Synthesis of 2′-C-methyl ribonucleoside analogues with modified heterocyclic base moieties

Article abstract of DOI:10.1080/00397910903349984

Recently, 2′-C-methyl nucleoside analogues have been reported to exhibit potent anti-hepatitis C virus (HCV) activity through inhibition of HCV RNA replication without significant cytotoxicity. As a part of our continuous efforts of searching for novel antiviral agents, we now report the synthesis of heterobase-modified 2′-C-methyl ribonucleoside analogues. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903349984

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Synthesis of 2′-C-Methyl Ribonucleoside
Analogues with Modified Heterocyclic
Base Moieties
Myong Jung Kim a
a Foundation for Applied Molecular Evolution , Gainesville, Florida,
USA
Published online: 13 Sep 2010.
To cite this article: Myong Jung Kim (2010) Synthesis of 2′-C-Methyl Ribonucleoside Analogues with
Modified Heterocyclic Base Moieties, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:20, 2988-2999, DOI: 10.1080/00397910903349984
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Synthetic Communications1, 40: 2988–2999, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903349984
SYNTHESIS OF 2’-C-METHYL RIBONUCLEOSIDE
ANALOGUES WITH MODIFIED HETEROCYCLIC
BASE MOIETIES
Myong Jung Kim
Foundation for Applied Molecular Evolution, Gainesville, Florida, USA
Recently, 20-C-methyl nucleoside analogues have been reported to exhibit potent anti–
hepatitis C virus (HCV) activity through inhibition of HCV RNA replication without
significant cytotoxicity. As a part of our continuous efforts of searching for novel antiviral
agents, we now report the synthesis of heterobase-modified 20-C-methyl ribonucleoside
analogues.
Keywords: Antiviral agent; HCV; 20-C-methyl nucleoside
INTRODUCTION
The Flaviviridae, a family of single-stranded RNA viruses that have a spherical
virion with a capsid composed of a single protein and a lipid envelope containing two
or three proteins, are transmitted by mosquitoes and ticks and include three genera:
hepativirus, flavivirus, and pestivirus. Hepatitis C virus (HCV) is a blood-borne infec-
tious disease of the liver, which infects 170 million people worldwide and 2.7 million
Americans are chronically infected with HCV. The current treatment for hepatitis C
is combination therapy of pegylated interferon-a[1] and ribavirin.[2] However, this
therapy is only 50% effective for HCV genotype 1 and 80% effective for genotypes
2 and 3. There is not currently alternative therapy for nonresponders. In addition,
infections with arthropod-borne flaviviruses (such as dengue fever, Japanese
encephalitis, tick-borne encephalitis, St. Louis encephalitis, Murray Valley encepha-
litis, West Nile, and yellow fever viruses) are emerging throughout the world. The
pestiviruses include bovine viral diarrhea virus (BVDV), classical swine fever virus
(CSFV), and border disease virus (BDV) of sheep. They have a serious impact on
livestock and cause significant economic losses worldwide. Unfortunately, no specific
antiviral therapy is available for the treatment or the prevention of infections with
members of the Flaviviridae.
Nowadays, several classes of compounds are currently in development as
potential inhibitors of the replication of RNA viruses. Among them, 20-substituted
Received May 6, 2009.
Address correspondence to Myong Jung Kim, Foundation for Applied Molecular Evolution, P.O.
Box 13174, Gainesville, FL 32604, USA. E-mail: mkim@ffame.org
2988

SYNTHESIS OF 20-C-METHYL RIBONUCLEOSIDE ANALOGUES
2989
Figure 1. Structure of anti-HCV and target nucleosides.
nucleoside analogues, 20-O-methyl-cytidine (20-O-Me-C) and 20-C-methyl-adenosine
(20-C-Me-A), exhibited anti-HCV activity without significant cytotoxicity[3,4]
through inhibition of RNA-dependent RNA polymerase (NS5B) of HCV, which
is essential for the replication of viral RNA and is therefore an attractive target
for the development of novel antiviral agents.[5] Furthermore, it has been reported
that 20-C-methyl nucleosides inhibited replication of other RNA viruses such as
bovine diarrhea virus, yellow fever, and West African Nile viruses genetically
related with HCV.[6] To date, a number of 20-C-methyl ribonucleoside derivatives
have been synthesized and evaluated. Also, many nucleoside analogues with
modified heterocyclic base moieties, such as T-1106 (3,4-dihydro-3-oxo-4-b-
D-ribofuranosyl-2-pyrazinecarboxamide),[7] and ribavirin [1-(b-D-ribofuranosyl)-
1H-1,2,4-triazole-3-carboxamide)[8] have shown antiviral activity against several
RNA viruses.
On the basis of these findings, it was very interesting to design and synthesize
20-C-methyl ribonucleoside derivatives. Here, we report the synthesis of a series of
heterobase-modified 20-C-methyl ribonucleosides (Fig. 1).
RESULTS AND DISCUSSION
For the synthesis of the target 20-C-methyl ribonucleoside analogues, we
synthesized pyrazine base moiety and 2,6-dichloro-3-deazapurine[9] as shown in
Scheme 1.
The 3-amino group of 3-aminopyrazine-2-carboxylic acid (1) was converted
into a hydroxy group using diazotization to give 3-hydroxy pyrazine derivative
(2), which was treated with thionyl chloride in methyl alcohol to afford the corre-
sponding methyl ester derivative 3. 4-Amino-2,6-dichloropyridine (4) was converted
to the nitrosoamine 5 using standard conditions, in which the nitro group was
migrated by treatment with sulfuric acid to give the nitro amine 6. The nitro group
of 6 was reduced using iron and aqueous HCl to give the diamine 7. The ring closure
of diamine 7 was accomplished by refluxing in a 1=1 mixture of triethylorthoformate
and acetic anhydride to afford the 3-deazapurine derivative 8.

2990
M. J. KIM
Scheme 1. (a) c-H2SO4, NaNO2, reflux, 30 min; (b) SOCl2, MeOH, rt, overnight, (c) c-H2SO4, HNO3, rt,
1 h; (d) c-H2SO4, 80 ꢀC, 30 min; (e) Fe, HCl, 95 ꢀC, 16 h; (f) triethylorthoformate=Ac2O (1=1), reflux, 4.5 h.
Synthesis of 20-C-methyl ribonucleoside using condensation with heterocyclic
bases is outlined in Scheme 2. The glycosyl donor 10 could be easily synthesized from
1,3,5-tri-O-benzoyl-a-D-ribofuranose (9) by a known procedure.[10] First, we tried to
condense the glycosyl donor 10 with pyrazine base (3) using N,O-bis(trimethylsilyl)-
acetamide (BSA) in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf)
as a Lewis acid or 1,8-diazabicycloundec-7-ene (DBU) and TMSOTf in CH3CN. How-
ever, the isolated product was a 1=1 mixture of a=b diastereoisomers (determined by 1H
NMR), which could not be separated by silica-gel column chromatography. On the
other hand, compound 10 was condensed with silylated pyrazine base resulting from
refluxing with hexamethyldisilazane (HMDS) in the presence of SnCl4 as a Lewis acid
to give the desired b-nucleoside 11. Glycosylation reactions of 2-C-methyl ribofuranose
(10) with methyl-1,2,4-triazole-3-carboxylate, methyl-imidazole-4,5-dicarboxylate, and
2,6-dichloro-3-deazapurine (8) under Vorbruggen conditions using DBU and TMSOTf
¨
as a catalyst in CH3CN at 60 ꢀC afforded the 20-C-methyl nucleoside derivatives 12, 13,
and 14, respectively. Ammonolysis of methyl ester and debenzoylation of 11 and 12
using methanolic ammonia gave the desired nucleosides 15 and 16, respectively. Ring
closure of imidazole nucleoside 13 with guanidine[11] afforded the ring-expanded purine
nucleoside analogue 17. The benzoyl group in 14 was removed using methanolic
ammonia to give 2,6-dichloro-3-deazapurine nucleoside 18. To covert the 6-chloro
group into an amino group, compound 18 was treated with saturated methanolic
ammonia at 120 ꢀC, but no product was formed. The amination could be accomplished
by treatment with liquid ammonia at 160ꢀC for 5 days to afford the 2-chloro-3-
deazapurine nucleoside 19. Finally, the chloro group of 19 was removed by catalytic
hydrogenation to yield the 3-deazapurine nucleoside 20.
Synthesis of 20-C-methyl ribonucleoside with 1,2,3-triazole base moieties is shown
in Scheme 3. The glycosyl donor 10 reacted with TMSN3 in the presence of SnCl4 in
dichloromethane to give the azido sugar 21. 1,3-Dipolar cycloaddition of 21 with methyl
propiolate and dimethyl acetylenedicaboxylate in dimethoxyethane (DME) gave the

SYNTHESIS OF 20-C-METHYL RIBONUCLEOSIDE ANALOGUES
2991
Scheme 2. (a) 3, HMDS, dichloroethane, SnCl4, rt to 70 ꢀC, 12 h; (b) methyl-1,2,4-triazole-3-carboxylate,
methyl-imidazole, 4,5-dicarboxylate or 8, DBU, TMSOTf, CH3CN, 60 ꢀC, 3 h; (c) NH3=MeOH, rt,
overnight; (d) guanidine HCl, NaOMe, MeOH, rt, overnight; (e) liq. NH3, 160 ꢀC, 5days; (f) Pd=C, 1 N
NaOH, EtOH, H2, rt, overnight.
1,2,3-triazole nucleosides 22 and 23, respectively. In the reaction with methyl propiolate,
1,4- and 1,5-regioisomers were obtained in a ratio of 95=5. The structural assignment of
regioisomers was made by the comparison of their 1H NMR spectra. The signal of 10-H
of 1,5-regioisomer (d6.96) appeared at a lower field than that of 1,4-regioisomer (d6.89)
because of the deshielding effect of carbonyl group.[12] Treatment of 22 and 23 with
methanolic ammonia afforded the 20-C-methyl-1,2,3-triazole nucleoside derivatives 24
and 25, respectively. The benzoyl group in 21 was removed to give the
1-azido-ribofuranose 26. 1,3-Cycloaddition of azido compound 26 using 2-cyanoaceta-
mide afforded the 5-amino-1,2,3-triazole-4-carboxamide nucleoside 27.
In summary, a series of 20-C-methyl ribonucleoside analogues with modified
heterobase moieties have been synthesized. Results of the antiviral evaluation of
the synthesized nucleosides will be published in due course.

2992
M. J. KIM
Scheme 3. (a) TMSN3, SnCl4, CH2Cl2, rt, 18 h; (b) methyl propiolate or dimethylacetylenedicarboxylate,
DME, reflux, overnight; (c) NH3=MeOH, rt, overnight; (d) 2-cyanoacetamide, K2CO3, DMSO, 50 ꢀC,
16 h.
EXPERIMENTAL
NMR spectra were recorded on a 500-MHz Fourier transform spectrometer
using tetramethylsilane (TMS) as an internal standard, and the chemical shifts
are reported in ppm (d). Coupling constants are reported in hertz (Hz). Thin-layer
chromatography (TLC) was carried out on Merck silica-gel 60 F254 precoated plates,
and silica-gel column chromatography was performed on silica gel 60, 230–400
mesh, Merck. All anhydrous solvents were distilled over CaH2 or Na=benzophenone
prior to use.
3-Hydroxypyrazine-2-carboxylic Acid (2)
3-Aminopyrazine-2-carboxylic acid (2 g, 14.38 mmol) was dissolved in a
mixture of water (16 mL) and 3.75 M H2SO4 (16 mL) and heated to 50 ꢀC. A
3.3 M solution of NaNO2 in water (5.2 mL) was added to this solution over
30 min at 10–15 ꢀC. The reaction mixture was refluxed for 30 min and cooled to rt.
The solid was collected by filtration, dissolved in a dilute NaHCO3 solution,
and reprecipitated by treatment with 10% HCl solution. The solid was collected
by filtration and recrystallized from water to give compound 2 as a colorless solid
1
(1.2 g, 8.6 mmol, 60%). H NMR (DMSO-d6, 500 MHz): d 7.83 (d, 1H, J ¼ 3.5 Hz),
7.68 (d, 1H, J ¼ 4.0 Hz), 3.45 (brs, 1H).
Methyl 3-Hydroxypyrazine-2-carboxylic Acid (3)
SOCl2 (0.75 mL, 10.3 mmol) was added to a stirred solution of compound 2
(1.2 g, 8.6 mmol) in MeOH (20 mL) at rt. The reaction mixture was stirred at rt over-
night and evaporated. The solid was recrystallized from EtOH to give compound 3

SYNTHESIS OF 20-C-METHYL RIBONUCLEOSIDE ANALOGUES
2993
as a colorless solid (1 g, 6.5 mmol, 76%). 1H NMR (CDCl3, 500 MHz): d 8.34
(brs, 1H), 8.22 (brs, 1H), 4.08 (s, 3H), 2.10 (s, 1H); 13C NMR (CDCl3, 125 MHz):
d 184.36, 184.05, 184.04, 184.03, 150.00, 53.75.
4-Amino-2,6-dichloro-3-nitropyridine (6)
4-Amino-2,6-dichloropyridine (1.2 g, 7.4 mmol) was added to 5 mL of c-H2SO4.
The mixture was cooled to 0 ꢀC, and nitric acid (3 mL) was added dropwise at 0 ꢀC.
The mixture was stirred at rt for 1 h and then poured into crushed ice. The solution
was allowed to cool at 10 ꢀC overnight and filtered. The precipitate was washed with
water and dried to give compound 5.
Compound 5 was carefully added to 11 mL of c-H2SO4. The solution was
stirred at 80 ꢀC for 30 min, cooled to rt, and poured into ice water. The mixture
was neutralized with NH4OH and cooled to 10 ꢀC overnight. The precipitate was
filtered, washed with ice water, and dried to give compound 6 as a colorless solid
1
(1.26 g, 6.06 mmol, 82%). H NMR (DMSO-d6, 500 MHz): d 7.69 (brs, 2H), 6.90
(s, 1H); 13C NMR (DMSO-d6, 125 MHz): d 188.84, 151.21, 149.29, 142.33, 110.66.
3-Deaza-2,6-dichloropurine (8)
Iron powder (1.69 g, 30.3 mmol), water (5.5 mL), and HCl (3.3 mL) were added
to a stirred solution of compound 6 (1.26 g, 6.06 mmol) in EtOH (30 mL). After stir-
ring at 95 ꢀC for 16 h, the reaction mixture was cooled to rt, neutralized, and filtered.
The filtrate was evaporated to give compound 7, which was dissolved in a mixture of
triethylorthoformate=Ac2O (1=1, 12 mL). The reaction mixture was refluxed for 4.5 h
and evaporated. The residue was dissolved in 10% NaOH (10 mL) and heated at
50 ꢀC for 40 min. The resulting solution was cooled to rt, neutralized with AcOH,
and cooled to 0 ꢀC. The precipitate was filtered to give compound 8 as a pale brown
solid (920 mg, 4.9 mmol, 81%). 1H NMR (DMSO-d6, 500 MHz): d 8.36 (s, 1H), 7.65
(s, 1H); 13C NMR (DMSO-d6, 125 MHz): d 179.30, 173.08, 150.47, 142.33, 138.35,
109.42; UV (pH ¼ 11): kmax 287 nm.
Methyl 3-Oxo-1-(2-C-methyl-2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)-
pyrazine Carboxylate (11)
A mixture of compound 3 (223 mg, 1.45 mmol) and (NH4)2SO4 (50 mg) in
HMDS (10 mL) was refluxed for 4.5 h, and the solvent was removed in vacuo. The
residue was dissolved in dichloroethane (10 mL), and a solution of compound 10
(420 mg, 0.72 mmol) in dichloroethane (10 mL) was added. The mixture was cooled
to 0 ꢀC, and 1 M SnCl4 in dichloromethane (1.45 mL) was added. The reaction mix-
ture was stirred at rt for 2 h, heated at 70 ꢀC for 12 h, and cooled to rt. Saturated
NaHCO3 solution was added, and the mixture was extracted with CH2Cl2 (ꢁ3).
The combined organic layers were washed with brine, dried (MgSO4), filtered, and
evaporated. The residue was purified by silica-gel column chromatography
(hexane=EtOAc ¼ 2=1) to give compound 11 as a colorless foam (90 mg, 0.15 mmol,
20%). 1H NMR (CDCl3, 500 MHz): d 7.17–8.13 (m, 17H), 6.69 (s, 1H), 5.89 (d, 1H,
J ¼ 2.5 Hz), 5.03 (m, 1H), 4.75 (m, 2H), 4.06 (s, 3H), 2.18 (s, 3H); 13C NMR (CDCl3,

2994
M. J. KIM
125 MHz): d 166.8, 164.71, 164.42, 163.60, 159.39, 139.80, 133.54, 133.49, 129.90,
129.58, 129.55, 128.60, 128.58, 128.51, 128.43, 127.47, 122.20, 92.28, 85.53, 83.87,
76.67, 63.81, 53.11, 22.96; UV (MeOH): kmax 230 nm. Anal. calcd. for
C33H28N2O10: C, 64.70; H, 4.61; N, 4.57. Found: C, 64.56; H, 4.66; N, 4.43.
Methyl 1-(2-C-Methyl-2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)-
1,2,4-triazole-3-carboxylate (12)
TMSOTf (0.26 mL, 1.44 mmol) was added to a stirred solution of compound
10 (210 mg, 0.36 mmol), methyl-1,2,4-triazole-3-carboxylate (55 mg, 0.43 mmol),
and DBU (0.17 mL, 1.08 mmol) in CH3CN (7 mL) at 0 ꢀC. The mixture was stirred
at 60 ꢀC for 3 h and poured into aq. NaHCO3 solution. The mixture was extracted
with CH2Cl2 (ꢁ3). The combined organic layers were washed with brine, dried
(MgSO4), filtered, and evaporated. The residue was purified by silica-gel column
chromatography (hexane=EtOAc ¼ 2=1) to give compound 12 as a pale yellow foam
1
(170 mg, 0.29 mmol, 80%). H NMR (CDCl3, 500 MHz): d 8.49 (s, 1H), 7.36–8.12
(m, 15H), 6.80 (s, 1H), 6.16 (d, 1H, J ¼ 8.0 Hz), 4.82–4.89 (m, 2H), 4.76 (dd, 1H,
J ¼ 4.0 Hz, 11.0 Hz), 4.09 (s, 3H), 1.54 (s, 3H); 13C NMR (CDCl3, 125 MHz): d
166.28, 165.50, 165.24, 159.82, 159.24, 145.31, 133.92, 133.85, 133.23, 129.93,
129.86, 129.81, 129.73, 128.73, 128.65, 128.45, 90.87, 86.68, 79.62, 76.11, 64.09,
52.86, 17.23; UV (MeOH): kmax 229 nm. Anal. calcd. for C31H27N3O8: C, 63.59;
H, 4.65; N, 7.18. Found: C, 63.66; H, 4.68; N, 7.09.
Methyl 1-(2-C-Methyl-2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)-
imidazole-4,5-di-carboxylate (13)
Compound 10 (380 mg, 0.65 mmol) was condensed with methyl-imidazole-
4,5-dicarboxylate (145 mg, 0.79 mmol) to give compound 13 as a pale yellow foam
(hexane=EtOAc ¼ 2=1, 250 mg, 0.39 mmol, 59%) according to the same procedure
1
used in the synthesis of compound 12. H NMR (CDCl3, 500 MHz): d 7.26–8.11
(m, 16H), 6.91 (s, 1H), 5.73 (d, 1H, J ¼ 5.5 Hz), 4.88 (m, 1H), 4.78 (m, 1H), 4.66
(m, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 1.51 (s, 3H); 13C NMR (CDCl3, 125 MHz): d
166.27, 165.33, 165.17, 162.39, 137.68, 133.72, 133.52, 129.88, 129.82, 129.74,
129.56, 129.37, 128.67, 128.52, 128.46, 89.72, 84.84, 80.31, 75.35, 62.95, 52.98,
52.39, 18.01; UV (MeOH): kmax 231 nm. Anal. calcd. for C34H30N2O11: C, 63.55;
H, 4.71; N, 4.36. Found: C, 63.34; H, 4.70; N, 4.26.
2,6-Dichloro-9-(2-C-methyl-2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)-
3-deazapurine (14)
Compound 10 (650 mg, 1.12 mmol) was condensed with 2,6-dichloro-3-
deazapurine (253 mg, 1.35 mmol) to give compound 14 as a pale yellow foam
(hexane=EtOAc ¼ 2=1, 510 mg, 0.79 mmol, 70%) according to the same procedure
1
used in the synthesis of compound 12. H NMR (CDCl3, 500 MHz): d 8.44 (s,
1H), 7.99–8.16 (m, 6H), 7.88 (s, 1H), 7.40–7.71 (m, 6H), 6.60 (s, 1H), 5.84 (d, 1H,
J ¼ 6.0 Hz), 4.99 (dd, 1H, J ¼ 3.0, 13.0 Hz), 4.92 (dd, 1H, J ¼ 5.0, 13.0 Hz), 4.76
(m, 1H), 1.54 (s, 3H); 13C NMR (CDCl3, 125 MHz): d 166.36, 165.20, 150.01,

SYNTHESIS OF 20-C-METHYL RIBONUCLEOSIDE ANALOGUES
2995
143.33, 142.91, 141.84, 140.66, 137.62, 134.13, 134.05, 133.72, 133.59, 130.18, 129.87,
129.79, 129.22, 128.89, 128.81, 128.66, 128.49, 128.99, 106.62, 89.95, 85.08, 80.44,
74.93, 62.46, 17.61; UV (MeOH): kmax 275 nm. Anal. calcd. for C33H25Cl2N3O7:
C, 61.31; H, 3.90; N, 6.50. Found: C, 61.28; H, 3.96; N, 6.48.
2-Oxo-1-(2-C-methyl-b-D-ribofuranosyl)-pyrazine-3-carboxamide (15)
A solution of compound 11 (80 mg, 0.13 mmol) in methanolic ammonia
(10 mL) was stirred at rt overnight and evaporated. The residue was purified by
silica-gel column chromatography (CH2Cl2=MeOH ¼ 5=1) to give compound 15 as
1
a white solid (30 mg, 0.10 mmol, 80%). H NMR (CD3OD, 500 MHz): d 7.94 (d,
1H, J ¼ 4.0 Hz), 7.74 (d, 1H, J ¼ 4.0 Hz), 6.47 (s, 1H), 4.24 (m, 1H), 4.01 (d, 1H,
J ¼ 9.0 Hz), 3.93 (dd, 1H, J ¼ 2.0, 12.5 Hz), 3.71 (dd, 1H, J ¼ 4.5, 12.0 Hz), 1.46 (s,
1H); 13C NMR (CD3OD, 125 MHz): d 131.13, 128.97, 123.87, 122.97, 92.16,
90.08, 83.67, 78.95, 74.63, 60.70, 20.91; UV (MeOH): kmax 230 nm. Anal. calcd.
for C11H15N3O6: C, 46.32; H, 5.30; N, 14.73. Found: C, 46.10; H, 5.48; N, 14.56.
1-(2-C-Methyl-b-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (16)
Compound 12 (170 mg, 0.29 mmol) was converted to compound 16 as a white
solid (CH2Cl2=MeOH ¼ 5=1, 61 mg, 0.24 mmol, 81%) using the same conditions used
1
in the synthesis of compound 15. H NMR (DMSO-d6, 500 MHz): d 8.95 (s, 1H),
7.85 (brs, 1H), 7.66 (brs, 1H), 5.81 (s, 1H), 5.31 (s, 1H), 5.24 (d, 1H, J ¼ 7.0 Hz),
4.99 (t, 1H, J ¼ 5.0 Hz), 3.99 (m, 1H), 3.94 (m, 1H), 3.78 (m, 1H), 3.65 (m, 1H),
0.82 (s, 3H); 13C NMR (DMSO-d6, 125 MHz): d 160.88, 157.72, 145.05, 95.38,
84.10, 78.91,73.00, 61.43, 20.00; UV (MeOH): kmax 230 nm. Anal. calcd. for
C9H14N4O5: C, 41.86; H, 5.46; N, 21.70. Found: C, 41.70; H, 5.67; N, 21.47.
6-Amino-4,5-dihydro-8H-1-(2-C-methyl-b-D-
ribofuranosyl)imidazo[4,5-e][1,3]diazepine-4,8-dione (17)
To a stirred solution of compound 13 (210 mg, 0.33 mmol) and guanidine
hydrochloride (125 mg, 1.31 mmol) in MeOH (20 mL), 1 mL of 25% NaOMe in
MeOH was added. The reaction mixture was stirred at rt overnight and evaporated.
The solid was recrystallized from MeOH to give compound 17 as a white solid
1
(70 mg, 0.22 mmol, 66%). H NMR (D2O, 500 MHz): d 8.28 (s, 1H), 6.70 (s, 1H),
3.91–3.99 (m, 3H), 3.79 (dd, 1H, J ¼ 4.5, 14.0 Hz), 0.84 (s, 3H); 13C NMR (D2O,
125 MHz): d 169.05, 165.13, 163.31, 139.03, 129.23, 92.31, 81.78, 79.52, 72.08,
59.82, 57.54, 18.88; UV (H2O): kmax 234 nm. Anal. calcd for C12H15N5O6: C,
44.31; H, 4.65; N, 21.53. Found: C, 44.17; H, 4.64; N, 21.41.
2,6-Dichloro-9-(2-C-methyl-b-D-ribofuranosyl)-3-deazapurine (18)
Compound 14 (580 mg, 0.90 mmol) was converted to compound 18 as a white
solid (CH2Cl2=MeOH ¼ 8=1, 220 mg, 0.66 mmol, 73%) using the same conditions
1
used in the synthesis of compound 15. H NMR (CD3OD, 500 MHz): d 8.95 (s,
1H), 7.93 (s, 1H), 6.02 (s, 1H), 4.06–4.13 (m, 3H), 3.87 (dd, 1H, J ¼ 2.5, 13.0 Hz),

2996
M. J. KIM
0.91 (s, 3H); 13C NMR (CD3OD, 125 MHz): d 145.06, 141.87, 141.02, 140.08, 136.65,
106.62, 93.10, 83.41, 76.72, 71.98, 59.28, 18.95; UV (MeOH): kmax 276 nm. Anal.
calcd. for C12H13Cl2N3O4: C, 43.13; H, 3.92; N, 12.58. Found: C, 43.10; H, 3.96;
N, 12.48.
6-Amino-2-chloro-9-(2-C-methyl-b-D-ribofuranosyl)-3-deazapurine (19)
A solution of compound 18 (190 mg, 0.57 mmol) in liquid ammonia (20 mL)
was heated in a sealed steel reaction vessel at 160 ꢀC for 5 days and cooled to rt.
The residue was purified by silica-gel column chromatography (CH2Cl2=
MeOH ¼ 5=1) to give compound 19 as a white solid (105 mg, 0.33 mmol, 60%).
1H NMR (DMSO-d6, 500 MHz): d 8.46 (s, 1H), 6.99 (s, 1H), 6.76 (brs, 2H), 5.81 (s,
1H), 5.78 (s, 1H), 5.34 (brs, 1H), 5.25 (t, 1H, J ¼ 5.0 Hz), 5.20 (m, 1H), 3.91 (m,
1H), 3.85 (dd, 1H, J ¼ 5.0, 12.5 Hz), 3.68 (dd, 1H, J ¼ 4.5, 12.0 Hz), 0.74 (s, 3H);
13C NMR (DMSO-d6, 125 MHz): d 156.92, 150.01, 146.42, 144.55, 100.36, 97.30,
87.82, 83.58, 76.91, 64.39, 60.17, 25.17; UV (MeOH): kmax 274 nm. Anal. calcd. for
C12H15ClN4O4: C, 45.80; H, 4.80; N, 17.80. Found: C, 45.66; H, 4.92; N, 17.68.
6-Amino-9-(2-C-methyl-b-D-ribofuranosyl)-3-deazapurine (20)
A solution of compound 19 (130 mg, 0.41 mmol), Pd=C (100 mg), and
1N-NaOH (2 mL) in EtOH (20 mL) was stirred at rt overnight under a hydrogen
atmosphere. The reaction mixture was filtered through a celite pad, and the filtrate
was evaporated. The residue was purified by silica-gel column chromatography
(CH2Cl2=MeOH ¼ 5=1) to give compound 20 as a white solid (75 mg, 0.27 mmol,
1
65%). H NMR (CD3OD, 500 MHz): d 8.70 (s, 1H), 7.74 (d, 1H, J ¼ 6.5 Hz), 7.10
(d, 1H, J ¼ 6.5 Hz), 5.97 (s, 1H), 4.06–4.13 (m, 3H), 3.89 (dd, 1H, J ¼ 2.5,
13.0 Hz), 0.91 (s, 3H); 13C NMR (CD3OD, 125 MHz): d 140.72, 138.48, 136.88,
98.02, 92.78, 83.07, 78.82, 72.03, 60.16, 59.48, 18.96; UV (H2O): kmax 265 nm. Anal.
calcd. for C12H16N4O4: C, 51.42; H, 5.75; N, 19.99. Found: C, 51.22; H, 5.56; N,
19.68.
1-Azido-2-C-methyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose (21)
To a stirred solution of compound 10 (333 mg, 0.57 mmol) and TMSN3
(0.09 mL, 0.69 mmol) in CH2Cl2 (3 mL), 1 M SnCl4 in CH2Cl2 (0.03 mL) was added.
The reaction mixture was stirred at rt for 18 h, quenched with aqueous NaHCO3
solution, and extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered,
and evaporated. The residue was purified by silica-gel column chromatography
(hexane=EtOAc ¼ 6=1) to give compound 21 as a colorless oil (217 mg, 0.43 mmol,
1
75%). H NMR (CDCl3, 500 MHz): d 7.37–8.09 (m, 15H), 6.14 (s, 1H), 5.73 (d,
1H, J ¼ 7.5 Hz), 4.73 (dd, 1H, J ¼ 4.5, 12.5 Hz), 4.63 (m, 1H), 4.54 (dd, 1H,
J ¼ 5.0, 12.5 Hz), 1.79 (s, 3H); 13C NMR (CDCl3, 125 MHz): d 166.22, 165.48,
165.05, 133.76, 133.57, 133.17, 129.92, 129.76, 129.72, 128.95, 128.62, 128.61,
128.40, 93.45, 86.65, 78.68, 76.20, 64.06, 16.68. Anal. calcd. for C27H23N3O7: C,
64.67; H, 4.62; N, 8.38. Found: C, 64.52; H, 4.58; N, 8.37.

SYNTHESIS OF 20-C-METHYL RIBONUCLEOSIDE ANALOGUES
2997
Methyl 1-(2-C-Methyl-2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)-
1,2,3-triazole-4-carboxylate (22)
A solution of compound 21 (177 mg, 0.35 mmol) and methyl propiolate
(0.04 mL, 0.46 mmol) in DME (5 mL) was refluxed overnight. The mixture was cooled
to rt and evaporated. The residue was purified by silica-gel column chromatography
(hexane=EtOAc ¼ 1=1) to give compound 22 as a pale yellow foam (130 mg,
0.22 mmol, 63%) and 1,5-regioisomer as a pale yellow foam (7 mg, 0.01 mmol, 3%).
1H NMR (CDCl3, 500 MHz): d 7.38–8.11 (m, 15H), 7.27 (s, 1H), 6.89 (s, 1H), 6.12
(d, 1H, J ¼ 7.0 Hz), 4.79–4.90 (m, 3H), 3.97 (s, 3H), 1.51 (s, 3H); 13C NMR (CDCl3,
125 MHz): d 166.26, 165.32, 165.17, 160.82, 139.81, 133.93, 133.84, 133.30, 129.92,
129.89, 129.82, 129.62, 129.44, 128.72, 128.62, 128.49, 127.73, 91.53, 86.16, 80.12,
75.80, 63.76, 52.34, 17.27; UV (MeOH): kmax 228 nm. Anal. calcd. for
C31H27N3O9: C, 63.59; H, 4.65; N, 7.18. Found: C, 63.50; H, 4.68; N, 7.12.
1H NMR (CDCl3, 500 MHz) of 1,5-isomer: d 7.40–8.18 (m, 15H), 7.01 (s, 1H),
6.96 (s, 1H), 6.37 (d, 1H, J ¼ 7.0 Hz), 5.04 (m, 1H), 4.76–4.86 (m, 2H), 3.99 (s, 3H),
1.62 (s, 3H).
Methyl 1-(2-C-Methyl-2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)-
1,2,3-triazole-4,5-di-carboxylate (23)
A solution of compound 21 (190 mg, 0.38 mmol) and dimethyl acetylenedicar-
boxylate (0.06 mL, 0.49 mmol) in DME (8 mL) was refluxed overnight. The mixture
was cooled to rt and evaporated. The residue was purified by silica-gel column
chromatography (hexane=EtOAc ¼ 1=1) to give compound 23 as a pale yellow foam
1
(140 mg, 0.22 mmol, 57%). H NMR (CDCl3, 500 MHz): d 7.32–8.15 (m, 15H), 6.30
(d, 1H, J ¼ 9.0 Hz), 4.93 (m, 1H), 4.84 (m, 1H), 4.7 (m, 1H), 4.11 (s, 3H), 4.01 (s, 3H),
1.51 (s, 3H); 13C NMR (CDCl3, 125 MHz): d 166.20, 165.16, 160.16, 158.59, 133.85,
133.80, 133.13, 132.14, 130.37, 129.97, 129.82, 129.48, 128.91, 128.70, 128.67, 128.63,
128.39, 128.33, 90.31, 87.44, 79.67, 76.23, 64.27, 54.05, 52.82, 17.04; UV (MeOH):
kmax 230 nm. Anal. calcd. for C33H29N3O11: C, 61.58; H, 4.54; N, 6.53. Found: C,
61.49; H, 4.56; N, 6.50.
1-(2-C-Methyl-b-D-ribofuranosyl)-1,2,3-triazole-4-carboxamide (24)
Compound 22 (130 mg, 0.22 mmol) was converted to compound 24 as a white
solid (CH2Cl2=MeOH ¼ 5=1, 50 mg, 0.19 mmol, 87%) using the same conditions used
in the synthesis of compound 15. 1H NMR (CD3OD, 500 MHz): d 8.84 (s, 1H), 6.10
(s, 1H), 4.14 (m, 2H), 4.00 (dd, 1H, J ¼ 2.0, 12.5 Hz), 3.85 (dd, 1H, J ¼ 3.0, 12.5 Hz),
0.92 (s, 3H); 13C NMR (CD3OD, 125 MHz): d 163.13, 142.42, 124.88, 96.03, 83.78,
78.99, 72.22, 60.15, 18.42; UV (MeOH): kmax 212 nm. Anal. calcd. for C9H14N4O5:
C, 41.86; H, 5.46; N, 21.70. Found: C, 41.60; H, 5.56; N, 21.62.
1-(2-C-Methyl-b-D-ribofuranosyl)-1,2,3-triazole-4,5-di-carboxamide (25)
Compound 23 (120 mg, 0.19 mmol) was converted to compound 25 as a white
solid (CH2Cl2=MeOH ¼ 5=1, 40 mg, 0.13 mmol, 71%) using the same conditions used

2998
M. J. KIM
1
in the synthesis of compound 15. H NMR (CD3OD, 500 MHz): d 7.25 (s, 1H),
4.23–4.27 (m, 2H), 3.75–3.97 (m, 2H), 0.96 (s, 3H); 13C NMR (CD3OD,
125 MHz): d 163.74, 159.18, 138.95, 132.02, 94.89, 84.6, 79.55, 73.94, 62.59, 18.07;
UV (MeOH): kmax 217 nm. Anal. calcd. for C10H15N5O6: C, 39.87; H, 5.02; N,
23.25. Found: C, 39.66; H, 5.12; N, 23.12.
1-Azido-2-C-methyl-b-D-ribofuranose (26)
Compound 21 (250 mg, 0.50 mmol) was converted to compound 26 as a
colorless foam (CH2Cl2=MeOH ¼ 7=1, 80 mg, 0.42 mmol, 85%) using the same con-
ditions used in the synthesis of compound 15. 1H NMR (CD3OD, 500 MHz): d 5.13
(s, 1H), 4.11 (m, 1H), 3.78 (m, 2H), 3.63 (dd, 1H, J ¼ 6.0, 14.0 Hz), 1.30 (s, 3H);
13C NMR (CD3OD, 125 MHz): d 98.28, 87.80, 80.68, 78.06, 62.63, 18.29. Anal.
calcd. for C6H11N3O4: C, 38.10; H, 5.86; N, 22.21. Found: C, 37.98; H, 5.94; N,
22.10.
5-Amino-1-(2-C-methyl-b-D-ribofuranosyl)-1,2,3-triazole-4-
carboxamide (27)
K2CO3 (210mg, 1.27mmol) was added to a stirred solution of 2-cyanoacetamide
(107mg, 1.27mmol) in DMSO (5 mL) at rt. The mixture was stirred at rt for 1 h, and a
solution of compound 26 (80 mg, 0.42mmol) in DMSO (5 mL) was added. The reaction
mixture was stirred at 50ꢀC for 16h and evaporated. The residue was purified by
silica-gel column chromatography (CH2Cl2=MeOH¼ 5=1) to give compound 27 as a
1
white solid (50 mg, 0.18mmol, 43%). H NMR (CD3OD, 500 MHz): d 5.99 (s, 1H),
4.24 (d, 1H, J ¼ 9.0 Hz), 4.03 (m, 1H), 3.98 (dd, 1H, J ¼ 5.0, 12.0Hz), 3.85 (dd, 1H,
J ¼ 3.5, 12.5Hz), 1.03 (s, 3H); 13C NMR (CD3OD, 125 MHz): d 165.65, 145.40,
121.68, 94.77, 82.82, 78.99, 73.04, 59.83, 19.02; UV (MeOH): kmax 260 nm, 234 nm.
Anal. calcd. for C9H15N5O5: C, 39.56; H, 5.53; N, 25.63. Found: C, 39.36; H, 5.46;
N, 25.40.
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