Synthesis and biological evaluation of novel isonucleosides with 1,2,4-triazole-3-carboxamide

Article abstract of DOI:10.1080/00397910500213864

Novel 1,2,4-triazole isonucleosides (1 and 2) were efficiently synthesized starting from D-ribose and D-xylose, respectively. The key steps were condensation of cyclic sulfate 8 with methyl-1,2,4-triazole-3-carboxylate and nucleophilic displacement of the

Full text of DOI:10.1080/00397910500213864

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Synthesis and Biological
Evaluation of Novel
Isonucleosides with
1,2,4‐Triazole‐3‐Carboxamide
Myong Jung Kim a b , Soon Yong Chung a & Moon Woo
Chun a
a Research Institute of Pharmaceutical Sciences,
College of Pharmacy , Seoul National University ,
Seoul, Korea
b Department of Pharmaceutical and Biomedical
Sciences, College of Pharmacy , University of
Georgia , Athens, Georgia, USA
Published online: 22 Aug 2006.
To cite this article: Myong Jung Kim , Soon Yong Chung & Moon Woo Chun
(2005) Synthesis and Biological Evaluation of Novel Isonucleosides with
1,2,4‐Triazole‐3‐Carboxamide, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 35:20, 2653-2663
To link to this article: http://dx.doi.org/10.1080/00397910500213864
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Synthetic Communicationsw, 35: 2653–2663, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500213864
Synthesis and Biological Evaluation of Novel
Isonucleosides with 1,2,4-Triazole-
3-Carboxamide
Myong Jung Kim
Research Institute of Pharmaceutical Sciences, College of Pharmacy,
Seoul National University, Seoul, Korea and Department of
Pharmaceutical and Biomedical Sciences, College of Pharmacy,
University of Georgia, Athens, Georgia, USA
Soon Yong Chung and Moon Woo Chun
Research Institute of Pharmaceutical Sciences, College of Pharmacy,
Seoul National University, Seoul, Korea
Abstract: Novel 1,2,4-triazole isonucleosides (1 and 2) were efficiently synthesized
starting from D-ribose and D-xylose, respectively. The key steps were condensation
of cyclic sulfate 8 with methyl-1,2,4-triazole-3-carboxylate and nucleophilic displace-
ment of the tosylate 15 with methyl-1,2,4-triazole-3-carboxylate, respectively.
Keywords: Antiviral agent, IMPDH, isonucleoside, 1,2,4-trizole
INTRODUCTION
Ribavirin (1-b-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a synthetic
purine nucleoside analog that is structurally similar to guanine and inosine.
It shows broad-spectrum antiviral activity against a variety of both DNA
and RNA viruses[1–3] and is currently clinically used in combination with
interferon-a (IFN-a) to treat hepatitis C virus[4] infection and as monotherapy
for Lassa fever virus infection[5] and severe respiratory syncytial virus
infection.[6] It has been suggested that ribavirin monophosphate (RMP), the
Received in the USA May 18, 2005
Address correspondence to Myong Jung Kim, Research Institute of Pharmaceutical
Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
2653

2654
M. J. Kim, S. Y. Chung, and M. W. Chun
active form of ribavirin, inhibits inosine monophosphate dehydrogenase
(IMPDH) activity in vitro and in vivo.[7] IMPDH catalyzes the NADþ-
dependent oxidation of inosine 50-monophosphate (IMP) to xanthine 50-
monophosphte (XMP), the rate limiting step in de novo biosynthesis of
guanine nucleotides. Therefore, inhibition of IMPDH results in a decrease
in the intracellular concentration of guanine nucleotide,[8] blocking DNA
and RNA synthesis. An alternative mechanism of action for ribavirin is
inhibition of viral-encoded polymerase and genomic RNA capping.
In antiviral chemotherapy, toxicity and emerging drug-resistant virus
strains are major problems.[9] To overcome these drawbacks, a number
of structurally modified nucleosides have been synthesized. Among them,
isonucleosides in which the base is transposed from the natural 10-position to
isomeric 20-position have been reported to have antiviral activities.[10] This
class of nucleosides has attracted much attention because of the stabilization
of the glycosyl bond and metabolic resistance to adenosine deaminase.[10a,11,12]
Based on these findings, it was very interesting to design and synthesize
1,2,4-triazole isonucleosides. Here we report the synthesis of novel (2S,4S)-
isonucleosides with triazole base moiety (Figure 1).
RESULTS AND DISCUSSION
Our synthetic strategies to the target 1,2,4-triazole isonucleosides are to
condense cyclic sulfate and alkylate 1,4-anhydro-D-ribitol derivative with
methyl-1,2,4-triazole-3-carboxylate, respectively.
Figure 1. Rationale to the target nucleosides.

Evaluation of Novel Isonucleosides
2655
Synthesis of cyclic sulfate derivative 8, a key intermediate for
3-carboxamido-1-(3-hydroxy-2-hydroxymethyl-tetrahydrofuran-4-yl)-1,2,4-
triazole 1, could be achieved starting from 2,3-isopropylidene-1-methyl-
D-furanoside 3, which could be easily synthesized from D-ribose and is
shown in Scheme 1.
The 5-hydroxy group of 3 was protected with a benzyl group to give the
benzylate 4, in which the 2,3-isopropylidene group was removed by treatment
of Dowex 50Hþ resin in MeOH to afford the diol 5. To remove the methoxy
group at the anomeric position, two hydroxy groups of compound 5 were
protected in situ as trimethylsilyl (TMS) ether on reflux with hexamethyldisi-
lazane (HMDS), and then this intermediate was treated with trimethylsilyl
triflate (TMSOTf) and triethylsilane to give the 1,4-anhydro ribitol derivative
6.[13] Compound 6 reacted with thionyl chloride to afford the cyclic sulfite 7,
which was oxidized with RuCl3/NaIO4 to give the cyclic sulfate 8 as a key
intermediate.
Cyclic sulfate 8 was condensed with methyl-1,2,4-triazole-3-carboxylate
by the procedure described by Nair[14] to give a mixture of two isomeric
Scheme 1. Reagents and conditions: (a) BnBr, NaH, TBAI, THF, rt, 18 h;
(b) Dowex50Hþ, MeOH, rt, 3 day; (c) (1) HMDS, (NH4)2SO4, reflux, 2 h; (2)
Et3SiH, TMSOTf, CH2Cl2, rt, 3 h; (d) SOCl2, pyridine, rt, 3 h; (e) NaIO4/RuCl3,
CCl4/CH3CN/H2O, rt, 30 min; (f) methyl-1,2,4-triazole-3-carboxylate, DBU,
CH3CN, 758C, 2 h; (g) 2% HCl, MeOH, 458C, 18 h; (h) NH3/MeOH, rt, 16 h;
(i) Pd/C, EtOH, H2, rt, 18 h.

2656
M. J. Kim, S. Y. Chung, and M. W. Chun
products 9a and 9b, which could not be separated by silica-gel column chro-
matography. The mixture was treated with 2% aqueous HCl in MeOH to afford
the 3-substituted N1-b-nucleoside 10a and 5-substituted N1-b-nucleoside 10b
in ratio of 3.7/1, respectively. The structural assignments of the regioisomers,
10a and 10b, were readily made by the comparison of their 1H NMR data. The
signals for 3-H of minor isomer 10b (d5.59) appeared at a lower field than did
the signal for the major isomer 10a (d4.88) because of the deshielding effect
of carbonyl group. Ammonolysis of 10a using methanolic ammonia gave the
amide 11, which was deprotected by catalytic dehydrogenation to provide the
desired 1,2,4-triazole isonucleoside 1.
The synthesis of 3-carboxamido-1-(2,3-di-hydroxymethyl-tetrahydrofuran-
4-yl)-1,2,4-triazol 2 is outlined in Scheme 2. 5-O-Benzyl-3-benzyloxymethyl-
3-deoxy-1,2-O-isopropylidene-a-D-ribofuranose 12 was easily prepared from
D-xylose,[15] which was treated with 1% HCl in MeOH to afford the methyl
riboside 13. The methoxy group at the anomeric position was removed as
described for compound 5 to afford the 1,4-anhydro-D-ribitol 14. To
introduce the triazole base moiety into the sugar ring, the hydroxy group of
14 was converted into the tosylate and triflate, respectively. Attempted nucleo-
philic displacements of the tosylate and triflate derivative with the sodium salt
of methyl-1,2,4-triazole-3-carboxylate in DMF provided the desired product
16 in low yield (,10%). However, the triazole anion derived from deprotona-
tion of methyl-1,2,4-triazole-3-carboxylate with DBU in acetonitrile reacted
with the tosylate 15 to afford the desired triazole-isonucleoside 16 in 55%
yield. Compound 16 was treated with methanolic ammonia to give the
amide 17, of which the benzyl group was deprotected using catalytic hydro-
genation to yield the 1,2,4-triazole isonucleoside 2.
In summary, we have efficiently synthesized 1,2,4-triazole isonucleosides
1 and 2 by condensation of cyclic sulfate 8 with methyl-1,2,4-triazole-3-
carboxylate and nucleophilic displacement of the tosylate 15 with methyl-
1,2,4-triazole-3-carboxylate, respectively.
Scheme 2. Reagents and conditions: (a) 1% HCl in MeOH, rt, 3h; (b) (1) HMDS,
(NH4)2SO4, reflux, 2 h; (2) Et3SiH, TMSOTf, CH2Cl2, rt, 3 h; (c) TsCl, CH2Cl2,
DMAP, rt, 18 h; (d) methyl-1,2,4-triazole-3-carboxylate, DBU, CH3CN, 758C, 18 h;
(e) NH3/MeOH, rt, 14 h; (f) H2, Pd/C, EtOH, rt, 20 h.

Evaluation of Novel Isonucleosides
EXPERIMENTAL
2657
General Methods
NMR spectra were recorded in a 300-MHz apparatus using tetramethylsilane
(TMS) as an internal standard, and the chemical shifts are reported in ppm (d).
Coupling constants are reported in hertz (Hz). Infrared spectra were recorded
in a Perkin-Elmer 1710 FTIR spectrophotometer. Mass spectra recorded by
FAB (fast atom bombardment) on a VG Tro-2, GC-MS. TLC were 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.
1-O-Methyl-5-O-benzyl-2,3-O-isopropylidene-
b-D-ribofuranoside (4)
A solution of 3 (4.26 g, 20.9 mmol) in anhydrous THF (15 mL) was added to a
stirred solution of 60% suspension of NaH in mineral oil (1.24 g, 31.3 mmol)
and n-Bu4NI (2.31 g, 6.26 mmol) in anhydrous THF (40 mL). The mixture was
stirred for 30 min at rt and cooled to 08C. BnBr (3.7 mL, 31.3 mmol) was
added to this solution. After being stirred for 18 h at rt, the reaction mixture
was quenched with ice water and poured into EtOAc. The organic layer was
washed with sat. NaHCO3 solution and brine, dried (MgSO4), filtrated, and
evaporated. The residue was purified by silica-gel column chromatography
(Hex : EtOAc ¼ 6 : 1) to give 4 (4.91 g, 16.7 mmol, 80%).
1H NMR (CDCl3, 300 MHz): d 7.27–7.35 (m, 5H), 4.96 (s, 1H), 4.69 (dd,
1H, J ¼ 0.8, 5.9 Hz), 4.51–4.59 (m, 3H), 4.35–4.40 (m, 1H), 3.39–3.55
(m, 2H), 3.29 (s, 3H), 1.48, 1.31 (2s, 6H); FAB-MS m/z: 295 [M þ H]þ.
Anal. calcd. for C16H22O5: C, 65.29; H, 7.53. Found: C, 65.08; H, 7.69.
1-O-Methyl-5-O-benzyl-b-D-ribofuranoside (5)
A suspension of 4 (2.05 g, 6.96 mmol) and Dowex 50 Hþ in MeOH (20 mL)
was stirred for 3 days at rt and filtered through a silica-gel pad (washed
with CH2Cl2). The filtrate was evaporated. The residue was purified by
silica-gel column chromatography (Hex : EtOAc ¼ 1 : 2) to give 5 (1.5 g,
5.9 mmol, 85%).
1H NMR (CDCl3, 300 MHz): d 7.27–7.48 (m, 5H), 4.81 (s, 1H),
4.53–4.62 (m, 2H), 4.05–4.15 (m, 2H), 3.97 (d, 1H, J ¼ 4.6 Hz), 3.59
(d, 2H, J ¼ 5.5 Hz), 3.32 (s, 3H), 3.12, 2.05 (2s, 2H); FAB-MS m/z:
255[M þ H]þ. Anal. calcd. for C13H18O5: C, 61.40; H, 7.14. Found: C,
61.28; H, 7.22.

2658
M. J. Kim, S. Y. Chung, and M. W. Chun
1,4-Anhydro-5-O-benzyl-D-ribitol (6)
A solution of 5 (1.4 g, 5.51 mmol) and ammonium sulfate (catalytic amount,
73 mg, 0.6 mmol) in HMDS (15 mL) was refluxed for 2 h and evaporated
under anhydrous conditions. The residue was dissolved in CH2Cl2 (15 mL),
and then Et3SiH (4.4 mL, 27.6 mmol) and TMSOTf (5.3 mL, 27.6 mmol)
were added to this solution. The mixture was stirred for 1.5 h at rt,
quenched with sat. NaHCO3 solution, and extracted with CH2Cl2 (ꢀ3). The
combined organic layers were washed with brine, dried (MgSO4), filtrated,
and evaporated. The residue was purified by silica-gel column chromato-
graphy (Hex : EtOAc ¼ 1 : 3) to give 6 (1.01 g, 4.5 mmol, 82%).
1H NMR (CDCl3, 300 MHz): d 7.26–7.37 (10H, m), 4.60–4.52 (m, 4H),
4.18 (m, 1H), 4.06 (dd, 1H, J ¼ 4.8, 10.0 Hz), 3.96–4.01 (m, 1H), 3.85–3.91
(m, 1H), 3.75(dd, 1H, J ¼ 3.5, 9.9 Hz), 3.63 (dd, 1H, J ¼ 4.0, 10.7 Hz), 3.56
(dd, 1H, J ¼ 5.0, 10.7 Hz), 3.17–3.19 (m, 2H); FAB-MS m/z: 225[M þ H]þ.
Anal. calcd. for C12H16O4: C, 64.27; H, 7.19. Found: C, 64.04; H, 7.16.
1,4-Anhydro-5-O-benzyl-2,3-cyclicsulfate-D-ribitol (7)
Thionyl chloride (1.65 mL, 22.5mmol) was added to a stirred solution of 6
(1.01 g, 4.5 mmol) in pyridine (20 mL) at 08C. The reaction mixture was
stirred for 3 h at rt and evaporated. The residue was partitioned between
CH2Cl2 and water. The organic layer was washed with brine, dried (MgSO4),
filtrated, and evaporated. The residue was purified by silica-gel column chrom-
atography (Hex : EtOAc ¼ 2 : 1) to give 7 (1.01g, 3.74mmol, 83%).
1H NMR (CDCl3, 300 MHz): d 7.26–7.39 (m, 10H), 5.31–5.36 (m, 1H),
5.27 (dd, 1H, dd, J ¼ 2.0, 5.8 Hz), 4.59–4.47 (2H, m, 2 ꢀ Bn), 4.35 (dd, 1H,
J ¼ 4.9, 10.6 Hz), 4.26 (dd, 1H, J ¼ 2.4, 10.6 Hz), 3.70 (m, 2H); FAB-MS
m/z: 271[M þ H]þ. Anal. calcd. for C12H14O5S: C, 53.32; H, 5.22; S,
11.86. Found: C, 53.14; H, 5.34; S, 11.78.
(30R,40R)-1-(20-Benzyloxymethyl-30-hydroxytetrahydrofuran-40-yl)-
3-methoxycarbonyl-1,2,4-triazole(10a) and (30R,40R)-1-(20-
Benzyloxymethyl-30-hydroxytetrahydrofuran-40-yl)-5-
carboxamido-1,2,4-triazole (10b)
.
NaIO4 (580 mg, 2.7 mmol) and RuCl3 H2O (catalytic amount, 10 mg) were
added to a stirred solution of 7 (488 mg, 1.8 mmol) in CCl4/CH3CN/H2O
(1/1/1.5, 17.5 mL). The reaction mixture was stirred for 30 min at rt and
filtered through a silica-gel pad (washed with EtOAc). The filtrate was
washed with brine, dried (MgSO4), filtrated, and evaporated to give crude 8.
DBU (0.28 mL, 3.8 mmol) was added to a suspension of methyl-1,2,4-
triazole-3-carboxylate (459 mg, 3.62 mmol) in anhydrous CH3CN (40 mL).

Evaluation of Novel Isonucleosides
2659
The suspension was stirred for 30 min at rt. A solution of sulfate (8) in CH3CN
(18 mL) was added to this resulting clear solution and the reaction mixture was
heated at 708C for 2 h. The solvent was removed under reduced pressure and
the residue was purified by silica-gel column chromatography
(CH2Cl2 : MeOH ¼ 10 : 1) to give 9a and 9b as mixture (740 mg,
1.44 mmol, 80%).
A solution of 9a and 9b (740 mg, 1.44 mmol) in 2% HCl in
MeOH(20 mL) was stirred at 458C for 18 h and evaporated. The residue was
purified by silica-gel column chromatography (Hex : EtOAc ¼ 1 : 2) to give
10a (320 mg, 0.96 mmol, 67%) and 10b (85 mg, 0.25 mmol, 18%)
1
10a: H NMR (CDCl3, 300 MHz):): d 8.37 (s, 1H), 7.19–7.46 (m, 5H),
4.88 (dd, 1H, J ¼ 4.6, 8.8 Hz), 4.52–4.62 (m, 2H), 4.31 (d, 2H, J ¼ 5.3 Hz),
3.96–4.01 (m, 4H), 3.67 (m, 2H), 2.97 (d, 1H, J ¼ 3.3 Hz); IR (KBr):
3394, 2870, 1738, 1467, 1231, 1170, 1087 cm21; FAB-MS m/z: 356
[M þ Na]þ, 334 [M þ H]þ. Anal. calcd. for C16H19N3O5: C, 57.65; H, 5.75;
N, 12.61. Found: C, 57.54; H, 5.84; N, 12.42.
1
10b: H NMR (CDCl3, 300 MHz): d 7.98 (s, 1H), 7.25–7.34 (m, 5H),
5.59 (dd, 1H, J ¼ 4.2, 8.0 Hz), 4.49–4.60 (m, 3H), 4.31–4.46 (m, 2H),
4.00–4.06 (m, 4H), 3.68–3.76 (m, 2H), 2.89 (brs, 1H); IR (KBr): 3332,
2868, 1733, 1273, 1094 cm21; FAB-MS m/z: 334 [M þ H]þ.
(30R,40R)-1-(20-Benzyloxymethyl-30-hydroxytetrahydrofuran-40-yl)-
3-carboxamido-1,2,4-triazole (11)
A solution of 10a (223 mg, 0.67 mmol) in methanolic ammonia (15 mL) was
stirred for 16 h at rt and evaporated. The residue was purified by silica-gel
column chromatography (Hex : EtOAc ¼ 1 : 4) to give 11 (181.4 mg,
0.57 mmol, 85%).
1H NMR (CDCl3, 300 MHz): d 8.36 (s, 1H), 7.25–7.31 (m, 10H), 7.15,
6.29 (2brs, 2H), 6.29 (s, 1H), 4.52–4.56 (m, 3H), 4.26–4.29 (m, 2H), 3.99
(m, 1H), 3.63–3.73 (m, 2H); IR (KBr): 3327, 2870, 1685, 1292,
1085 cm21; FAB-MS m/z: 319 [M þ H]þ, 341[M þ Na]þ. Anal. calcd. for
C15H18N4O4: C, 56.60; H, 5.70; N, 17.60. Found: C, 57.58; H, 5.80; N, 17.52.
(30R,40R)-3-Carboxamido-1-(30-hydroxy-20-hydroxymethyl-
tetrahydrofuran-40-yl)-1,2,4-triazole (1)
A suspension of 11 (181 mg, 0.57 mmol) and Pd/C (80 mg) in EtOH (10 mL)
was degassed and hydrogenated under hydrogen atmosphere for 18 h at rt. The
reaction mixture was filtered through silica-gel pad (washed with MeOH) and
the filtrate was evaporated. The residue was purified by silica-gel column
chromatography (CH2Cl2 : MeOH ¼ 7 : 1) to give 1 (118 mg, 0.52 mmol,
91%).

2660
M. J. Kim, S. Y. Chung, and M. W. Chun
1H NMR (300 MHz, DMSO-d6): d 8.65 (s, 1H), 7.77, 7.56 (2s, 2H), 5.76
(d, 1H, J ¼ 5.5 Hz), 4.81–4.88 (m, 2H), 4.26 (dd, 1H, J ¼ 5.1, 11.6 Hz), 4.12
(dd, 1H, J ¼ 6.7, 9.7 Hz), 4.04 (dd, 1H, J ¼ 5.3, 9.8 Hz), 3.42–3.68 (m, 3H);
IR (KBr): 3399, 1686, 1296, 1079 cm21; FAB-MS m/z: 229 [M þ H]þ, 251
[M þ Na]þ. Anal. calcd. for C8H12N4O4: C, 42.10; H, 5.30; N, 24.55.
Found: C, 41.95; H, 5.54; N, 24.12.
5-O-Benzyl-3-C-benzyloxymethyl-3-deoxy-1-O-methyl-a,b-D-
ribofuranoside (13)
A solution of 12 (3.39 g, 8.82 mmol) in 1% HCl in MeOH (25 mL) was stirred
for 1.5 h at rt, and then neutralized with pyridine and evaporated. The residue
was purified by silica-gel column chromatography (Hex : EtOAc ¼ 2 : 1) to
give 13 (2.97 g, 8.29 mmol, 94%).
1H NMR (CDCl3, 300 MHz): d 7.26–7.34 (m, 10H), 4.81 (s, 1H), 4.57–
4.62 (m, 4H), 4.31–4.38 (m, 1H), 4.23 (t, 1H, J ¼ 4.4 Hz), 3.72–3.80 (m, 2H),
3.54–3.56 (m, 2H), 3.32 (s, 3H), 2.94 (d, 1H, J ¼ 3.90 Hz), 2.37–2.44
(m, 1H); FAB-MS m/z: 381[M þ Na]þ. Anal. calcd. for C21H26O5: C,
70.37; H, 7.31. Found: C, 70.24; H, 7.40.
1,4-Anhydro-5-O-benzyl-3-C-benzyloxymethyl-3-deoxy-D-
ribitol (14)
A solution of 13 (2.97 g, 8.29 mmol) and ammonium sulfate (catalytic
amount) in HMDS (20 mL) was refluxed for 2 h, cooled to rt, and evaporated
to dryness. The residue was dissolved in CH2Cl2 (20 mL), and then Et3SiH
(6.63 mL, 41.5 mmol) and TMSOTf (8.02 mL, 41.5 mmol) were added to
this solution. The mixture was stirred for 1.5 h at rt, quenched with sat.
NaHCO3 solution, and extracted with CH2Cl2 (ꢀ3). The combined organic
layers were dried (MgSO4), filtrated, and evaporated. The residue was
purified by silica-gel column chromatography (Hex : EtOAc ¼ 1 : 1) to give
14 (2.4 g, 7.3 mmol, 88%).
1H NMR (CDCl3, 300 MHz): d 7.26–7.36 (m, 10H), 4.46–4.61 (m, 5H),
4.08 (m, 1H), 4.03 (dd, 1H, J ¼ 9.8, 4.1 Hz), 3.78 (dd, 1H, J ¼ 2.2, 9.8 Hz),
3.70 (d, 2H, J ¼ 6.3 Hz), 3.51–3.60 (m, 2H), 2.60 (s, 1H), 2.33 (m, 1H);
FAB-MS m/z: 329[M þ H]þ, 351[M þ Na]þ. Anal. calcd. for C20H24O4:
C, 73.15; H, 7.37. Found: C, 72.98; H, 7.52.
1,4-Anhydro-5-O-benzyl-3-C-benzyloxymethyl-3-deoxy-2-O-p-
toluenesulfonyl-D-ribitol (15)
A solution of 14 (528 mg, 7.3 mmol), DMAP (3.93 mg, 3.22 mmol), and TsCl
(460 mg, 2.41 mmol) in anhydrous CH2Cl2 (8 mL) was stirred for 18 h at rt.

Evaluation of Novel Isonucleosides
2661
The mixure was quenched with ice water and extracted with CH2Cl2 (ꢀ3).
The combined organic layers were washed with brine, dried (MgSO4),
filtrated, and evaporated. The residue was purified by silica-gel column
chromatography (Hex : EtOAc ¼ 3 : 1) to give 15a (740 mg, 1.54 mmol, 96%)
1H NMR (CDCl3, 300 MHz): 7.22–7.77 (m, 12H), 5.14 (m, 1H), 4.43–
4.58 (m, 2H), 4.32–4.39 (m, 2H), 3.89–4.09 (m, 3H), 3.44–3.70 (m, 4H),
2.56 (m, 1H); FAB-MS m/z: 505 [M þ Na]þ. Anal. calcd. for C27H30O6S:
C, 67.20; H, 6.27; S, 6.64. Found: C, 67.04; H, 6.44; S, 6.42.
(30R,40R)-1-(20,30-Di-benzyloxymethyl-tetrahydrofuran-40-yl)-3-
methoxycarbonyl-1,2,4-triazole (16)
A mixture of methyl-1,2,4-triazole-3-carboxylate (342 mg, 1.68 mmol) and
NaH (80 mg, 2.01 mmol) in DMF (10 mL) was stirred for 30 min at rt. A
solution of 15 (647 mg, 1.44 mmol) in DMF (5 mL) was added. The reaction
mixture was stirred at 758C for 18 h, quenched with ice water, and extracted
with EtOAc (ꢀ2). The combined organic layers were dried (MgSO4),
filtrated, and evaporated. The residue was purified by silica-gel column chro-
matography (Hex : EtOAc ¼ 1 : 1) to give 16 (346 mg, 0.79 mmol, 55%).
1H NMR (CDCl3, 300 MHz): d 8.43 (s, 1H), 7.25–7.37 (m, 10H), 4.91
(1H, m, H-40), 4.46–4.63 (m, 4H), 4.02–4.19 (m, 3H), 3.99 (s, 3H) 3.52–
3.77 (m, 4H), 2.75 (1H, m, H-30); IR (KBr): 2862, 1738, 1225, 1097 cm21
;
FAB-MS m/z: 438[M þ H]þ, 460[M þ Na]þ. Anal. calcd. for C24H22N3O5:
C, 65.89; H, 6.22; N, 9.60. Found: C, 65.72; H, 6.30; N, 9.48.
(30R,40R)-1-(20,30-Di-benzyloxymethyl-tetrahydrofuran-40-yl)-3-
carboxamido-1,2,4-triazole (17)
A solution of 16 (340 mg, 0.78 mmol) in methanolic ammonia (15 mL) was
stirred for 14 h at rt and evaporated to dryness. The residue was purified by
silica-gel column chromatography (Hex : EtOAc ¼ 1 : 2) to give 17 (295 mg,
0.70 mmol, 90%).
1H NMR (CDCl3, 300 MHz): d 8.32 (s, 1H), 7.25–7.38 (m, 10H), 6.99,
5.97 (2 ꢀ brs, 2H), 5.01–4.96 (m, 1H), 4.46–4.63 (m, 4H), 4.03–4.21
(m, 3H), 3.48–3.77 (m, 4H), 2.74, (m, 1H); IR (KBr): 3323, 2863, 1692,
1097 cm21; FAB-MS m/z: 423[M þ H]þ, 445[M þ Na]þ. Anal. calcd. for
C23H26N4O4: C, 65.39; H, 6.20; N, 13.26. Found: C, 65.24; H, 6.28; N, 13.19.
(30R,40R)-3-Carboxamido-1-(20,30-di-hydroxymethyl-
tetrahydrofuran-40-yl)-1,2,4-triazole (2)
A suspension of 17 (290 mg, 0.69 mmol) Pd/C (100 mg) in EtOH (10 mL) was
degassed and hydrogenated under a hydrogen atmosphere for 20 h at rt.

2662
M. J. Kim, S. Y. Chung, and M. W. Chun
The reaction mixture was filtered through a silica-gel pad (washed with
MeOH) and the filtrate was evaporated. The residue was purified by silica-
gel column chromatography (CH2Cl2 : MeOH ¼ 7 : 1) to give 2 (151 mg,
0.62 mmol, 91%).
1H NMR (DMSO-d6, 300 MHz): d 8.67 (s, 1H), 7.75, 7.56 (2s, 2H), 4.92–
4.98 (m, 3H), 3.99 (d, 2H, J ¼ 5.9 Hz), 3.70 (m, 1H), 3.47–3.62 (m, 4H), 2.49
(m, 1H); FAB-MS m/z: 243 [M þ H]þ, 265 [M þ Na]þ. Anal. calcd. for
C9H14N4O4: C, 44.63; H, 5.83; N, 23.13. Found: C, 44.38; H, 5.96; N, 22.98.
ACKNOWLEDGMENT
This work was supported by a postdoctoral fellowship from Korea Science &
Engineering Foundation (KOSEF).
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