F. Gallier, S. Peyrottes, C. Périgaud
FULL PAPER
β anomer), 128.4, 128.9, 129.2, 129.3, 133.9, 134.0 (C-Ar), 164.4,
168.8, 169.0, 169.1 (C=O, β anomer), 164.6, 169.1 (2s), 169.4 (C=O,
α anomer) ppm.31P NMR (121 MHz, [D6]DMSO, 20 °C): δ = 25.8
(α anomer), 26.1 (β anomer) ppm. MS (FAB, GT): m/z = 553 [M
GT): m/z = 1193 [2M + H]+, 597 [M + H]+, 289 [M – B – BzOH –
AcOH]+ and 1191 [2M – H]–, 595 [M – H]–, 125 [B]–. UV (EtOH,
95°) λmax (ε, Lmol–1 cm–1) = 229 (16100), 260 (11100) nm; λmin (ε,
Lmol–1 cm–1) = 247 (9100) nm. C26H33N2O12P (596.52): calcd. C
+ Na]+, 289 [M – Ac – BzOH – AcOH]+. UV (EtOH, 95°): λmax 52.35, H 5.58, N 4.70, P 5.19; found C 52.07, H 5.65, N 4.57, P
(ε, Lmol–1 cm–1) = 230 (12700) nm. C23H31O12P (530.46): calcd. C
5.06.
52.08, H 5.89, P 5.84; found C 51.91, H 6.06, P 5.80.
N4-Benzoyl-1-(5S)-[2,5-di-O-acetyl-3-O-benzoyl-6-deoxy-6-diethyl-
phosphono-β-D-ribohexofuranosyl]cytidine (17): Column chromatog-
General Glycosylation Procedure: The nucleobase (2 equiv.) was dis-
solved in anhydrous acetonitrile (2 mL/mmol) and N,O-bis(trime-
thylsilyl)acetamide (4 equiv.) was added. The solution was heated
at reflux for 1.5 h, and the reaction mixture was cooled to room
temperature. A solution of 1,2,5-tri-O-acetyl-3-O-benzoyl-6-deoxy-
6-diethylphosphono-(5S)-(α,β)--ribohexofuranose (14; 1 equiv.) in
acetonitrile (5 mL/mmol) was added, followed by tin(IV) chloride
(4 equiv.). The resulting solution was stirred for 30 h, and then
eventually warmed at 50 °C for few hours. The reaction mixture
was powdered onto a cold saturated NaHCO3 solution and filtered
through celite. The celite was washed with AcOEt. The organic
layer was extracted with saturated NaHCO3 and brine, dried with
Na2SO4 and concentrated under reduced pressure.
raphy of the crude material on silica gel (CH2Cl2/MeOH, 98:2) gave
protected nucleotide derivative 17 as a white foam (2 g, 76%).
[α]2D0 = –29.4 (c = 1.09, MeOH). Rf = 0.3 (CH2Cl2/MeOH, 95:5
v/v).1H NMR (300 MHz, [D6]DMSO, 20 °C): δ = 1.22–1.14 (m, 6
H, POCH2CH3), 1.94, 1.96 (2s, 6 H, CH3, Ac), 2.40–2.10 (m, 2 H,
6Ј-H, 6ЈЈ-H), 3.96 (m, 4 H, POCH2CH3), 4.43 (dd, J = 4.5 and
6.8 Hz, 1 H, 4Ј-H), 5.44 (m, 1 H, 5Ј-H), 5.74 (dd, J = 3.6 and
6.6 Hz, 1 H, 2Ј-H), 5.81 (dd, J = 6.7 and 6.8 Hz, 1 H, 3Ј-H), 5.90
(d, J = 3.6 Hz, 1 H, 1Ј-H), 7.36 (d, J = 7.6 Hz, 1 H, 5-H), 7.60 (m,
6 H, H-Ar), 8.00 (m, 4 H, H-Ar), 8.17 (d, J = 7.6 Hz, 1 H, 6-H),
11.4 (sl, 1 H exchangeable, NH) ppm. 13C NMR (75 MHz, [D6]-
DMSO, 20 °C): δ = 16.0, 16.1 (POCH2CH3), 20.1, 20.6 (CH3, Ac),
25.8 (d, J = 140.0 Hz, C-6Ј), 61.2, 61.3 (POCH2CH3), 66.8 (d, J =
3.8 Hz, C-5Ј), 69.8 (C-3Ј), 72.3 (C-2Ј), 81.4 (d, J = 12.8 Hz, C-4Ј),
92.4 (C-1Ј), 96.8 (C-5), 128.4, 128.5, 128.9, 129.3, 132.8, 133.0,
134.0 (C-Ar), 148.2 (C-6), 154.0 (C-2), 164.0 (C-4), 164.4, 169.1,
169.3 (C=O) ppm. 31P NMR (121 MHz, [D6]DMSO, 20 °C): δ =
26.5 ppm. MS (FAB, GT): m/z = 686 [M + H]+, 289 [M – B –
1-(5S)-[2,5-Di-O-acetyl-3-O-benzoyl-6-deoxy-6-diethylphosphono-β-
D
-ribohexofuranosyl]uracil (15): Column chromatography of the
crude material on silica gel (CH2Cl2/MeOH, 97:3) gave protected
nucleotide derivative 15 as a white foam (0.86 g, 79%). [α]2D0
=
–21.7 (c = 1.06, MeOH). Rf = 0.3 (CH2Cl2/MeOH, 95:5 v/v). 1H
NMR (300 MHz, [D6 ]DMSO, 20 °C): δ = 1.19 (m, 6 H,
POCH2CH3), 1.94, 1.97 (2s, 6 H, CH3, Ac), 2.0–2.4 (m, 2 H, 6Ј-H,
6ЈЈ-H), 3.96 (m, 4 H, POCH2CH3), 4.37 (dd, J = 4.6 and 6.1 Hz, 1
H, 4Ј-H), 5.41 (m, 1 H, 5Ј-H), 5.63 (dd, J = 4.6 and 6.7 Hz, 1 H,
2Ј-H), 5.73 (m, 2 H, 3Ј-H, 5-H), 5.86 (d, J = 4.6 Hz, 1 H, 1Ј-H),
7.59 (m, 2 H, H-Ar), 7.72 (m, 2 H, H-Ar, 6-H), 8.01 (m, 2 H, H-
Ar), 11.51 (sl, 1 H exchangeable, NH) ppm. 13C NMR (75 MHz,
[D6]DMSO, 20 °C): δ = 16.0, 16.1 (POCH2CH3), 20.2, 20.6 (CH3,
Ac), 25.9 (d, J = 140.4 Hz, C-6Ј), 61.2, 61.3 (POCH2CH3), 66.8 (d,
J = 3.8 Hz, C-5Ј), 69.4 (C-3Ј), 71.8 (C-2Ј), 81.1 (d, J = 12.8 Hz, C-
4Ј), 89.7 (C-1Ј), 102.2 (C-5), 128.5, 128.9, 129.3, 134.0 (C-Ar), 142.8
BzOH – AcOH]+, and 1369 [2M – H]–, 684 [M – H]–, 214 [BBz
–
H]–. UV (EtOH, 95°): λmax (ε, Lmol–1 cm–1) = 230 (21600), 261
(28000), 300 (9100) nm; λmin (ε, Lmol–1 cm–1) = 243 (18500), 291
(8600) nm. C32H36N3O12P (685.62): calcd. C 56.06, H 5.29, N 6.13,
P 4.52; found C 55.99, H 5.24, N 5.85, P 4.48.
N6-Benzoyl-9-(5S)-[2,5-di-O-acetyl-3-O-benzoyl-6-deoxy-6-diethyl-
phosphono-β-D-ribohexofuranosyl]adenine (18): Column chromatog-
raphy of the crude material on silica gel (CH2Cl2/MeOH, 98:2) gave
protected nucleotide derivative 18 as a white foam (0.22 g, 69%).
[α]2D0 = –47.8 (c = 0.9, MeOH). Rf = 0.2 (CH2Cl2/MeOH, 95:5
v/v).1H NMR (300 MHz, [D6]DMSO, 20 °C): δ = 1.16 (m, 6 H,
POCH2CH3), 1.92, 2.01 (2s, 6 H, CH3, Ac), 2.10–2.40 (m, 2 H, 6Ј-
H, 6ЈЈ-H), 3.96 (m, 4 H, POCH2CH3), 4.56 (t, J = 4.4 Hz, 1 H, 4Ј-
H), 5.50 (m, 1 H, 5Ј-H), 5.74 (dd, J = 4.5 and 5.9 Hz, 1 H, 3Ј-H),
6.26 (t, J = 6.0 Hz, 1 H, 2Ј-H), 6.46 (d, J = 5.9 Hz, 1 H, 1Ј-H),
7.60 (m, 6 H, H-Ar), 8.05 (m, 4 H, H-Ar), 8.68, 8.79 (2s, 2 H, 2-
H, 8-H), 11.3 (sl, 1 H exchangeable, NH) ppm. 13C NMR (75 MHz,
[D6]DMSO, 20 °C): δ = 16.0, 16.1 (POCH2CH3), 20.1, 20.7 (CH3,
Ac), 26.2 (d, J = 139.4 Hz, C-6Ј), 61.32, 61.34 (2d, J = 6.2 Hz,
POCH2CH3), 66.7 (d, J = 3.8 Hz, C-5Ј), 69.7 (C-3Ј), 71.3 (C-2Ј),
82.4 (d, J = 12.7 Hz, C-4Ј), 85.7 (C-1Ј), 126.0, 128.5, 129.0, 129.4,
132.5, 133.1, 134.1 (C-Ar), 144.2, 151.9 (C-2, C-8), 150.7, 151.7
(Cq), 164.5, 165.7, 169.19, 169.20 (C=O) ppm. 31P NMR
(121 MHz, [D6]DMSO, 20 °C): δ = 26.2 ppm. MS (FAB, GT): m/z
(C-6), 150.2 (C-2), 163.1 (C-4), 164.4, 169.1, 169.3 (C=O) ppm. 31
P
NMR (121 MHz, [D6]DMSO, 20 °C): δ = 26.4 ppm. MS (FAB,
GT): m/z = 583 [M + H]+, 289 [M – B – BzOH – AcOH]+, and
581 [M – H]–, 111 [B]–. UV (EtOH, 95°) λmax (ε, Lmol–1 cm–1) =
231 (14700), 253 (10400) nm; λmin (ε, Lmol–1 cm–1) = 247 (10100)
nm. C25H31N2O12P (582.49): calcd. C 51.55, H 5.36, N 4.81, P 5.32;
found C 51.58, H 5.50, N 4.45, P 5.16.
1-(5S)-[2,5-Di-O-acetyl-3-O-benzoyl-6-deoxy-6-diethylphosphono-β-
D-ribohexofuranosyl]thymine (16): Column chromatography of the
crude material on silica gel (CH2Cl2/MeOH, 98:2) gave protected
nucleotide derivative 16 as a white foam (1.2 g, 62%). [α]2D0 = –30.6
(c = 1.11, MeOH). Rf = 0.4 (CH2Cl2/MeOH, 95:5 v/v).1H NMR
(300 MHz, [D6]DMSO, 20 °C): δ = 1.27 (m, 6 H, POCH2CH3),
1.87 (s, 3 H, CH3), 2.01, 2.07 (2s, 6 H, CH3, Ac), 2.45–2.10 (m, 2
H, 6Ј-H, 6ЈЈ-H) 4.05 (m, 4 H, POCH2CH3), 4.44 (dd, J = 5.6 and
5.0 Hz, 1 H, 4Ј-H), 5.50 (m, 1 H, 5Ј-H), 5.68 (dd, J = 5.3 and
6.4 Hz, 1 H, 2Ј-H), 5.81 (dd, J = 6.5 and 6.3 Hz, 1 H, 3Ј-H), 5.96
(d, J = 4.9 Hz, 1 H, 1Ј-H), 7.68 (m, 3 H, H-Ar, 6-H), 7.81 (m, 1
H, H-Ar), 8.10 (m, 2 H, H-Ar), 11.6 (sl, 1 H exchangeable, NH)
ppm. 13C NMR (75 MHz, [D6]DMSO, 20 °C): δ = 11.8 (CH3),
16.0, 16.1 (POCH2CH3), 20.1, 20.6 (CH3, Ac), 25.9 (d, J =
140.0 Hz, C-6Ј), 61.2, 61.3 (2d, J = 6.3 Hz, POCH2CH3), 66.8 (d,
J = 3.8 Hz, C-5Ј), 69.3 (C-3Ј), 71.7 (C-2Ј), 81.2 (d, J = 12.8 Hz, C-
4Ј), 88.8 (C-1Ј), 109.9 (C-5), 128.5, 128.9, 129.3, 134.0 (C-Ar), 137.9
(C-6), 150.2 (C-2), 163.7 (C-4), 164.3, 169.1, 169.3 (C=O) ppm.31P
NMR (121 MHz, [D6]DMSO, 20 °C): δ = 26.4 ppm. MS (FAB,
= 710 [M + H]+, 289 [M – BBz – BzOH – AcOH]+, 240 [BBz
+
H]+, and 708 [M – H]–, 238 [BBz – H]–. UV (EtOH, 95°): λmax (ε,
Lmol–1 cm–1) = 230 (25100), 277 (22500) nm; λmin (ε, Lmol–1 cm–1)
= 250 (12700) nm. C33H36N5O11P (709.64): calcd. C 55.85, H 5.11,
N 9.87, P 4.36; found C 55.36, H 5.53, N 9.36, P 4.21.
Removal of Sugar and Nucleobase Protecting Groups: The protected
nucleotide derivative was dissolved in methanolic ammonia
(20 mL/mmol) at room temperature and stirred overnight. The
solution was then concentrated.
1-(5S)-[6-Deoxy-6-diethylphosphono-β-D-ribohexofuranosyl]uracil
(19): Reverse phase column chromatography of the crude material
(H2O/CH3CN 0 to 50%) gave title compound 19 as a white solid
930
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Eur. J. Org. Chem. 2007, 925–933