J. Shi et al. / Bioorg. Med. Chem. 13 (2005) 1641–1652
1649
25
tone gave a yellow solid: mp 182–184 ꢁC; ½aꢀ À6.66
J1 F = 15.6 Hz) 5.64 (d, 1H, 30-OH, D2O exchangeable),
0
D
1
5.44 (t, 1H, 50-OH, D2O exchangeable), 5.04 (dd, 1H, H-
(c 0.79, MeOH); H NMR (DMSO-d6) d 8.46 (s, 1H,
H-6), 7.91, 6.70 (2s, 2H, NH2, D2O exchangeable),
20, J2 F = 52.9 Hz) 4.19 (dm, 1H, H-30, J3 F = 23.8 Hz),
3.91 (m, 1H, H-40), 3.73 (m, 2H, H-50a,b). Anal. Calcd
for C9H10ClFN2O5+0.8H2O: C 36.61, H 3.93, N 9.49.
Found: C 16.96, H 4.02, N 9.17.
0
0
5.84 (d, 1H, H-10, J1 ,F = 17.0 Hz), 5.56 (d, 1H, 30-OH,
0
D2O exchangeable), 5.36 (t, 1H, 50-OH, D2O exchange-
able), 4.90 (dd, 1H, H-20, J2 ,F = 53.2 Hz), 4.15 (dm, 1H,
0
H-30, J3 ,F = 24.2 Hz), 3.88 (m, 1H, H-40), 3.70 (m, 2H,
0
4.1.20. (20S)-b-L-5-Bromo-20-deoxy-20-fluorouridine (34).
To a stirred mixture of 31 (1.0 g, 3.0 mmol) in Ac2O (20
mL) and AcOH (10 mL) was added Br2 (1 mL) in AcOH
(3.0 mL), and the mixture was sealed and stirred at
room temperature overnight. To this was added EtOH
slowly, and the mixture was evaporated to dryness and
collaborated with EtOH until no more fume formed.
The residue was then purified by silica gel column chro-
H-50a,b). Anal. Calcd for C9H11FIN3O4: C 29.13, H
2.99, N 11.32. Found: C 29.02, H 3.00, N 11.20.
4.1.24. (20S)-b-L-20-Deoxy-20-fluorocytidine (40). To a
stirred mixture of 31 (1.32 g, 4.0 mmol) and 1,2,4-triaz-
ole (2.20 g, 32.0 mmol) in pyridine (20 mL) was added
POCl3 (0.75 mL, 8.0 mmol), and the mixture was stirred
at room temperature for 17 h. The solvent was evapo-
rated and the residue was treated with NH4OH–dioxane
at room temperature for 4 h followed by satd NH3/
CH3OH at room temperature for 12 h. The removal of
the solvent gave a residue, which was recrystallized from
matography (9:1 CHCI3–CH3OH) to give a white
25
D
solid (0.89 g, 92%): mp 164–166 ꢁC; ½aꢀ À8.66 (c 0.47,
MeOH); 1H NMR (DMSO-d6) d 11.89 (s, 1H, NH,
D2O exchangeable), 8.50 (s, 1H, H-6), 5.86 (br d, 1H,
H-10, J1 ,F = 16.4 Hz), 5.63 (br s, 1H, 30-OH, D2O
cold water to give 40 as a white solid (750 mg, 77%): mp
0
0
25
164–167 ꢁC; ½aꢀ À68.85 (c 0.35, MeOH); 1H NMR
exchangeable), 5.44 (br s, 1H, 50-OH, D2O exchange-
D
able), 4.99 (dd, 1H, H-20, J2 ,F = 53.1 Hz), 4.18 (dm,
(DMSO-d6) d 7.90 (d, 1H, H-6, J = 7.3 Hz), 7.24 (br d,
0
1H, H-30, J3 ,F = 23.7 Hz), 3.90 (m, 1H, H-40), 3.73 (m,
2H, NH2, D2O exchangeable), 5.99 (d, 1H, H-10,
0
2H, H-50a,b). Anal. Calcd for C9H10BrFN2O5+0.6H2O:
C 32.15, H 3.33, N 8.34. Found: C 32.03, H 3.27, N 8.34.
J1 F = 17.8 Hz), 5.88 (d, 1H, H-5, J = 7.3 Hz), 5.73 (d,
0
1H, 30-OH, D2O exchangeable), 5.16 (t, 1H 50-OH,
D2O exchangeable), 4.89 (dd, 1H H-20, J2 F = 53.3 Hz),
0
4.1.21. (20S)-b-L-20-Deoxy-20-fluoro-5-iodouridine (35). A
mixture of 31 (3.3 g, 10 mmol) and ICl (2.4 g, 15 mmol)
in CH2C12 (100 mL) was stirred at reflux for 5 h. It was
then diluted with CH2C12 (150 mL), washed successively
with NaHSO3 (100 mL · 3), saturated NaHCO3
(50 mL · 2) and dried (MgSO4). After removal of the sol-
vent, the residue was treated with NaOCH3/CH3OH.
Trituration in ether followed by recrystallization from
4.11 (dm, IH, H-30, J3 F = 22.4 Hz), 3.86 (m, 1H, H-
0
40), 3.68 (m, 2H, H-50a,b). Anal. Calcd for
C9H12FN3O4+2H2O: C 38.41, H 5.69, N 14.94. Found:
C 38.49, H 5.72, N 14.87.
4.1.25.
(20S)-b-L-5-Chloro-20-deoxy-20-fluorocytidine
(41). To a solution of 40 (200 mg, 0.8 mmol) in DMF
(5 mL) was added a solution of HCl/DMF (2 M,
0.6 mL) followed by a solution of m-CPBA (350 mg,
1.6 mmol) in DMF (1 mL). The mixture was stirred at
room temperature for 2 h, then evaporated to dryness.
The residue was suspended in H2O and MeOH, filtered,
and washed with H2O. The combined filtrate was trea-
ted with concentrated NH4OH and then evaporated to
dryness. The residue was purified by silica gel column
chromatography (10:1 CHCI3/CH2OH) and collabo-
water gave 35 as a white solid (78%): mp 217–218 ꢁC;
25
½aꢀ +9.41 (c 0.36, MeOH); 1H NMR (DMSO-d6) d
D
11.75 (s, 1H, NH, D2O exchangeable), 8.54 (s, 1H, H-
6), 5.86 (br d, 1H, H-10, J1 ,F = 16.8 Hz), 5.62 (d, 1H,
0
30-OH, D2O exchangeable), 5.41 (t, 1H, 50-OH, D2O
exchangeable), 5.04 (dd, 1H, H-20, J2 ,F = 53.1 Hz), 4.18
0
(dm, 1H, H-30, J3 ,F = 23.4 Hz), 3.90 (m, 1H, H-40),
0
3.72 (m, 2H, H-50a,b). Anal. Calcd for C9H10FIN2O5:
C 29.05, H 2.71, N 7.53. Found: C 29.11, H 2.85, N 7.33.
rated with Et2O to give 41 as a white solid (65 mg,
25
D
28.5%): mp >105 ꢁC (dec); ½aꢀ À47.74 (c 0.19, MeOH);
4.1.22.
(20S)-b-L-5-Bromo-20-deoxy-20-fluorocytidine
1H NMR (DMSO-d6) d 8.54 (s, 1H, H-6), 8.54, 8.26 (2s,
(38). Compound 34 was treated with Ac2O in pyridine
to give 36, which was further treated in a similar manner
as described for the synthesis of 40. Trituration of
2H, NH2, D2O exchangeable), 5.82 (d, 1H, H-10,
J1 ,F = 16.4 Hz), 4.94 (dd, 1H, H-20. J2 ,F = 53.1 Hz),
0
0
4.14 (dm, 1H, H-30, J3 ,F = 25.42 Hz), 3.91 (m, 1H, H-
0
the crude product with acetone gave 38 as a white
40), 3.72 (dm, 2H, H-50a,b). Anal. Calcd for
C9H11ClFN3O4+HCl+0.5H2O: C 33.21, H 4.00, N
12.92. Found: C 32.98, H 3.75, N 12.86.
25
D
solid (38%): mp >145 ꢁC (dec); ½aꢀ À30.06 (c 0.54,
MeOH); 1H NMR (DMSO-d6) d 8.43 (s, 1H, H-6),
7.94, 7.08 (2s, 2H, NH2, D2O exchangeable), 5.85 (d,
1H, H-10, J1 ,F = 17.1 Hz), 5.56 (d, 1H, 30-OH, D2O
4.1.26. b-L-1,2-Di-O-acetyl-3,5-di-O-benzoylribofuranose
0
exchangeable), 5.38 (br s, 1H, 50-OH, D2O exchange-
(42).
l,2-Di-O-isopropylidene-3,5-di-O-benzoyl-a-L-
able), 4.91 (dd, 1H, H-20, J2 ,F = 53.1 Hz), 4.16 (dm,
ribofuranose27 (50 g, 125 mmol) was stirred in AcOH
(500 mL), Ac2O (1.50 mL), and concentrated H2SO4
(10 mL) at room temperature for 16 h. It was then
poured into ice-water, extracted with CHCl3, washed
with satd NaHCO3, dried (MgSO4). The evaporation
of the solvent gave a syrup, from which, a white crystal
was obtained (35 g, 63%), as well as a syrup of 20 g
0
1H, H-30, J3 ,F = 24.3 Hz), 3.86 (m, 1H, H-40), 3.72 (m,
0
2H, H-50a,b). Anal. Calcd for C9H11BrFN3O4+
0.5C2H5OH: C 34.57, H 4.03, N 12.09. Found: C
34.36, H 3.78, N 11.78.
4.1.23. (20S)-b-L-20-Deoxy-20-fluoro-5-iodocytidine (39).
Compound 39 was prepared from 35 in 40% yield as de-
scribed for 40. Trituration of the crude product in ace-
1
(36%): H NMR (CDCl3) d 8.10, 7.41 (m, 10H, Bz),
6.29 (br s, 1H, H-l), 5.80 (t, 1H, H-2), 5.58 (d, 1H,