The Journal of Organic Chemistry
Article
Synthesis of 1-O-Methyl-2-deoxy-3,5-bis[O-(p-toluoyl)]-D-ribofur-
anose (8). 7 (4.41 g, 0.0297 mol) was dissolved in dry pyridine, and
0.488 g (3.99 mmol) of DMAP was added. The solution was stirred
for 5 min and then cooled to 0 °C. p-Toluoyl chloride (8.5 mL, 60.784
mmol) was added dropwise, and the solution was stirred for 12 h at 0
°C. The reaction mixture was then extracted with DCM, washed with
NaHCO3, and coevaporated with toluene three times to remove the
pyridine. The product 8 was separated by column chromatography
(silica gel 60−120, hexane:EtOAc = 10:1), and the overall yield was
7.5 g (70%, 0.02 mol). This material was fully used for the next step.
Synthesis of 2-Deoxy-3,5-bis[O-(p-toluoyl)]-α-D-ribofuranosyl
Chloride (9). Dry HCl gas was passed through an ethereal solution
of 8 (7.5 g, 0.02 mol) at 0 °C. The white solid product obtained was
filtered and washed with dry ether. The product 9 was then dried in
8.71 (1H, d, J = 8.4 Hz), 8.77 (1H, d, J = 8.0 Hz); 13C NMR (CDCl3,
100 MHz) δ 21.5, 21.7, 29.7, 38.5, 63.9, 74.8, 83.7, 89.1, 121.7, 122.6,
122.9, 126.3, 126.5, 126.6, 126.8, 126.9, 127.0, 127.2, 128.5, 128.9,
129.3, 129.4, 129.6, 129.9, 130.0, 130.5, 130.7, 131.2, 144.1, 144.5,
147.3, 165.9, 166.3; ESI-TOF-MS m/z 598 [M + H]+; HRMS m/z
calcd for C37H32N3O5 ([M + H]+) 598.2342, found 598.2322.
1-[2′-Deoxy-3′,5′-bis{O-(p-toluoyl)}-β-D-ribofuranosyl]-4-(3,5-di-
methoxyphenyl)-1H-1,2,3-triazole (12). Using the general procedure,
starting from 200 mg (0.506 mmol) of 5 and 98.45 mg (0.607 mmol)
of 1-ethynyl-3,5-dimethoxybenzene (B), 280.0 mg (0.502 mmol) of
compound 12 was isolated as a white solid: yield 99%; mp155−158
1
°C; IR (KBr) 1715, 1611, 1276, 1204, 1156 cm−1; H NMR (CDCl3,
400 MHz) δ 2.35 (3H, s), 2.44 (3H, s), 2.88−2.93 (1H, m), 3.12−3.17
(1H, m), 3.49 (1H, s), 3.82 (6H, s), 4.57−4.61 (1H, m), 4.69−4.72
(2H, m), 5.78−5.79 (1H, m), 6.44 (1H, s), 6.54−6.57 (1H, t, J = 6.4
Hz), 6.88 (1H, s), 7.19 (2H, d, J = 8.0 Hz), 7.28 (2H, d, J = 8.0 Hz),
7.87 (2H, d, J = 8.0 Hz), 7.96 (2H, d, J = 7.6 Hz), 7.97 (1H, s); 13C
NMR (CDCl3, 100 MHz) δ 21.9, 38.9, 55.7, 64.1, 75.0, 83.9, 89.3,
101.0, 103.9, 118.5, 126.6, 126.8, 129.6, 129.8, 130.0, 144.5, 144.8,
148.3, 161.3, 166.1, 166.1; ESI-TOF-MS m/z 580 [M + Na]+; HRMS
m/z calcd for C31H32N3O7 ([M + H]+) 558.2240, found 558.2233.
1-[2′-Deoxy-3′,5′-bis{O-(p-toluoyl)}-β-D-ribofuranosyl]-4-(4-nitro-
phenyl)-1H-1,2,3-triazole (13). Using the general procedure, starting
from 200 mg (0.506 mmol) of 5 and 89.31 mg (0.607 mmol) of 1-
ethynyl-4-nitrobenzene (C), 255.6 mg (0.472 mmol) of compound 13
was isolated as a yellow solid: yield 93.23%; mp 185−190 °C; IR
1
vacuum, and the overall yield was 4.48 g (59%, 0.01 mol): H NMR
(CDCl3, 400 MHz) δ 2.41 (3H, s), 2.42 (3H, s), 2.75 (1H, d, J = 14.8
Hz), 2.84−2.91 (1H, m), 4.6 (1H, dd, J = 4.4, 12.4 Hz), 4.68 (1H, dd,
J = 3.2, 12.0 Hz), 4.86 (1H, q, J = 3.2 Hz), 5.56 (1H, dd, J = 2.8, 6.4
Hz), 6.48 (1H, d, J = 5.2 Hz), 7.21−7.28 (4H, m), 7.9 (2H, d, J = 8.0
Hz), 7.99 (2H, d, J = 8.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 21.9,
44.7, 63.7, 64.5, 73.8, 84.2, 84.9, 95.5, 126.9, 129.4, 129.9, 130.1, 144.3,
144.5, 166.3, 166.6.
Synthesis of 2-Deoxy-3,5-bis[O-(p-toluoyl)]-β-D-ribofuranosyl
Azide (5).20 To a solution of toluoyl-protected 9 (1.185 g, 3.048
mmol) in dry DCM were added BF3·Et2O (0.0376 mL, 0.305 mmol)
and trimethylsilyl azide [(TMS)N3] (0.481 mL, 3.66 mmol) at 0 °C.
The solution was stirred vigorously for 6 h. The reaction mixture was
partitioned between water and DCM. The organic layer was washed
with water followed by brine solution, dried over Na2SO4, and then
concentrated. The azide obtained was found to be 784.6 mg (64.9%,
1.98 mmol). The mixture of α- and β-isomers produced in a 3:1 ratio
(10) was then separated by column chromatography using 230−400
mesh size silica gel (solvent system hexane:EtOAc = 20:1) to isolate β-
epimer 5 in 21% yield (249.7 mg, 0.63 mmol), which was then
characterized: IR (KBr) 2110, 1715 cm−1; 1H NMR (CDCl3, 400
MHz) δ 2.41 (3H, s), 2.42 (3H, s), 4.52−4.61 (5H, m), 5.57−5.59
(1H, m), 5.72 (1H, t, J = 4.8 Hz), 7.22−7.26 (4H, m), 7.9 (2H, d, J =
8.4 Hz), 7.98 (2H, d, J = 8.4 Hz); 13C NMR (CDCl3, 100 MHz) δ
21.7, 38.9, 64.1, 74.7, 83.7, 92.1, 126.8, 126.9, 129.3, 129.7, 129.9,
144.0, 144.3, 166.2, 166.3; ESI-TOF-MS m/z 418 [M + Na]+.
General Procedure for the Preparation of Triazolyl Donor/
Acceptor Nucleosides 11−14 via Azide−Alkyne Cycloaddition
Reaction. In a round-bottom flask fitted with a septum, 5 (1.0 equiv)
was dissolved in dry THF and degassed for 10 min with N2. Then the
aromatic alkyne A−D (1.5 equiv) was added, and both stirring and
degassing were continued for the next 5 min. After that, 6 mol %
sodium ascorbate dissolved in a small quantity of water was added, and
the solution was degassed for another 5 min. Then 1 mol % copper
sulfate dissolved in a small quantity of water was added followed by
degassing. The final ratio of THF to H2O in the reaction mixture was
maintained as 3:1. Finally, diisopropylethylamine (DIPEA) was added
to the reaction mixture (1.5 equiv). The solution was refluxed at 75−
80 °C overnight with stirring. After full consumption of the starting
azide, the reaction mixture was evaporated and partitioned between
water and ethyl acetate. The organic layer was washed with water
followed by brine solution, dried over Na2SO4, and then concentrated.
The products 11−14 were then separated by column chromatography
(silicagel 60−120, hexane:EtOAc = 2:1) and characterized. The
average yields were between 90% and 99%.
1
(KBr) 1715, 1610, 1514, 1343, 1278, 1102 cm−1; H NMR (CDCl3,
400 MHz) δ 2.36 (3H, s), 2.44 (3H, s), 2.95−2.98 (1H, m), 3.17−3.22
(1H, m), 4.55 (1H, dd, J = 1.6, 11.6 Hz), 4.63−4.87 (2H, m), 5.68−
5.81 (1H, m), 6.58−6.59 (1H, m), 7.18 (2H, d, J = 7.2 Hz), 7.29 (2H,
d, J = 6.8 Hz), 7.77 (2H, d, J = 7.6 Hz), 7.85 (2H, d, J = 7.2 Hz), 7.96
(2H, d, J = 7.2 Hz), 8.09 (1H, s), 8.20 (2H, d, J = 8.0 Hz); 13C NMR
(CDCl3, 100 MHz) δ 21.8, 21.9, 38.9, 63.9, 74.6, 84.0, 89.4, 111.63,
118.88, 119.5, 126.2, 126.4, 126.7, 129.5, 129.8, 129.9, 132.7, 134.8,
144.5, 144.8, 146.4, 166.1, 166.2; ESI-TOF-MS m/z 565 [M + Na]+;
HRMS m/z calcd for C29H26N4O7Na ([M + Na]+) 565.1699, found
565.1677.
1-[2′-Deoxy-3′,5′-bis{O-(p-toluoyl)}-β-D-ribofuranosyl]-4-(4-cya-
nophenyl)-1H-1,2,3-triazole (14). Using the general procedure,
starting from 200 mg (0.506 mmol) of 5 and 77.199 mg (0.607
mmol) of 4-ethynylbenzonitrile (D), 237.84 mg (0.46 mmol) of
compound 14 was isolated as a white solid: yield 90%; mp175−180
1
°C; IR (KBr) 2228, 1719, 1613, 1277, 1122 cm−1; H NMR (CDCl3,
400 MHz) δ 2.28 (3H, s), 2.35 (3H, s), 2.83−2.89 (1H, m), 3.07−3.14
(1H, m), 4.46 (1H, dd, J = 4.0, 12.0 Hz), 4.61−4.63 (1H, m), 4.66
(1H, dd, J = 3.6, 12.0 Hz), 5.71−5.74 (m, 1H), 6.48 (1H, t, J = 6.4
Hz), 7.08 (2H, d, J = 8.0 Hz), 7.19 (2H, d, J = 7.6 Hz), 7.53 (2H, d, J
= 8.4 Hz), 7.63 (2H, d, J = 8.4 Hz), 7.75 (2H, d, J = 8.0 Hz), 7.87 (2H,
d, J = 8.0 Hz), 7.89 (1H, s); 13C NMR (CDCl3, 100 MHz) δ 21.8,
21.9, 38.9, 63.9, 74.6, 84.0, 89.4, 111.6, 118.9, 119.5, 126.2, 126.4,
126.7, 129.8, 130.0, 132.7, 134.8, 144.5, 144.8, 146.4, 166.1, 166.2;
ESI-TOF-MS m/z 523 [M + H]+; HRMS m/z calcd for
C30H26N4O5Na ([M + Na]+) 545.1801, found 545.1782.
General Procedure for Toluoyl Deprotection (1−4). The
bistoluoylated triazolyl donor/acceptor nucleosides 11−14 (1 equiv)
were dissolved in dry methanol. Sodium methoxide (3.5 equiv) was
subsequently added. The solution was allowed to stir overnight at
room temperature. The solution was evaporated, and the deprotected
products were isolated pure by column chromatography (silica gel 60−
120; pure EtOAc).
1-(2′-Deoxy-β-D-ribofuranosyl)-4-(phenanthren-9-yl)-1H-1,2,3-
triazole (1). Using the general procedure for deprotection starting
from 278.7 mg (0.467 mmol) of compound 11, 155.2 mg (0.429
mmol) of compound 1 was isolated as a yellow solid: yield 92.0%; mp
166−168 °C; IR (KBr) 3364, 1435, 1205, 1121, 1056, 1032 cm−1; 1H
NMR (CD3OD, 400 MHz) δ 2.59−2.64 (1H, m), 2.91−2.96 (1H, m),
3.71 (1H, dd, J = 4.4, 11.6 Hz), 3.79−3.82 (1H, m), 4.08−4.1 (1H,
m), 4.62−4.65 (1H, m), 6.57 (1H, t, J = 5.6, 6.0 Hz), 7.62−7.7 (4H,
m), 7.96 (2H, d, J = 10.8 Hz), 8.25 (1H, d, J = 8.4 Hz), 8.57 (1H, s),
8.78−8.86 (2H, m); 13C NMR (CD3OD, 100 MHz) δ 42.1, 63.5, 72.5,
1-[2′-Deoxy-3′,5′-bis{O-(p-toluoyl)}-β-D-ribofuranosyl]-4-(phe-
nanthren-9-yl)-1H-1,2,3-triazole (11). Using the general procedure,
starting from 200 mg (0.506 mmol) of 5 and 122.77 mg (0.607 mmol)
of 9-ethynylphenantherene (A), 288.7 mg (0.484 mmol) of compound
11 was isolated as a yellow solid: yield 95.6%; mp 148−151 °C; IR
1
(KBr) 1714, 1610, 1281, 1123, 1020 cm−1; H NMR (CDCl3, 400
MHz) δ 2.22 (3H, s), 2.45 (3H, s), 2.98−3.01 (1H, m), 3.29−3.33
(1H, m), 4.62−4.65 (1H, m), 4.73 (2H, s), 5.83−5.84 (1H, m), 6.66
(1H, t, J = 8.0 Hz), 7.06 (2H, d, J = 7.6 Hz), 7.29 (2H, d, J = 7.6 Hz),
7.57−7.61 (2H, m), 7.69 (2H, t, J = 6.8, 7.2 Hz), 7.84 (4H, d, J = 6.8
Hz), 7.98 (2H, d, J = 7.6 Hz), 8.08 (1H, s), 8.33 (1H, d, J = 8.4 Hz),
J
dx.doi.org/10.1021/jo302033f | J. Org. Chem. XXXX, XXX, XXX−XXX