Synthesis of the First C3 Ribosylated Imidazo[1,2-a]pyridine C-Nucleoside by Enantioselective Construction of the Ribose Moiety

Article abstract of DOI:10.1021/jo9711145

The metabolic instability of the glycosidic linkage in 2,5,6-trichloro-1-(β-D-ribofuranosyl)benzimidazole prompted us to synthesize the structurally related C-nucleoside 2,6,7-trichloro-3-(β-D-ribofuranosyl)imidazor[1,2-α]pyridine. Synthesis of this first C3-ribofuranosylimidazo[1,2-a]pyridine was accomplished by developing a modification of existing iodocyclization methodology for obtaining a 1′,4′-syn furanosyl precursor, without an extensive protection scheme. This 1′,4′-syn precursor was elaborated into the desired ribofuranosyl C-nucleoside. X-ray crystallography was used to unambiguously determine structure and absolute stereochemistry of this C-nucleoside.

Full text of DOI:10.1021/jo9711145

984
J . Org. Chem. 1998, 63, 984-989
Syn th esis of th e F ir st C3 Ribosyla ted Im id a zo[1,2-a ]p yr id in e
C-Nu cleosid e by En a n tioselective Con str u ction of th e Ribose
Moiety
Kristjan S. Gudmundsson, 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 49019-1065
Received J une 19, 1997X
The metabolic instability of the glycosidic linkage in 2,5,6-trichloro-1-(â-D-ribofuranosyl)benzimi-
dazole prompted us to synthesize the structurally related C-nucleoside 2,6,7-trichloro-3-(â-D-
ribofuranosyl)imidazo[1,2-a]pyridine. Synthesis of this first C3-ribofuranosylimidazo[1,2-a]pyridine
was accomplished by developing a modification of existing iodocyclization methodology for obtaining
a 1′,4′-syn furanosyl precursor, without an extensive protection scheme. This 1′,4′-syn precursor
was elaborated into the desired ribofuranosyl C-nucleoside. X-ray crystallography was used to
unambiguously determine structure and absolute stereochemistry of this C-nucleoside.
In tr od u ction
2,5,6-Trichloro-1-(â-D-ribofuranosyl)benzimidazole (1),1
shows potent activity against human cytomegalovirus2
with low cellular toxicity at concentrations inhibiting
viral growth. However, pharmacokinetic studies of 1 in
rats and monkeys3 revealed that 1 disappears rapidly
from the bloodstream following either intravenous or oral
dosage. The disappearance of 1 was correlated with an
increased blood concentration of 2,5,6-trichlorobenzimi-
dazole (2) and would suggest that the glycosidic bond in
1 (aminal linkage) is unstable in vivo. This instability
of the glycosidic bond prompted us to initiate studies on
the synthesis of a C-nucleoside analogue of 1, since a
C-glycosidic bond would be more stable in vivo.4 On the
basis of computer (molecular) modeling studies involving
the structural correlation of the exocyclic groups, we
elected to synthesize 2,6,7-trichloro-3-(â-D-ribofuranosyl)-
imidazo[1,2-a]pyridine (3) due to the very close structural
resemblance of 3 to 1. In addition, several C-nucleosides,
both naturally occurring and synthetic, have exhibited
significant antibacterial, antiviral, and antitumor activi-
ties.5 Some of these biological activities have been
F igu r e 1. TCRB (1) is metabolically unstable in vivo and is
cleaved at the glycosidic bond to give the aglycon 2. The
imidazo[1,2-a]pyridine C-nucleoside 3 has a C-glycosidic bond
that should be more stable in vivo.
postulated to depend on the resistance of the C-C
linkage to hydrolytic or enzymatic cleavage.4
Resu lts a n d Discu ssion
X Abstract published in Advance ACS Abstracts, December 15, 1997.
(1) (a) Revankar, G. R.; Townsend, L. B. Chem. Rev. (Washington,
D.C.) 1970, 70, 389-438. (b) Revankar, G. R.; Townsend, L. B. J .
Heterocycl. Chem. 1968, 5, 477-483. (c) Townsend, L. B.; Devivar, R.
V.; Turk, S. R.; Nassiri, M. R.; Drach, J . C. J . Med. Chem. 1995, 38,
4098-4105. (d) Gudmundsson, K. S.; Drach, J . C.; Wotring, L. L.;
Townsend, L. B. J . Med. Chem. 1997, 40, 785-793.
(2) (a) Underwood, M. R.; Biron, K. K.; Hemphill, M. L.; Miller, T.
J .; Stanat, S. C.; Drach, J . C.; Townsend, L. B.; Harvey, R. J . The
Benzimidazole Riboside, 2-Bromo-1-â-D-ribofuranosyl Benzimidazole
(BDCRB) Prevents Maturation of Concatemeric Viral DNA in HCMV-
Infected Cells, 4th International CMV Conference, Institute Pasteur,
Paris, France, April 1993. (b) Underwood, M. R.; Stanat, S. C.; Drach,
J . C.; Harvey, R. J .; Biron, K. K. Inhibition of HCMV DNA Processing
by a new class of Anti-HCMV Compounds is Mediated through the
UL89 Gene Product, abstract 309, Herpesvirus Workshop, Vancouver,
B. C., August 1994. (c) Underwood, M. R.; Stanat, S. C.; Townsend, L.
B.; Drach, J . C.; Biron, K. K. Inhibition of HCMV DNA Processing by
a New Class of Anti-HCMV Compounds (Benzimidazole Ribosides) is
Mediated through the UL89 Gene Product, abstract 132, 8th Inter-
national Conference on Antiviral Research, Santa Fe, NM, April 1995.
(3) Good, S. S.; Owens, B. S.; Townsend, L. B.; Drach, J . C. Presented
at the 7th International Conference on Antiviral Research, abstract
128, Charleston, SC, March 1994.
This synthesis presented a significant challenge since
we had previously explored several unsuccessful routes
toward the synthesis of 3. Our initial attempts involved
the reaction of lithiated imidazo[1,2-a]pyridines with
ribonolactone derivatives which unexpectedly led to
ribosylation at the C-5 position.6 Other approaches
toward obtaining the C 3 ribosylated C-nucleoside 3 by
(5) (a) Hacksell, U.; Daves, G. D., J r. Prog. Med. Chem. 1985, 22,
1-65. (b) Daves, G. D., J r.; Cheng, C. C. Prog. Med. Chem. 1976, 13,
303-349. (c) Watanabe, K. A. In Chemistry of Nucleosides and
Nucleotides; Townsend, L. B., Ed.; Plenum Press: New York, 1994;
Vol. 3, pp 421-535. (d) J aramillo, C.; Knapp, S. Synthesis 1994, 1-20.
(e) Postema, M. H. D. Tetrahedron 1992, 40, 8545-8599. (e) Daves,
G. D., J r. Acc. Chem. Res. 1990, 23, 201-206. (f) Daves, G. D., J r. In
Carbohydrates. Synthetic Methods and Applications in Medicinal
Chemistry; Ogura, H., Hasegawa, A., Suami, T., Eds.; VCH Publish-
ers: New York, 1992; pp 49-65.
(6) (a) Gudmundsson, K. S.; Drach, J . C.; Townsend, L. B. Tetra-
hedron Lett. 1996, 37, 2365-2368. (b) Gudmundsson, K. S.; Drach, J .
C.; Townsend, L. B. J . Org. Chem., in press.
(4) Daves, G. D., J r. Acta Pharm. Suec. 1987, 24, 275-288.
S0022-3263(97)01114-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/03/1998

C3 Ribosylated Imidazo[1.2-a]pyridine C-Nucleoside
J . Org. Chem., Vol. 63, No. 4, 1998 985
Sch em e 1a
F igu r e 2. ORTEP diagram of 3.
a palladium coupling7 of 3-iodoimidazo[1,2-a]pyridines
with ribofuranoid glycals, Lewis acid catalyzed ribosyl-
ations of imidazo[1,2-a]pyridines and attempts to con-
struct the imidazo[1,2-a]pyridine heterocycle onto func-
tionalized ribose derivatives were also unsuccessful.
However, the construction of a ribose ring via an in-
tramolecular iodocyclization process has recently been
employed to prepare a limited number of C-nucleosides
containing phenyl or furan aglycons.8 This led us to
investigate a similar approach for the synthesis of 3. We
now report an enantioselective synthesis of 3 by con-
structing the ribose moiety onto a heterocyclic moiety.
This approach involved a iodocyclization of an unpro-
tected diol intermediate to form 1′,4′-syn substituted
furanose derivatives.
a
Reagents and conditions: (a) n-BuLi (1.1 equiv), THF, 0 °C,
10 min; 5 (1 equiv) in THF, 0 °C, 1 h, 75%; (b) PPTS in MeOH-
H2O, 25 °C, 95%; (c) TBDPSCl (1.2 equiv), DMAP (0.2 equiv),
pyridine-CH2Cl2, 25 °C, 87%; (d) TESOTf (1.3 equiv), 2,6-lutidine
(1.3 equiv), CH2Cl2, 0 °C; (e) the TES-derivative added to a solution
of I2 (5-10 equiv) and K2CO3 (2 equiv), 25 °C, yield 20% of 8:9 in
1:2 ratio (addition of t-BuOH and Et3N to the reaction mixture as
described in ref 8 did not improve yield or syn selectivity); (f) see
Table 1.
Since 2,6-dichloro-3-formylimidazo[1,2-a]pyridine (5)9
was easier to synthesize than 3-formyl-2,6,7-trichloroimi-
dazo[1,2-a]pyridine,9 we elected to conduct our initial
studies on 5 and racemic 3,4-O-isopropylidene-3,4-hy-
droxybut-1-yl triphenyl phosphonium iodide (4).10 Wittig
olefination of 4 in THF at 0 °C gave, after deprotection
with pyridinium p-toluenesulfonate in aqueous methanol,
2,6-dichloro-3-(1,2-dihydroxy-pent-4(E)-en-5-yl)imidazo-
[1,2-a]pyridine (6) as the only isomer. Treatment of 6
with TBDPSCl in a pyridine-CH2Cl2 mixture in the
presence of a catalytic amount of DMAP gave 2,6-
dichloro-3-(1-O-(tert-butyldiphenylsilyl)-1,2-dihydroxypent-
4(E)-en-5-yl)imidazo[1,2-a]pyridine (7). Compound 7 was
treated with TESOTf and 2,6-lutidine in CH2Cl2, and this
diprotected derivative was subjected to the conditions of
iodocyclization as described in the literature.8 However,
these conditions provided 8 and 9 in a combined yield
less than 20% with the desired 1′,4′-syn derivative 8
being present in a lower yield than the 1′,4′-anti deriva-
tive 9.11 Repeated attempts to iodocyclize derivatives of
6 with other primary and secondary protecting groups
(reported to direct iodocyclization of other diprotected
pent-4-ene-1,2-diols to give 1′,4′-syn derivatives in higher
yield than the corresponding 1′,4′-anti derivatives8) failed
to improve the yield or selectivity for formation of the
desired 1′,4′-syn derivative 8.
However, we subsequently found that iodocyclization
of the unprotected diol 6 proceeded in better yield and
selectivity. In all cases, using 6 as substrate, a third
product was isolated and characterized by 1H NMR, mass
spectral, and analytical data as being the pyranose
product 12. As shown in Table 1, product ratios were
highly dependent on reaction conditions, e.g. iodocycliza-
tion of the diol 6 in the presence of base (entries 1-3)
gave consistently the anti product 11 in a 2-3-fold excess
over the syn product 10. The highest yield of the syn
(7) For synthesis of the related imidazo[1,2-a]pyridine erythrofura-
nosyl C-nucleosides see: Gudmundsson, K. S.; Drach, J . C.; Townsend,
L. B. Tetrahedron Lett. 1996, 37, 6275-6278.
(8) (a) Kang, S. H.; Hwang, T. S.; Lim, J . K.; Kim, W. J . Bull. Korean
Chem. Soc. 1990, 11, 455-460. (b) Kang, S. H.; Hwang, T. S.; Kim, W.
J .; Lim, J . K. Tetrahedron Lett. 1990, 31, 5917-5920. (c) Kang S. H.;
Lee S. B. Tetrahedron Lett. 1993, 34, 1955-1958. (d) Kang S. H.; Lee
S. B. Tetrahedron Lett. 1993, 34, 7579-7582. (e) Kang, S. H.; Hwang,
T. S.; Kim, W. J .; Lim, J . K. Tetrahedron Lett. 1991, 32, 4015-4018.
(f) Kang S. H.; Lee S. B. Tetrahedron Lett. 1995, 36, 4089-4092. (g)
Kang S. H.; Lee S. B. J . Chem. Soc., Chem. Commun. 1995, 1017-
1018.
(9) (a) Kazunari, O.; Yasuo, I.; Harutoshi, Y. European Patent 0 383
319 A2, 1990. (b) Ishida, Y.; Ohta, K.; Nakahama, T.; Yoshikawa, H.
European Patent 0 238 070 A2, 1987.
(10) (a) Meyers, A. I.; Lawson, J . P. Tetrahedron Lett. 1982, 23,
4883-4886. (b) Hayashi, H.; Nakanishi, K.; Brandon, C.; Marmur, J .
J . Am. Chem. Soc. 1973, 95, 8749-8757. (c) Reference 8a.
(11) Assignment of 8 as the syn derivative and 9 as the anti
derivative was based on NOE experiments, where an NOE (2.2%) was
observed between the 1′ and the 4′-H for 8. Such an NOE was not
observed for compound 9.

986 J . Org. Chem., Vol. 63, No. 4, 1998
Gudmundsson et al.
Sch em e 2a
Ta ble 1. Selected Con d ition s for th e Iod ocycliza tion of
Un p r otected Diol 6
methoda
(temp)
product ratio
10:11:12
combined
yield (%)
entry
solvent
1
2
3
4
5
6
CH2Cl2
THF
CH3CN
CH2Cl2
THF
A (25 °C)
A (25 °C)
A (25 °C)
B (25 °C)
B (25 °C)
B (25 °C)
25:71:14
30:54:16
24:51:25
25:71:4
57:18:25
51:21:28
82
94
88
75
91
80
CH3CN
a
Method A: The diol 6 was dissolved in the specified solvent
and added to a solution of 5-10 equiv of I2 and 2 equiv of K2CO3.
Whether 6 was added to the I2 and K2CO3 solution or the I2 added
to a solution of 6 and K2CO3 did not affect the yield of the
lactonization. Method B: Same as method A except K2CO3 was
not initially added to the I2 solution. Two equivalents of K2CO3
were added in two portions, 30 min and 60 min after the addition
of substrate to the I2 solution.
product 10, using method A, was obtained by iodoetheri-
fication of 6 in THF at rt. Using other solvents or lower
temperatures gave lower yields of 10 and a higher yield
of the anti product 11. The pyranose side product 12 was
obtained in yields ranging from 14 to 25% with the
highest yields of 12 being obtained in CH3CN at rt.
Certain iodolactonization and iodocyclization reac-
tions12 have been reported to give different product ratios
when conducted in the absence of base (K2CO3). In the
presence of base, those reactions are irreversible and are
considered kinetic, whereas in the absence of base these
reactions become reversible and are considered more
thermodynamic in nature. These reports prompted us
to attempt the iodine catalyzed cyclization of 6 in the
absence of K2CO3. We found that the cyclization did not
proceed to completion in the absence of base, but by
adding K2CO3 portionally, at 30 and 60 min after the
addition of iodine to a solution of 6, the reaction went to
completion and the ratio of products 10, 11, and 12 was
different from the ratio obtained by adding iodine to a
solution of 6 containing K2CO3. These conditions (method
B) gave 10 in a 3-fold excess over 11 when the cyclization
was carried out in a polar solvent. Formation of 12 could
not be avoided, as all attempts to protect the primary
hydroxyl group resulted in the formation of 11 in a
greater yield than 10 under the iodocyclization condi-
tions.
Having developed an efficient synthesis for the prepa-
ration of the 1′,4′-syn derivative 10 as the major iodocy-
clization product, we applied this methodology to the
enantioselective preparation of the desired 2,6,7-trichloro-
3-(â-D-ribofuranosyl)imidazo[1,2-a]pyridine (3) from 3,4-
(S)-O-isopropylidene-3,4-dihydroxybut-1-yl triphenylphos-
phonium iodide (13)10 and 3-formyl-2,6,7-trichloroimid-
azo[1,2-a]pyridine (14).9
Wittig olefination of 14 gave, after deprotection, the
diol 2,6,7-trichloro-3-(1,2(S)-dihydroxypent-4(E)en-5-yl)-
imidazo[1,2-a]pyridine (15) in a 63% yield. This diol 15
was treated with iodine in THF and the subsequent
addition of K2CO3 (method B) to give three isomeric
compounds, separable by flash chromatography. Two of
these were identified as the 1′,4′-syn product 2,6,7-
trichloro-3-(2,3-dideoxy-2-iodo-â-D-ribofuranosyl)imidazo-
[1,2-a]pyridine (16) and the 1′,4′-anti product 2,6,7-
a
Reagents and conditions: (a) n-BuLi (1.1 equiv), THF, 0 °C,
10 min; 14 (1 equiv) in THF, 0 °C, 1 h, 70%; (b) PPTS in MeOH-
H2O, 25 °C, 90%; (c) 15 treated as described for method B in Table
1, 16 (45%), 17 (16%), 18 (21%); (d) DBU (5 equiv), DMF, 90 °C,
followed by aqueous workup, 19 (62%), 20 (15%); (e) OsO4, NMO
(1.5 equiv), acetone-H2O 4:1, 25 °C, 95%.
trichloro-3-(2,3-dideoxy-2-iodo-R-D-lyxofuranosyl)imid-
azo[1,2-a]pyridine (17) by a comparison of their spectral
data with the analogous 2,6-dichloroimidazo[1,2-a]pyri-
dine derivatives. The spectral data for the third com-
pound was compared with 12 and assumed to be 2,6,7-
trichloro-3-(2,3-dideoxy-2-iodo-R-D-lyxopyranosyl)imid-
azo[1,2-a]pyridine (18). The structure and absolute
stereochemistry of 18 was unequivocally determined by
X-ray crystallography.13
Treatment of 16 with DBU in DMF at 80 °C for 24 h
gave after aqueous workup the dideoxy-didehydro de-
rivative 19 in 67% yield and a side product in 15% yield.
Structural assignment of the side product was based on
the fact that 13C-spectra showed it contained a carbonyl
1
functionality. The H NMR showed that the resonance
for the C5-H on the imidazo[1,2-a]pyridine heterocycle
was shifted downfield from 9.5 to 10.0 ppm. This
downfield shift of 0.5 ppm is characteristic for imidazo-
[1,2-a]pyridine containing a carbonyl group attached to
(12) (a) Bartlett, P. A.; Myerson, J . J . Am. Chem. Soc. 1978, 100,
3950-3952. (b) Bartlett, P. A.; Gonzales, F. B. Org. Synth. 1985, 64,
175-179. (c) Freeman, F.; Robarge, K. D. Carbohydr. Res. 1985, 137,
89-97. (d) Boivin, T. L. B. Tetrahedron 1987, 43, 3309-3362.
(13) An ORTEP diagram and other crystallographic data are
included in the Supporting Information.

C3 Ribosylated Imidazo[1.2-a]pyridine C-Nucleoside
J . Org. Chem., Vol. 63, No. 4, 1998 987
the C3 position.14 This led us to assign structure 20 to
the byproduct. Attempts to improve the yield of 19, by
using lower reaction temperatures or other bases to affect
the elimination (such as sodium methoxide), failed.
Finally, dihydroxylation of 18 was accomplished using
osmium tetraoxide in the presence of morpholine N-oxide
in an acetone-water mixture to give, as the only product,
the desired 2,6,7-trichloro-3-(â-D-ribofuranosyl)imidazo-
[1,2-a]pyridine (3). The structure and absolute stereo-
chemistry of the new C-nucleoside 3 was unequivocally
determined by X-ray crystallography.15
We have successfully synthesized the first C3-ribo-
furanosylimidazo[1,2-a]pyridine C-nucleoside (3). This
was accomplished by developing a modification of existing
iodocyclization methodology for obtaining a 1′,4′-syn
furanosyl precursor, without an extensive protection
scheme.
Antiviral evaluation revealed that the reported imi-
dazo[1,2-a]pyridine C-nucleosides did not have significant
activity against human cytomegalovirus (IC50 > 100 µM
in a plaque reduction assay)16 or HSV-1 (IC50 > 100 µM
in an ELISA assay).17 These derivatives were not cyto-
toxic.
Further investigation on the application of this meth-
odology for the synthesis of C-nucleosides is in progress
in our laboratories.
filtered, and concentrated. The solid residue was purified by
flash chromatography (Et2O/hexane 4:1, 15 cm × 4 cm).
Fractions containing the product were combined and concen-
trated to dryness to give, after recrystallization from EtOH,
625 mg (75%) of a white crystalline solid. This solid was
dissolved in a 1:1 mixture of H2O and MeOH (50 mL). To this
solution was added pyridinium p-toluenesulfonate (0.7 g, 3.6
mmol) and the reaction mixture heated at 60 °C for 12 h.
Methanol was removed under reduced pressure, and the
resulting aqueous mixture was extracted with EtOAc (3 × 80
mL). The organic phase was dried (MgSO4), filtered, and
concentrated. The resulting residue was purified by flash
chromatography (EtOAc/hexane 2:1, 15 cm × 5 cm). Fractions
containing the product were combined and evaporated to
dryness to give, after recrystallization from EtOH, 0.52 g (95%)
of 6 as a white solid: mp 67-70 °C; Rf 0.12 (EtOAc/hexane
2:1); 1H NMR (360 MHz, DMSO-d6) δ 8.85 (d, 1H, J ) 1.8 Hz),
7.60 (d, 1H, J ) 9.5 Hz), 7.39 (dd, J ) 1.8 Hz, J ) 9.5 Hz),
6.77 (d, 1H, J ) 16.2 Hz), 6.60 (dt, 1H, J ) 16.2 Hz, J ) 7.1
Hz, J ) 7.1 Hz), 4.71 (d, 1H, D2O exchangeable, J ) 5.0 Hz),
4.61 (t, 1H, D2O exchangeable, J ) 5.7 Hz), 3.59 (m, 1H), 3.35
(m, 3H), 2.30 (m, 1H). Anal. Calcd for
C12H12Cl2N2O2‚
1/2EtOH: C, 50.34; H, 4.87; N, 9.03. Found: C, 50.22; H, 5.22;
N, 8.76.
2,6-Dich lor o-3-(1-O-(ter t-bu tyld ip h en ylsilyl)-1,2-d ih y-
d r oxyp en t-4(E)-en -5-yl)im id a zo[1,2-a ]p yr id in e (7). Com-
pound 6 (140 mg, 0.49 mmol) was suspended in CH2Cl2 (5 mL),
and to this suspension were added sequentially pyridine (0.5
mL, 6.2 mmol), DMAP (10 mg, 0.08 mmol), and TBDPSCl (0.16
mL, 0.6 mmol). The resulting reaction mixture was stirred
for 12 h at ambient temperature. Water was added and the
mixture extracted with EtOAc (3 × 40 mL). The organic
extracts were dried (MgSO4), filtered, and concentrated. The
resulting residue was purified by flash chromatography (EtOAc/
hexane 1:2, 15 cm × 2 cm). Fractions containing the product
were combined and evaporated to dryness to give, after
recrystallization from EtOH, 225 mg (87%) of 7 as a white
crystalline solid: mp 155-156 °C; Rf 0.46 (EtOAc/hexane 1:2);
H NMR (360 MHz, CDCl3) δ 8.10 (d, 1H, J ) 2.0 Hz), 7.7 (m,
4H), 7.49 (d, 1H), 7.40 (m, 6H), 7.19 (dd, 1H, J ) 9.5 Hz, J )
2.0 Hz), 6.46 (m, 2H), 3.94 (m, 1H), 3.77 (dd, 1H), 3.65 (dd,
1H), 2.52 (t, 2H), 1.70 (broad s, 1H, D2O exchangeable), 1.10
(s, 9H); 1H NMR (360 MHz, DMSO-d6) δ 8.80 (d, 1H), 7.62 (m,
5H), 7.38 (m, 7H), 6.78 (d, 1H, J ) 16.2 Hz), 6.57 (dt, 1H, J )
16.2 Hz, J ) 7.4 Hz, J ) 7.4 Hz), 4.9 (d, 1H, D2O exchangeable,
J ) 5.1 Hz), 3.79 (m, 1H), 3.62 (m, 1H), 3.56 (m, 1H), 2.59 (m,
1H), 2.47 (m, 1H), 1.00 (s, 9H); 13C NMR (90 MHz, DMSO-d6)
δ 140.2, 135.1, 133.1, 132.4, 131.1, 129.8, 127.8, 126.2, 122.6,
120.6, 118.1, 117.2, 115.3, 70.3, 67.5, 38.1, 26.7, 18.8. Anal.
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
360 or 300 MHz. Flash column chromatography was per-
formed using silica gel 60 230-400 mesh (ICN). Thin-layer
chromatography (TLC) was performed on prescored Silica gel
GHLF. Compounds 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 water bath at below
40 °C. All solvents were dried prior to use as described by
the handbook Purification of Laboratory Chemicals18 and
stored over 4 Å sieves, under argon. Materials obtained from
commercial suppliers were used without purification.
2,6-Dich lor o-3-(1,2-dih ydr oxypen t-4(E)-en -5-yl)im idazo-
[1,2-a ]p yr id in e (6). The phosphonium iodide 4 (1.32 g, 2.55
mmol) was suspended in dry THF (10 mL). The suspension
was cooled to 0 °C (ice-water bath) under an argon atmo-
sphere and n-BuLi (1.8 mL of 1.6 M solution in hexanes, 2.81
mmol) was added dropwise to this suspension. The reddish
solution that formed was stirred at 0 °C for 10 min, and then
a solution of the formyl compound 5 (0.55 g, 2.55 mmol) in
THF (10 mL) was added. The reaction mixture was stirred
at 0 °C for 1 h and then poured into a saturated solution of
NaHCO3 (100 mL). The resulting mixture was extracted with
EtOAc (3 × 70 mL) and the organic phase dried (MgSO4),
Calcd for
C28H30Cl2N2O2Si: C, 63.99; H, 5.75; N, 5.33.
Found: C, 63.78; H, 5.92; N, 5.26.
2,6-Dich lor o-3-(2,3-d id eoxy-2-iod o-5-O-(ter t-b u t yld i-
p h e n ylsilyl)-â-D /L -r ib ofu r a n osyl)im id a zo[1,2-a ]p yr i-
d in e (8) a n d 2,6-Dich lor o-3-(2,3-d id eoxy-2-iod o-5-O-(ter t-
bu tyld ip h en ylsilyl)-r-D/L-lyxofu r a n osyl)im id a zo[1,2-a ]-
p yr id in e (9). A solution of 7 (178 mg, 0.34 mmol) in dry
CH2Cl2 (5 mL) was cooled to 0 °C, and 2,6-lutidine (51 µL, 0.44
mmol) and TESOTf (95 µL, 0.42 mmol) were then added. This
reaction mixture was stirred at 0 °C for 30 min and then
concentrated in vacuo to a syrup. The residue was purified
by flash chromatography (EtOAc/hexane 1:10, 15 cm × 2 cm),
fractions containing the product were pooled and concentrated
to dryness to give the TES-intermediate19 as a syrup. The
TES-intermediate was dissolved in dry CH3CN (7 mL) con-
taining Et3N (30 µL, 0.17 mmol) and added dropwise to a
solution of iodine (860 mg, 3.4 mmol), K2CO3 (94 mg, 0.68
mmol), and t-BuOH (130 µL, 1.3 mmol) in CH3CN (6 mL) at 0
°C. The reaction mixture was stirred at 0 °C for 1 h and then
at rt for an additional 1 h. The reaction mixture was
subsequently poured into EtOAc (100 mL) and extracted with
saturated aqueous Na2S2O3 (50 mL × 2), dried (MgSO4),
filtered, and concentrated to a solid. This solid contained two
(14) 1H NMR information reported in ref 9 shows similar shift
differences for the C5-H proton of 2,6-dichloroimidazo[1,2-a]pyridine
and 2,6-dichloro-3-formylimidazo[1,2-a]pyridine and also for the C5-H
proton of 2,6,7-trichloroimidazo[1,2-a]pyridine and 2,6-trichloro-3-
formylimidazo[1,2-a]pyridine.
(15) The crystal was grown in methanol and the X-ray obtained from
the X-ray laboratory of The Department of Chemistry at The University
of Michigan. Crystal data for 3: white crystals, orthorhombic,
P2(1)2(1)2(1); a ) 6.8890(10) A, b ) 13.349(2) A, c ) 17.1340(10) A.; V
) 1575.9(3) Å3; Z ) 4; Dcalc )1.626. Of 6939 reflections collected, 3093
were unique; R ) 0.0239 and Rw ) 0.0620.
(16) Turk, S. R.; Shipman, C., J r.; Nassiri, R.; Genzlinger, G.;
Krawczyk, S. H.; Townsend, L. B.; Drach, J . C. Antimicrob. Agents
Chemother. 1987, 31, 544-550.
(17) Prichard, M. N.; Shipman, C., J r. Antiviral Res. 1990, 14, 181-
206.
(18) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: New York, 1988.
(19) This intermediate was characterized by 1H NMR and mass
spectroscopy, but was not purified to homogeneity.

988 J . Org. Chem., Vol. 63, No. 4, 1998
Gudmundsson et al.
compounds that were separated by flash chromatography
(EtOAc/hexane 1:5, 15 cm × 2 cm). Fractions containing the
individual products were pooled and concentrated to dryness
to give 32 mg (13%) of 8 and 10 mg (4%) of 9 as white solids.
8: mp 130-132 °C; Rf 0.35 (EtOAc/hexane 1:5); 1H NMR (360
MHz, CDCl3) δ 8.36 (d, 1H, J ) 2.0 Hz), 7.66 (m, 4H), 7.50 (d,
1H, J ) 9.5 Hz), 7.4 (m, 6H), 7.21 (dd, 1H, J ) 2.0 Hz, J ) 9.5
Hz), 5.43 (d, 1H, J ) 9.2 Hz), 4.58 (q, 1H), 4.35 (m, 1H), 3.97
(dd, 1H, J ) 11.4 Hz, J ) 3.5 Hz), 3.76 (dd, 1H, J ) 11.4 Hz,
J ) 4.0 Hz), 2.80 (m, 1H), 2.54 (m, 1H), 1.14 (s, 9H). Anal.
were combined and evaporated to dryness to give, after
recrystallization from EtOH, 3.34 g (70%) of a white crystalline
solid. To a solution of this solid (0.7 g, 1.9 mmol) in a 1:1
mixture of H2O and MeOH (40 mL) was added pyridinium
p-toluenesulfonate (0.7 g, 2.8 mmol) and the reaction mixture
heated to 60 °C for 24 h. The methanol was removed under
reduced pressure, and the resulting aqueous mixture was
extracted with EtOAc (3 × 50 mL). The combined organic
extracts were dried over MgSO4, filtered, and concentrated,
and the resulting solid was purified by flash chromatography
(EtOAc/hexane 2:1, 15 cm × 2 cm). Fractions containing the
product were combined and evaporated to dryness, and the
solid was recrystallized from EtOH to give 0.56 g (90%) of 15
as a white solid: mp 161-163 °C; Rf 0.25 (EtOAc/hexane 2:1);
1H NMR (360 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.00 (s, 1H), 6.79
(d, 1H, J ) 16.2 Hz), 6.62 (dt, 1H, J ) 16.2 Hz, J ) 7.1 Hz),
4.71 (d, 1H, D2O exchangeable), 4.61 (t, 1H, D2O exchange-
Calcd for
C28H29Cl2IN2O2Si: C, 51.62; H, 4.49; N, 4.30.
Found: C, 51.73; H, 4.67; N, 4.14. 9: mp 80-82 °C; Rf 0.32
(EtOAc/hexane 1:5); 1H NMR (300 MHz, CDCl3) δ 8.16 (d, 1H,
J ) 2.0 Hz), 7.7 (m, 4H), 7.52 (d, 1H, J ) 9.5 Hz), 7.40 (m,
6H), 7.26 (dd, 1H, J ) 9.5 Hz, J ) 2.0 Hz), 5.59 (d, 1H, 10.4
Hz), 4.56 (m, 1H), 4.39 (m, 1H), 3.92 (dd, 1H, J ) 11.2 Hz, J
) 3.3 Hz), 3.71 (dd, 1H, J ) 11.2 Hz, J ) 3.2 Hz), 2.8 (m, 2H),
1.14 (s, 9H). Anal. Calcd for C28H29Cl2IN2O2Si‚H2O: C, 50.23;
H, 4.79; N, 4.18. Found: C, 50.01; H, 4.65; N, 4.14.
able), 3.61 (m, 1H), 3.33 (m, 2H), 2.5 (m, 1H), 2.3 (m, 1H); 13
C
NMR (90 MHz, DMSO-d6) δ 140.1, 132.8, 132.2, 128.9, 124.2,
119.1, 118.2, 116.3, 114.8, 71, 65.5, 38.1. Anal. Calcd for
C12H11Cl3N2O2: C, 44.82; H, 3.45; N, 8.71. Found: C, 45.13;
H, 3.81; N, 8.58.
2,6-Dich lor o-3-(2,3-dideoxy-2-iodo-â-D/L-r ibofu r an osyl)-
im id a zo[1,2-a ]p yr id in e (10), 2,6-d ich lor o-3-(2,3-d id eoxy-
2-iod o-r-D/L-lyxofu r a n osyl)im id a zo[1,2-a ]p yr id in e (11)
a n d 2,6-d ich lor o-3-(2,3-d id eoxy-2-iod o-r-D-lyxop yr a n o-
syl)im id a zo[1,2-a ]p yr id in e (12). A solution of 6 (570 mg,
2 mmol) in dry THF (20 mL) was added to a solution of iodine
(2.5 g, 9.85 mmol) in THF (10 mL). The reaction mixture was
stirred for 30 min at rt, and then K2CO3 (285 mg, 2.1 mmol)
was added, followed by the addition of another portion of
K2CO3 (285 mg, 2.1 mmol) after an additional 60 min. Once
all the starting material had reacted as observed by TLC, the
reaction mixture was poured into EtOAc (100 mL) and
extracted with saturated aqueous Na2S2O3 (50 mL × 2). The
organic phase was dried over MgSO4, filtered, and concen-
trated to an oil. The resulting oil contained three products
that were separated by flash chromatography (EtOAc/hexane
1:2, 15 cm × 5 cm). Fractions containing the individual
products were pooled and volatiles removed in vacuo, and each
component was crystallized from aqueous EtOH to give 430
mg (52%) of 10, 130 mg (16%) of 11, and 185 mg (23%) mg of
12, all as white solids. 10: mp 190-191 °C; Rf 0.55 (EtOAc/
hexane 1:1); 1H NMR (360 MHz, DMSO-d6) δ 9.18 (d, 1H), 7.65
(d, 1H, J ) 9.6 Hz), 7.46 (dd, 1H, J ) 9.6 Hz, J ) 1.9 Hz), 5.39
(d, 1H, J ) 10.1 Hz), 5.34 (t, 1H, D2O exchangeable, J ) 4.8
Hz), 4.57 (q, 1H), 4.30 (m, 1H), 3.68 (m, 1H), 3.54 (m, 1H),
2.70 (m, 1H), 2.53 (m, 1H); 13C NMR (90 MHz, DMSO-d6) δ
142, 135.8, 127.2, 125.1, 120.4, 117.3, 114.1, 80.3, 79.2, 62.5,
39.1, 19.1. Anal. Calcd for C12H11Cl2IN2O2: C, 34.89; H, 2.68;
N, 6.78. Found: C, 35.09; H, 2.85; N,6.73. 11: mp 158-160
2,6,7-Tr ich lor o-3-(2,3-dideoxy-2-iodo-â-D-r ibofu r an osyl)-
im idazo[1,2-a ]pyr idin e (16), 2,6,7-Tr ich lor o-3-(2,3-dideoxy-
2-iodo-r-D-lyxofu r an osyl)im idazo[1,2-a ]pyr idin e (17), an d
2,6,7-Tr ich lor o-3-(2,3-d id eoxy-2-iod o-r-D-lyxop yr a n osyl)-
im id a zo[1,2-a ]p yr id in e (18). A solution of 15 (340 mg, 1.1
mmol) in dry THF (10 mL) was added to a stirred solution of
iodine (1.3 g, 5.3 mmol) in THF (10 mL). After 30 min K2CO3
(150 mg, 1.1 mmol) was added, followed by the addition of a
second portion of K2CO3 (150 mg, 1.1 mmol) after 60 min. Once
all the starting material had reacted, as determined by TLC,
the reaction mixture was poured into EtOAc (100 mL) and
extracted with saturated aqueous Na2S2O3 (50 mL × 2), dried
over MgSO4, filtered, and concentrated to a solid. This solid
contained three compounds that were separated by flash
chromatography (EtOAc/hexane 1:2, 15 cm × 5 cm). Fractions
containing each component were pooled, and solvent was
removed in vacuo to give, after recrystallization from aqueous
EtOH, 193 mg (45%) of 16, 70 mg (16%) of 17, and 120 mg
(27%) of 18 as white solids. 16: mp 206-207 °C; Rf 0.27
1
(EtOAc/hexane 1:2); H NMR (360 MHz, DMSO-d6) δ 9.40 (s,
1H), 8.08 (s, 1H), 5.42 (t, 1H, D2O exchangeable), 5.39 (d, 1H,
J ) 10.0 Hz), 4.56 (q, 1H), 4.31 (m, 1H), 3.69 (m, 1H), 3.56 (m,
1H), 2.70 (m, 1H), 2.55 (m, 1H); 13C NMR (90 MHz, DMSO-
d6) δ 142.2, 136.4, 130.2, 126.6, 119.1, 116.5, 114.3, 80.3, 79.3,
62.4, 39.1, 19.3. Anal. Calcd for C12H10Cl3IN2O2: C, 32.21;
H, 2.25; N, 6.26. Found: C, 32.13; H, 2.35; N, 5.86. 17: mp
167-168 °C; Rf 0.14 (EtOAc/hexane 1:2); 1H NMR (360 MHz,
DMSO-d6) δ 8.77 (s, 1H), 8.11 (s, 1H), 5.38 (d, 1H, J ) 9.5
Hz), 4.97 (t, 1H, D2O exchangeable), 4.75 (q, 1H), 4.36 (m, 1H),
3.56 (m, 1H), 3.47 (m, 1H), 2.76 (m, 1H), 2.33 (m, 1H); 13C
NMR (90 MHz, DMSO-d6) δ 142, 136.3, 130.2, 125.4, 119.2,
116.7, 114.53, 80, 79, 63.1, 39.5, 19.8. Anal. Calcd for
1
°C; Rf 0.40 (EtOAc/hexane 1:1); H NMR (360 MHz, DMSO-
d6) δ 8.59 (d, 1H), 7.66 (d, 1H, J ) 9.6 Hz), 7.47 (dd, 1H), 5.38
(d, 1H, J ) 10.6 Hz), 4.98 (t, 1H, D2O exchangeable, J ) 5.6
Hz), 4.77 (m, 1H), 4.34 (m, 1H), 3.57 (m, 1H), 3.47 (m, 1H),
2.77 (m, 1H), 2.32 (m, 1H); 13C NMR (90 MHz, DMSO-d6) δ
141.9, 135.7, 127.2, 124, 120.4, 117.4, 114.3, 80, 79.1, 63.1, 39.6,
19.7. Anal. Calcd for C12H11Cl2IN2O2: C, 34.89; H, 2.68; N,
6.78. Found: C, 34.81; H, 2.71; N, 6.80. 12: mp 205 °C; Rf
0.45 (EtOAc/hexane 1:1); 1H NMR (360 MHz, DMSO-d6) δ 8.85
(d, 1H, J ) 1.9 Hz), 7.67 (d, 1H, J ) 9.6 Hz), 7.47 (dd, 1H, J
) 9.6 Hz, J ) 1.9 Hz), 5.34 (m, 1H, D2O exchangeable), 5.1-
5.2 (m, 2H), 3.91 (m, 2H), 3.71 (m, 1H), 2.55 (m, 2H). Anal.
Calcd for C12H11Cl2IN2O2: C, 34.89; H, 2.68; N, 6.78. Found:
C, 34.89; H, 2.53; N, 6.64.
2,6,7-Tr ich lor o-3-(1,2(S)-d ih yd r oxy-p en t-4(E)-en -5-yl)-
im id a zo[1,2-a ]p yr id in e (15). A suspension of 13 (7.18 g,
0.014 mol) in dry THF (30 mL) was cooled to 0 °C under an
argon atmosphere. To this suspension was added dropwise
n-BuLi (9.9 mL of 1.6 M solution in hexanes, 0.016 mol). The
reddish solution obtained was stirred at 0 °C for 10 min, and
then a solution of 14 (3.3 g, 0.013 mol) in THF (30 mL) was
added. The reaction mixture was stirred at 0 °C for 1 h and
then poured into a saturated aqueous solution of NaHCO3 (200
mL) and extracted with EtOAc (3 × 150 mL). The organic
phase was dried over MgSO4, filtered, and concentrated to a
solid. This solid was purified by flash chromatography (Et2O/
hexane 4:1, 15 cm × 5 cm). Fractions containing the product
C
12H10Cl3IN2O2: C, 32.21; H, 2.25; N, 6.26. Found: C, 32.40;
H, 2.32; N,6.10. 18: mp 199-200 °C; Rf 0.17 (EtOAc/hexane
1:2); 1H NMR (360 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.09 (s, 1H),
5.34 (m, 1H, D2O exchangeable), 5.18 (d, 1H, J ) 11.3 Hz),
5.10 (m, 1H), 3.92 (m, 2H), 3.71 (m, 1H), 3.56 (m, 2H);13C
NMR (90 MHz, DMSO-d6) δ 141.4, 135.2, 129.9, 125.2, 119.2,
118.5, 116.7, 74.2, 71.9, 65.9, 43.1, 24; HRMS m/z calcd for
C
C
12H11Cl2IN2O2 445.8853, found 445.8842. Anal. Calcd for
12H10Cl3IN2O2: C, 32.21; H, 2.25; N, 6.26. Found: C, 32.02;
H, 2.29; N,5.99. Structure and absolute stereochemistry of 18
was determined by X-ray crystallography.
2,6,7-Tr ich lor o-3-(2,3-d id eoxy-2,3-d id eh yd r o-â-D-r ibo-
fu r an osyl)im idazo[1,2-a ]pyr idin e (19) an d 2,6,7-Tr ich lor o-
3-(4(S),5-d ih yd r oxy-1-oxop en t a n e)im id a zo[1,2-a ]p yr i-
d in e (20). To a solution of 16 (400 mg, 0.89 mmol) in dry
DMF (10 mL) was added DBU (0.67 mL, 4.4 mmol), and the
resulting solution was stirred at 90 °C for 16 h. The reaction
mixture was partitioned between water (50 mL) and CH2Cl2
(100 mL), and the phases were separated. The organic phase
was dried over MgSO4 and concentrated under reduced pres-
sure, and the resulting solid was purified by flash chromatog-

C3 Ribosylated Imidazo[1.2-a]pyridine C-Nucleoside
J . Org. Chem., Vol. 63, No. 4, 1998 989
raphy (EtOAc/hexane 1:5, 15 cm × 2 cm). Fractions containing
a faster migrating minor product were pooled and concentrated
in vacuo to give, after recrystallization from aqueous CH3CN,
48 mg (15%) of 20 as a white powder. Fractions containing
the slower migrating major product were subsequently com-
bined and concentrated in vacuo to give, after recrystallization
from aqueous CH3CN, 170 mg (62%) of 19 as white powder:
19: mp 147-148 °C; Rf 0.40 (EtOAc/hexane 1:2); 1H NMR (360
MHz, DMSO-d6) δ 9.42 (d, 1H, J ) 0.4 Hz), 8.05 (d, 1H, J )
0.4 Hz), 6.34 (m, 1H), 6.15 (m, 1H), 6.10 (m, 1H), 5.20 (t, 1H),
4.85 (m, 1H), 3.70 (m, 2H); 13C NMR (90 MHz, DMSO-d6) δ
141.8, 135.3, 132.8, 130, 127.2, 126.1, 118.6, 117.3, 116.3, 87,
76.9, 62.5. Anal. Calcd for C12H9Cl3N2O2: C, 45.10; H, 2.84;
N, 8.76. Found: C, 45.20; H, 2.89; N, 8.63. 20: mp 165-166
and concentrated under reduced pressure to give a solid which
was purified by flash chromatography (EtOAc/hexane 2:1, 10
cm × 2 cm). Fractions containing product were combined,
concentrated to a solid, and crystallized from CH3CN to give
73 mg (95%) of 3 as a white solid: mp 239-240 °C; Rf 0.30
1
(EtOAc/hexane 2:1); [R]20 ) -232.7° (MeOH); H NMR (360
D
MHz, DMSO-d6) δ 9.45 (s, 1H), 8.06 (s, 1H), 5.41 (t, 1H, D2O
exchangeable), 5.13 (d, 1H, D2O exchangeable), 5.10 (d, 1H,
D2O exchangeable), 5.02 (d, 1H, J ) 9.1 Hz, 1′-H), 4.30 (m,
1H), 4.10 (m, 1H), 3.95 (m, 1H), 3.6-3.7 (m, 2H); 13C NMR
(90 MHz, DMSO-d6) δ 141.8, 136, 129.6, 126.3, 118.9, 116.9,
116.5, 86.4, 74.6, 71.3, 71, 61.40; UV λmax (MeOH) 325 (1555),
245 (11652), 238 (9935), 229 (8194); (pH 11) 295 (8226), 243
(61612), 335 (58064), 230 (48710); (pH 1) 294 (12290), 236
(59225); HRMS m/z calcd for C12H11Cl3N2O4 351.9783, found
351.9771. Anal. Calcd for C12H11Cl3N2O4: C, 40.73; H, 3.14;
N, 7.92. Found: C, 40.76; H, 3.07; N, 7.89. Structure and
absolute stereochemistry of 3 was determined by X-ray
crystallography.
1
°C; Rf 0.20 (EtOAc/hexane 1:2); H NMR (360 MHz, DMSO-
d6) δ 9.80 (s, 1H), 8.30 (s, 1H), 4.57 (d, 1H), 4.54 (t, 1H), 3.5
(m, 1H), 3.3 (m, 2H), 3.14 (m, 2H), 1.90 (m, 1H), 1.60 (m, 1H);
1H NMR (360 MHz, CDCl3) δ 9.96 (s, 1H), 7.79 (s, 1H), 3.84
(m, 1H), 3.74 (m, 1H), 3.52 (m, 1H), 3.32 (t, 2H), 2.59 (d, 1H),
1.98 (m, 3H); 13C NMR (90 MHz, DMSO-d6) δ 190.3, 143.7,
142.1, 134, 127.5, 121.5, 119, 116.8, 70.3, 65.8, 37.5, 27.7;
HRMS m/z calcd for C12H11Cl3N2O3 335.9834, found 335.9823.
Anal. Calcd for C12H11Cl3N2O3‚1/4H2O: C, 42.13; H, 3.39; N,
8.20. Found: C, 41.89; H, 3.14; N, 8.05.
2,6,7-Tr ich lor o-3-(â-D-r ibofu r a n osyl)im id a zo[1,2-a ]p y-
r id in e (3). Compound 19 (70 mg, 0.22 mmol) was dissolved
in a 4:1 mixture of acetone and water (5 mL), and then
N-methylmorpholine N-oxide (40 mg, 0.33 mmol) and osmium
tetraoxide (150 µL of 2.5% OsO4 in tert-butyl alcohol) were
added. After stirring at rt for 16 h, Na2HSO3 (20 mL,
concentrated aqueous solution) was added and the solution
stirred for 1 h and then extracted with EtOAc (40 mL x 3).
The combined EtOAc extracts were dried (MgSO4), filtered,
Ack n ow led gm en t. This work was supported by
NCDDG research grant U19-AI31718 from the National
Institute of Allergy and Infectious Disease of the
National Institute of Health.
Su p p or tin g In for m a tion Ava ila ble: An ORTEP diagram
of 18 and crystallographic data for 18 and 3 (11 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O9711145