2044 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12
von J anta-Lipinski et al.
108.20 (C-5), 126.90-128.19 (aromatic trityl), 136.64 (C-6),
150.39 (C-2), 163.71 (C-4). Anal. (C29H28N2O5) C, H, N.
λmin 253 nm (ꢀ 4320); UV (H2O, pH 1) λmax 286 nm (ꢀ 11 360),
1
λmin 244 nm (ꢀ 800); [R]D -31.91° (c ) 1.0, MeOH); H NMR
(Me2SO-d6) δ 1.85 (s, 3H, CH3), 2.11-2.17 (m, 1H, H-2’), 2.20-
2.25 (m, 1H, 2-H’’), 3.59-3.52 (m, 2H, H-5’, H-5’’), 4.13 (m,
1H, J 4’ - F ) 27.4, H-4’), 5.18 (d, 1H, OH-5’), 5.22 (m, 1H, J 3’ -
1-(2,3-Did eoxy-3-flu or o-5-O-(tr ip h en ylm eth yl)-â-L-r ibo-
fu r a n osyl)th ym in e (7). To a solution of 5 (2.55 g, 5.9 mmol)
in dichloromethane (60 mL) was added DAST (1.4 mL), and
the reaction mixture was stirred at room temperature for 1 h.
The mixture was diluted with chloroform (60 mL) and poured
into saturated sodium bicarbonate solution (200 mL). The
organic phase was separated, washed with water (20 mL),
dried (Na2SO4), filtrated, and evaporated in vacuo. The
residue was purified by chromatography on a silica gel column
using chloroform (1% methanol, 0.1% triethylamine) as eluant.
7 was isolated as a foam (1.45 g, 50.5%): [R]20D -23.20° (c ) 1,
) 53.7, H-3’), 6.13 (dd, 1H, J 1’ - 2’ ) 5.4, J 1’ - 2’’ ) 5.9, H-1’),
F
7.79 (s, 1H, H-6), 8.09 (br s, 1H, NH2), 8.23 (br s, 1H, NH2);
13C NMR (Me2SO-d6) δ 30.59 (CH3), 42.88 (C-2’, J F - 2’ ) 20.3),
65.86 (C-5’), 90.17 (C-1’), 90.50 (C-4’), 99.97 (C-3’, J F
174.2), 107.30 (C-5), 144.81 (C-6), 156.17 (C-2), 167.46 (C-4).
)
-
3’
Anal. (C10H14N3O3F‚HCl) C, H, N.
1-(2-Deoxy-3-O-(m eth ylsu lfon yl)-5-O-(tr iph en ylm eth yl)-
â-L-r ibofu r a n osyl)u r a cil (4). 2’-Deoxy-â-L-uridine (11.41 g,
50 mmol) was dissolved in pyridine (250 mL), and triphenyl-
methyl chloride (16.7 g, 60 mmol) was added. The mixture
was heated to 100 °C for 1 h. The solution was chilled to 0 °C
followed by the addition of methanesulfonyl chloride (12 mL,
60 mmol). After workup similar to that for 2, precipitation in
water yielded 4 as a solid (21.4 g, 39 mmol, 78%): 1H NMR
(Me2SO-d6) δ (2H-2’, 3H (mesyl group) under Me2SO), 3.32-
3.35 (m, 2H, H-5’, H-5’’), 4.17 (t, 1H, H-4’), 5.30 (d, 1H, H-3’),
1
CHCl3); H NMR (Me2SO-d6) δ 1.36 (s, 3H, CH3), 3.04-3.18
(m, 2H, H-2’, H-2’’), 3.30-3.62 (m, 2H, H-5’, H-5’’), 4.17 (dt,
1H, J 4’ - F ) 27.6, H-4’), 5.36 (dd, 1H, J 3’ - F ) 53.7, H-3’), 6.17
(dd, 1H, J ) 5.6 and 8.9, H-1’), 7.27-7.35 (m, trityl), 7.44 (s,
1H, H-6), 11.34 (br s, 1H, NH); 13C NMR (Me2SO-d6) δ 12.27
(CH3), 37.36 (C-2’), 63.37 (d, C-5’, J F - C5’ ) 9.8), 82.86 (d, C-4’,
J F C4’ ) 25.7), 86.67 (quaternary trityl), 94.20 (d, C-3’, J F
-
-
) 174.7), 109.79 (C-5), 127.18-128.13 (aromatic trityl),
C3’
135.32 (C-6), 150.27 (C-2), 163.45 (C-4). Anal. (C29H27N2O4F)
C, H, N.
5.46 (d, 1H, H-5, J 5
(m, 15H, trityl), 7.64 (d, 1H, H-6, J 6
) 8.1), 6.15 (dd, 1H, H-1’), 7.32-7.38
-
6
) 8.1), 11.41 (s, 1H,
-
5
NH); 13C NMR (Me2SO) δ 36.49 (mesyl), 37.62 (C-2’), 62.70
(C-5’), 79.54 (C-3’), 82.42 (C-4’), 84.16 (C-1’), 86.56 (quaternary
trityl), 101.74 (C-5), 127.89-128.17 (aromatic trityl), 140.42
(C-6), 150.15 (C-2), 163.38 (C-4). Anal. (C29H28N2O7S) C, H,
N.
1-(2,3-Did eoxy-3-flu or o-â-L-r ibofu r a n osyl)th ym in e (9).
A solution of 7 (1.45 g, 2.98 mmol) in aqueous acetic acid (80%,
50 mL) was heated to 90 °C for 1 h. After cooling the solvent
was removed under reduced pressure, and the residue was
purified chromatographically on silica gel with chloroform
(1.5% methanol) as eluant. Evaporation of the appropriate
fractions afforded the title compound (360 mg, 49.5%) which
crystallized from ethyl acetate: mp 176-177 °C (methanol);
UV (H2O, pH 7) λmax 265 nm (ꢀ 7620), λmin 234 nm (ꢀ 2070);
1-(2-Deoxy-5-O-(tr ip h en ylm eth yl)-â-L-xylofu r a n osyl)-
u r a cil (6). A mixture of 4 (28.0 g, 51 mmol), sodium hydroxide
(3.4 g, 85 mmol), and ethanol (400 mL) was refluxed for 2 h.
After workup similar to that for 3, purification by silica gel
column chromatography (chloroform-methanol-triethylamine,
98:2:0.1) gave 6 (11.2 g, 23.8 mmol, 46.6%) which was crystal-
MS m/z 244 (M+), 126 (base + H), 119 (C5H5O2F, sugar moiety);
1
[R]20 +1.44° (c ) 0.9, methanol); H NMR (Me2SO-d6) δ 1.85
D
(s, 3H, CH3), 2.19-2.26 (m, 2H, H-2’, H-2’’), 3.54-3.75 (m, 2H,
lized from methanol: mp 224-226 °C; [R]20 -6.37° (c ) 1,
D
H-5’, H-5’’), 4.08 (dt, 1H, H-4’, J 4’ - ) 27.9), 5.17 (br s, 1H,
CHCl3); 1H NMR (Me2SO-d6) δ (2H-2’ under Me2SO), 3.20-
3.34 (m, 1H, H-5’), 3.37-3.40 (m, 1H, H-5’’), 4.08-4.12 (m, 1H,
H-4’), 4.18 (m, 1H, H-3’), 5.27 (d, 1H, OH-3’), 5.55 (d, 1H, H-5,
F
5’-OH), 5.24 (dd, 1H, J ) 4.4, J 3’ - ) 54.2, H-3’), 6.15 (dd,
F
1H, J ) 5.4 and 9.1, H-1’), 7.63 (s, 1H, H-6), 11.35 (br s, 1H,
NH); 13C NMR (Me2SO-d6) δ 12.16 (CH3), 36.78 (C-2’, J ) 20.1),
60.75 (C-5’, J ) 11.1), 83.58 (C-1’), 84.67 (C-4’, J ) 22.4), 94.75
J 5
) 8.1), 6.12 (dd, 1H, H-1’), 7.36-7.44 (m, 15H, trityl),
-
6
7.73 (d, 1H, H-6, J 6
) 8.1), 11.28 (s, 1H, NH); 13C NMR
-
5
(C-3’, J F C3’ ) 173.8), 109.66 (C-5), 135.64 (C-6), 150.37 (C-
(Me2SO) δ 40.79 (C-2’), 60.79 (C-5’), 68.73 (C-3’), 83.40 (C-4’),
84.28 (C-1’), 85.98 (quaternary trityl), 100.88 (C-5), 126.92-
128.19 (aromatic trityl), 140.95 (C-6), 150.41 (C-2), 163.14 (C-
4). Anal. (C28H26N2O5) C, H, N.
-
2), 163.54 (C-4). Anal. (C10H13N2O4F) C, H, N.
1-(5-O-Acetyl-2,3-d id eoxy-3-flu or o-â-L-r ibofu r a n osyl)-
th ym in e (11). A mixture of 9 (240 mg, 0.98 mmol) and acetic
anhydride (1.5 mL, mmol) in pyridine (6 mL) was kept at room
temperature overnight. After removal of the solvent under
reduced pressure, the residue was purified by silica gel column
chromatography with chloroform (1% methanol) as eluant to
give 11 as a white foam (262 mg, 93%): [R]20D -8.74° (c ) 0.9,
1-(2,3-Did eoxy-3-flu or o-5-O-(tr ip h en ylm eth yl)-â-L-r ibo-
fu r a n osyl)u r a cil (8). Compound 6 (10.3 g, 21.8 mmol) was
suspended in dichloromethane (250 mL), and DAST (3.3 mL,
25 mmol) was added. Treatment according to the procedure
for 7 gave 8 as a solid material (4.9 g, 10.4 mmol, 47.7%): [R]20
D
1
CHCl3); H NMR (Me2SO-d6) δ 1.73 (s, 3H, CH3), 2.02 (s, 3H,
-28.51° (c ) 0.9, CHCl3); 1H NMR (Me2SO-d6) δ 2.33-2.38
CH3, acetyl), 2.33-2.43 (m, 2H, H-2’, H-2’’), 4.13-4.19 (m, 2H,
(m, 1H, H-2’), 2.41-2.48 (m, 1H, H-2’’), 3.20-3.24 (m, 1H,
H-5’, H-5’’), 4.26 (dt, 1H, H-4’, J 4’
) 26.8), 5.28 (dd, 1H,
H-5’), 3.32-3.38 (m, 1H, H-5’’), 4.26 (dt, 1H, H-4’, J F
- 4’
)
-
F
H-3’, J 3’ - F ) 54.7), 6.24 (dd, 1H, H-1’, J 1’ - 2’ ) 8.3, J 1’ - 2’’
6.8), 7.42 (d, 1H, H6), 11.32 (br s, 1H, H-N3); 13C NMR (Me2-
SO-d6) δ 11.70 (CH3), 20.14 (CH3, acetyl), 35.70 (C-2’, J F
)
26.2), 5.35 (dd, 1H, H-3’, J F - 3’ ) 54.3), 5.43 (d, 1H, H-5, J 5
-
) 8.2), 6.16 (m, 1H, H-1’), 7.35-7.39 (m, 15 H, trityl), 7.59
6
)
(d, 1H, H-6, J 6 - 5 ) 8.2), 11.38 (br s, 1H, NH); 13C NMR (Me2-
- 2’
20.5), 62.77 (C-5’), 81.09 (C-4’, J F - 4’ ) 24.1), 83.77 (C-1’), 93.01
(C-3’, J F - 3’ ) 175.5), 109.46 (C-5), 135.24 (C-6), 149.98 (C-2),
163.15 (C-4), 169.63 (CdO, acetyl). Anal. (C12H15N2O5F) C,
H, N.
SO) δ 36.91 (C-2’, J F
82.98 (C-4’, J F
) 20.9), 63.16 (C-5’, J F
- 5’
) 9.8),
-
2’
) 25.2), 84.26 (C-1’), 86.60 (quaternary
-
4’
trityl), 93.37 (C-3’, J F 3’ ) 175.1), 127.94-128.14 (aromatic
-
trityl), 140.14 (C-6), 150.18 (C-2), 162.78 (C-4). Anal.
(C28H25N2O7F) C, H, N.
1-(2,3-Did eoxy-3-flu or o-â-L-r ibofu r a n osyl)-5-m eth ylcy-
tosin e (13). A mixture of 1-(5-O-acetyl-2,3-dideoxy-3-fluoro-
â-L-ribofuranosyl)thymine (286 mg, 1 mmol), 1,2,4-triazole (136
mg, 2 mmol), and 4-chlorophenyl dichlorophosphate (0.244 mL,
1.53 mmol) in pyridine (6 mL) was kept for 3 days at room
temperature. Ammonium hydroxide (40 mL) was added, and
the solution was allowed to stand overnight. The solvent was
removed in vacuo. The resulting residue was dissolved in
water (50 mL) and applied on a column of DOWEX W ×8 (H+-
form). Elution with water (800 mL) and with ammonia (5%,
300 mL) gave 13 as crude product. This material was purified
by chromatography (silica gel, eluant: chloroform/15% metha-
nol) to give 13 which was isolated as the hydrochloride from
methanol/HCl (314 mg, 41%): mp 139-142 °C (2-propanol);
MS m/z 243 (M+ - HCl); UV (H2O, pH 7) λmax 278 nm (ꢀ 8350),
1-(2,3-Did eoxy-3-flu or o-â-L-r ibofu r a n osyl)u r a cil (10).
Compound 8 (4.9 g, 10.4 mmol) was treated according to the
procedure for 7 to give 10 (2.1 g, 9.1 mmol, 87.7%) as a white
solid which crystallized from methanol: mp 187-188 °C; [R]20
D
-11.27° (c ) 1, H2O); UV (H2O, pH 7) λmax 261 nm (ꢀ 10 100),
λmin 230 nm (ꢀ 2400); 1H NMR (Me2SO-d6) δ 2.18-2.23 (m, 1H,
H-2’), 2.32-2.39 (m, 1H, H-2’’), 3.61 (m, 2H, H-5’, H-5’’), 4.16
(dt, 1H, H-4’, J 4’ - F ) 27.6), 5.20 (d, 1H, OH-5’), 5.28 (dd, 1H,
H-3’, J 3’ - ) 54.3), 5.67 (d, 1H, H-5, J 5
) 8.1), 6.19 (m,
F
- 6
1H, H-1’), 7.85 (d, 1H, H-6, J 6 - 5 ) 8.1), 11.36 (br s, 1H, NH);
13C NMR (Me2SO) δ 37.14 (C-2’, J F - 2’ ) 20.1), 60.73 (C-5’, J F
5’ ) 11.3), 83.99 (C-1’), 84.88 (C-4’, J F 4’ ) 22.9), 94.79 (C-
-
-
3’, J F
) 173.7), 102.04 (C-5), 140.12 (C-6), 150.33 (C-2),
-
3’
162.91 (C-4). Anal. (C9H11N2O4F) C, H, N.