N. Tzioumaki et al. / European Journal of Medicinal Chemistry 46 (2011) 993e1005
1003
0
0
0
0
11b: (0.99 g, 79%, Rf ¼ 0.42 in EtOAc). [
a]
22 ꢃ4.0 (c 0.298, CHCl3);
4.37 (dd, 1H, J4 ,5b ¼ 1.9 Hz, H-40), 3.98 (d, 1H, J5a ,5b ¼ 13.4 Hz,
H-5a0), 3.56 (dd, 1H, H-5b0), 1.64, 1.45 (2s, 6H, 2CH3); ESI-MS (m/z)
299.25 [M þ Hþ]; Anal. Calcd for C13H15FN2O5: C 52.35, H 5.07, N
D
UV (CHCl3): lmax 257 nm (
e
8850); 1H NMR (CDCl3):
d
9.02 (br s, 1H,
NH), 7.15 (d, 1H, J5,6 ¼ 8.1 Hz, H-6), 6.16 (s, 1H, H-10), 5.79 (d, 1H, H-
5), 4.74 (d, 1H, J3 ,4 ¼ 5.6 Hz, H-30), 4.67 (d, 1H, H-40), 4.49 (d, 1H,
9.39. Found: C 52.11, H 5.21, N 9.55.
0
0
22
J5a ,5b ¼ 13.7 Hz, H-5a0), 4.26 (dd, 1H, J4 ,5b ¼ 1.0 Hz, H-5b0), 1.49,
1.44 (2s, 6H, 2CH3); ESI-MS (m/z) 283.22 [M þ Hþ]; Anal. Calcd for
C12H14N2O6: C 51.06, H 5.00, N 9.93. Found: C 51.38, H 5.11, N 9.68.
12d: (0.63 g, 49%, Rf ¼ 0.42 in EtOAc). [
a]
ꢃ34.0 (c 0.500,
0
0
0
0
D
CHCl3); UV (CHCl3): lmax 261 nm (
e
21256); 1H NMR (CDCl3):
d 7.92
(d, 1H, J5,6 ¼ 7.9 Hz, H-6), 7.91e7.63 (m, 6H, Bz and H-5), 6.67 (s, 1H,
0
0
11c: (1.12 g, 85%, Rf ¼ 0.36 in EtOAc/hexane, 9:1), m.p.
H-10), 5.64, 5.58 (br s, 2H, methylene), 4.85 (d, 1H, J3 ,4 ¼ 7.2 Hz, H-
22
146e148 ꢀC. [
a]
16.0 (c 0.500, CHCl3); UV (CHCl3): lmax 265 nm
D
30), 4.37 (dd, 1H, J4 ,5b ¼ 2.3 Hz, H-40), 4.03 (d, 1H, J5a ,5b ¼ 13.4 Hz,
H-5a0), 3.66 (dd, 1H, H-5b0), 1.59, 1.43 (2s, 6H, 2CH3); ESI-MS (m/z)
384.41 [M þ Hþ]; Anal. Calcd for C20H21N3O5: C 62.65, H 5.52, N
10.96. Found: C 62.72, H 5.63, N 10.89.
0
0
0
0
(e d
2354); 1H NMR (CDCl3): 8.47 (s, 1H, H-6), 6.11 (s, 1H, H-10),
4.73e4.69 (m, 2H, J3 ,4 ¼ 5.6 Hz, H-30, H-40), 4.52 (d, 1H,
0
0
0
0
0
0
0
0
J5a ,5b ¼ 13.7 Hz, H-5a ), 4.26 (dd, 1H, J4 ,5b ¼ 1.2 Hz, H-5b ), 1.53 and
1.46 (2s, 6H, 2CH3); ESI-MS (m/z) 301.25 [M þ Hþ]; Anal. Calcd for
C12H13FN2O6: C 48.00, H 4.36, N 9.33. Found: C 48.38, H 4.08, N 9.12.
4.13. Synthesis of 1-(2-deoxy-2-methylene-a-D-erythro-
pentopyranosyl)nucleosides 13(aec)
11d: (1.3 g, 83%, Rf ¼ 0.43 in EtOAc/MeOH, 9.5:0.5). [
a]
22 ꢃ36.0 (c
D
0.250, CHCl3); UV (CHCl3): lmax 261 nm (
e
17661); 1H NMR (CDCl3):
d
7.97 (d, 1H, J5,6 ¼ 7.3 Hz, H-6), 7.72e7.50 (m, 6H, Bz and H-5), 6.40
4.13.1. 1-(2-Deoxy-2-methylene-a-D-erythro-pentopyranosyl)
thymine (13a)
Compound 12a (0.57 g, 1.94 mmol) was dissolved in a mixture of
CH2Cl2 (6.9 mL) and formic acid (6.9 mL, 90%). The solution was
stirred for 3h at room temperature and then was concentrated
under reduced pressure. The residue was purified by flash chro-
(s, 1H, H-10), 4.88 (d, 1H, J3 ,4 ¼ 4.7 Hz, H-3 ), 4.70 (d, 1H, H-4 ), 4.51,
4.38 (q, AB-system, 2H, J ¼ 13.4 Hz, H-50), 1.47, 1.43 (2s, 6H, 2CH3);
ESI-MS (m/z) 386.39 [M þ Hþ]; Anal. Calcd for C19H19N3O6: C 59.22,
H 4.97, N 10.90. Found: C 59.38, H 5.05, N 10.88.
0
0
0
0
4.12. Synthesis of 1-(2-deoxy-3,4-O-isopropylidene-2-methylene-
matography (EtOAc/hexane, 9:1) to give 13a (0.43 g, 87%, Rf ¼ 0.14)
22
a-D
-erythro-pentopyranosyl)nucleosides 12(aed)
as a white foam. [
a
]
ꢃ2.0 (c 0.500, MeOH); UV (MeOH): lmax
D
262 nm (e d 7.69 (s, 1H, H-6), 6.16 (s, 1H, H-
8524); 1H NMR (CDCl3):
4.12.1. 1-(2-Deoxy-3,4-O-isopropylidene-2-methylene-
a-D
-erythro-
10), 5.47, 4.83 (br s, 2H, methylene),0 4.41 (m, 1H, H-40), 4.06e4.04
0
0
0
0
0
pentopyranosyl)thymine (12a)
(m, 2H, J5a ,5b ¼ 12.5 Hz, H-5a , H-5b ), 3.92 (d, 1H, J2 ,3 ¼ 5.1 Hz, H-
To a stirred suspension of Ph3PCH3Br (3.94 g, 11.02 mmol) and
t-amyl alcohol (1.32 mL, 12.02 mmol) in dry THF (34 mL) was added
NaH (0.46 g, 60% in oil, 19.23 mmol) at 0 ꢀC under nitrogen and the
reaction mixture was stirred for 2 h at ambient temperature. To this
yellow phosphorous ylide was added a solution of 11a (0.99 g,
3.34 mmol) in dry THF (5 mL) dropwise, at 0 ꢀC under nitrogen.
After the mixture was stirred for 30 min at ambient temperature,
the reaction mixture was quenched with saturated sodium bicar-
bonate and extracted with EtOAc. The organic layer was washed
with water, dried with sodium sulfate and evaporated. The residue
30),1.91 (s, 3H, 5-CH3); 13C NMR (CDCl3):
d 13.23, 65.78, 67.82, 76.38,
83.16, 112.11, 113.42, 139.43, 153.12, 154.01, 161.94; ESI-MS (m/z)
255.26 [M þ Hþ]; Anal. Calcd for C11H14N2O5: C 51.97, H 5.55, N
11.02. Found: C 52.23, H 5.76, N 10.88.
4.13.2. 1-(2-Deoxy-2-methylene-a-D-erythro-pentopyranosyl)
uracil (13b), 5-fluorouracil (13c)
Uracil and 5-fluorouracil derivatives 13b and 13c were synthe-
sized by similar procedure as described for 13a.
13b: (0.46 g, 85%, Rf ¼ 0.15 in EtOAc/hexane, 9:1). [
a
]
22 ꢃ8.0 (c 0.300,
D
was purified by flash chromatography (EtOAc/hexane, 1:1) to give
MeOH); UV (MeOH): lmax 259 nm (e d 7.75 (d,
8241); 1H NMR (CDCl3):
22
12a (0.57 g, 58%, Rf ¼ 0.3), as a white solid, m.p. 110e112 ꢀC. [
a
]
1H, J5,6 ¼ 8.1 Hz, H-6), 6.14 (s,1H, H-10), 5.73 (d,1H, H-5), 5.43, 4.81 (br s,
D
e
9276); 1H NMR
2H, methylene), 4.38 (m, 1H, H-40), 4.02 (dd, 1H, J4 ,5b ¼ 2.3 Hz,
0
0
ꢃ20.0 (c 0.500, CHCl3); UV (CHCl3): lmax 264 nm (
J5a ,5b ¼ 12.6 Hz, H-5b ), 3.91 (d,1H, H-5a ), 3.88(brs,1H, H-3 ); 13CNMR
0
0
0
8.27 (br s, 1H, NH), 7.81 (s, 1H, H-6), 6.47 (s, 1H,0 H-10),
0
0
(CDCl3):
d
0
0
5.66, 5.50 (br s, 2H, methylene), 4.86 (d,1H, J3 ,4 ¼ 7.4 Hz, H-3 ), 4.35
(CDCl3): d 62.85, 70.29, 75.37, 86.22, 103.59, 117.29, 139.98, 151.27,
(dd, 1H, J4 ,5b ¼ 1.7 Hz, H-40), 3.98 (d, 1H, J5a ,5b ¼ 13.5 Hz, H-5a0),
3.58 (dd, 1H, H-5b0), 1.92 (s, 3H, 5-CH3), 1.61, 1.44 (2s, 6H, 2CH3);
ESI-MS (m/z) 295.32 [M þ Hþ]; Anal. Calcd for C14H18N2O5: C 57.13,
H 6.16, N 9.52. Found: C 57.40, H 6.42, N 9.43.
152.02, 162.90; ESI-MS (m/z) 241.22 [M þ Hþ]; Anal. Calcd for
0
0
0
0
C10H12N2O5: C 50.00, H 5.04, N 11.66. Found: C 50.36, H 5.22, N 11.43.
13c: (0.5 g, 89%, Rf
¼
0.14 in EtOAc/hexane, 9:1), m.p.
182e184 ꢀC. [
a]
22 ꢃ8.0 (c 0.500, MeOH); UV (MeOH): lmax 265 nm
D
(e
1407); 1H NMR (CDCl3):
d
8.04 (d, 1H, JF5,6 ¼ 6.7 Hz, H-6), 6.16 (s,
4.12.2. 1-(2-Deoxy-3,4-O-isopropylidene-2-methylene-
a
-
D
-
1H, H-10), 5.49, 4.92 (br s, 2H, methylene), 4.41 (m, 1H, H-40), 4.05
erythro-pentopyranosyl)uracil (12b), 5-fluorouracil (12c), N4-
(dd, 1H, J4 ,5b ¼ 2.0 Hz, J5a ,5b ¼ 12.6 Hz, H-5b0), 3.95 (d, 1H, H-5a0),
0
0
0
0
benzoyl cytosine (12d)
3.91 (br s, 1H, H-30); 13C NMR (CDCl3):
d 66.03, 67.98, 75.89, 84.02,
Uracil, 5-fluorouracil and N4-benzoyl cytosine derivatives 12b,
12c and 12d were synthesized by similar procedure as described for
113.58, 132.93, 141.39, 153.12, 153.97, 160.07; ESI-MS (m/z) 259.22
[M þ Hþ]; Anal. Calcd for C10H11FN2O5: C 46.52, H 4.29, N 10.85.
Found: C 46.43, H 4.20, N 10.78.
12a.
22
12b: (0.64 g, 65%, Rf ¼ 0.6 in EtOAc), m.p. 213e215 ꢀC. [
a]
D
ꢃ28.0 (c 0.600, CHCl3); UV (CHCl3): lmax 259 nm (
e
5157); 1H NMR
4.14. Synthesis of 1-(2,3,4-trideoxy-2-methylene-a-pent-3-
enopyranosyl)nucleosides 10(aec)
(CDCl3):
d
8.51 (br s, 1H, NH), 7.92 (d, 1H, J5,6 ¼ 8.2 Hz, H-6), 6.46 (s,
1H, H-10), 5.72 (d, 1H, H-5), 5.67, 5.49 (br s, 2H, methylene), 4.85 (d,
1H, J3 ,4 ¼ 7.3 Hz, H-30), 4.35 (dd, 1H, J4 ,5b ¼ 2.3 Hz, H-40), 3.97 (d,
4.14.1. 1-(2,3,4-Trideoxy-2-methylene-
a-pent-3-enopyranosyl)
0
0
0
0
1H, J5a ,5b ¼ 13.4 Hz, H-5a0), 3.58 (dd, 1H, H-5b0), 1.56, 1.42 (2s, 6H,
2CH3); ESI-MS (m/z) 281.29 [M þ Hþ]; Anal. Calcd for C13H16N2O5: C
55.71, H 5.75, N 9.99. Found: C 56.02, H 5.93, N 9.85.
thymine (10a)
0
0
Ph3P (1.33 g, 5.07 mmol), iodine (0.64 g, 2.53 mmol), and imid-
azole (0.17 g, 2.53 mmol) were added tothe suspension of 13a (0.43 g,
1.69 mmol) in 47 mL of dry Tol/DMF (4:1). The reaction mixture was
heated(80ꢀC, oilbath)undernitrogenfor15minandconcentratedin
vacuum. The residue was purified by flash chromatography (EtOAc/
hexane, 9:1) yielded 10a (0.21 g, 57%), as a white foam.
12c: (0.65 g, 58%, Rf ¼ 0.71 in EtOAc/hexane, 9:1). [
a]
22 ꢃ20.0 (c
D
0.500, CHCl3); UV (CHCl3): lmax 265 nm (
e
8347); 1H NMR (CDCl3):
d
8.81 (br s, 1H, NH), 8.18 (d, 1H, JF5,6 ¼ 6.5 Hz, H-6), 6.49 (s, 1H, H-
10), 5.71, 5.58 (br s, 2H, methylene), 4.87 (d, 1H, J3 ,4 ¼ 7.4 Hz, H-3 ),
0
0
0