232
K. R. Kim et al. / Bioorg. Med. Chem. 15 (2007) 227–234
NMR (50 MHz, CDCl3) d 168.6, 161.9, 149.9, 141.7,
136.0, 135.9, 135.6, 133.3, 133.2, 131.7, 130.8, 130.3,
129.6, 128.2, 103.5, 94.9 (d, J = 189.7 Hz), 65.8 (d,
J = 25.6 Hz), 65.0 (d, J = 1.7 Hz), 48.9 (d, J = 19.5 Hz),
28.2 (d, J = 7.1 Hz), 27.2, 19.7; LRMS(FAB) m/z 589
(M+H)+; Anal. Calcd for C32H33FN2O4SSi: C, 65.28;
H, 5.65; N, 4.76; S, 5.45. Found: C, 64.97; H, 5.70; N,
4.97; S, 5.66.
4.11. (ꢀ)-1-[(3S,4S,5R)-5-(tert-Butyl-diphenyl-silanyl-
oxymethyl)-4-fluoro-tetrahydro-thiophen-3-yl]-5-methyl-
1H-pyrimidine-2,4-dione (16)
Compound 14 (84 mg, 0.14 mmol) was converted to 16
(65 mg, 94%) as a colorless sticky oil according to the
similar procedure used in the preparation of compound
25
15: UV (CHCl3) kmax 266 nm; ½aꢁ ꢀ6.4 (c 2.44, CHCl3);
1H NMR (500 MHz, CDCl3) dD8.57 (s, 1H, imide-H),
7.71–7.41 (m, 10 H, 2· Ar), 7.05 (s, 1H, H-6), 5.31
(ddd, 1H, J = 7.0, 8.0, 53.0 Hz, 4-H), 5.08–5.00 (m,
1H, 3-H), 3.90 (dd, 1H, J = 6.0, 10.0 Hz, TBDP-
SOCHaHb), 3.87 (dd, 1H, J = 5.5, 10.5 Hz, TBDPSO-
CHaHb), 3.64 (qd, 1H, J = 6.0, 19.0 Hz, 5-H), 3.16 (t,
1H, J = 10.5 Hz, SCHaHb), 3.07 (dd, 1H, J = 7.5,
11.5 Hz, SCHaHb), 1.94 (s, 3H, CH3), 1.10 (s, 9H, t-
Bu); 13C NMR (125 MHz, CDCl3) d 163.1, 150.4,
137.0, 135.6, 135.6, 133.0, 132.8, 129.9, 129.9, 127.8,
127.8, 111.8, 94.3 (d, J = 190.0 Hz), 64.5, 64.0 (d,
J = 25.1 Hz), 48.3 (d, J = 19.6 Hz), 27.5 (d,
J = 7.4 Hz), 26.8, 19.3, 12.5; 19F NMR (470 MHz,
CDCl3) d ꢀ188.06; LRMS(FAB) m/z 499 (M+H)+;
Anal. Calcd for C26H31FN2O3SSi: C, 62.62; H, 6.27;
N, 5.62; S, 6.43. Found: C, 62.47; H, 6.60; N, 5.39; S,
6.68.
4.9. (ꢀ)-3-Benzoyl-1-[(3S,4S,5R)-5-(tert-butyl-diphenyl-
silanyloxymethyl)-4-fluoro-tetrahydro-thiophen-3-yl]-5-
methyl-1H-pyrimidine-2,4-dione (14)
Compound 12 (100 mg, 0.26 mmol) was converted to 14
(102 mg, 66%) as a colorless sticky oil according to the
similar procedure used in the preparation of compound
25
13: UV (CHCl3) kmax 253 nm; ½aꢁ ꢀ0.7 (c 1.45, CHCl3);
1H NMR (500 MHz, CDCl3) d D7.95–7.36 (m, 15H, 3·
Ar), 7.15 (d, 1H, J = 1.0 Hz, H-6), 5.35 (ddd, 1H,
J = 6.5, 8.0, 53.0 Hz, 4-H), 5.04–4.96 (m, 1H, 3-H),
3.91 (dd, 1H, J = 6.0, 11.0 Hz, TBDPSOCHaHb), 3.84
(dd, 1H, J = 6.0, 10.5 Hz, TBDPSOCHaHb), 3.64 (qd,
1H, J = 6.0, 19.0 Hz, 5-H), 3.22 (irregular t, 1H,
J = 10.0, 11.0 Hz, SCHaHb), 3.08 (dd, 1 H, J = 7.5,
11.0 Hz, SCHaHb), 1.98 (d, 3H, J = 1.0 Hz, CH3), 1.08
(s, 9H, t-Bu); 13C NMR (125 MHz, CDCl3) d 168.6,
162.4, 149.6, 137.1, 135.6, 135.6, 135.1, 132.9, 132.8,
131.5, 130.4, 129.9, 129.2, 127.8, 127.8, 111.9, 94.4 (d,
J = 190.0 Hz), 64.6, 62.2, 48.2 (d, J = 19.1 Hz), 27.4 (d,
J = 7.8 Hz), 26.8, 19.3, 12.6; 19F NMR (470 MHz,
CDCl3) d ꢀ187.58; LRMS(FAB) m/z 625 (M+Na)+;
Anal. Calcd for C33H35FN2O4SSi: C, 65.75; H, 5.85;
N, 4.65; S, 5.32. Found: C, 65.40; H, 5.83; N, 4.75; S,
5.17.
4.12. (ꢀ)-1-((3S,4S,5R)-4-Fluoro-5-hydroxymethyl-tetra-
hydrothiophen-3-yl)-1H-pyridine-2,4-dione (1)
To a stirred solution of uracil nucleoside 15 (57 mg,
0.12 mmol) in THF (4 mL) was added 1 M tetrabuty-
lammonium fluoride solution (0.34 mL, 0.34 mmol,
TBAF, in THF) at 0 ꢁC, and the reaction mixture was
stirred at room temperature for 2 h. After the reaction
mixture was concentrated in vacuo, the resulting residue
was purified by silica gel column chromatography using
methylene chloride and methanol (15:1) as the eluent to
give the final uracil nucleoside 1 (28 mg, 97%) as a col-
orless oil, which was crystallized in ether and a small
4.10. (ꢀ)-1-[(3S,4S,5R)-5-(tert-Butyl-diphenyl-silanyl-
oxymethyl)-4-fluoro-tetrahydro-thiophen-3-yl]-1H-pyrim-
idine-2,4-dione (15)
To a stirred solution of 13 (110 mg, 0.19 mmol) in
methanol (4.5 mL) and CH2Cl2 (1.5 mL) was added
1 M NaOMe (0.40 mL, 0.40 mmol, in MeOH) at 0 ꢁC
and the reaction mixture was stirred for 6 h at room
temperature. The mixture was partitioned between
EtOAc and water, dried over MgSO4, filtered, and
evaporated under reduced pressure. The resulting resi-
due was purified by silica gel column chromatography
using hexane and ethyl acetate (1.5:1) as the eluent to
amount of methanol to produce a white solid: mp
25
D
143.4–145.2 ꢁC; UV (MeOH) kmax 262 nm; ½aꢁ ꢀ23.6
1
(c 0.63, MeOH); H NMR (500 MHz, CD3OD) d 7.72
(d, 1H, J = 7.5 Hz, H-6), 5.70 (d, 1H, J = 8.5 Hz, H-5),
5.33 (ddd, 1H, J = 6.0, 8.0, 53.0 Hz, 4-H), 5.10–5.01
(m, 1H, 3-H), 3.81 (dd, 1H, J = 6.0, 11.0 Hz, HO-
CHaHb), 3.70 (dd, 1H, J = 6.5, 12.0 Hz, HOCHaHb),
3.54 (qd, 1H, J = 6.0, 19.5 Hz, 5-H), 3.23 (t, 1H,
J = 11.0 Hz, SCHaHb), 3.03 (dd, 1H, J = 8.0, 11.0 Hz,
SCHaHb); 13C NMR (125 MHz, CD3OD) d 166.2,
152.7, 144.7, 103.2, 96.0 (d, J = 187.3 Hz), 66.0 (d,
give the uracil nucleoside 15 (74 mg, 82%) as a colorless
25
D
sticky oil: ½aꢁ ꢀ2.9 (c 0.90, CHCl3); 1H NMR
(500 MHz, CDCl3) d 8.68 (br s, 1H, NH), 7.69–7.40
(m, 10H, 2· Ar), 7.22 (d, 1H, J = 8.0 Hz, H-6), 5.73
(d, 1H, J = 7.5 Hz, H-5), 5.29 (td, 1H, J = 7.0,
53.0 Hz, 4-H), 5.06–4.98 (m, 1H, 3-H), 3.87 (d, 1H,
J = 1.0 Hz, CHaHbOTBDPS), 3.86 (s, 1H, CHaH-
bOTBDPS), 3.68–3.61 (m, 1H, 5-H), 3.15–3.10 (m,
2H, SCH2), 1.10 (s, 9H, t-Bu); 13C NMR (125 MHz,
CDCl3) d 162.7, 150.5, 141.3, 135.6, 135.6, 132.9,
132.8, 129.9, 129.9, 127.8, 103.1, 94.5 (d, J =
190.0 Hz), 64.3 (d, J = 26.0 Hz), 62.2, 48.6 (d,
J = 19.5 Hz), 27.8 (d, J = 7.3 Hz), 26.8, 19.3; Anal.
Calcd for C25H29FN2O3SSi: C, 61.95; H, 6.03; N,
5.78; S, 6.62. Found: C, 62.08; H, 5.74; N, 5.99; S, 6.45.
J = 24.6 Hz),
64.4
(d,
J = 1.4 Hz),
49.7
(d,
J = 19.1 Hz), 27.8 (d, J = 7.8 Hz); 19F NMR
(470 MHz, CD3OD) d ꢀ186.21; LRMS(FAB) m/z 247
(M+H)+; Anal. Calcd for C9H11FN2O3S: C, 43.90; H,
4.50; N, 11.38; S, 13.02. Found: C, 43.65; H, 4.61; N,
11.59; S, 13.30.
4.13. (ꢀ)-1-((3S,4S,5R)-4-Fluoro-5-hydroxymethyl-tetra-
hydro-thiophen-3-yl)-5-methyl-1H-pyrimidine-2,4-dione
(2)
Compound 16 (66 mg, 0.13 mmol) was converted to 2
(34 mg, 98%) as a white solid according to the similar