0.135 g, 0.31 mmol) was dissolved
in NH3/MeOH (2 M, 8 ml) and the solution was stirred at 0 °C for 2 h, then
evaporated to dryness to give the impure 1. The impure product was purified
on a silica gel column using ethyl acetate/hexanes (45 : 55, v/v) to afford
0.105 g (96%) pure 1. mp 138 °C. 1H-NMR (CD3OD) d: 3.55 (dd, J4ꢀ,5ꢃꢁ6.5
Hz, Jgemꢁ10.5 Hz, 1H, H-5ꢃ), 3.61 (dd, Jgemꢁ10.5 Hz, J4ꢀ,5ꢀꢁ6.1 Hz, 1H, H-
5ꢀ), 4.06—4.10 (m, 2H, H-4ꢀ, H-3ꢀ), 4.48 (d, J3ꢀ,2ꢀꢁ3.4 Hz of d, J1ꢀ,2ꢀꢁ4.5
Hz, 1H, H-2ꢀ), 6.70 (d, J2ꢀ,1ꢀꢁ4.5 Hz, 1H, H-1ꢀ), 7.16 (d, J5,4ꢁ0.9 Hz, 1H, H-
4) and 7.76 (d, J4,5ꢁ0.9 Hz, 1H, H-5). 13C-NMR (CDCl3) d: 5.22 (C-5ꢀ),
1-b-D-[2,3-di-O-Acetyl-arabinofuranosyl]-2-nitroimidazole (12)
A
solution of 11 (1.60 g, 2.81 mmol) in CH3CN (80 ml) was heated with potas-
sium fluoride (1.14 g, 19.67 mmol) and benzoic acid (2.40 g, 19.67 mmol) at
75 °C for 16 h. The mixture was then cooled, filtered and the filtrate was sub-
jected to evaporation. Removal of the solvent led to a viscous mass that was
purified on a silica gel column. Elution, at first with 40% ethyl acetate/
hexane (v/v) and then with 90% ethyl acetate in hexane gave 0.85 g (92%) of