K. Yamada et al. / Bioorg. Med. Chem. 17 (2009) 5928–5932
5931
and treated with a 3 M HCl aqueous solution. The resulting mixture
was extracted with Et2O. The organic extracts were combined, con-
centrated, dried over Na2SO4, filtered, and concentrated under re-
duced pressure to yield compound 4 (4.65 g, 80%). This product
was identified by 1H NMR analysis compared with that of the
authentic sample: 1H NMR (CDCl3) d 0.37 (9H, s), 7.49 (1H, t,
J = 7.5 Hz), 7.58 (1H, t, J = 7.5 Hz), 7.75 (1H, d, J = 7.5 Hz), 8.20
(1H, d, J = 7.5 Hz); 13C NMR (CDCl3) d 0.0, 128.6, 130.6, 132.1,
133.8, 135.3, 143.5, 173.7. HRMS (ESI) calcd for [C10H14O2Si+H]+
195.0841, found 195.0722.
which was purified by C-200 silica gel column chromatography
with CHCl3–MeOH to give 7 as a white solid (330 mg, 82%): 1H
NMR (CDCl3) d 0.48 (9H, s), 0.70 (3H, s), 1.24–1.42 (2H, m), 3.17–
3.18 (1H, m), 3.459 (1H, br s), 3.55- 3.65 (2H, m), 4.64 (1H, d,
J = 4.1 Hz), 5.36 (1H, t, J = 6.8 Hz), 6.40–6.61 (4H, m), 6.68 (1H, d,
J = 8.1), 10.46 (1H, br s); 13C NMR (CDCl3) d 11.88, 31.19, 35.68,
40.12, 64.59, 71.18, 84.07, 84.71, 111.12, 125.49, 127.07, 128.13,
130.19, 131.91, 135.31, 147.68, 150.74, 164.20, 171.40; HRMS
(ESI) calcd for [C21H26N2O6+Na]+ 425.1683, found 425.1691.
4.1.5. Synthesis of compound 8
4.1.2. Synthesis of compound 1
Thymidine (484 mg, 2.0 mmol) was dissolved in anhydrous
DMF (2.0 mL) solution under argon atmosphere. PPh3 (525 mg,
2.0 mmol) was added and stirred vigorously for 1 h. (Z)-3-(Tri-
methylsilyl)acrylic acid (0.27 mL, 3.0 mmol) and diethyl azodicar-
boxylate (0.91 mL, 3.0 mmol) dissolved in dry DMF (2.0 mL) was
added via a syringe. The reaction mixture was stirred for 12 h at
room temperature and quenched by addition of water (2 mL) and
extracted with ethyl acetate. The combined organic layer was
washed with water, and brine. The organic solution was dried over
anhydrous Na2SO4 and concentrated under reduced pressure re-
sulted in suspension, which was purified by C-200 silica gel col-
umn chromatography with CHCl3–MeOH to give 8 as a white
solid (320 mg, 76%): 1H NMR (CDCl3) d 0.87 (9H, s), 1.89 (3H, s),
2.09–2.20 (1H, m), 2.40–2.49 (1H, m), 2.88 (1H, br s), 4.18–4.20
(1H, m), 4.33–4.46 (3H, m), 6.32 (1H, t, J = 6.6), 6.49 (1H, d,
J = 14.3), 6.68 (1H, s, J = 14.0), 7.30 (1H, s), 9.05(1H, br s); 13C
NMR (CDCl3) d 0.00, 12.60, 40.37, 63.86, 71.69, 84.48, 85.16,
111.22, 133.50, 135.24, 150.73, 155.17, 164.14, 166.01; HRMS
(ESI) calcd for [C20H26N2O6Si+Na]+ 441.1452, found 441.1446.
Thymidine (242 mg, 1.0 mmol) was dissolved in anhydrous
DMF (1.0 mL) solution under argon atmosphere. PPh3 (262 mg,
1.0 mmol) was added and stirred vigorously for 1 h. Compound 4
(233 mg, 1.2 mmol) and diethyl azodicarboxylate (0.46 mL,
1.2 mmol) dissolved in dry DMF (1.0 mL) was added using a syr-
inge. The reaction mixture was stirred for 4 h at room temperature
and quenched by adding water (2 mL) and extracted with ethyl
acetate. The combined organic layer was washed with water and
brine. The organic solution was collected, dried over anhydrous
Na2SO4 and concentrated under reduced pressure to produce a sus-
pension, which was purified by C-200 silica gel column chromatog-
raphy with CHCl3–MeOH to yield 1 as a white solid (320 mg, 76%):
1H NMR (CDCl3) d 0.32 (9H, s), 1.62 (3H, s), 2.15–2.25 (1H, m),
2.41–2.50 (1H, m), 4.24–4.25 (1H, m), 4.52–4.54 (1H, m), 4.57–
4.66 (2H, m), 6.32 (1H, t, J = 6.5 Hz), 7.42 (1H, t, J = 7.4 Hz), 7.54
(1H, t, J = 7.4 Hz), 7.73 (1H, d, J = 7.6 Hz), 7.96 (1H, d, J = 8.0 Hz),
8.24 (1H, br s); 13C NMR (CDCl3) d 0.0, 12.0, 43.4, 64.2, 71.6, 84.5,
84.9, 111.3, 128.8, 129.3, 131.9, 134.5, 135.0, 135.7, 143.4, 150.6,
163.9, 167.6. HRMS (ESI) calcd for [C20H26N2O6Si+Na]+ 441.1452,
found 441.1446.
4.1.6. Synthesis of compound 11
A solution of compound 9 (2.6 g, 12 mmol) in dry CH2Cl2
(20 mL) was added to a solution of 30,50-O-bis(tert-butyldimethylsi-
lyl)deoxycytidine (4.56 g, 10 mmol) in dry pyridine (20 mL). The
mixture was stirred at room temperature for 2 h, and the mixture
was diluted with CHCl3. The CHCl3 solution was washed succes-
sively with H2O and saturated NaHCO3. The organic layer was col-
lected, dried over Na2SO4, filtered, and evaporated under reduced
pressure. The crude product was purified by C-200 silica gel col-
umn chromatography with hexane–ethyl acetate to yield the prod-
uct 11 (4.74 g, 75%): 1H NMR (DMSO-d6) d 0.03–0.08 (12H, m), 0.25
(9H, s), 0.87–0.89 (18H, m), 2.14–2.23 (1H, m), 2.29–2.39 (1H, m),
3.73–3.85 (2H, m), 3.90–3.92 (1H, m), 4.37 (1H, m), 6.10 (1H, t,
J = 5.9 Hz), 7.34 (1H, d, J = 7.3 Hz), 7.46–7.52 (2H, m), 7.62–7.68
(2H, m), 8.25 (1H, d, J = 7.6 Hz); 13C NMR (CDCl3) d ꢁ5.6, ꢁ5.5,
ꢁ5.0, ꢁ4.6, 0.1, 17.9, 18.3, 25.7, 25.9, 42.3, 61.9, 70.3, 87.0, 88.0,
126.2, 129.0, 130.9, 135.9, 140.2, 141.2, 144.9, 162.0. HRMS (ESI)
calcd for [C31H53N3O5Si3+H]+ 632.3366, found 632.3364.
4.1.3. Synthesis of compound 6
Thymidine (2.4 g, 15 mmol) was dissolved in anhydrous DMF
(10 mL) solution under argon atmosphere. PPh3 (3.9 g, 15 mmol)
was added and stirred vigorously for 1 h at room temperature. 2-
Methylbenzoic acid (2.0 g, 15 mmol) and diethyl azodicarboxylate
(2.7 mL, 15 mmol) dissolved in dry DMF (10 mL) was added via a
syringe. The reaction mixture was stirred for 12 h at room temper-
ature and quenched by addition of water (20 mL) and extracted
with ethyl acetate. The combined organic layer was washed with
water, and brine. The organic solution was dried over anhydrous
Na2SO4 and concentrated under reduced pressure resulted in sus-
pension, which was purified by C-200 silica gel column chromatog-
raphy with CHCl3–MeOH to give 6 as a white solid (2.2 g, 37%): 1H
NMR (CDCl3) d 3.30 (3H, s), 2.11–2.22 (1H, m), 2.43–2.52 (1H, m),
3.17 (1H, d, J = 3.2 Hz), 4.24–4.28 (1H, m), 4.50–4.52 (1H, m), 4.54–
4.58 (2H, m), 6.33 (1H, d, J = 6.2 Hz), 7.20–7.23 (2H, m), 7.28 (1H,
m), 7.42 (1H, t, J = 7.6 Hz), 7.85 (1H, d, J = 7.6 Hz), 9.18 (1H, br s);
13C NMR (CDCl3) d 12.83, 22.00, 39.60, 65.20, 71.31, 84.61, 84.81,
110.77, 127.03, 130.10, 130.97, 132.66, 133.29, 136.71, 140.27,
151.40, 164.61, 167.57. HRMS (ESI) calcd for [C18H20N2O6+Na]+
383.1219, found 383.1236.
4.1.7. Synthesis of compound 2
Compound 11 (3.26 g, 5.0 mmol) was rendered anhydrous by
repeated coevaporation with pyridine, toluene, and CH2Cl2, and fi-
nally dissolved in anhydrous THF (46 mL). TEAꢀ3HF (4.0 mL,
25 mmol) was added to the solution, and the resulting mixture
was stirred at room temperature for 1 h. The mixture was parti-
tioned between CHCl3 and H2O. The organic layer was collected,
dried over Na2SO4, filtered, and evaporated under reduced pres-
sure. The crude product was purified by C-200 silica gel column
chromatography with CHCl3–MeOH to yield the product 2 (1.9 g,
94%): 1H NMR (CDCl3) d 0.28 (9H, s), 2.32–2.37 (1H, m), 2.53–
2.59 (1H, m), 3.72 (1H, br s), 3.90 (2H, m), 4.06–4.07 (1H, m),
4.17 (1H, br s), 4.55–4.57 (1H, m), 6.15 (1H, t, J = 5.9 Hz), 7.41–
7.48 (2H, m), 7.57–7.60 (2H, m), 7.68 (1H, d, J = 3.8 Hz), 8.36 (1H,
d, J = 7.6 Hz), 8.87 (1H, br s); 13C NMR (CDCl3) d 0.0, 26.1, 28.5,
4.1.4. Synthesis of compound 7
Thymidine (242 mg, 1.0 mmol) was dissolved in anhydrous
DMF (1.0 mL) solution under argon atmosphere. PPh3 (262 mg,
1.0 mmol) was added and stirred vigorously for 1 h. 2-(tert-
Butyl)benzoic acid (267 mg, 1.2 mmol) and diethyl azodicarboxyl-
ate (0.46 mL, 1.2 mmol) dissolved in dry DMF (1.0 mL) was added
via a syringe. The reaction mixture was stirred for 4 h at rt and
quenched by addition of water (2 mL) and extracted with ethyl
acetate. The combined organic layer was washed with water, and
brine. The organic solution was dried over anhydrous Na2SO4 and
concentrated under reduced pressure resulted in suspension,