Azido-Tetrazole Tautomerism in Nucleoside Derivatives
FULL PAPER
(C-4), 156.4 (C-2), 157.5 (C-6) ppm. Tetrazole Tautomer: 1H NMR: H), 8.59 (s, 1 H, 6-H), 9.40 (s, 2 H, 8-NH2), 13C NMR: δ ϭ 26.2
δ ϭ 3.91Ϫ3.62 (m, 2 H, 5Ј-H and 5"-H), 3.96 (m, 1 H, 4Ј-H), 4.17 (C-3Ј), 32.6 (C-2Ј), 63.4 (C-5Ј), 82.7 (C-4Ј), 85.2 (C-1Ј), 112.5 (C-
(t, J ϭ 4.2 Hz, 1 H, 3Ј-H), 4.54 (m, 1 H, 2Ј-H), 5.12 (t, J ϭ 5.1 Hz,
1 H, 5Ј-OH), 5.21 (d, J ϭ 4.8 Hz, 1 H, 3Ј-OH), 5.51 (d, J ϭ 5.9 Hz,
1 H, 2Ј-OH), 5.95 (d, J ϭ 5.3 Hz, 1 H, 1Ј-H), 8.56 (s, 1 H, 6-H),
9.42 (s, 1 H, 8-NH2) ppm. 13C NMR: δ ϭ 62.0 (C-5Ј), 71.0 (C-3Ј),
74.4 (C-2Ј), 86.3 (C-4Ј), 88.3 (C-1Ј), 112.3 (C-12), 141.9 (C-11),
143.6 (C-6), 153.0 (C-10), 154.6 (C-8) ppm.
12), 142.4 (C-6), 142.5 (C-11), 152.0 (C-10), 157.2 (C-8) ppm.
2-Azido-9-(2,3-dideoxy-β- -glycero-pent-2-ene-furanosyl)adenine
D
(9): Compound 5 (0.350 g, 1.3 mmol) was added to a solution of
hydrazine monohydrate (16 mL). The reaction mixture was stirred
at room temperature for 16 h. The solution was concentrated to
dryness and co-evaporated with 2-propanol (3 ϫ 30 mL) until a
white gum was obtained. The residue was dissolved in a 2% acetic
acid solution (15 mL) and then cooled in an ice bath. Sodium ni-
trite (0.300 g, 4.3 mmol) was added, and the reaction mixture was
stirred for 2 h. The solvent was removed under reduced pressure.
The residue was subjected to silica gel column chromatography
with a stepwise gradient of methanol (0Ϫ6%) in dichloromethane
to afford compound 9 (0.205 g, 75%), which was crystallized from
2-Azido-9-(2-deoxy-β-D-erythro-pentofuranosyl)adenine (7): Com-
pound 3 (0.205 g, 0.72 mmol) was added to a solution of hydrazine
monohydrate (10 mL). The reaction mixture was kept at room tem-
perature for 16 h. The solution was concentrated to dryness and
co-evaporated with 2-propanol (3 ϫ 20 mL) until a white gum was
obtained. The residue was dissolved in a 10% aqueous acetic acid
solution (10 mL) and then cooled in an ice bath. Sodium nitrite
(0.075 g, 1.1 mmol) was added, and the reaction mixture was
stirred for 1 h. The solid was collected by filtration, washed with
water, and dried with P2O5 at 80 °C to give compound 7 (0.192 g,
20
methanol, m.p. 182Ϫ184 °C. [α]D ϭ Ϫ39.1 (c ϭ 0.64, DMSO).
UV (95% EtOH): λmax (ε) ϭ 268 nm (16200). MS (FAB): m/z ϭ
275 [M ϩ H]ϩ, 273 [M Ϫ H]Ϫ. IR (KBr): ν˜ ϭ 2144 cmϪ1; (DMSO):
ν˜ ϭ 2128 cmϪ1. C10H10N8O2·1/7H2O (276.94): calcd. C 43.37, H
3.75, N 40.46; found C 43.80, H 3.93, N 40.05. Azido Tautomer:
1H NMR: δ ϭ 3.55 (m, 2 H, 5Ј-H and 5"-H), 4.86 (m, 1 H, 4Ј-H),
4.91 (t, J ϭ 5.3 Hz, 1 H, 5Ј-OH), 6.11 (d, J ϭ 5.9 Hz, 1 H, 3Ј-H),
6.45 (d, J ϭ 5.9 Hz, 1 H, 2Ј-H), 6.81 (s, 1 H, 1Ј-H), 7.58 (s, 2 H,
6-NH2), 8.08 (s, 1 H, 8-H) ppm. 13C NMR: δ ϭ 63.6 (C-5Ј), 88.6
(C-1Ј), 88.9 (C-4Ј), 117.3 (C-5), 126.1 (C-3Ј), 135.3 (C-2Ј), 139.8
(C-8), 151.3 (C-4), 156.4 (C-2), 157.5 (C-6) ppm. Tetrazole Tau-
20
91%), m.p. 181Ϫ182 °C. [α]D ϭ Ϫ25.6 (c ϭ 0.78, DMSO). UV
(95% EtOH): λmax (ε) ϭ 268 nm (18800). IR (KBr): ν˜ ϭ 2146
cmϪ1; (DMSO): ν˜ ϭ 2124 cmϪ1. MS (FAB): m/z ϭ 293 [M ϩ
H]ϩ, ϭ 291 [M Ϫ H]Ϫ. C10H12N8O3·2/5H2O (299.46): calcd. C
40.11, H 4.31, N 37.42; found C 40.50, H 4.24, N 37.10. Azido
Tautomer: 1H NMR: δ ϭ 2.27 (m, 1 H, 2"-H), 2.65 (m, 1 H, 2Ј-
H), 3.56 (m, 2 H, 5Ј-H and 5"-H), 3.83 (m, 1 H, 4Ј-H), 4.36 (m, 1
H, 3Ј-H), 4.95 (t, J ϭ 5.6 Hz, 1 H, 5Ј-OH), 5.29 (d, J ϭ 4.1 Hz, 1
H, 3Ј-OH), 6.22 (dd, J ϭ 7.3, 6.5 Hz, 1 H, 1Ј-H), 7.60 (s, 2 H, 6-
NH2), 8.25 (s, 1 H, 8-H) ppm. 13C NMR: δ ϭ 39.9 (C-2Ј), 62.6 (C-
5Ј), 71.7 (C-3Ј), 84.3 (C-1Ј), 88.7 (C-4Ј), 117.7 (C-5), 140.1 (C-8),
1
tomer: H NMR: δ ϭ 3.59 (m, 2 H, 5Ј-H and 5"-H), 4.86 (m, 1 H,
4Ј-H), 4.96 (t, J ϭ 5.4 Hz, 1 H, 5Ј-OH), 6.16 (d, J ϭ 5.9 Hz, 1 H,
3Ј-H), 6.50 (d, J ϭ 5.9 Hz, 1 H, 2Ј-H), 7.00 (s, 1 H, 1Ј-H), 8.35 (s,
1 H, 6-H), 9.39 (s, 2 H, 8-NH2) ppm. 13C NMR: δ ϭ 63.4 (C-5Ј),
88.5 (C-1Ј), 89.0 (C-4Ј), 112.0 (C-12), 126.1 (C-3Ј), 135.6 (C-2Ј),
141.8 (C-11), 143.5 (C-6), 152.9 (C-10), 154.7 (C-8) ppm.
1
151.1 (C-4), 156.3 (C-2), 157.5 (C-6) ppm. Tetrazole Tautomer: H
NMR: δ ϭ 2.27 (m, 1 H, 2"-H), 2.65 (m, 1 H, 2Ј-H), 3.56 (m, 2 H,
5Ј-H and 5"-H), 3.88 (m, 1 H, 4Ј-H), 4.42 (m, 1 H, 3Ј-H), 5.00 (t,
J ϭ 5.5 Hz, 1 H, 5Ј-OH), 5.33 (d, J ϭ 4.1 Hz, 1 H, 3Ј-OH), 6.38
(t, J ϭ 6.8 Hz, 1 H, 1Ј-H), 8.53 (s, 1 H, 6-H), 9.40 (s, 2 H, 8-NH2)
ppm. 13C NMR: δ ϭ 39.7 (C-2Ј), 62.4 (C-5Ј), 71.5 (C-3Ј), 84.3 (C-
1Ј), 88.7 (C-4Ј), 112.3 (C-12), 141.8 (C-11), 153.5 (C-6), 156.3 (C-
2), 157.5 (C-6) ppm.
Biological Evaluation: The anti-HIV and anti-HBV assays on cell
culture were performed by previously established procedures.[19]
Acknowledgments
We gratefully thank Prof. P. La Colla (Universita di Cagliari,
Cagliari, Italy) for the biological results. One of us (T. L.) is par-
ticularly grateful to the Ministere de l’Education Nationale, de la
2-Azido-9-(2,3-dideoxy-β-
D
-glycero-pentofuranosyl)adenine
(8):
Compound 4 (0.269 g, 1 mmol) was added to a solution of hydra-
zine monohydrate (14 mL). The reaction mixture was stirred at
room temperature for 16 h. The solution was concentrated to dry-
ness and co-evaporated with 2-propanol (3 ϫ 30 mL) until a white
gum was obtained. The residue was dissolved in a 5% acetic acid
solution (15 mL) and then cooled in an ice bath. Sodium nitrite
(0.108 g, 1.5 mmol) was added, and the reaction mixture was
stirred for 2 h. The solvent was removed under reduced pressure.
The residue was purified by silica gel column chromatography with
methanol/dichloromethane (1:9) as eluent to afford compound 8
(0.205 g, 74%), which was crystallized from water, m.p. 198Ϫ200
`
`
Recherche et de la Technologie, France, for a doctoral fellowship.
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20
°C. [α]D ϭ Ϫ20.5 (c ϭ 1.27, DMSO). UV (95% EtOH): λmax
Med. Chem. 1989, 32, 1135Ϫ1140.
S. Patai, in The Chemistry of the Azido Group, John Wiley &
(ε) ϭ 268 nm (16200). MS (FAB): m/z ϭ 277 [M ϩ H]ϩ, 275 [M
[4]
Ϫ H]Ϫ. IR (KBr): ν˜ ϭ 2142 cmϪ1; (DMSO): ν˜ ϭ 2128 cmϪ1
.
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[5]
C10H12N8O2 (276.11): calcd. C 43.48, H 4.38, N 40.56; found C
43.54, H 4.53, N 40.36. Azido Tautomer: H NMR: δ ϭ 2.06 (m, 2
H. J. Schaeffer, H. J. Thomas, J. Am. Chem. Soc. 1958, 80,
1
3738Ϫ3742.
[6]
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H, 3Ј-H and 3"-H), 2.39 (m, 2 H, 2Ј-H and 2"-H), 3.56 (m, 2 H,
5Ј-H and 5"-H), 4.10 (m, 1 H, 4Ј-H), 4.94 (m, 1 H, 5Ј-OH), 6.13
(m, 1 H, 1Ј-H), 7.60 (s, 2 H, 6-NH2), 8.29 (s, 1 H, 8-H) ppm. 13C
NMR: δ ϭ 26.6 (C-3Ј), 32.4 (C-2Ј), 63.7 (C-5Ј), 82.6 (C-4Ј), 85.0
(C-1Ј), 117.6 (C-5), 139.8 (C-8), 150.8 (C-4), 154.8 (C-2), 157.4 (C-
6) ppm. Tetrazole Tautomer: 1H NMR: δ ϭ 2.06 (m, 2 H, 3Ј-H and
3"-H), 2.39 (m, 2 H, 2Ј-H and 2"-H), 3.56 (m, 2 H, 5Ј-H and 5"-
H), 4.10 (m, 1 H, 4Ј-H), 5.02 (m, 1 H, 5Ј-OH), 6.30 (m, 1 H, 1Ј-
wahara, M. Ishikawa, M. Sekine, Tetrahedron Lett. 2001, 42,
9215Ϫ9219.
[7]
S. Higashiya, C. Kaibara, K. Fukuoka, F. Suda, M. Ishikawa,
M. Yoshida, T. Hata, Bioorg. Med. Chem. Lett. 1996, 6, 39Ϫ42.
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M. Saneyoshi, E. Satoh, Chem. Pharm. Bull. 1979, 27,
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[9]
M. J. Robins, J. S. Wilson, F. Hansske, J. Am. Chem. Soc. 1983,
105, 4059Ϫ4065.
Eur. J. Org. Chem. 2003, 3997Ϫ4002
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4001