´
R. Rico-Gomez et al.
FULL PAPER
CHCl3). IR (KBr): ν˜ ϭ 2954, 2895, 1732, 1684, 1210, 1065, 761 CHCl3). IR (KBr): ν˜ ϭ 2950, 2900, 1730, 1680, 1200, 1060, 760
cmϪ1. UV (MeOH): λmax (ε ) ϭ 276 (6800), 206 (24111) nm. EI cmϪ1. UV (MeOH): λmax (ε) ϭ 276 (15360), 222 (13840) nm. EI
MS: m/z (%) ϭ 438 (6) [Mϩ], 259 (100), 180 (44). 1H NMR
MS: m/z (%) ϭ 452 (10) [Mϩ], 259 (80), 194 (100). 1H NMR
(200 MHz, CDCl3, 298 K): δ ϭ 1.86, 2.03, 2.23 (3 ϫ s, 9 H, 3 ϫ (400 MHz, CDCl3, 363 K): δ ϭ 1.82, 2.04, 2.25 (3 ϫ s, 9 H, 3 ϫ
CH3CO), 3.56 (s, 3 H, NCH3), 3.41 (s, 3 H, NCH3), 3.97 (t, J ϭ CH3CO), 2.60 (s, 3 H, C-8ϪCH3), 3.56 (s, 3 H, NCH3), 3.42 (s, 3
10.5 Hz, 1 H, H-5), 4.02 (dd, J ϭ 10.5, 6.4 Hz, 1 H, H-5Ј), 5.20
(ddd, J ϭ 10.5, 6.4, 2.6 Hz, 1 H, H-4Ј), 5.54 (dd, J ϭ 9.7, 2.6 Hz, 5.7 Hz, 1 H, H-5Ј), 5.27 (ddd, J ϭ 10.8, 5.7, 3.1 Hz, 1 H, H-4Ј),
1 H, H-2Ј), 5.78 (t, J ϭ 2.6 Hz, 1 H, H-3Ј), 6.24 (bd, J ϭ 9.7 Hz, 5.74 (dd, J ϭ 8.9, 3.1 Hz, 1 H, H-2Ј), 5.82 (t, J ϭ 3.1 Hz, 1 H, H-
1 H, H-1Ј), 7.77 (s, 1 H, H-8) ppm. 13C NMR (50 MHz, CDCl3, 3Ј), 6.40 (bd, J ϭ 8.9 Hz, 1 H, H-1Ј) ppm. 1H NMR (400 MHz,
298 K): δ ϭ 20.2, 20.4, 20.6, 28.1, 29.8, 63.5, 65.7, 68.1, 68.3, 80.3, CDCl3, 233 K, anti conformer): δ ϭ 1.87, 2.03, 2.26 (3 ϫ s, 9 H, 3
H, NCH3), 3.99 (t, J ϭ 10.8 Hz, 1 H, H-5), 4.10 (dd, J ϭ 10.8,
106.6, 139.9, 148.9, 151.3, 154.6, 168.8, 169.3, 169.9 ppm. ϫ CH3CO), 2.59 (s, 3 H, C-8ϪCH3), 3.40 (s, 3 H, NCH3), 3.53 (s,
C18H22N4O9·H2O (456.1): calcd. C 47.35, H 5.30, N 12.28; found 3 H, NCH3), 3.93Ϫ4.08 (m, 2 H, H-5, H-5Ј), 5.10 (m, 1 H, H-4Ј),
C 47.58, H 5.52, N 12.15.
5.42 (dd, J ϭ 9.9, 2.6 Hz, 1 H, H-2Ј), 5.71 (m, 1 H, H-3Ј), 6.76 (d,
J ϭ 9.9 Hz, 1 H, H-1Ј) ppm. H NMR (400 MHz, CDCl3, 233 K,
1
7-(2Ј,3Ј,4Ј-Tri-O-acetyl-β-
D
-ribofuranosyl)theophylline (10): White
syn conformer): δ ϭ 1.87, 2.06, 2.30 (3 ϫ s, 9 H, 3 ϫ CH3CO),
2.66 (s, 3 H, C-8ϪCH3), 3.39 (s, 3 H, NCH3), 3.54 (s, 3 H, NCH3),
3.93Ϫ4.08 (m, 2 H, H-5, H-5Ј), 5.35 (m, 1 H, H-4Ј), 6.26 (dd, J ϭ
9.3, 2.9 Hz, 1 H, H-2Ј), 5.78 (m, 1 H, H-3Ј), 5.50 (d, J ϭ 9.3 Hz,
1 H, H-1Ј) ppm. 13C NMR (100 MHz, CDCl3, 298 K): δ ϭ 15.4,
20.3, 20.5, 20.8, 23.3, 29.7, 63.7, 65.9, 67.4, 68.4, 80.2, 106.6, 148.3,
151.2, 151.6, 154.2, 168.7, 169.3, 169.8 ppm. C19H24N4O9 (452.2):
calcd. C 50.43, H 5.35, N 12.39; found C 50.56, H 5.31, N 12.10.
solid (0.63 g, 43%). M.p. 106 °C (ref.[27a] 99Ϫ100 °C). [α]D23 ϭ ϩ34
(c ϭ 1.0, CHCl3). IR (KBr): ν˜ ϭ 2975, 1737, 1699, 1664, 1222,
1017 cmϪ1. UV (CHCl3): λmax (ε) ϭ 274 (8060), 240 (2524) nm. EI
MS: m/z (%) ϭ 438 (6) [Mϩ], 259 (100), 180 (19), 139 (83), 97 (46).
1H NMR (200 MHz, CDCl3, 298 K): δ ϭ 2.07, 2.09, 2.12 (3 ϫ s,
9 H, 3 ϫ CH3CO), 3.36 (s, 3 H, NCH3), 3.56 (s, 3 H, NCH3), 4.39
(m, 3 H, H-4Ј, H-5, H-5Ј), 5.37 (t, J ϭ 5.5 Hz, 1 H, H-3Ј), 5.65
(dd, J ϭ 5.5, 4.2 Hz, 1 H, H-2Ј), 6.31 (d, J ϭ 4.2 Hz, 1 H, H-1Ј),
7.90 (s, 1 H, H-8) ppm. 13C NMR (50 MHz, CDCl3, 298 K): δ ϭ
20.3, 20.4, 20.7, 28.2, 29.9, 62.4, 69.3, 74.2, 79.8, 88.6, 106.4, 139.2,
149.4, 151.4, 154.7, 169.2, 169.4, 170.2 ppm. C18H22N4O9 (438.1):
calcd. C 49.30, H 5.06, N 12.78; found C 49.37, H 5.04, N 12.78.
7-(2Ј,3Ј,4Ј-Tri-O-acetyl-β-
90%).
D
D
D
-ribopyranosyl)theophylline (6): (1.64 g,
7-(2Ј,3Ј,4Ј-Tri-O-acetyl-β-
99%).
-ribofuranosyl)theophylline (10): (1.73 g,
Deacetylation of Protected Nucleosides 6 and 10: A catalytic
amount of Na (3 mg) was added to a solution of compound 6 or
10 (70 mg, 0.16 mmol) in methanol (5 mL). The reaction mixture
was stirred overnight at 20 °C. Recrystallisation from methanol
gave pure nucleosides 5 and 9.
7-(2Ј,3Ј,4Ј-Tri-O-acetyl-β-
-ribofuranosyl)-6-thiotheophylline (12):
22
(1.18 g, 65%). Yellow crystals. M.p. 107 °C. [α]D ϭ ϩ56 (c ϭ 0.7,
CHCl3). IR (KBr): ν˜ ϭ 2934, 1762, 1741, 1687, 1598, 1222 cmϪ1
.
UV (CHCl3): λmax (ε) ϭ 344 (15500) nm. EI MS: m/z (%) ϭ 454
(17) [Mϩ], 259 (80), 331(21), 197 (49), 196 (37), 139 (100), 97 (70).
1H NMR (200 MHz, CDCl3, 298 K): δ ϭ 2.01, 2.15 (2 ϫ s, 9 H, 3
ϫ CH3CO), 3.60 (s, 3 H, NCH3), 3.75 (s, 3 H, NCH3), 4.39Ϫ4.49
(m, 3 H, H-4Ј, H-5, H-5Ј), 5.26 (dd, J ϭ 8.4, 4.9 Hz, 1 H, H-3Ј),
5.58 (dd, J ϭ 4.9, 1.7 Hz, 1 H, H-2Ј), 7.21 (d, J ϭ 1.7 Hz, 1 H, H-
1Ј), 8.22 (s, 1 H, H-8) ppm. 13C NMR (50 MHz, CDCl3, 298 K):
δ ϭ 20.3, 20.4, 20.8, 30.4, 34.4, 61.4, 67.5, 75.0, 78.7, 89.1, 117.3,
140.5, 145.5, 149.8, 169.0, 169.3, 170.1, 176.6 ppm. C18H22N4O8S
(454.1): calcd. C 47.56, H 4.88, N 12.33; found C 47.63, H 4.75,
N 12.03.
7-β-D-(Ribopyranosyl)theophylline (5): Colourless crystals (45 mg,
30
90%). M.p. 232 °C (ref.[27b] 235Ϫ236 °C). [α]D ϭ Ϫ33 (c ϭ 0.8,
H2O). IR (KBr): ν˜ ϭ 3482, 2954, 1681, 1389, 1045, 752 cmϪ1. UV
(MeOH): λmax (ε) ϭ 276 (9453) nm. EI MS: m/z (%) ϭ 312 (4)
[Mϩ], 209 (6), 180 (100). 1H NMR (200 MHz, D2O ϩ CD3OD,
298 K): δ ϭ 3.36 (s, 3 H, NCH3), 3.56 (s, 3 H, NCH3), 3.90 (m, 2
H, H-5 and H-5Ј), 4.05 (m, 1 H, H-4Ј), 4.38 (m, 2 H, H-3Ј and H-
2Ј), 5.89 (d, J ϭ 9.0 Hz, 1 H, H-1Ј), 8.28 (s, 1 H, H-8) ppm. 13C
NMR (50 MHz, D2O, reference CD3OD, 298 K): δ ϭ 29.3, 31.0,
65.8, 67.1, 69.9, 71.8, 83.7, 107.9, 143.7, 150.3, 153.4, 156.4 ppm.
C12H16N4O6 (312.1): calcd. C 46.14, H 5.17, N 17.95; found C
46.20, H 5.10, N 17.85.
8-Methyl-7-(2Ј,3Ј,4Ј-tri-O-acetyl-β-D-ribofuranosyl)theophylline
28
(14): (1.60 g, 88%). Colourless crystals. M.p. 105 °C. [α]D ϭ ϩ32
(c ϭ 1.0, CHCl3). IR (KBr): ν˜ ϭ 2950, 2900, 1730, 1680, 1200,
1060, 760 cmϪ1. UV (CHCl3): λmax (ε) ϭ 280 (12484) nm. EI MS:
7-β-D-(Ribofuranosyl)theophylline (9): (47 mg, 95%).
1
m/z (%) ϭ 452 (2) [Mϩ], 259 (44), 194 (26), 139 (100), 97 (65). H
Synthesis of Nucleosides by Silyl Coupling: A mixture of the base
[theophylline, 8-(methyl)theophylline or thiotheophylline,
NMR (200 MHz, CDCl3, 298 K): δ ϭ 2.06, 2.09, 2.13 (3 ϫ s, 9 H,
3 ϫ CH3CO), 2.55 (s, 3 H, C-8ϪCH3), 3.38 (s, 3 H, NCH3), 3.55
(s, 3 H, NCH3), 4.26Ϫ4.41 (m, 2 H, H-4Ј, H-5), 4.55 (dd, J ϭ 11.5,
3.3 Hz, 1 H, H-5Ј), 5.59 (dd, J ϭ 7.3, 5.8 Hz, 1 H, H-2Ј), 5.77 (dd,
J ϭ 7.3, 5.8 Hz, 1 H, H-3Ј), 6.04 (d, J ϭ 5.8 Hz, 1 H, H-1Ј) ppm.
13C NMR (50 MHz, CDCl3, 298 K): δ ϭ 14.5, 20.3, 20.4, 20.8,
28.3, 29.8, 63.3, 69.8, 73.1, 79.9, 88.1, 106.5, 148.8, 151.4, 151.5,
154.1, 169.4 (2 C), 170.5 ppm. C19H24N4O9 (452.2): calcd. C 50.43,
H 5.35, N 12.39; found C 50.39, H 5.28, N 12.25.
4.80 mmol] and BSTFA (1.4 mL, 5.80 mmol) in dry CHCl3 (15 mL)
was stirred under nitrogen for 40 min at 20 °C. A solution of tetra-
acetyl ribose (4.00 mmol) and trimethylsilyl trifluoromethanesul-
fonate (0.1 mL, 5.80 mmol) in CHCl3 (5 mL) was then added, and
the reaction mixture was heated at reflux under nitrogen for 4 h.
Saturated aqueous NaHCO3 (120 mL) and dichloromethane were
then added. After the system had been stirred for 15 min, two lay-
ers were separated, and the aqueous one was extracted with di-
chloromethane (3 ϫ 120 mL). The combined organic layers and
extracts were washed with brine, dried with anhydrous MgSO4 and
filtered, and the solvents were evaporated to dryness. The residue
was crystallised from MeOH to provide 2, 6, 10, 12 and 14.
8-Methyl-7-β-D-(ribofuranosyl)theophylline (13): Compound 14
(0.20 g, 0.44 mmol) was dissolved in methanol (5 mL). Na (10 mg)
was then added, and the reaction mixture was stirred at 20 °C over-
night. Recrystallisation from methanol gave pure 13 (0.13 g, 91%).
29
Colourless crystals. M.p. 209 °C. [α]D ϭ ϩ160 (c ϭ 0.4, H2O).
8-Methyl-7-(2Ј,3Ј,4Ј-tri-O-acetyl-β-
D
-ribopyranosyl)theophylline (2):
IR (KBr): ν˜ ϭ 3600Ϫ3200, 1677, 1600 cmϪ1. UV (MeOH): λmax
Colourless solid (1.44 g, 80%). M.p. 248 °C. [α]D22 ϭ ϩ48 (c ϭ 1.0, (ε) ϭ 278 (13516) nm. EI MS: m/z (%) ϭ 326 (1) [Mϩ], 194 (100).
4030
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2003, 4023Ϫ4032