Synthesis and antiviral activity of novel erythrofuranosyl imidazo[1,2-α]pyridine C-nucleosides constructed via palladium coupling of iodoimidazo[1,2-α]pyridines and dihydrofuran

Article abstract of DOI:10.1021/jm020339r

2,5,6-Trichloro-1-(β-D-ribofuranosyl)benzimidazole (TCRB) and certain analogues have shown significant activity against human cytomegalovirus. The metabolic instability of the glycosidic linkage in TCRB prompted us to synthesize the structurally similar imidazo[1,2-α]pyridine erythrofuranosyl C-nucleosides. As an approach to the synthesis of polychlorinated imidazo-[1,2-α]pyridine C-3-erythrofuranosides, a palladium-based methodology for coupling 2,3-dihydrofuran with chlorinated 3-iodoimidazo[1,2-α]pyridines was developed and optimized to give 80-90% yields of 2,6-dichloro- and 2,6,7-trichloro-3-(2,3-dideoxy-2,3-didehydro-D/L-erythrofuranosyl)- imidazo[1,2-α]pyridine. Dihydroxylation of these didehydro derivatives with osmium tetroxide or with AD-mix α gave a mixture of erythrofuranosyl C-nucleosides that were separated by standard and then chiral chromatography. When screened for anti-HCMV and HSV-1 activity, the α-D anomer of 2,6,7-trichloro-3-(erythrofuranosyl)imidazo[1,2-a]pyridine proved to be the most active member of the series, while the α-anomers all proved to be inactive.

Full text of DOI:10.1021/jm020339r

J . Med. Chem. 2003, 46, 1449-1455
1449
Syn th esis a n d An tivir a l Activity of Novel Er yth r ofu r a n osyl
Im id a zo[1,2-a ]p yr id in e C-Nu cleosid es Con str u cted via P a lla d iu m Cou p lin g of
Iod oim id a zo[1,2-a ]p yr id in es a n d Dih yd r ofu r a n
†
Kristjan S. Gudmundsson, J ohn D. Williams, J ohn C. Drach, and Leroy B. Townsend*
Department of Medicinal Chemistry, College of Pharmacy; Department of Chemistry, College of Literature,
Sciences and the Arts; and Department of Biologic and Materials Sciences, School of Dentistry;
The University of Michigan, Ann Arbor, Michigan 48019-1065
Received August 6, 2002
2
,5,6-Trichloro-1-(â-D-ribofuranosyl)benzimidazole (TCRB) and certain analogues have shown
significant activity against human cytomegalovirus. The metabolic instability of the glycosidic
linkage in TCRB prompted us to synthesize the structurally similar imidazo[1,2-a]pyridine
erythrofuranosyl C-nucleosides. As an approach to the synthesis of polychlorinated imidazo-
[
1,2-a]pyridine C-3-erythrofuranosides, a palladium-based methodology for coupling 2,3-dihydro-
furan with chlorinated 3-iodoimidazo[1,2-a]pyridines was developed and optimized to give 80-
0% yields of 2,6-dichloro- and 2,6,7-trichloro-3-(2,3-dideoxy-2,3-didehydro-D/L-erythrofuranosyl)-
9
imidazo[1,2-a]pyridine. Dihydroxylation of these didehydro derivatives with osmium tetroxide
or with AD-mix R gave a mixture of erythrofuranosyl C-nucleosides that were separated by
standard and then chiral chromatography. When screened for anti-HCMV and HSV-1 activity,
the R-D anomer of 2,6,7-trichloro-3-(erythrofuranosyl)imidazo[1,2-a]pyridine proved to be the
most active member of the series, while the â-anomers all proved to be inactive.
In tr od u ction
The C-nucleosides differ from the more commonly
occurring N-nucleosides by virtue of a hydrolytically
resistant carbon-carbon bond linking the carbohydrate
moiety and heterocycle instead of the labile aminal
linkage (carbon-nitrogen bond). The C-nucleosides of
several different heterocycles, such as purines, pyrim-
1
idines, and pyridines, have been reported. Several
C-nucleosides, both naturally occurring and synthetic,
have significant antibacterial, antiviral, and antitumor
2
activities. Some of these biological activities have been
postulated to depend on the resistance of the carbon-
3
carbon linkage to hydrolytic or enzymatic cleavage.
The nucleoside 2,5,6-trichloro-1-(â-D-ribofuranosyl)-
benzimidazole (TCRB, 1)4
-7
shows potent and very
selective activity against human cytomegalovirus with
low cellular toxicity at concentrations inhibiting viral
6
-8
F igu r e 1. Benzimidazole and imidazo[1,2-a]pyridine nucleo-
sides.
growth.
However, pharmacokinetic studies in rats
and monkeys revealed that TCRB disappears rapidly
from the bloodstream following either intravenous or
We have previously described the synthesis of 2,6,7-
trichloro-3-(â-D-ribofuranosyl)imidazo[1,2-a]pyridine (3)
via an enantioselective construction of the ribose moiety
and a synthesis of the regioisomeric 2,6,7-trichloro-5-
9
oral dosage. The disappearance of TCRB was correlated
with a concomitant increase in blood concentration of
its heterocyclic base, 2,5,6-trichlorobenzimidazole (2).
This indicated that the glycosidic bond (aminal linkage)
is unstable in vivo. The metabolic instability of the
glycosidic bond in this benzimidazole nucleoside prompted
us to consider the synthesis of the structurally related
imidazo[1,2 -a]pyridine C-nucleosides (3 and 4), which
should be more stable than their N-nucleoside counter-
parts.
(â-D-ribofuranosyl)imidazo[1,2-a]pyridine by condensing
a lithiated imidazo[1,2-a]pyridine with a suitably pro-
1
0,11
tected ribonolactone derivative.
,5,6-trichloro-1-(â-D-erythrofuranosyl)benzimidazole (5)
had greater antiviral activity (10-fold) than the corre-
As the erythroside
2
1
2
sponding riboside 1, we became interested in the
synthesis of the novel C-3 erythrofuranosyl imidazo[1,2-
a]pyridine C-nucleoside 4. The most direct route to the
desired C-nucleoside appeared to be a palladium cou-
pling of an iodinated imidazo[1,2-a]pyridine with 2,3-
dihydrofuran. The synthetic utility of the palladium
*
To whom correspondence should be addressed: University of
Michigan, College of Pharmacy, 428 Church St., Ann Arbor, MI 48109-
065, phone: (734) 764-7547; fax: (734) 763-5633; e-mail: ltownsen@
umich.edu.
1
†
Present address: GlaxoSmithKline, Five Moore Dr., PO Box 13398,
Research Triangle Park, NC 27709.
1
3-15
coupling reaction
for the formation of C-glycosides
1
0.1021/jm020339r CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/07/2003

1
450 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 8
Gudmundsson et al.
Sch em e 1
Ta ble 1. Coupling of 3-Iodoimidazo[1,2-a]pyridine 7a and
imidazo[1,2-a]pyridine (9). Initial yields from the
palladium catalyzed coupling reaction were low, but
have been optimized by changing several reaction
conditions as outlined in Table 1.
2
,3-dihydrofuran
base
ligand
Ag2CO3
(2 mol temp
equiv)
%
8
yieldsb
9
(
2 mol (0.2 mol
entrya equiv)
equiv)
solvent
(°C)
The ratio of base (Et3N or Bu3N):Pd(OAc)2:ligand
c
1
2
3
4
5
6
7
8
9
Et3N
Et3N
Et3N
Et3N
Ph3P
Ph3P
Ph3As
Ph3As
CH3CN
DMF
CH3CN
CH3CN
-
-
-
-
-
-
-
+
+
25
25
25
60
25
25
25
60
45
10
20
20
15
30
55
55
60
81
11
10
25
30
15
35
35
25
0
(Ph3P or Ph3As or tri-(o-tolyl)phosphine) was kept
c
constant for all entries. The selected ratio was based
2
0
13,25
26
on results from Daves, Heck,
and Czerneski.
Bu3N (o-tol)3P DMF
Et3N
Bu3N Ph3As
Et3N
Et3N
Variations in the use of ligands were based on the fact
Ph3As
DMF
DMF
DMF
DMF
27
28
that triphenylarsine and tri-(o-tolyl)phosphine have
been reported to accelerate the rate of coupling over
those rates obtained by using triphenylphosphine. Sub-
sequent experiments showed that the amount of Pd(OAc)2
may be varied between 0.05 and 0.3 equiv and that the
ratio of Pd(OAc)2 to Ph3As (as long as the equivalent
ratio of Ph3As/Pd(OAc)2 is greater than 2) did not
adversely affect yields. Replacing the Pd(OAc)2 with
other palladium species (Pd(Ph3P)4 or other Pd° species)
did not improve the yield. DMF proved to be a superior
solvent to CH3CN, CH3NO2, or toluene, presumably due
to improved solubilization of salts formed during the
reaction. Once conditions that gave an excellent com-
bined yield of 8 and 9 were realized, reaction conditions
were adjusted so that 8 could be obtained selectively as
shown in entries 8 and 9. This was accomplished by
adding silver salts to the reactions, as silver salts are
known to prevent double bond migration in palladium
d
d
Ph3As
Ph3As
a
A typical procedure is outlined in the Experimental Section.
b
c
Isolated yields. Increasing reaction temperature decreased the
reaction time but did not improve the yield. Other silver species,
such as AgNO3, did not improve the yield.
d
and C-nucleosides is impressive.16-19 Among the C-
nucleosides that have been synthesized via palladium
2
0
coupling are various pyrazolo[4,3-d]pyrimidine, pyr-
2
1
22,23
azine, and pyrimidine
C-nucleosides. To date pal-
ladium coupling has not been used for the synthesis of
imidazo[1,2-a]pyridine C-nucleosides. We now describe
the synthesis of novel erythrofuranosyl imidazo[1,2-a]-
pyridine C-nucleosides via palladium coupling and
dihydroxylation, and the preliminary antiviral activities
of these compounds.
2
3,29-31
reactions.
The addition of silver salts, however,
Resu lts a n d Discu ssion
slowed the coupling reaction to such an extent that it
was not complete even after several days at room
temperature. This effect was offset by increasing the
reaction temperature. If the coupling reactions were run
in the presence of a silver salt at 60 °C or a higher
temperature, the formation of significant quantities of
Ch em istr y. As an initial approach, we chose to study
the coupling of 2,3-dihydrofuran with 2,6-dichloro-3-
iodoimidazo[1,2-a]pyridine (7). 2,6-Dichloroimidazo[1,2-
a]pyridine (6)24 was iodinated using N-iodosuccinimide
in CH3CN to give 2,6-dichloro-3-iodoimidazo[1,2-a]-
pyridine (7) (Scheme 1). Iodination occurred only at the
C3 position as shown by the splitting pattern of the
heterocyclic protons, where the signal from the 5-H at
9
was still observed. However, by lowering the temper-
ature to 45 °C, 8 was formed exclusively and in good
yield.
8
.44 ppm is a doublet of doublets as a result of coupling
Finally, dihydroxylation of 8 using catalytic OsO4 in
the presence of N-methylmorpholine N-oxide (NMO)32
gave a 1:2 mixture of the erythrofuranosyl C-nucleosides
2,6-dichloro-3-(R-D/L-erythrofuranosyl)imidazo[1,2-a]-
pyridine (10) and its â anomer 11, which were separated
by column chromatography. Compounds 10 and 11 were
assigned as being hydroxylated from the â- and R-face,
to both 7-H and 8-H. Compound 7 was coupled to 2,3-
dihydrofuran using palladium acetate under various
conditions (see Table 1) to give racemic mixtures of
2
,6-dichloro-3-(2,3-dideoxy-2,3-didehydro-â-D/L-erythro-
furanosyl)imidazo[1,2-a]pyridine (8) and 2,6-dichloro-
-(2,3-dideoxy-3,4-didehydro-â-D/L-erythrofuranosyl)-
3

Erythrofuranosyl Imidazo[1,2-a]pyridine C-Nucleosides
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 8 1451
Sch em e 2
respectively, based on the shift of their anomeric
with AD-mix R was greater. This was presumably
because the proportion of the active component (i.e., 20)
was higher in the reactions using AD-mix R than in the
reactions using AD-mix â. Therefore, AD-mix R was
then chosen for all subsequent syntheses. Compound 15
was separated into two components, 15a and 15b;
compound 15a was ultimately assigned as a mixture of
R-anomers. This assignment was based upon an X-ray
crystal structure of the derivative 18. Compound 15b
was consequently assigned as a mixture of â-anomers
because of the previous assignment of its anomer 15a .
Antiviral evaluation of 15a and 15b revealed that the
most active mixture was actually the mixture of R-ano-
mers, 15a .
It was further hypothesized that only one of the
enantiomers of 15a could be responsible for the activity
of the mixture. To determine the activity of the different
enantiomers of 15a , we needed to effect a chiral resolu-
tion of the two enantiomers. To facilitate the separation
of the anomers as well as later chiral chromatography,
the acetonide of the mixture 15 was synthesized using
2,2-dimethoxypropane and acetone catalyzed by p-
toluenesulfonic acid. The acetonide-protected 2,6,7-
trichloro-3-(R-D/L-erythrofuranosyl)imidazo[1,2-a]pyri-
dine (16) was then easily separated from its â anomer
17 (the ratio of 16:17 was 46:54) and then separated
into the enantiomerically purified compounds 18 and
19 using chiral chromatography (the ratio of 18:19 was
64:36). Hydrolysis of the acetonides 18 and 19 using 90%
aqueous TFA provided the erythrosides 2,6,7-trichloro-
3-(R-D-erythrofuranosyl)imidazo[1,2-a]pyridine (20) and
2,6,7-trichloro-3-(R-L-erythrofuranosyl)imidazo[1,2-a]-
protons.3
3,34
The signal from the 1′-H in 10 appeared at
5
.26 ppm while the 1′-H signal from 11 appeared at 5.03
ppm. Further support for this stereochemical assign-
ment was obtained by NOE studies on 11 which showed
positive NOE between the 2′-H on the erythrose moiety
and the C5-H on the imidazo[1,2-a]pyridine moiety. A
similar NOE was not observed for derivative 10. 2′,3′-
Dideoxy-2′,3′-didehydro ribose nucleoside derivatives
have been hydroxylated selectively from the R-face
because the â-face is sterically hindered.35 However, it
was not surprising that the erythrose analogue gave a
significant amount of 10 resulting from hydroxylation
on the â-face, since the lack of a 4′-substituent signifi-
cantly reduces steric hindrance to the â-face.
2
,6,7-Trichloro-3-(â-D/L-erythrofuranosyl)imidazo[1,2-
a]pyridines (15b) and its R-anomer (15a ) were prepared
using a similar palladium coupling and hydroxylation
2
4
method. Thus, 2,6,7-trichloroimidazo[1,2-a]pyridine (12)
was iodinated to give 3-iodo-2,6,7-trichloroimidazo[1,2-
a]pyridine (13) (Scheme 2). Compound 13 was coupled
to 2,3-dihydrofuran in the presence of silver salts to give
only the 2′,3′-dideoxy-2′,3′-didehydro erythroside 14 and
not any of the isomeric 2′,3′-dideoxy-3′,4′-didehydro
analogue. Compound 14 was dihydroxylated using AD-
mix R to give a mixture of R and â anomers of 2,6,7-
trichloro-3-(D/L-erythrofuranosyl)imidazo[1,2-a ]pyri-
dine (15). The use of AD-mix instead of osmium tetroxide/
NMO was based upon the expectation that the desired
enantiomer could be synthesized in excess, and later
separated. Both AD-mix R and AD-mix â were utilized,
but the biological activity of the compounds synthesized

1
452 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 8
Gudmundsson et al.
congener12 against HCMV where the â-anomers are
active, and the R-anomers are completely inactive.
Evaluation of the enantiomerically purified 2,6,7-
trichloro-3-(R-D-erythrofuranosyl)imidazo[1,2-a]pyri-
dine (20) and the L-enantiomer (21) revealed that all of
the activity against the two herpes viruses resided in
2
0 whereas the L-enantiomer 21 was completely devoid
of antiviral activity and was also noncytotoxic. Further
details regarding the antiviral activity and mechanism
of action of 2,6,7-trichloro-3-(R-D-erythrofuranosyl)-
imidazo[1,2-a]pyridine (20) will be published elsewhere.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points are uncorrected.
Nuclear magnetic resonance (NMR) spectra were obtained at
3
60 or 300 MHz. Flash column chromatography was performed
using silica gel 60 230-400 mesh. Thin-layer chromatography
TLC) was performed on prescored Silica gel GHLF. Com-
F igu r e 2. ORTEP diagram of intermediate 18.
(
Ta ble 2. Antiviral Activity and Cytotoxicity of
Imidazo[1,2-a]pyridine C-Nucleosides
pounds were visualized by illumination under UV light (254
nm) or by spraying with 20% methanolic sulfuric acid followed
by charring on a hot plate. Evaporations were carried out
under reduced pressure with a water bath at or below 40 °C.
All solvents were dried prior to use as described by the
handbook Purification of Laboratory Chemicals36 and stored
over 4 Å sieves, under argon. Materials obtained from com-
mercial suppliers were used without purification.
2
,6-Dich lor o-3-iod oim id a zo[1,2-a ]p yr id in e (7). To a sus-
pension of 2,6-dichloroimidazo[1,2-a]pyridine (6, 4.0 g, 0.02
mol) in dry CH CN (50 mL) was added N-iodosuccinimide (5.3
g, 0.024 mol) and the mixture stirred at room temperature for
h. The reaction mixture was heated at reflux for 10 min and
then cooled to room temperature. Chloroform (200 mL) was
added to the reaction mixture and the organic phase washed
successively with 10% NaOH (100 mL), sodium thiosulfate
5
0% inhibitory concentration (µM)
3
antiviral activity
1
HCMVa
plaque
HSV-1b
cytotoxicityc
enan-
tiomer anomer
no.
X
H
ELISA visual growth
1
1
1
1
2
2
1
0
5a
5b
0
D/L
D/L
D/L
D/L
D
R
â
R
â
R
R
>100d
Cl >100
Cl 8 ( 1
Cl >100
Cl 2.9 ( 1.6 14 ( 15
Cl >100
>100
>100
24 ( 33
>100
>100 >100
>100 >100
>100 >100
>100 >100
100 68 ( 4
>100 >100
238 210
(
100 mL), and water (2 × 100 mL) and then dried over
magnesium sulfate, filtered, and concentrated to dryness under
reduced pressure. The resulting solid was suspended in MeOH
and filtered to give 5.0 g (80%) of 7 as a white crystalline
1
solid: mp 234-235 °C; R
360 MHz, DMSO-d
7.63 (dd, 1H, J ) 0.8 Hz, J ) 9.5 Hz), 7.45 (dd, 1H, J
f
0.43 (EtOAc/hexane 1:5); H NMR
1
L
>100
102
(
6
):δ 8.44 (dd, 1H, J ) 0.8 Hz, J ) 2.0 Hz),
) 9.5
):δ 144.39, 141.02,
7 3
27.45, 125.17, 121.33, 117.39, 66.49. Anal. Calcd for C H -
e
TCRB
DHPG
2.9
f
7
7.4 ( 6.5 3.5 ( 2.1 >100 >100
1
3
Hz, J ) 2.0 Hz). C NMR (90 MHz, DMSO-d
6
a
Plaque reduction assays were performed in duplicate as
1
described in the text. Results are presented as means of 2-5
Cl
2
IN
2
: C, H, N.
b
experiments ( standard deviations. Compounds were assayed
2
,6-Dich lor o-3-(2,3-d id eoxy-2,3-d id eh yd r o-â-D/L-er yth -
c
by ELISA in quadruplicate wells. Visual cytotoxicity was scored
r ofu r a n osyl)im id a zo[1,2-a ]p yr id in e (8) a n d 2,6-Di-
ch lor o-(2,3-dideoxy-3,4-dideh ydr o-â-D/L-er yth r ofu r an osyl)-
on HFF cells at time of HCMV plaque enumeration. Inhibition of
KB cell growth was determined as described in the text in
d
im id a zo[1,2-a ]p yr id in e (9). P r oced u r e A: Pd(OAc)
2
(85 mg,
quadruplicate assays. >100 indicates IC50 greater than the noted
e
0.38 mmol) and Ph As (0.24 g, 0.77 mmol) were placed in a
3
(
highest) concentration tested. Data for TCRB published previ-
f
flame-dried flask under argon. Dry DMF (7 mL) was added
and the solution stirred at room temperature for 1 h. 2,6-
Dichloro-3-iodoimidazo[1,2-a]pyridine (7, 0.5 g, 1.6 mmol) was
then added to the reaction mixture, followed by the addition
of Et N (1 mL, 6.4 mmol) and 2,3-dihydrofuran (0.6 mL, 8
3
mmol). The reaction mixture was stirred under argon over-
night, EtOAc (30 mL) was added, and the resulting slurry was
ously as compound 9 in ref 6. Average ( standard deviation from
08, 33, and 3 experiments, respectively.
1
pyridine (21), respectively. The absolute configuration
as well as the anomeric configuration of these com-
pounds were determined through X-ray crystallography
of the acetonide-protected intermediate 18 (Figure 2).
Biologica l Eva lu a tion . The new C-nucleosides were
evaluated for activity against two selected herpes
viruses and for cytotoxicity. The racemic 2,6-dichloro-
-(â-D/L-erythrofuranosyl)imidazo[1,2-a]pyridine (10) and
,6-dichloro-3-(R-D/L-erythrofuranosyl)imidazo[1,2-a]-
pyridine (11) were both inactive against HCMV and
HSV-1 and not cytotoxic in uninfected cells (Table 2).
In contrast, the enantiomeric mixture of 2,6,7-trichloro-
2
filtered through SiO (30 g). The silica pad was washed with
EtOAc (100 mL), and the organic phase was concentrated to
dryness. The resulting solid was purified by flash column
chromatography (EtOAc/hexane 1:5, 15 cm × 2 cm). The
fractions containing each product (as determined by UV
absorbance) were pooled, concentrated to dryness under
3
2
reduced pressure, and recrystallized from a H O/MeOH mix-
2
ture to give 219 mg (55%) of 8 as a white crystalline solid and
1
40 mg (35%) of 9 as a white crystalline solid.
P r oced u r e B: Same as procedure A except that 2 equiv of
Ag
as the heterocycle 7. Following the addition of Et
dihydrofuran, the reaction mixture was heated at 45 °C for
8 h. The reaction mixture was worked up as described for
procedure A to give an 80% yield of 8 after recrystallization.
2
CO
3
were added to the reaction mixture at the same time
3
-(R-D/L-erythrofuranosyl)imidazo[1,2-a]pyridine (15a )
3
N and
was active against both HCMV and HSV-1. Surpris-
ingly, the R-anomers (15a ) were more active than the
â-anomers (15b). These results are in direct contrast
to the activity of TCRB6 and its erythrofuranosyl
4
1
f
8: mp 95-96 °C; R 0.21 (EtOAc/hexane 1:5); H NMR (300

Erythrofuranosyl Imidazo[1,2-a]pyridine C-Nucleosides
MHz, CDCl
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 8 1453
3
):δ 7.99 (dd, 1H, J ) 0.8 Hz, J ) 1.5 Hz), 7.46
obtained (163 mg, 98%) as a white crystalline solid. 14: mp
1
(
)
(
dd, 1H, J ) 0.8 Hz, J ) 9.5 Hz), 7.19 (dd, 1H, J ) 1.5 Hz, J
134-135 °C; R
f
0.21 (EtOAc/hexane 1:10); H NMR (300 MHz,
1
9.5 Hz), 6.29 (m, 2H), 5.92 (m, 1H), 4.90 (m, 2H). H NMR
):δ 8.34 (d, 1H, J ) 1.9 Hz), 7.65 (d, 1H,
CDCl
3
): δ 8.10 (d, 1H, J ) 0.6 Hz), 7.66 (d, 1H, 0.6 Hz), 6.32
(m, 1H), 6.27 (m, 1H), 5.94 (m, 1H), 4.9 (m, 2H); C NMR (90
1
3
360 MHz, DMSO-d
6
J ) 9.5 Hz), 7.46 (dd, 1H, J ) 1.9 Hz, J ) 9.5 Hz), 6.40 (m,
MHz, CDCl3): δ 142.59, 136.52, 131.46, 130.31, 125.78, 123.76,
1
H), 6.28 (m, 1H), 6.07 (m, 1H), 4.86 (m, 1H), 4.70 (m, 1H).
7
120.58, 117.2, 116.99, 78.53, 75.86. Anal. Calcd for C11H -
1
3
1
C NMR (90 MHz, DMSO-d
26.82; 125.14; 122.61; 120.32; 117.78; 117.71; 77.27; 75.34.
Cl O 254.0013, found 254.0002.
O: C, H, N. 9: mp 109-110 °C; R
): δ
6
): δ 141.41; 134.06; 130.00;
Cl
3
N
2
O‚ /
4 2
H O: C, H, N.
1
2
,6,7-Tr ich lor o-3-(â-D/L-er yth r ofu r a n osyl)im id a zo[1,2-
HRMS m/z calcd for C11
Anal. Calcd for C11 Cl
0
8
1
9
H
8
2 2
N
a ]p yr id in e (15b) a n d 2,6,7-Tr ich lor o-3-(r-D/L-er yth r o-
fu r an osyl)im idazo[1,2-a ]pyr idin e (15a). Compound 14 (1.18
g, 4.1 mmol) was added in one portion to a solution of water
H
8
2
N
2
1
f
.29 (EtOAc/hexane 1:5); H NMR (300 MHz, DMSO-d
6
.21 (d, 1H, J ) 1.9 Hz), 7.65 (d, 1H, J ) 9.6 Hz), 7.45 (dd,
H, J ) 9.6 Hz, J ) 1.9 Hz), 6.68 (d, 1H), 6.01 (dd, 1H, J )
.4 Hz, J ) 11.8 Hz), 5.26 (m, 1H), 2.95 (m, 2H). 13C NMR (90
(30 mL) and tert-butyl alcohol (30 mL) and stirred until mostly
dissolved. The solution was cooled in an ice bath while AD-
mix R (9.27 g) and methanesulfonamide (0.40 g, 4.2 mmol)
were added with vigorous stirring. The resulting two-phase
suspension was stirred vigorously at 4 °C for 36 h. The reaction
was quenched by adding sodium bisulfite until the yellow color
of the suspension disappeared. The reaction was then diluted
with water (100 mL) and extracted with EtOAc (3 × 100 mL).
The combined organic extracts were washed with brine (50
mL), dried over magnesium sulfate, filtered, and evaporated
to dryness under reduced pressure to give 1.28 g of 15a and
15b as a cream-colored powder (97%). Analytical samples of
15a and 15b were prepared by purifying a portion of the crude
material by flash chromatography (EtOAc/hexane 2:1). 15b:
mp 190-192 °C; R 0.11 (4% MeOH in CHCl ); R 0.41 (EtOAc/
MHz, DMSO-d
1
6
): δ 145.334; 141.338; 128.597; 126.648; 122.738;
20.388; 118.536; 117.425; 99.951; 71.876; 31.750. HRMS m/z
calcd for C11
for C11 Cl
H
N
8
Cl
2 2
N O 254.0013, found 254.0002. Anal. Calcd
H
8
2
2
O: C, H, N.
2
,6-Dich lor o-3-(â-D/L-er yth r ofu r a n osyl)im id a zo[1,2-a ]-
p yr id in e (10) a n d 2,6-Dich lor o-3-(r-D/L-er yth r ofu r a n o-
syl)im id a zo[1,2-a ]p yr id in e (11). Compound 8 (260 mg, 1
mmol) was added to a solution of acetone (8 mL) and water (3
mL) containing N-methylmorpholine N-oxide (158 mg, 1.4
mmol) and osmium tetroxide (2.5 mg, 0.01 mmol). The mixture
was stirred at room temperature for 12 h. Sodium sulfite (1 g)
was added and the mixture stirred for an additional 1 h and
then partitioned between EtOAc (50 mL) and water (50 mL).
The organic phase was separated and the aqueous phase
extracted with EtOAc (3 × 50 mL). The combined organic
extracts were subsequently washed with 2 N NaOH (20 mL),
dried over magnesium sulfate, filtered, and evaporated to
dryness under reduced pressure to give a yellowish residue.
This residue was purified by flash chromatography (EtOAc/
f
3
f
1
hexane 2:1); H NMR (360 MHz, DMSO-d ):δ 8.69 (s, 1H), 8.06
6
(s, 1H), 5.18 (d, 1H, J ) 6.8 Hz, D O exchangeable), 5.11 (d,
2
1H, J ) 3.8 Hz, D O exchangeable), 5.04 (d, 1H, J ) 8.9 Hz,
2
1′-H), 4.42 (m, 1H), 4.33 (dd, 1H, J ) 9.5 Hz, J ) 4.3 Hz), 4.2
(m, 1H), 3.75 (dd, 1H, J ) 9.5 Hz, J ) 1.6 Hz); 13C NMR (90
MHz, DMSO-d ): δ 141.48, 135.42, 129.47, 124.79, 118.99,
6
117.40, 116.58, 73.73, 73.40, 72.64, 70.26; UV λmax (ethanol)
325 (3103), 296 (3000), 287 (3008), 237 (19676); (pH 11) 320
(1000), 295 (2697), 243 (22889); (pH 1) 297 (3553), 237 (18940).
HRMS m/z calcd for C H Cl N O 321.9679, found 321.9683.
hexane 2:1, 15 cm × 2 cm) to give in order of elution 10 (R
f
0
.43 EtOAc/hexane 2:1) and 11 (R 0.38 EtOAc/hexane 2:1).
f
Appropriate fractions were combined, solvent removed under
reduced pressure and each solid recrystallized from aqueous
methanol to give 66 mg (23%) of 11 and 135 mg (47%) of 10.
1
1
10
3
2
3
15a : mp 224 °C (dec); R 0.18 (4% MeOH in CHCl ); R 0.45
f
3
f
1
(EtOAc/hexane 2:1); H NMR (360 MHz, DMSO-d ):δ 9.03 (s,
6
1
1
1: mp 183 °C; R
MHz, DMSO-d
.6 Hz), 7.40 (dd, 1H, J ) 9.6 Hz, J ) 2.0 Hz), 5.40 (d, 1H, J
4.2 Hz, D O exchangeable), 5.26 (m, 2H, simplifies to d, 1H,
J ) 4.3 Hz upon D O wash), 4.40 (t, 1H, J ) 5.3 Hz), 4.26 (m,
H), 3.82 (q, 1H), 3.89 (q, 1H); C NMR (90 MHz, DMSO-d
δ 141.44, 134.85, 126.60, 123.36, 120.22, 117.37, 117.11, 73.65,
3.44, 72.32, 70.28; UV λmax (ethanol) 291 (4162), 233 (19596);
pH 11) 289 (4458), 233 (26566); (pH 1) 288 (6416), 226 (26295);
HRMS m/z calcd for C11 288.0068, found 288.0079.
Anal. Calcd for C11 : C, H, N. 10: mp 180-181 °C;
0.38 (EtOAc/hexane 2:1); H NMR (360 MHz, DMSO-d ): δ
.49 (d, 1H, J ) 2.0 Hz), 7.64 (d, 1H, J ) 9.6 Hz), 7.45 (dd,
H, J ) 9.6 Hz, J ) 2.0 Hz), 5.19 (d, 1H, J ) 6.3 Hz, D
O exchangeable), 5.03 (d,
H, J ) 9.03 Hz), 4.43 (m, 1H), 4.32 (m, 1H), 4.20 (m, 1H),
f
0.43 (EtOAc/hexane 2:1); H NMR (360
1H), 8.00 (s, 1H), 5.40 (d, 1H, J ) 4.5 Hz, D O exchangeable),
2
6
): δ 8.83 (d, 1H, J ) 2.0 Hz), 7.58 (d, 1H, J )
5.31 (d, 1H, J ) 5.5 Hz, D O exchangeable), 5.24 (d, 1H, J )
2
1
3
9
)
4.8 Hz, 1′-H), 4.39 (m, 1H), 4.28 (m, 1H), 3.84 (m, 2H);
C
2
NMR (90 MHz, DMSO-d ): δ 141.82, 134.87, 129.39, 127.08,
6
2
117.59, 116.74, 115.93, 75.49, 73.79, 71.07, 71.02; UV λmax
(ethanol) 320 (1040), 296 (1080), 285 (1012), 235 (14600); (pH
11) 320 (3700), 296 (4100), 243 (29600); (pH 1) 297 (5500), 236
(24691); HRMS m/z calcd for C H Cl N O 321.9679, found
1
3
1
6
):
7
(
1
1
10
3
2
3
321.9694.
,6,7-Tr ich lor o-3-(2,3-O-isop r op ylid en e-â-D/L-er yth r o-
fu r an osyl)im idazo[1,2-a ]pyr idin e (17) an d 2,6,7-Tr ich lor o-
-(2,3-O-isop r op ylid en e-r-D/L-er yth r ofu r a n osyl)im id a zo-
1,2-a ]p yr id in e (16). The crude compound 15 (1.08 g, 3.3
H
2 2 3
10Cl N O
2
H
2 2 3
10Cl N O
1
R
8
1
f
6
3
[
2
O
mmol) and p-toluenesulfonic acid hydrate (20 mg, 0.1 mmol)
were suspended in a mixture of 10 mL of dry acetone and 10
mL of 2,2-dimethoxypropane and stirred at room temperature
until completely dissolved. The solvent was removed under
reduced pressure, and the resulting viscous residue was
dissolved in EtOAc (100 mL). The organic phase was washed
exchangeable), 5.11 (broad s, 1H, D
2
1
3
1
7
1
3
.75 (m, 1H); C NMR (90 MHz, DMSO-d ): δ 141.79, 134.14,
26.50, 125.85, 118.77, 116.68, 116.56, 75.74, 73.83, 71.10,
0.96; UV λmax (ethanol) 291 (3740), 234 (25960); (pH 11) 288
4339), 233 (27841); (pH 1) 287 (7748), 227 (28099); HRMS
6
(
2 3
with 5% aqueous Na CO then brine, dried over magnesium
m/z calcd for C11
Calcd for C11
-Iod o-2,6,7-tr ich lor oim id a zo[1,2-a ]p yr id in e (13). Fol-
H
10Cl
2
N
2
O
3
288.0068, found 288.0065. Anal.
sulfate, filtered, and evaporated to dryness under reduced
pressure to give a clear oil which solidified upon standing. This
solid was purified by flash chromatography (hexane/EtOAc 3:1,
H
10Cl
N O : C, H, N.
2 2 3
3
lowing the preparation of 7, compound 12 (1.7 g, 7.7 mmol)
was treated with NIS to give 2.2 g (82%) of 13 as a white
4
5 cm × 5 cm) to give, in order of elution, 17 (R
f
) 0.33, 3:1
hexane:EtOAc) and 16 (R ) 0.20, 3:1 hexane:EtOAc). Ap-
f
crystalline solid: mp 215-216 °C; R
f
0.54 (EtOAc/hexane 1:2);
): δ 8.62 (s, 1H), 7.69 (s, 1H);
) δ 8.20 (d, 1H, J ) 0.5 Hz), 7.69 (d,
H, J ) 0.5 Hz); C NMR (90 MHz, DMSO-d ): δ 144.08,
41.85, 130.14, 126.64, 119.98, 116.49, 66.67; HRMS m/z calcd
Cl IN 345.8329, found 345.8332. Anal. Calcd for C
: C, H, N.
,6,7-Tr ich lor o-3-(2,3-dideoxy-2,3-dideh ydr o-â-D/L-er yth -
propriate fractions were combined, and the solvent was
removed under reduced pressure to give 0.60 g of 17 and 0.51
g of 16 (92% combined yield) as a cream-colored powder. 17:
1
H NMR (360 MHz, DMSO-d
6
1
H NMR (360 MHz, CDCl
3
1
3
1
1
6
1
mp 178-181 °C; R
MHz, CDCl ): δ 8.87 (s, 1H), 7.60 (s, 1H), 4.98 (s, 1H), 4.93 (s,
H), 4.87 (s, 1H), 4.31 (d, 1H, J ) 10 Hz), 3.70 (d, 1H, J ) 10
f
0.33 (hexane:EtOAc 3:1); H NMR (500
3
for C
7
H
2
3
2
7 2
H -
1
Cl
3
IN
2
13
Hz), 1.53 (s, 3H), 1.30 (s, 3H); C NMR (125 MHz, CDCl
3
): δ
2
142.93, 135.80, 131.42, 127.23, 119.23, 116.31, 113.80, 112.55,
r ofu r a n osyl)im id a zo[1,2-a ]p yr id in e (14). Following the
preparation of 8, compound 13 (200 mg, 0.58 mmol) was
treated according to procedure B, described above, and 14 was
82.48, 80.64, 73.07, 25.89, 23.63. HRMS m/z calcd for C14
H
H
13
13
-
-
Cl
Cl
3
N
N
2
O
O
3
361.9992, found 361.9979. Anal. Calcd for C14
: C, H, N. 16: mp 174-175°C; R
3
2
3
f
0.20 (hexane:EtOAc

1
454 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 8
Gudmundsson et al.
1
3
5
)
:1); H NMR (500 MHz, CDCl
3
): δ 8.36 (s, 1H), 7.67 (s, 1H),
were enumerated under 20-fold magnification in wells having
the dilution which gave 5 to 20 plaques per well. Virus titers
were calculated according to the following formula: Titer (pfu/
.59 (dd, 1H, J ) 6 Hz, J ) 2 Hz), 5.33 (s, 1H), 5.06 (t, 1H, J
5 Hz), 4.03 (d, 1H, J ) 9 Hz), 3.74 (dd, 1H, J ) 4 Hz, J ) 11
1
3
n
Hz), 1.60 (s, 3H), 1.42 (s, 3H); C NMR (125 MHz, CDCl
3
): δ
mL) ) number of plaques x 5 × 3 ; where n represents the
1
8
Cl
Cl
42.47, 135.43, 132.23, 123.46, 121.42, 116.59, 115.66, 113.50,
1.95, 81.26, 73.04, 26.77, 25.12. HRMS m/z calcd for C14
nth dilution of the virus used to infect the well in which
plaques were enumerated.
H
H
13
13
-
-
3
N
N
2
O
O
3
361.9992, found 361.9984. Anal. Calcd for C14
: C, H, N.
HCMV P la qu e Red u ction Assa y. HFF cells in 24-well
cluster dishes were infected with approximately 100 pfu of
3
2
3
2
2
,6,7-Tr ich lor o-3-(2,3-O-isop r op ylid en e-r-D-er yt h r o-
HCMV per cm cell sheet using the procedures detailed above.
fu r an osyl)im idazo[1,2-a ]pyr idin e (18) an d 2,6,7-Tr ich lor o-
-(2,3-O-isop r op ylid en e-r-L-er yt h r ofu r a n osyl)im id a zo-
1,2-a ]p yr id in e (19). Compound 16 (1.00 g, 2.8 mmol) was
Following virus adsorption, compounds dissolved in growth
medium were added to duplicate wells in four to eight selected
concentrations. After incubation at 37 °C for 7 days, cell sheets
were fixed, stained with crystal violet and microscopic plaques
enumerated as described above. Drug effects were calculated
as a percentage of reduction in number of plaques in the
presence of each drug concentration compared to the number
observed in the absence of drug.
3
[
submitted to Chiral Technologies, Inc. of Exton, PA for chiral
resolution. The sample was subjected to chiral HPLC (CHIRAL-
PAK AD, 50 cm × 5 cm, 89.95:10:0.05 acetonitrile:2-propanol:
diethylamine) to give, in order of elution, compound 18 (3.65
2
min, 1.0 mL/min., 21 kg/cm ) in 99% ee and compound 19 (5.22
2
40
min, 1.0 mL/min., 21 kg/cm ) in 98% ee. Appropriate fractions
HSV-1 ELISA. An ELISA was employed to detect HSV-
were combined, and the solvent removed under reduced
pressure to give 0.61 g (61%) of 18 as a white powder and 0.34
1. Ninety-six-well cluster dishes were planted with 10000
BSC-1 cells per well in 200 µL per well of MEM(E) plus 10%
calf serum. After overnight incubation at 37 °C, selected drug
concentrations in quadruplicate and HSV-1 at a concentration
of 100 pfu/well were added. Following a 3-day incubation at
37 °C, medium was removed, plates were blocked and rinsed,
and horseradish peroxidase conjugated rabbit anti-HSV-1
antibody was added. Following removal of the antibody
containing solution, plates were rinsed and then developed by
adding 150 µL per well of a solution of tetramethylbenzidine
g (34%) of 19 as a white powder. 18: mp 174-175 °C; R
f
0.20
(
hexane:EtOAc 3:1); spectroscopic data matches that for
f
compound 16. 19: mp 174-175 °C; R 0.20 (hexane:EtOAc 3:1);
spectroscopic data matches that for compound 16.
2
,6,7-Tr ich lor o-3-(r-D-er yth r ofu r a n osyl)im id a zo[1,2-a ]-
p yr id in e (20). Compound 18 (209 mg, 0.57 mmol) was
suspended in 10 mL of 90% TFA/water and stirred at room
temperature for 10 min. The solvent was then removed under
vacuum, and the resulting residue was suspended in 30 mL
of 5% sodium carbonate. The aqueous suspension was ex-
tracted with EtOAc (2 × 25 mL). The organic extract was then
washed with brine (25 mL), dried over magnesium sulfate, and
evaporated to yield a pale yellow powder. This residue was
purified by flash chromatography (4:1 EtOAc:hexane, 35 cm
2 4
as substrate. The reaction was stopped with H SO and
absorbance was read at 450 and 570 nm. Drug effects were
calculated as a percentage of the reduction in absorbance in
the presence of each drug concentration compared to absorb-
ance obtained with virus in the absence of drug.
Cytotoxicity Assa ys. Two different assays were used for
routine cytotoxicity testing. (i) Cytotoxicity produced in sta-
tionary HFF cells was determined by microscopic inspection
×
4 cm). The fractions containing the product were pooled and
concentrated to dryness under reduced pressure to give 76 mg
of 20 (41%) as a white powder: mp 212-215 °C; R 0.45
EtOAc/hexane 2:1); spectroscopic data matches that found
3 2 3
for compound 15a , except: Anal. Calcd for C11 Cl N O ‚
3
8
of cells not affected by the virus used in plaque assays. (ii)
The effect of compounds during two population doublings of
KB cells was determined by crystal violet staining and
spectrophotometric quantitation of dye eluted from stained
cells as described earlier.41 Briefly, 96-well cluster dishes were
planted with KB cells at 3000-5000 cells per well. After
overnight incubation at 37 °C, test compound was added in
quadruplicate at six to eight concentrations. Plates were
f
(
H
9
1
/
5
EtOAc: C, H, N.
2
,6,7-Tr ich lor o-3-(r-L-er yth r ofu r a n osyl)im id a zo[1,2-a ]-
p yr id in e (21). Following the preparation of compound 20,
compound 19 (112 mg, 0.31 mmol) was treated with 90% TFA/
water to yield 52 mg (53%) of 21 as a white powder: mp 213-
2
incubated at 37 °C for 48 h in a CO incubator, rinsed, fixed
2
f
16 °C; R 0.45 (EtOAc/hexane 2:1); spectroscopic data matches
with 95% ethanol, and stained with 0.1% crystal violet.
Acidified ethanol was added and plates read at 570 nm in a
spectrophotometer designed to read 96-well ELISA assay
plates.
Da ta An a lysis. Dose-response relationships were used to
quantitate drug effects by linearly regressing the percent
inhibition of parameters derived in the preceding assays
against log drug concentrations. Fifty percent inhibitory
concentrations (IC50’s) were calculated from the linear portions
of the regression lines. Samples containing positive controls
that found for compound 15a .
Biologica l Eva lu a tion . Cell Cu ltu r e P r oced u r es. The
routine growth and passage of KB, BSC-1, and HFF cells was
performed in monolayer cultures using minimal essential
medium (MEM) with either Hanks salts [MEM(H)] or Earle
salts [MEM(E)] supplemented with 10% calf serum or 10%
fetal bovine serum (HFF cells). The sodium bicarbonate
concentration was varied to meet the buffering capacity
required. Cells were passaged at 1:2 to 1:10 dilutions according
to conventional procedures by using 0.05% trypsin plus 0.02%
(
acyclovir for HSV-1, ganciclovir for HCMV, and 2-acetyl-
3
7
EDTA in a HEPES buffered salt solution.
Vir ologica l P r oced u r es. The Towne strain, plaque-puri-
fied isolate P , of HCMV was kindly provided by Dr. Mark
pyridine thiosemicarbazone for cytotoxicity) were used in all
assays.
o
Stinski, University of Iowa. The KOS strain of HSV-1 was used
in most experiments and was provided by Dr. Sandra K.
Weller, University of Connecticut. Stock HCMV was prepared
by infecting HFF cells at a multiplicity of infection (moi) of
Ack n ow led gm en t. We thank J ulie M. Breitenbach,
Kathy Z. Borysko, and Roger G. Ptak for expert perfor-
mance of antiviral and cytotoxicity assays. These studies
were supported by research grants U19-AI31718 and
5-P01-AI46390 from the National Institute of Allergy
and Infectious Diseases, and by Training Grant T32-
GM07767 from the National Institutes of Health.
<
0.01 plaque-forming units (pfu) per cell as detailed previ-
3
8
ously. High titer HSV-1 stocks were prepared by infecting
3
8
KB cells at an moi of <0.1 also as detailed previously. Virus
titers were determined using monolayer cultures of HFF cells
for HCMV and monolayer cultures of BSC-1 cells for HSV-1
3
9
as described earlier. Briefly, HFF or BSC-1 cells were planted
as described above in 96-well cluster dishes and incubated
overnight at 37° C. The next day cultures were inoculated with
HCMV or HSV-1 and serially diluted 1:3 across the remaining
eleven columns of the 96-well plate. After virus adsorption the
inoculum was replaced with fresh medium and cultures were
incubated for 7 days for HCMV, 2 or 3 days for HSV-1. Plaques
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