Design, Synthesis, and Activity of R-Nucleosides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1247
and the mixture was allowed to stir for an additional 3 h. At
6.8 Hz, D
2
O exchangeable), 5.30 (d, 1 H, J ) 4.2 Hz, D
2
O
this time NaHCO
evolution of gas ceased. The clear solution was washed with
NaHCO (saturated, 50 mL) and brine (50 mL) and dried over
3
(saturated) was added slowly until the
exchangeable), 4.71 (m, 2 H), 4.58 (m, 1 H), 4.2 (m, 1 H), 3.6
(m, 2 H). HRMS: calcd for C12
found, 351.9782 (M ). Anal. (C12
+
H
H
11
O
4
N
2
Cl
Cl
3
, M , 351.9784;
3
) C, H, N.
+
3
11
O
4
N
2
magnesium sulfate. The solvent was evaporated and coevapo-
1-(R-D-Lyxofu r an osyl)-2,5,6-tr ich lor oben zim idazole (6b).
The procedure is the same as that described for 6a , except 3b
(632 mg, 1.07 mmol) was used instead of 3a . The TLC (cospots
in solvent system 2) and proton spectrum were identical with
that obtained for 6a . Yield: 175 mg (76%) as a white foam.
rated with diethyl ether under reduced pressure to yield a
1
yellow glass. R
f
) 0.53 (solvent system 3). H NMR (DMSO-
d
6
): δ 8.18 (s, 1 H), 8.01 (s, 1 H), 6.25 (d, 1 H, J ) 7.8 Hz),
.97 (m, 1 H), 5.74 (m, 1 H), 5.17 (m, 1 H), 4.26 (m, 2 H), 2.19
5
(s, 3 H), 2.03 (s, 3 H), 1.97 (s, 3 H).
Mp: 175-176 °C. HRMS: calcd for C H O N Cl , M
+
,
1
2
11
4
2
3
+
The yellow glass was then dissolved in a stirred (1:1:1)
solution of ethanol, MeOH, and water (50 mL). The solution
was charged with sodium carbonate (380 mg, 3.6 mmol). After
351.9784; found, 351.9773 (M ). Anal. (C12
C, H; N: calcd, 7.07; found, 7.54.
H
11
O
4
N
2
Cl
3
2
‚H O)
5,6-Dich lor o-2-(isop r op yla m in o)-1-(r-L-lyxofu r a n osyl)-
b en zim id a zole (7a ). 1-(R-L-Lyxofuranosyl)-2,5,6-trichloro-
benzimidazole (6a ; 300 mg, 0.85 mmol) was dissolved in
ethanol (5 mL), and isopropylamine (10 mL) was then added.
The flask was sealed, and the reaction mixture stirred at 70
°C for 2 days. The mixture was then evaporated under
reduced pressure and subjected to silica gel chromatography
(3 × 25 cm), eluting with solvent system 5. After the solvent
was evaporated under reduced pressure, the resultant solid
was stirred in 10 mL of benzene for 12 h and then collected
by filtration. The solid was dried under reduced pressure at
78 °C for 2 days to give 202 mg (63%) of analytically pure 7a .
1
00 min, glacial acetic acid (0.5 mL) was added and the alcohol
was evaporated under reduced pressure. An additional 25 mL
of cold water was added, and the mixture was filtered. The
resulting solid was recrystallized from methanol/water and
dried at 78 °C under reduced pressure for 2 days to give 194
mg (64%) of 4a as white crystals. R
), R ) 0.30 (solvent system 2). Mp: 178-179 °C. H NMR
DMSO-d ): δ 8.00 (s, 1 H), 7.91 (s, 1 H), 5.96 (d, 1 H, J ) 8.1
Hz), 5.58 (d, 1 H, J ) 6.6 Hz, D O exchangeable), 5.29 (d, 1 H,
O exchangeable), 4.71 (m, 2 H), 4.59 (m, 1 H),
f
) 0.06 (solvent system
1
5
f
(
6
2
J ) 4.3 Hz, D
2
4
.19 (m, 1 H), 3.65 (m, 2 H). HRMS: calcd for C12
H
H
11
O
4
N
2
-
-
+
+
1
Cl
2
Br, 395.9279 (M ); found, 395.9273 (M ). Anal. (C12
Br) C, H, N.
-Br om o-5,6-d ich lor o-1-(r-D-lyxofu r a n osyl)ben zim id -
a zole (4b). The procedure is the same as that described for
a , except that 3b was used instead of 3a . The TLC (cospots
11
O
4
N
2
Mp: 198-201 °C. H NMR (DMSO-d ): δ 7.40 (s, 1 H), 7.32
6
Cl
2
(s, 1 H), 6.57 (bs, 1 H, D O exchangeable), 5.79 (m, 1 H), 5.28
2
2
(m, 1 H, D
4.67 (bs, 1 H, D
4.17 (m, 1 H), 4.03 (m, 1 H), 3.68 and 3.59 (m, 2 H), 1.21 (bs,
6 H). Anal. (C15 Cl ) C, H, N.
2
O exchangeable), 5.21 (m, 1 H, D
2
O exchangeable),
2
O exchangeable), 4.54 (m, 1 H), 4.42 (m, 1 H),
4
in solvent system 2) and proton spectrum were identical with
H
19
O
4
N
3
2
that obtained for 4a . Yield: 255 mg (84%, two steps) as white
5,6-Dich lor o-2-(isop r op yla m in o)-1-(r-D-lyxofu r a n osyl)-
ben zim id a zole (7b). The procedure is the same as that
described for 7a , except that 6b (274 mg, 0.77 mmol) was used
instead of 6a . The TLC (cospots in solvent system 1) and
proton spectrum were identical with that obtained for 7a .
Yield: 205 mg (64%) as a white solid. Mp: 201-202 °C. Anal.
crystals. Mp: 178-179 °C. HRMS: calcd for C12
H
11
O
4
N
2
Cl
2
-
-
+
+
Br, M , 395.9279; found, 395.9261 (M ). Anal. (C12
11 4
H O N
2
Cl
2
Br) C, H, N.
5
,6-Dich lor o-1-(r-L-lyxofu r a n osyl)-2-(m et h yla m in o)-
ben zim id a zole (5a ). A 250-mL pressure bottle was charged
with 3a (480 mg, 1.0 mmol) and a 33% solution of methylamine
in absolute ethanol (25 mL). The vessel was sealed, and the
reaction mixture was stirred at room temperature for 16 h.
The solvent was then evaporated and coevaporated with
hexanes and diethyl ether under reduced pressure. The
remaining solid was recrystallized twice from a methanol and
water mixture and dried at 78 °C under reduced pressure to
(C15
19 4 3 2
H O N Cl ) C, H, N.
2-(Cyclop r op yla m in o)-5,6-d ich lor o-1-(r-L-lyxofu r a n o-
syl)ben zim id a zole (8a ). The procedure is the same as that
described for 7a , except that cyclopropylamine was used
instead of isopropylamine and 6a (300 mg, 0.80 mmol) was
used. Yield: 299 mg (65%) as a white solid. Mp: 184-186
1
°C. H NMR (DMSO-d ): δ 7.47 (s, 1 H), 7.36 (s, 1 H), 7.05
6
yield 259 mg (72%) of 5a as a white solid. R
f
) 0.09 (solvent
system 1). Mp: 131-132 °C. H NMR (DMSO-d ): δ 7.40 (s,
O exchangeable), 5.73 (d,
H, J ) 8.1 Hz), 5.27 (d, 1 H, J ) 4.4 Hz, D O exchangeable),
.24 (d, 1 H, J ) 4.3 Hz, D O exchangeable), 4.66 (t, 1 H, J )
.6 Hz, D O exchangeable), 4.57 (m, 1 H), 4.44 (m, 1 H), 4.16
(bs, 1 H, D O exchangeable), 5.72 (m, 1 H), 5.24 (m, 1 H, D O
2
2
1
6
exchangeable), 5.17 (m, 1 H, D O exchangeable), 4.65 (bs, 2
2
1
1
5
5
H), 7.36 (s, 1 H), 6.81 (m, 1 H, D
2
H, D O exchangeable), 4.53 (m, 1 H), 4.42 (m, 1 H), 4.15 (m, 1
2
2
H), 3.66 and 3.57 (m, 2 H), 2.75 (m, 1 H), 0.86 (m, 2 H), 0.57
(m, 1 H), 0.50 (m, 1H). Anal. (C H O N Cl ) C, H, N.
2
1
5
17
4
3
2
2
2
-(Cyclop r op yla m in o)-5,6-d ich lor o-1-(r-D-lyxofu r a n o-
(
m, 1 H), 3.63 (m, 2 H), 2.88 (d, 3 H, J ) 4.40 Hz). Anal.
Cl ) C, H, N.
,6-Dich lor o-1-(r-D-lyxofu r a n osyl)-2-(m et h yla m in o)-
syl)ben zim id a zole (8b). The procedure is the same as that
described for 7a , except that cyclopropylamine was used
instead of isopropylamine and 6b (248 mg, 0.66 mmol) was
used instead of 6a . The TLC (cospots in solvent system 1) and
proton spectrum were identical with that obtained for 8a .
Yield: 247 mg (67%) as a white solid. Mp: 183-185 °C. Anal.
(C
13
H
15
O
4
N
3
2
5
ben zim id a zole (5b). The procedure is the same as that
described for 5a , except that 3b was used instead of 3a . The
TLC (cospots in solvent system 1) and proton spectrum were
identical with that obtained for 5a . Yield: 223 mg (62%) as a
(C15
H
17
O
4
N
3
Cl
2
) C, H, N.
white solid. Mp: 126-128 °C. Anal. (C13
15 4 3 2
H O N Cl ) C, H,
5
,6-Dich lor o-1-(r-L-lyxofu r a n osyl)b e n zim id a zole -2-
N.
th ion e (9a ). Meth od A: A 500-mL round-bottom flask
equipped with a Claisen adapter and a stirrer was evacuated
and backflushed with argon. Dry 5,6-dichlorobenzimidazole-
1
-(r-L-Lyxofu r an osyl)-2,5,6-tr ich lor oben zim idazole (6a).
A 200-mL round-bottom flask was charged with 3a (464 mg,
.0 mmol) which was then dissolved in 75 mL of an equimolar
1
2-thione15 (10; 1.53 g, 7.0 mmol) was then suspended in CH
3
CN
mixture (v/v) of ethanol and water. Anhydrous sodium
carbonate (370 mg, 3.5 mmol) was added to the stirred
solution, and then the reaction mixture was allowed to stir at
room temperature for an additional 3 h. Acetic acid (4 mL)
was added, and the solvent was evaporated under reduced
pressure. The resultant solid was dissolved in ethyl acetate,
(80 mL). Bis(trimethylsilyl)acetamide (1.95 mL, 7.9 mmol)
was added dropwise via a syringe, and the mixture was heated
until the heterocycle went into solution (30-40 °C). Compound
2
3,38
2a
3
(2.5 g, 7.9 mmol) dissolved in CH CN (40 mL) was added
to the stirred solution followed immediately by TMSOTf (1.5
mL, 7.9 mmol). After 24 h, the solvent was evaporated under
reduced pressure and the remaining residue was subjected to
silica gel chromatography (3 × 25 cm), eluting first with
solvent system 4 and then solvent system 3. Both 10 (40 mg)
and the protected nucleoside (2.84 g, 87% based on consumed
and the solution was washed successively with water, NaHCO
3
(
saturated), and brine (1 × 50 mL each). The organic layers
were collected and dried over sodium sulfate. The solvent was
evaporated under reduced pressure to yield, upon vacuum-
drying, 200 mg (57%) of 6a as a white foam. R
f
) 0.30 (solvent
system 2). Mp: 159-161 °C. H NMR (DMSO-d ): δ 7.98 (s,
H), 7.92 (s, 1 H), 5.97 (d, 1 H, J ) 9.3 Hz), 5.49 (d, 1 H, J )
heterocycle) were obtained as separate compounds. R
f
) 0.45
(compound 10, solvent system 3). H NMR (DMSO-d ): δ
13.33 (bs, 1 H), 7.93 (s, 1 H), 7.41 (s, 1 H), 6.75 (d, 1 H, J )
1
1
6
6
1