M. Meurillon, L. Chaloin, C. Périgaud, S. Peyrottes
FULL PAPER
(0.75 g, 62%). Rf (CH2Cl2/acetone, 1:2) = 0.26. [α]2D0 = –37.8 (c =
1
H, OCH2CH3) ppm. H NMR (200 MHz, CDCl3): δ = 10.23 (br.
0.555, MeOH). UV/Vis (95% EtOH): λmax (ε, dm3 mol–1 cm–1) = s, 1 H exchangeable, NH), 7.54 (d, J = 8.05 Hz, 1H, 6-H), 5.76 (d,
257 (9600), 229 (2800) nm. C15H21N2O9P (404.09): calcd. C 44.56,
H 5.24, N 6.93; found C 43.89, H 5.78, N 6.73. 1H NMR
(300 MHz, [D6]DMSO): δ = 11.50 (br. s, 1 H exchangeable, NH),
J = 2.75 Hz, 1H, 1Ј-H), 5.66 (d, J = 8.01 Hz, 1H, 5-H), 4.89–4.70
(m, 2 H, 2Ј-H, 3Ј-H), 4.35–3.99 (m, 6 H, OCH2CH3, 4Ј-H, 5Ј-H),
2.11–1.81 (m, 2 H, 6Ј-H, 6ЈЈ-H), 1.52–1.20 [m, 12 H, C(CH3)2,
7.91 (d, J = 7.99 Hz, 1H, 6-H), 5.90 (s, 1 H, 1Ј-H), 5.71 (d, J = OCH2CH3] ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 163.6 (C-
7.94 Hz, 1H, 5-H), 5.16 (m, 2 H, 2Ј-H, 3Ј-H), 4.53 (d, J = 1.06 Hz,
4), 150.8 (C-2), 142.8 (C-6), 113.5 [C(CH3)2], 102.3 (C-5), 91.5 (C-
1H, 4Ј-H), 3.71 (m, 6 H, OCH3), 3.57 (dd, J = 14.23, 21.55 Hz, 1 1Ј), 88.9 (d, J = 15.1 Hz, C-4Ј), 83.8 (C-2Ј), 80.5 (C-3Ј), 66.0 (d, J
H, 6Ј-H), 2.93 (dd, J = 14.23, 22.21 Hz, 1 H, 6Ј-HЈ), 1.53, 1.37 [2 = 4.0 Hz, C-5Ј), 61.5 (2 d, J = 6.0 Hz, OCH2CH3), 30.3 (d, J =
1
s, 6 H, C(CH3)2] ppm. H NMR (300 MHz, CDCl3): δ = 9.63 (br.
s, 1 H exchangeable, NH), 7.27 (d, J = 8.06 Hz, 1H, 6-H), 5.69 (d,
138.7 Hz, C-6Ј), 27.5, 25.7 [C(CH3)2], 16.72, 16.66 (OCH2CH3)
ppm. 31P NMR (121 MHz, [D6]DMSO): δ = 30.3 ppm. MS
J = 7.97 Hz, 1H, 5-H), 5.50 (s, 1 H, 1Ј-H), 5.23 (m, 1 H, 3Ј-H), (FAB+): m/z = 435 [M + H]+, 869 [2M + H]+. MS (FAB–): m/z =
4.96 (d, J = 6.37 Hz, 1H, 2Ј-H), 4.62 (d, J = 1.87 Hz, 1H, 4Ј-H), 111 [B]–, 433 [M – H]–, 867 [2M – H]–.
3.73 (m, 6 H, OCH3), 3.40 (dd, J = 13.82, 22.55 Hz, 1 H, 6Ј-H),
Luche Conditions: To a solution of 7 (0.25 g, 0.58 mmol) in dry
MeOH (4.3 mL) at –30 °C under an argon atmosphere was added
CeCl3·7H2O (181 mg, 0.49 mmol) and NaBH4 (34 mg, 0.90 mmol).
After 3 h stirring at –30 °C, the reaction mixture was neutralized
with 1 n HCl, evaporated under reduced pressure, and co-evapo-
rated with toluene. The crude was purified by column chromatog-
raphy (CH2Cl2 to acetone) to give 8 as a mixture of the two dia-
stereoisomers [215 mg, 86%, (S)/(R) = 44:56]. Rf (CH2Cl2/MeOH,
9:1) = 0.4. 1H NMR (200 MHz, CDCl3): δ = 10.23 (br. s, 1 H
exchangeable, NH), 7.72 (d, J = 8.11 Hz, 1H, 6-H), 5.93 (d, J =
3.60 Hz, 1H, 1Ј-H), 5.68 (d, J = 8.10 Hz, 1H, 5-H), 4.89–4.70 (m,
2 H, 2Ј-H, 3Ј-H), 4.35–3.99 (m, 6 H, OCH2CH3, 4Ј-H, 5Ј-H), 2.11–
1.81 (m, 2 H, 6Ј-H, 6ЈЈ-H), 1.52–1.20 [m, 12 H, C(CH3)2,
OCH2CH3] ppm.
2.93 (dd, J = 13.78, 22.83 Hz, 1 H, 6Ј-HЈ), 1.48, 1.29 [2 s, 6 H,
C(CH3)2] ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 199.8 (d, J
= 6.04 Hz, C-5Ј), 163.4 (C-4), 151.0 (C-2), 144.6 (C-6), 112.3
[C(CH3)2], 101.7 (C-5), 96.7 (C-1Ј), 93.5 (C-4Ј), 84.2, 83.0 (C-2Ј,
C-3Ј), 52.6 (2d, J = 6.04 Hz, OCH3), 35.2 (C-6Ј), 26.3, 24.7
[C(CH3)2] ppm. 31P NMR (121 MHz, [D6]DMSO): δ = 22.6 ppm.
MS (ESI+): m/z = 405 [M + H]+, 809 [2M + H]+. MS (ESI–): m/z
= 403 [M – H]–, 807 [2M – H]–. HRMS: calcd. for C15H22N2O9P
[M + H]+ 405.1063; found 405.1064.
1-(6Ј-Deoxy-6Ј-diethylphosphono-2Ј,3Ј-O-isopropylidene-5Ј-oxo-β-
D
-ribohexofuranosyl)uracil (7): Compound 5 (0.50 g, 1.29 mmol)
was treated with method A. Eluent: CH2Cl2/EtOAc (1:1) to EtOAc/
MeOH (9:1). Compound 7 was obtained as a white foam (254 mg,
46%). Rf (CH2Cl2/MeOH, 95:5) = 0.4. [α]2D0 = –32.7 (c = 1.00,
MeOH). UV/Vis (95 % EtOH): λmax (ε, dm3 mol–1 cm–1) = 256
(10100), 231 (2900) nm. 1H NMR (300 MHz, [D6]DMSO): δ =
11.45 (br. s, 1 H exchangeable, NH), 7.87 (d, J = 7.9 Hz, 1 H, 6-
H), 5.85 (d, J = 2.4 Hz, 1 H, 1Ј-H), 5.56 (d, J = 7.9 Hz, 1 H, 5-H),
5.1 (m, 2 H, 2Ј-H, 3Ј-H), 4.50 (d, J = 1.5 Hz, 1 H, 4Ј-H), 3.80 (m,
4 H, OCH2CH3), 3.49 (dd, J = 16.2 Hz, 1 H, 6Ј-H), 2.83 (dd, J =
16.2 Hz, 1 H, 6ЈЈ-H), 1.50, 1.30 [2 s, 6 H, C(CH3)2], 1.23 (t, J =
7.0 Hz, 6 H, OCH2CH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 199.8 (d, J = 6.0 Hz, C-5Ј), 163.5 (C-4), 151.0 (C-2), 144.6 (C-
6), 112.4 [C(CH3)2], 101.7 (C-5), 96.7 (C-1Ј), 93.5 (C-4Ј), 84.2 (C-
3Ј), 83.0 (C-2Ј), 61.9 (2 d, J = 6.0 Hz, OCH2CH3), 36.3 (d, J =
124.8 Hz, C-6Ј), 26.4, 24.7 [C(CH3)2], 16.1, 16.0 (OCH2CH3) ppm.
31P NMR (121 MHz, [D6]DMSO): δ = 20.8 ppm. MS (FAB+): m/z
= 433 [M + H]+, 865 [2M + H]+. MS (FAB–): m/z = 111 [B]–, 431
[M – H]–, 863 [2M – H]–.
1-[6Ј-Deoxy-6Ј-diethylphosphono-β-D-ribo-(5ЈS)-hexofuranosyl]-
uracil (9):[3] Protected β-hydroxyphosphonate 8 (117 mg,
0.27 mmol) was dissolved in an aqueous solution of 70% trifluoro-
acetic acid (2.15 mL) at room temperature, and the mixture was
stirred for 3 h. The solution was evaporated under reduced pressure
and co-evaporated with absolute ethanol. The crude material was
purified by reverse-phase chromatography (H2O/MeOH 0 to 50%)
to give 9 as a white foam (106 mg, 91%). Rf (CH2Cl2/MeOH, 9:1)
= 0.2. [α]2D0 = –5.8 (c = 1.04, MeOH). UV/Vis (95% EtOH): λmax
(ε, dm3 mol–1 cm–1) = 260 (10000), 228 (2000) nm. C14H23N2O9P
(394.11): calcd. C 42.64, H 5.88, N 7.10; found C 42.53, H 6.14,
N 7.03. 1H NMR (300 MHz, [D6]DMSO): δ = 11.3 (br. s, 1 H
exchangeable, NH), 7.80 (d, J = 8.1 Hz, 1 H, 6-H), 5.78 (d, J =
6.4 Hz, 1 H, 1Ј-H), 5.63 (d, J = 8.1 Hz, 1 H, 5-H), 5.50 (d, J =
5.0 Hz, 1 H exchangeable, 5Ј-OH), 5.36 (br. s, 1 H exchangeable,
2Ј-OH), 5.10 (br. s, 1 H exchangeable, 3Ј-OH), 4.1–3.9 (m, 7 H, 3Ј-
H, 2Ј-H, 5Ј-H, OCH2CH3), 3.80 (t, J = 3.0 Hz, 1 H, 4Ј-H), 2.10–
1.80 (m, 2 H, 6Ј-H, 6ЈЈ-H), 1.23 (t, J = 7.0 Hz, 6 H, OCH2CH3)
ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 163.0 (C-4), 150.8 (C-
2), 140.9 (C-6), 101.9 (C-5), 87.3 (d, J = 14.3 Hz, C-4Ј), 86.9 (C-
1Ј), 73.1 (C-2Ј), 68.5 (C-3Ј), 65.6 (d, J = 3.0 Hz, C-5Ј), 61.1, 60.8
(2 d, J = 6.0 Hz, OCH2CH3), 29.5 (d, J = 137.3 Hz, C-6Ј), 16.2,
16.1 (OCH2CH3) ppm. 31P NMR (121 MHz, [D6]DMSO): δ =
29.2 ppm. MS (FAB+): m/z = 395 [M + H]+, 789 [2M + H]+. MS
(FAB–): m/z = 393 [M – H]–, 787 [2M – H]–.
1-[6Ј-Deoxy-6Ј-diethylphosphono-2Ј,3Ј-O-isopropylidene-β-
(5ЈR/S)-hexofuranosyl]uracil (8)
D-ribo-
Standard Conditions: To a solution of 7 (250 mg, 0.58 mmol) in dry
MeOH (9 mL) at –50 °C under an argon atmosphere was added
NaBH4 (87.6 mg, 2.31 mmol). After stirring for 5 h at –30 °C, the
reaction was complete. The reaction mixture was neutralized with
1 n HCl, evaporated under reduced pressure, and co-evaporated
twice with toluene. The crude was purified by column chromatog-
raphy (CH2Cl2 to acetone) to give 8 as a white foam [224 mg, 89%,
mixture of two diastereoisomers, (S)/(R) = 91:9]. An analytical
sample of the pure (S) isomer was obtained for spectral characteri-
zation. Rf (CH2Cl2/MeOH, 9:1) = 0.4. [α]2D0 = –18.1 (c = 1.04,
MeOH). UV/Vis (95 % EtOH): λmax (ε, dm3 mol–1 cm–1) = 258
(10000), 228 (2000) nm. 1H NMR (300 MHz, [D6]DMSO): δ =
11.40 (br. s, 1 H exchangeable, NH), 7.78 (d, J = 8.0 Hz, 1 H, 6-
H), 5.83 (d, J = 2.4 Hz, 1 H, 1Ј-H), 5.65 (d, J = 8.0 Hz, 1 H, 5-H),
5.50 (d, J = 5.8 Hz, 1 H exchangeable, 5Ј-OH), 4.9 (m, 2 H, 2Ј-H,
3Ј-H), 3.80 (m, 6 H, OCH2CH3, 4Ј-H, 5Ј-H), 2.00–1.90 (m, 2 H,
1-[6Ј-Deoxy-6Ј-phosphono-β-D-ribo-(5ЈS)-hexofuranosyl]uracil (Di-
sodium salt) (10):[3] Compound 9 (355 mg, 0.90 mmol) was treated
by method B. Reverse-phase column chromatography of the crude
materials (H2O) gave 10 as a white solid (250 mg, 82%). Rf (iPrOH/
30% NH4OH/H2O, 7:1:2) = 0.2. [α]2D0 = –22.7 (c = 0.88, H2O).
C10H13N2Na2O9P·0.4H2O (389.21): C 30.85, H 3.57, N 7.19, P
7.95; found C 31.15, H 4.07, N 7.26, P 8.19. UV/Vis (H2O): λmax
(ε, dm3 mol–1 cm–1) = 259 (10600), 228 (2300) nm. 1H NMR
6Ј-H, 6ЈЈ-H), 1.50, 1.30 [2 s, 6 H, C(CH3)2], 1.23 (t, J = 7.0 Hz, 6 (300 MHz, D2O): δ = 7.83 (d, J = 8.1 Hz, 1 H, 6-H), 5.87 (d, J =
3800
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Eur. J. Org. Chem. 2011, 3794–3802