106
M. Saudi et al. / European Journal of Medicinal Chemistry 76 (2014) 98e109
d
7.89 (s, 1H), 7.79e7.76 (m, 2H), 7.60e7.58 (m, 2H), 7.43e7.40 (m,
was separated, washed with water (3 ꢂ 50 mL) and dried over
Na2SO4, filtered and concentrated in vacuo. The residue was puri-
fied by silica gel column chromatography to afford 380 mg (94%) of
29. TLC (ethyl acetate/hexane, 1:1): Rf ¼ 0.70. 1H NMR (300 MHz,
1H), 7.40e7.35 (m, 2H), 7.30e7.26 (m, 2H), 6.30e6.22 (m, 1H, H-10),
4.65e4.62 (m, 1H, H-30), 4.50e3.47 (m, 1H), 4.44e4.41 (m, 1H),
4.31e4.23 (m, 3H), 4.07e4.04 (m, 1H), 2.25e2.20 (m, 1H, H-20/H-
200), 2.03e1.97 (m, 1H, H-20/H-200), 1.67 (s, 3H, 5-CH3). 13C NMR
CDCl3):
d
8.81 (bs, 1H), 7.27 (s, 1H), 6.35e6.30 (m, 1H, H-10), 5.23e
(125 MHz, CDCl3):
d
166.3, 156.4, 152.2, 144.7, 144.6, 142.7, 142.6,
5.21 (m, 1H), 4.41e4.24 (m, 3H), 2.50e2.35 (m, 1H), 2.27e2.24 (m,
137.4, 129.0, 128.9, 128.2, 128.1, 126.0, 125.9, 121.1, 111.7, 86.4, 86.0,
72.2, 70.7, 68.4, 40.9, 12.6; HRMS (EIþ): m/z for [C25H24N2O7Na]þ
calcd. 487.1475; found 487.1470.
1H), 2.13 (s, 3H), 2.12 (s, 3H), 1.68 (s, 3H, 5-CH3); 13C NMR (75 MHz,
CDCl3): d 170.4, 170.2, 163.5, 150.3, 134.5, 111.6, 84.8, 82.1, 74.1, 63.8,
37.5, 20.9, 20.8, 12.7; HRMS (EIþ): m/z for [C14H18N2O7K]þ calcd.
365.0751; found 365.0748.
4.2.21. 30,50-bis-O-fmoc-thymidine (26)
Thymidine 4 (50 mg, 0.21 mmol) was dissolved and co-
evaporated 3 times with 2 mL of dry pyridine and dissolved in
1 mL of dry pyridine. Fmoc chloride (128 mg, 0.50 mmol) was
added to the reaction mixture. The mixture was allowed to stir at
room temperature for 18 h under argon atmosphere. After 18 h,
mixture was evaporated to dryness. The obtained crude compound
was purified by column chromatography to obtain 88 mg (62%) of
4.2.24. 30,50-di-O-(tert-butyldimethylsilyl)-thymidine (30) [34]
Thymidine 4 (200 mg, 0.826 mmol) was dissolved in dry DMF
(4 mL). Tert-butyldimethylsilyl chloride (871 mg, 5.78 mmol) and
imidazole (562 mg, 8.26 mmol) were added to the reaction mixture.
The clear solution was allowed to stir at room temperature for 18 h.
Water (40 mL) was added, the aqueous layer was extracted with
ethyl acetate (3 ꢂ 50 mL), and the combined organic layers were
washed with brine (3 ꢂ 50 mL), dried over Na2SO4, and concen-
trated to dryness. The oily residue was purified by silica gel column
chromatography to give pure compound 30 (360 g, 92%) as a white
foam. TLC (ethyl acetate/hexane, 1:1): Rf ¼ 0.70. 1H NMR (500 MHz,
26. TLC (ethyl acetate): Rf ¼ 0.90. 1H NMR (500 MHz, CDCl3):
d 8.40
(bs, 1H, NH), 7.80e7.74 (m, 4H), 7.63e7.54 (m, 4H), 7.45e7.38 (m,
4H), 7.37e7.27 (m, 5H), 6.41e6.38 (m, 1H, H-10), 5.15e5.13 (m, 1H),
4.63e4.59 (m, 1H, H-30), 4.51e4.44 (m, 4H), 4.42e4.39 (m, 1H),
4.30e4.24 (m, 3H), 2.54e2.50 (m, 1H, H-20/H-200), 2.16e2.10 (m, 1H,
CDCl3):
d
8.81 (bs, 1H), 7.45 (s, 1H), 6.35e6.33 (m, 1H, H-10), 4.42e
H-20/H-200), 1.78 (s, 3H, 5-CH3). 13C NMR (125 MHz, CDCl3):
d
163.2,
4.40 (m, 1H), 3.94e3.93 (m, 1H), 3.89e3.86 (m, 1H), 3.78e375 (m,
154.6, 154.4, 150.1, 143.0, 142.9, 141.4, 134.7, 128.1, 128.0, 127.2, 127.1,
125.1, 124.9, 124.8, 120.2, 111.7, 84.7, 82.0, 77.8, 70.3, 70.1, 67.2, 46.8,
46.7, 37.3, 12.6; HRMS (EIþ): m/z for [C40H35N2O9]þ calcd.
687.2336; found 687.2335.
1H), 2.27e2.24 (m, 1H), 2.03e1.98 (m, 1H), 1.91 (s, 3H, 5-CH3); 13C
NMR (125 MHz, MeOD): d 163.8, 150.3, 135.5, 110.8, 87.8, 84.8, 72.2,
63.0, 41.4, 29.7, 25.9, 25.7, 12.5, ꢃ4.7, ꢃ4.9, ꢃ5.4, ꢃ5.5; HRMS (EIþ):
m/z for [C22H42N2O5Si2K]þ calcd. 509.2269; found 509.2263.
4.2.22. 50-O-adamantyl-thymidine (27) and 30,50-bis-O-adamantyl-
thymidine (28)
4.2.25. 30,50-di-O-(triisopropylsilyl)-thymidine (31) [35]
Thymidine 4 (200 mg, 0.826 mmol) was dissolved in dry DMF
(4 mL). Triisopropylsilyl chloride (1.24 mL, 5.78 mmol) and imid-
azole (562 mg, 8.26 mmol) were added to the reaction mixture at
room temperature. The obtained clear solution was allowed to stir
at room temperature for 18 h. Water (40 mL) was added and the
aqueous layer was extracted with ethyl acetate (3 ꢂ 50 mL). The
combined organic layers were washed with brine (3 ꢂ 50 mL), dried
over Na2SO4, and concentrated to dryness. The oily residue was
purified by silica gel column chromatography to get 430 mg (94%)
of pure compound 31 as white foam. TLC (ethyl acetate/hexane,
Thymidine 4 (300 mg, 1.24 mmol) was co-evaporated 3 times
with 5 mL of dry pyridine and dissolved in 2 mL of dry pyridine
under argon atmosphere. A solution of adamantyl chloride in
CH2Cl2 (2.3 mL, 2.27 mmol) was added dropwise to the reaction
mixture. The mixture was stirred at 70 ꢀC and reaction progress was
monitored using TLC. After 18 h, the mixture was cooled to room
temperature. The mixture was evaporated to dryness. The obtained
crude compound was purified by column chromatography (CH2Cl2/
MeOH, 95:5) to obtain the title compounds 28 (180 mg, 26%) and 27
(75 mg, 15%). TLC (ethyl acetate/hexane, 1:1): Rf ¼ 0.70 and 0.60.
50-O-adamantyl-thymidine (27) 1H NMR (500 MHz, MeOD):
1:1): Rf ¼ 0.70. 1H NMR (500 MHz, CDCl3):
d 8.46 (bs, 1H), 7.46 (s,
1H), 6.38e6.35 (m, 1H, H-10), 4.63e4.61 (m, 1H), 4.03e4.02 (m, 1H),
3.97e3.94 (m, 1H), 3.90e3.88 (m, 1H), 2.33e2.39 (m, 1H), 2.06e
2.02 (m, 1H), 1.91 (s, 3H, 5-CH3), 1.17e1.13 (m, 3H), 1.10e1.05 (m,
d
8.79 (bs, 1H), 7.26 (s, 1H), 6.31e6.28 (m, 1H), 4.45e4.42 (m, 1H),
4.37e4.35 (m, 1H), 4.30e4.27 (m, 1H), 4.25e4.22 (m, 1H), 4.18e4.16
(m, 1H), 2.71 (bs, 1H), 2.49e2.44 (m, 1H), 2.12e2.07 (m, 1H), 2.04
45H); 13C NMR (75 MHz, CDCl3):
d 163.6, 150.1, 135.4, 110.7, 88.4,
(bs, H), 1.94 (s, 3H, 5-CH3), 1.91e1.88 (m, 6H), 1.77e1.71 (m, 9H); 13
C
84.8, 72.7, 63.6, 41.8, 18.0, 17.9, 17.9, 17.7, 12.3, 12.3, 12.0, 11.8; HRMS
NMR (75 MHz, CDCl3):
d
177.6, 163.5, 150.2, 134.9, 101.2, 84.9, 85.0,
(EIþ): m/z for [C28H55N2O5Si2]þ calcd. 555.3644; found 555.3656.
71.5, 63.5, 41.0, 40.6, 39.0, 36.3, 27.8, 12.5; HRMS (EIþ): m/z for
[C21H28N2O6Na]þ calcd. 427.1840; found 427.1835.
4.2.26. 30,50-di-O-(tert-butyldiphenylsilyl)-thymidine (32)
30,50-bis-O-adamantyl-thymidine (28) 1H NMR (500 MHz,
Tert-butyldiphenylsilyl chloride (1.5 mL, 5.78 mmol) and imid-
azole (562 mg, 8.26 mmol) was added to a solution of 200 mg
(0.826 mmol) of 4 in dry DMF (4 mL). The clear solution was stirred
at room temperature for 18 h. Reaction was quenched by adding
40 mL of water. The aqueous layer was extracted with ethyl acetate
(3 ꢂ 50 mL). The combined organic layers were washed with brine
(3 ꢂ 50 mL), dried over Na2SO4, and concentrated to dryness. The
oily residue was purified by silica gel column chromatography to
obtain compound 510 mg (87%) of 32 as white foam. TLC (ethyl
MeOD):
d 7.30 (s, 1H), 6.30e6.27 (m, 1H), 5.19e5.17 (m, 1H), 4.46e
4.42 (m, 1H), 4.30e4.27 (m, 1H), 4.20e4.18 (m, 1H), 2.50e2.46 (m,
1H), 2.13e2.04 (m, 1H), 2.03 (bs, 6H), 1.94 (s, 3H, 5-CH3), 1.90e1.84
(m, 12H), 1.77e1.67 (m, 12H); 13C NMR (75 MHz, CDCl3):
d 177.2,
177.0, 150.0, 134.5, 111.4, 84.8, 82.8, 73.8, 63.7, 40.6, 39.1, 38.6, 37.9,
36.3, 29.7, 27.8, 12.5; HRMS (EIþ): m/z for [C32H42N2O7Na]þ calcd.
589.2884; found 589.2886.
4.2.23. 30,5-di-O-acetyl-thymidine (29) [33]
acetate/hexane, 1:1): Rf ¼ 0.60. 1H NMR (500 MHz, CDCl3):
d 8.02
A suspension of compound 4 (300 mg,1.24 mmol) in acetonitrile
(5 mL) was treated with triethylamine (0.692 mL, 4.95 mmol) and
acetyl chloride (0.213 mL, 2.85 mmol) in the presence of a catalytic
amount of 4-(dimethylamino)pyridine (DMAP) (15 mg, 0.12 mmol).
The resulting mixture was stirred at room temperature for 5 h and
was then diluted with CH2Cl2 and water (1:1). The organic phase
(bs, 1H), 7.65e7.63 (m, 2H), 7.59e7.58 (m, 2H), 7.53e7.53 (m, 2H),
7.48e7.45 (m, 3H), 7.42e7.40 (m, 6H), 7.34e7.28 (m, 6H), 6.53e6.51
(m, 1H, H-10), 4.56e4.55 (d, 1H), 4.00e3.99 (m, 1H), 3.76e3.74 (m,
1H), 3.31e3.29 (m, 1H), 2.35e2.32 (m, 1H), 2.00e1.96 (m, 1H), 1.49
(s, 3H, 5-CH3), 1.09 (s, 9H), 0.94 (s, 9H); 13C NMR (75 MHz, CDCl3):
d
163.3, 150.1, 135.7, 135.7, 135.4, 135.4, 135.1, 133.2, 133.1, 133.0,