3′-C-Branched-Chain-Substituted Nucleosides, Nucleotides
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 18 3819
diluted with CH2Cl2 (50 mL), washed with saturated aqueous
NaHCO3 (50 mL), and dried over anhydrous MgSO4. The
solvent was removed under diminished pressure to give the
crude mesylate. The obtained residue was dissolved in DMF
(16 mL) and treated with NaN3 (574 mg 8.83 mmol) at 95 °C
for 1.5 h to complete the reaction. The reaction mixture was
evaporated to dryness in vacuo, and the residue was dissolved
in CH2Cl2 (50 mL). The organic layer was washed with water
(50 mL), dried over anhydrous MgSO4, and evaporated to give
a sirup which was purified by column chromatography (CH2-
Cl2-MeOH, 99:1), yielding 30 (260 mg, 79%) as a white foam.
1H NMR (300 MHz, DMSO-d6): δ 1.52 (3 H, d, 5-CH3), 2.50
(2H, m, H-2′), 2.60 (1H, m, H-3′), 3.46-3.59 (2H, 2dd, H-6′),
3.66 (1H, dd, H-5′B), 3.83 (1H, dd, J 5′A,5′B ) -10.4 Hz, H-5′A),
3.93 (1H, m, H-4′), 4.57 (2H, app s, CH2Ph), 6.04 (1H, app t, J
) 5.9 Hz, H-1′), 7.31 (5H, m, CH2Ph), 7.62 (1H, br s, H-6);
HRMS (ESI-MS) for C18H21N5O4Na [M + Na]+: found, 394.1489;
calcd, 394.1491.
1-[3-(Azidom eth yl)-2,3-dideoxy-â-D-er yth r o-pen tofu r an -
osyl]th ym in e (9). To a solution of 30 (1.49 g, 4.01 mmol) in
CH2Cl2 (160 mL) at -78 °C was slowly added a 1 M solution
of BCl3 in CH2Cl2 (16.1 mL, 16.1 mmol). After 15 min MeOH
(5 mL) was added, and the reaction mixture was evaporated
to dryness under reduced pressure. The resulting residue was
purified by column chromatography (CH2Cl2-MeOH, 90:10),
affording 9 (1.00 g, 89%) as a white foam. 1H NMR (300 MHz,
DMSO-d6): δ 1.78 (3 H, d, 5-CH3), 2.13 (2H, m, H-2′), 2.51
(1H, m, H-3′), 3.51 (2H, app d, H-6′), 3.55-3.61 (1H, m, H-4′),
3.69-3.74 (2H, m, H-5′), 5.13 (1H, app t, 5′-OH), 6.02 (1H, dd,
J ) 5.0 and 6.3 Hz, H-1′), 7.82 (1H, d, J ) 1.1 Hz, H-6); 13C
NMR (125 MHz, DMSO-d6): δ 12.96 (5-CH3), 36.36 (C-2′),
38.07 (C-3′), 52.71 (C-6′), 61.90 (C-5′), 84.45 and 84.13 (C-1′
and C-4′), 109.56 (C-6), 136.97 (C-5), 151.05 (C-4), 164.51 (C-
2); HRMS (ESI-MS) for C11H15N5O4Na [M + Na]+: found,
304.1033; calcd, 304.1021. Anal. (C11H15N5O4) C, H, N.
solution was allowed to stir for an additional 6.5 h. Pyridine
was removed at reduced pressure, water (200 mL) was added,
and the unreacted triphenylphosphine and triphenylphosphine
oxide were removed by filtration. The filtrate was extracted
with toluene, and the water layer was evaporated under
reduced pressure to give a syrup. The syrup was purified by
column chromatography (iPrOH-NH4OH-H2O, 77.5:15:2.5 f
60:30:5). The resulting white powder was further purified by
HPLC (C-18, CH3CN-MeOH-0.05% HCOOH in H2O, 45:45:10,
3 mL/min), and the fractions containing the title compound
were lyophilized to yield 4 (306 mg, 69%) as a white powder.
1H NMR (300 MHz, D2O): δ 1.92 (3 H, s, 5-CH3), 2.32-2.50
(2H, m, H-2′), 2.74-2.82 (1H, m, H-3′), 3.12-3.26 (2H, 2dd,
H-6′), 4.05-4.12 (3H, m, H-4′ and H-5′), 6.17 (1H, dd, J ) 3.7
and 7.3 Hz, H-1′), 7.78 (1H, d, J ) 1.2 Hz, H-6); 13C NMR (75
MHz, D2O): δ 11.76 (5-CH3), 166.79 (C-2), 151.74 (C-4), 137.70
(C-5), 111.40 (C-6), 85.29 (C-1′), 82.72 (C-4′), 63.94 (C-5′), 40.80
(C-6′), 36.88 (C-3′), 35.95 (C-2′); 31P NMR (500 MHz, D2O): δ
2.82; HRMS (ESI-MS) for C11H19N3O7PNa [M + Na]+: found,
336.0980; calcd, 336.0960.
1-[5-O-Ben zyl-3-d eoxy-3-(h yd r oxym eth yl)-â-D-r ibofu r -
a n osyl]th ym in e (31). This compound was synthesized from
23 (346 mg, 0.74 mmol) using the procedure described for 28
to yield 130 mg (49%) of the title compound as a foam. 1H NMR
(300 MHz, DMSO-d6): δ 1.42 (3 H, s, 5-CH3), 2.31 (1H, m, J 3′,6′
) 6.6 Hz, H-3′), 3.49 and 3.68 (2H, 2m, 6′-H), 3.64 (1H, m,
H-5′B), 3.98 (1H, m, J 5′A,5′B ) -11.1 Hz, H-5′A), 4.13 (1H, m,
H-4′), 4.19 (1H, m, H-2′), 4.58 (3H, m, CH2Ph and 6′-OH), 5.60
(1H, d, J ) 5.0 Hz, 2′-OH), 5.67 (1H, d, J ) 1.9, H-1′), 7.37
(5H, m, CH2Ph), 7.70 (1H, br s, 6-H); HRMS (ESI-MS) for
C
18H22N2O6Na [M + Na]+: found, 385.1386; calcd, 385.1375.
1-[3-Azid om eth yl-5-O-ben zyl-3-d eoxy-â-D-r ibofu r a n o-
syl]th ym in e (32). This compound was synthesized from 31
(130 mg, 0.36 mmol) using the same procedure as described
for the synthesis of 30 to yield 123 mg (89%, 2 steps) of the
1
title compound as a foam. H NMR (300 MHz, DMSO-d6): δ
1-[3-(Am in om et h yl)-2,3-d id eoxy-â-D-er yth r o-p en t ofu -
r a n -osyl]th ym in e (10). Compound 9 (169 mg, 0.60 mmol) and
triphenylphosphine (252 mg, 0.96 mmol) were dissolved in
pyridine (7 mL) and stirred at room temperature. After 1 h,
concentrated NH4OH (6 mL) was added, and the solution was
allowed to stir for an additional 2 h. Pyridine was removed
under reduced pressure, water (8 mL) was added, and the
unreacted triphenylphosphine and triphenylphosphine oxide
were removed by filtration. The filtrate was extracted with
toluene, and the water layer was evaporated under reduced
pressure to give a syrup. The syrup was purified by column
chromatography (0.175 N NH3 in CH2Cl2-MeOH, 80:20) to
1.42 (3 H, s, 5-CH3), 2.46 (1H, m, H-3′), 3.35-3.90 (4H, m, H-5′
and H-6′), 4.10 (1H, m, H-4′), 4.22 (1H, m, H-2′), 4.59 (2H, s,
CH2Ph), 5.67 (1H, d, J ) 1.6 Hz, H-1′), 5.93 (1H, d, J ) 5.1
Hz, 2′-OH), 7.37 (CH2Ph), 7.67 (1H, br s, H-6); HRMS (ESI-
MS) for C18H21N5O5Na [M + Na]+: found, 410.1504; calcd,
410.144.
1-[3-Azid o m e t h y l-3-d e o x y -â-D -r ib o fu r a n o s y l]t h y -
m in e (13). Debenzylation of 32 (346 mg, 0.89 mmol) was
performed as described for the synthesis of 9 to yield 210 mg
(79%) of the title compound as a foam. 1H NMR (300 MHz,
DMSO-d6): δ 1.76 (3 H, s, 5-CH3), 2.37 (1H, m, H-3′), 3.35-
3.78 4H, m, H-5′ and H-6′), 3.91 (1H, m, H-4′), 4.20 (1H, app
d, H-2′), 5.24 (1H, br s, 5′-OH), 5.66 (1H, d, J 1′,2′ ) 1.9 Hz,
H-1′), 5.94 (1H, br s, 2′-OH), 7.95 (1H, br s, H-6). The
assignment, done by a cosy-experiment, differs from that
reported in ref 8. 13C NMR (75 MHz, DMSO-d6): δ 12.95 (5-
CH3), 41.35 (C-3′), 47.90 (C-6′), 61.14 (C-5′), 75.36 (C-2′), 82.90
(C-4′), 91.26 (C-1′), 164.53 (C-2), 151.11 (C-4), 136.93 (C-5),
109.10 (C-6); HRMS (ESI-MS) for C11H15N5O5Na [M + Na]+:
found, 320.0975; calcd, 320.0971. Anal. (C11H15N5O5) C, H, N.
1
yield amine 10 (112 mg, 73%) as a white foam. H NMR (300
MHz, DMSO-d6): δ 1.78 (3 H, s, 5-CH3), 2.3-2.14 (2H, m,
H-2′), 2.24 (1H, m, H-3′), 2.55-2.65 (2H, m, H-6′), 3.55-3.71
(3H, m, H-5′ and H-4′), 5.95 (1H, dd, J ) 3.9 and 6.9 Hz, H-1′),
7.8 (1H, d, J ) 1.1 Hz, H-6); 13C NMR (75 MHz, DMSO-d6): δ
12.98 (5-CH3), 43.38, 41.60 and 37.05 (C-6′, C-3′ and C-2′),
62.27 (C-5′), 85.49 (C-4′), 85.24 (C-1′), 109.37 (C-6), 136.95 (C-
5), 151.04 (C-4), 164.51 (C-2); HRMS (ESI-MS) for C11H18N3O4
[M + H]+: found, 256.1293; calcd, 256,1296. Anal. (C11H17N3O4)
C, H, N.
1-[3-Am in om e t h yl-3-d e oxy-â-D-r ib ofu r a n osyl]t h y-
m in e (14). Reduction of azide 13 (173 mg, 0.58 mmol) was
accomplished using the procedure described for the synthesis
1-[3-(Azid om et h yl)-2,3-d id eoxy-5-O-p h osp h or yl-â-D-
er yth r o-p en tofu r a n osyl]th ym in e (3). 9 was phosphorylated
as described in the general procedure to yield 53% of the title
1
of 11 to yield 123 mg (73%) of amine 14 as a foam. H NMR
1
compound. H NMR (300 MHz, D2O): δ 1.91 (3 H, s, 5-CH3),
(300 MHz, DMSO-d6): δ 1.76 (3 H, d, 5-CH3), 2.16 (1H, m,
H-3′), 2.63-2.89 (2H, 2dd, H-6′), 3.59 (1H, dd, H-5′B), 3.76 (1H,
dd, J 5′A,5′B ) -12.3 Hz, H-5′A), 3.92 (1H, m, H-4′), 4.21 (1H,
app d, H-2′), 5.63 (1H, d, J ) 1.4 Hz, H-1′), 7.94 (1H, d, J )
1.1 Hz, H-6); HRMS (ESI-MS) for C11H18N3O5 [M + H]+: found,
272.1245; calcd, 272.1246. Anal. (C11H17N3O5) C, H, N.
2.33 (2H, app dd, H-2′), 2.68 (1H, m, H-3′), 3.54 (2H, app d,
J 6′,3′ ) 6.3 Hz, H-6′), 4.00-4.19 (3H, m, H-5′ and H-4′), 6.16
(1H, app t, J ) 5.8 Hz, H-1′), 7.80 (1H, d, J ) 1.1 Hz, 6-H);
13C NMR (75 MHz, D2O): δ 11.75 (5-CH3), 35.36 (C-2′), 37.71
(C-3′), 52.15 (C-6′), 65.13 (C-5′), 82.62 (C-4′), 85.36 (C-1′),
111.36 (C-6), 137.71 (C-5), 151.79 (C-4), 166.79 (C-2); 31P NMR
(500 MHz, D2O): δ 1.14; HRMS (ESI-MS) for C11H16N5O7P [M
+ H]+: found, 362.0889; calcd, 362.0865.
1-[3-Azid om eth yl-3-d eoxy-5-O-p h osp h or yl-â-D-r ibofu r -
a n osyl]th ym in e (7). 13 was phosphorylated as described in
1
the general procedure to yield 51% of nucleotide 7. H NMR
1-[3-(Am in om et h yl)-2,3-d id eoxy-5-O-p h osp h or yl-â-D-
er yth r o-p en tofu r a n osyl]th ym in e (4). Compound 3 (476 mg,
1.26 mmol) and triphenylphosphine (528 mg, 2.01 mmol) were
dissolved in pyridine (15 mL) and stirred at room temperature.
After 1 h, concentrated NH4OH (12.6 mL) was added, and the
(300 MHz, D2O): δ 1.92 (3 H, d, 5-CH3), 2.59 (1H, m, H-3′),
3.56 and 3.66 (2H, 2dd, J 6′,3′ ) 5.8 and 8.1 Hz, H-6′), 4.04 (1H,
m, H-5′B), 4.26 (1H, m, H-5′A), 4.32 (1H, app d, H-4′), 4.52
(1H, dd, H-2′), 5.86 (1H, d, J ) 2.0 Hz, H-1′), 7.89 (1H, d, J )
1.0 Hz, H-6); 13C NMR (125 MHz, D2O): δ 14.28 (5-CH3), 43.40