Synthesis of novel bicyclic nucleosides with 3,6-anhydro sugar moiety

Article abstract of DOI:10.1080/15257770802341269

Based on the biological importance of conformationally restricted nucleoside analogues, we have efficiently synthesized 3,6-anhydro sugar moiety with 3-C-hydroxymethyl substituent from 1,2;5,6-di-O-isopropylidene-D-glucose and condensed 15 with silylated

Full text of DOI:10.1080/15257770802341269

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Synthesis of Novel Bicyclic Nucleosides
with 3,6-Anhydro Sugar Moiety
Myong Jung Kim a b
a Foundation for Applied Molecular Evolution , Gainesville, Florida,
USA
b Department of Chemistry , University of Florida , Gainesville,
Florida, USA
Published online: 11 Sep 2008.
To cite this article: Myong Jung Kim (2008) Synthesis of Novel Bicyclic Nucleosides with 3,6-
Anhydro Sugar Moiety, Nucleosides, Nucleotides and Nucleic Acids, 27:10-11, 1097-1106, DOI:
10.1080/15257770802341269
To link to this article: http://dx.doi.org/10.1080/15257770802341269
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Nucleosides, Nucleotides and Nucleic Acids, 27:1097–1106, 2008
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770802341269
SYNTHESIS OF NOVEL BICYCLIC NUCLEOSIDES WITH
3,6-ANHYDRO SUGAR MOIETY
Myong Jung Kim
Foundation for Applied Molecular Evolution, Gainesville, Florida, USA, and Department of
Chemistry, University of Florida, Gainesville, Florida, USA
Based on the biological importance of conformationally restricted nucleoside analogues, we have
2
efficiently synthesized 3,6-anhydro sugar moiety with 3-C-hydroxymethyl substituent from 1,2;5,6-
di-O-isopropylidene-D-glucose and condensed 15 with silylated nucleobases to afford the bicyclic
nucleoside with 3,6-anhydro skeleton as potential antiviral agent.
Keywords Bicyclic nucleoside; antiviral agents; intramolecular cyclization
INTRODUCTION
Since 3ꢁ-azido-3ꢁ-deoxythymidine (AZT) was approved for the treatment
of acquired immunodeficiency syndrome (AIDS) by the U.S. Food and Drug
Administration (FDA), a number of 2ꢁ,3ꢁ-dideoxynucleosides have been
synthesized and evaluated for antiviral and/or anticancer agents.[1]
It has been suggested that the proper conformation of dideoxynu-
cleosides is required for them to exhibit antiviral activity.[2] The natural
nucleosides equilibrate rapidly between S-type (2ꢁ-endo/3ꢁ-exo) and N-type
(2ꢁ-exo/3ꢁ-endo) conformation in solution state due to the low energy
barrier between these two conformers.[3] However, nucleosides adopt only
one conformation when binding to the target enzyme. Therefore, a con-
siderable amount of work to probe conformational preference for binding
with enzymes and receptors has been done in the synthesis of nucleoside
derivatives with fixed sugar-ring puckering.[4]
In particular, nucleoside analogues containing bicyclic carbohydrate
moiety have been synthesized to lock the puckering of the furanose
Received 8 January 2008; accepted 6 June 2008.
Address correspondence to Myong Jung Kim, Foundation for Applied Molecular Evolution,
1115 NW 4th St., Gainesville, FL, 32601, USA. E-mail: mkim@ffame.org
1097

1098
M. J. Kim
FIGURE 1 The rationale for the design of the target nucleosides.
ring and evaluated for their biological activities. Among them, bicyclic
nucleosides fused with cyclopropane (1),[5] oxirane (2),[6] and oxetane
(3)[7] have been reported to show anti-HIV activity through inhibition of
HIV reversetranscriptase. Similar bicyclic nucleoside (4)[8] also has shown
antiviral activity (Figure 1) and other nucleosides with bicyclic backbone
were synthesized even though no activity was found or reported.
As a part of our ongoing research on the synthesis of conformationally
restricted nucleoside derivatives,[9] we wish to report the synthesis of
novel 3ꢁ-hydroxymethyl bicyclic nucleoside derivatives (5a and 5b) with
3,6-anhydro sugar moiety, starting from 1,2;5,6-di-O-isoprpylidene-D-glucose
as potential antiviral agent.
RESULTS AND DISCUSSION
Our synthetic strategy to the desired bicyclic nucleoside is to synthesize
3,6-anhydro sugar derivative as the key intermediate, and then to carry out a
condensation reaction with nucleosidic base. Synthesis of the key intermedi-
ate from 1,2;5,6-di-O-isopropylidene-D-glucose is depicted in Schemes 1 and
2.
Diacetone-D-glucose 6 was converted to the 3-C-methylene deriva-
tive 7[10] by oxidation with pyridinium dichromate/acetic anhydride in
CH2Cl2 and subsequent Wittig reaction of resulting ketoone with methyl

Synthesis of Novel Bicyclic Nucleosides
1099
triphenylphosphonium bromide/n-butyl lithium in THF. The initial at-
tempt to synthesize the 3-C-branched sugar derivative via regioselective
opening of epoxide ring of 8 with benzyl alcohol in the presence of n-BuLi
was highly motivated, as it was known in the literature.[11] However, in our
hands, the epoxidation of 7 with m-CPBA was problematic. The reaction
yield was poor and long reaction time was required (Scheme 1).
SCHEME 1 (a) i) PDC, Ac2O, CH2Cl2, reflux, 2h; ii) PPh3PCH3Br, n-BuLi, THF, −78◦C to 55◦C; (b)
m-CPBA, CH2Cl2; (c) PhCH2OH, NaH, THF.
To overcome these difficulties, we attempted the alternative synthetic
approach to obtain the 3-C-branched sugar derivative as shown in Scheme 2.
Stereoselective cis-dihydroxylation of 7 using catalytic amount of OsO4 and
NMO led to the diol 10 due to the steric effect of 1,2-isopropylidene group,
and primary hydroxy group of 10 was regioselectively benzylated using
organotin chemistry[12] to afford monobenzyl ether 9. Tertiary hydroxy
group of 9 was acetylated with acetic anhydride in pyridine in the presence
of DMAP at 100◦C to give 3-C-branched derivative 11. For the synthesis of
the key intermediate, we tried to construct the bicyclic system using the
SCHEME 2 (a) OsO4, NMO, acetone:H2O (4:1), rt, 4h, 90%; (b) n-Bu2SnO, toluene, 140◦C, 2 h and
then, n-Bu4NBr, 90◦C, overnight, 75%; (c) Ac2O, pyridine, DMAP, 100◦C, overnight, 90%; (d) i) 75%
AcOH, 55◦C, 2h; ii) SOCl2, pyridine, rt, 3h: (e) NaOMe, MeOH, rt, overnight, 70% from 11.

1100
M. J. Kim
intramolecular regioselective ring opening of cyclic sulfite. After selective
hydrolysis of 5,6-isopropylidene group in 11 with 75% acetic acid, the
resulting diol was treated with thionyl chloride to afford the cyclic sulfite
12. 3,6-Anhydro sugar 13, a key intermediate was prepared by treatment of
compound 12 with sodium methoxide in MeOH.[13]
SCHEME 3 (a) Ac2O, pyridine, rt, 3h, 95%; (b) i) 88% HCO2H, 55◦C, 2h; ii) Ac2O, pyridine, rt,
overnight, 90%; (c) thymine or 6-Chloropurine, TMSOTf, DBU, CH3CN, 60◦C, 3h, 70% (16a), 75%
(16b); (d) H2, Pd/C, EtOH.rt.overnight, 85% (17), 60% (5b from 16b); (e) NH3/MeOH, rt (for 17) or
80◦C (for 16b), overnight, 85% (5a).
With the desired bicyclic sugar derivative in hand, the synthesis of a bi-
cyclic nucleoside with 3,6-anhydro skeleton is shown in Scheme 3. Hydroxy
group of 13 was acetylated to give the acetate 14, which was hydrolyzed
with 88% formic acid and then subsequently treated with acetic anhydride
in pyridine to afford the glycosyl donor 15. Condensation of the glycosyl
donor 15 with thymine and 6-chloropurine under Vorbru¨gen conditions
gave the protected nucleoside 16a and 16b, respectively. Deprotection of
benzyl group in 16a under hydrogenolytic condition afforded the bicyclic
nucleoside 17, which was treated with methanolic ammonia to yield the
desired 3,6-anhydro nucleoside 5a. 6-Chlropurine derivative 16b was treated
with methanolic ammonia at 80◦C to give the adenine derivative 18, in which
benzyl group was removed to yield the bcyclic nucleoside 5b.

Synthesis of Novel Bicyclic Nucleosides
1101
The antiviral activity of bicyclic nucleoside analogues 5a and 5b were
evaluated against HIV-1 in MT-4 cells. However, no significant anti-HIV
activity was observed up to 100 µM with no cytotoxicity.
In summary, we have efficiently synthesized 3,6-anhydro bicyclic nu-
cleosides via stereoselective dihydroxylation and regioselective opening
of cyclic sulfite, starting from 1,2;5,6-di-O-isoporpylidene-D-glucose. This
methodology can be used for the synthesis of other bicyclic nucleosides.
EXPERIMETAL
NMR spectra were recorded in a 300 MHz apparatus using tetramethylsi-
lane (TMS) as an internal standard, and the chemical shifts are reported in
ppm (δ). Coupling constants are reported in hertz (Hz). Infrared spectra
were recorded with 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 solvents were distilled over CaH2 or Na/benzophenone prior to
use.
3-C-hydroxymethyl-1,2;5,6-di-O-isopropylidene-α-D-
glucofuranose (10)
To a stirred solution of the olefin 7[10] (2.05 g, 8 mmol) in acetone
(40 mL) and water (10 mL) were added dropwise osmium tetroxide
(1 mL, 0.08 mmol, 2.5 wt%) and N -methyl morpholine-N -oxide (5.6 g,
47.8 mmol) at 0◦C. The reaction mixture was stirred for 4 hours at room
temperature, quenched with saturated aqueous Na2S2O3 solution, and then
extracted with EtOAc. The organic layer was washed with water, dried over
MgSO4, and evaporated. The residue was purified by silica gel column
chromatography (methylene chloride/methanol = 10:1) to give the diol 10
1
(2.09 g, 7.2 mmol, 90%). H NMR (300 MHz, CDCl3) 5.87 (d, 1H, J = 3.7
Hz), 4.39 (d, 1H, J = 3.5 Hz), 4.23 (m, 1H), 4.15 (dd, 1H, J = 6.0, 8.8 Hz),
4.04 (dd, 1H, J = 4.9, 8.8 Hz), 3.77–3.88 (m, 3H), 3.20–3.29 (m, 2H), 1.52,
1.45, 1.37, 1.31 (4s, 12H); FAB-MS m/z: 313[M+Na]+; Found: C 53.52, H
7.35. Calc. for C13H22O7: C 53.78, H 7.64.
3-C-benzyloxymethyl-1,2;5,6-di-O-isopropylidene-α-D-
glucofuranose (9)
To a stirred solution of the diol 10 (2 g, 6.9 mmol) in toluene (50 mL)
was added n-Bu2SnO (2.8 g, 11.25 mmol). The reaction mixture was stirred
at 140◦C for 2 hours, cooled to 90–100◦C, and n-Bu4NBr (1.12 g, 3.47 mmol)
and benzyl bromide (1.24 mL, 10.37 mmo1) were added to this mixture.

1102
M. J. Kim
The reaction mixture was stirred at 90◦C overnight and evaporated. The
residue was purified by silica gel column chromatography (hexanes/ethyl
acetate = 2:1) to give the benzyl ether 11 (1.97 g, 5.18 mmol, 75%). IR
(KBr): 3467, 2986, 1375, 1214, 1072, 1004 cm−1; 1H NMR (300 MHz, CDCl3)
7.25–7.41 (m, 5H), 5.85 (d, 1H, J = 3.5 Hz), 4.67 (br s, 1H), 4.61 (d, 1H, J
= 2.2 Hz), 4.41 (d, 1H, J = 3.5 Hz), 4.31–4.37 (m, 1H), 4.06 (dd, 1H, J =
6.2, 8.6 Hz), 3.98 (dd, 1H, J = 5.1, 8.7 Hz), 3.74–3.82 (m, 3H), 2.92 (d, 1H,
J = 1.1 Hz), 1.50, 1.41, 1.33 (3s, 12H); FAB-MS m/z: 403[M+Na]+; Found:
C 62.98, H 7.56. Calc. for C20H28O7: C 63.17, H 7.42.
3-O-acetyl-3-C-benzyloxymethyl-1,2;5,6-di-O-isopropylidene-α-D-
glucofuranose (11)
To a stirred solution of 9 (1.9 g, 4.99 mmol) and DMAP (915 mg,
7.49 mmol) in pyridine (30 mL) was added acetic anhydride (0.95 mL,
10.07 mmol). The reaction mixture was stirred at 100◦C overnight. After
removal of solvent, the residue was diluted with EtOAc and extracted with
water. The organic layer was washed with water, dried over MgSO4, and
evaporated. The residue was purified by silica gel column chromatography
(hexane/ethyl acetate = 2:1) to give the acetate 11 (1.9 g, 4.50 mmol, 90%).
1
IR (KBr): 2986, 1746, 1373, 1231, 1074 cm−1; H NMR (300 MHz, CDCl3)
7.25–7.37 (m, 5H), 5.89 (d, 1H, J = 3.8 Hz), 4.94 (d, 1H, J = 3.8 Hz), 4.60
(td, 1H, J = 3.1, 6.8 Hz), 4.51 (d, 1H, J = 12.0 Hz), 4.46 (d, 1H, J = 12.0
Hz), 4.36–4.41 (m, 2H), 4.08 (dd, 1H, J = 6.8, 8.2 Hz), 3.98 (dd, 1H, J =
6.8, 8.2 Hz), 3.86 (d, 1H, J = 10.4 Hz), 2.03 (s, 3H), 1.48, 1.43, 1.36, 1.29
(4s, 12H); FAB-MS m/z: 445[M+Na]+; Found: C 62.44, H 7.32. Calc. for
C22H30O8: C 62.55, H 7.16.
3,6-Anhydro-3-C-benzyloxymethyl-1,2-O-isopropylidene-α-D-
glucofuranose (13)
A mixture of 11 (1.85 g, 4.38 mmol) in 75% acetic acid (30 mL) was
stirred for 2 hours at 55◦C. The reaction mixture was cooled to room
temperature, evaporated and co-evaporated with toluene to give the diol.
This diol was dissolved in pyridine (20 mL) and thionyl chloride (1.6 mL,
21.93 mmol) was added at 0◦C. The reaction mixture was stirred for 3 hours
at room temperature and evaporated. The residue was partitioned between
CH2Cl2 and water. The organic layer was washed with brine, dried over
MgSO4, and evaporated to give the cyclic sulfite 12. To a stirred solution
of 12 in MeOH (20 mL) was added 28% sodium methoxide in MeOH
(2.11 mL, 10.95 mmol) at 0◦C. The reaction mixture was stirred overnight
at room temperature and evaporated. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate = 1:1) to give 13 (988 mg,
1
3.06 mmol, 70%). IR (KBr): 3420, 2934, 1377, 1216, 1074, 1003 cm−1; H

Synthesis of Novel Bicyclic Nucleosides
1103
NMR (300 MHz, CDCl3) 7.33–7.42 (m, 5H), 5.88 (d, 1H, J = 3.7 Hz), 4.64 (s,
2H), 4.38 (d, 1H, J = 3.7 Hz), 3.80–3.95 (m, 5H), 3.75 (m, 1H), 3.57 (d, 1H,
J = 3.5 Hz), 2.89 (s, 1H), 1.49, 1.31 (2s, 6H). FAB-MS m/z: 323[M+Na]+;
Found: C 63.12, H 7.04. Calc. for C17H22O6: C 63.34, H 6.88.
5-O-acetyl-3,6-Anhydro-3-C-benzyloxymethyl-1,2-O-
isopropylidene-α-D-glucofuranose (14)
To a stirred solution of 13 (950 mg, 2.95 mmol) in pyridine (20 mL)
was added acetic anhydride (0.42 mL, 4.45 mmol) at room temperature,
After being stirred for 3 hours at room temperature, the reaction mixture
was evaporated. The residue was diluted with EtOAc and washed with water.
The organic layer was dried over MgSO4, and evaporated. The residue was
purified by silica gel column chromatography (hexane/ethyl acetate = 2:1)
to give 14 (1.02 g, 2.80 mmol, 95%). IR (KBr): 2986, 1742, 1372, 1239, 1169,
1
1080, 1003 cm−1; H NMR (300 MHz, CDCl3) 7.25–7.45 (m, 5H), 5.96 (d,
1H, J = 3.5 Hz), 5.27 (td, 1H, J = 4.1, 7.7 Hz), 4.77 (d, 1H, J = 4.1 Hz),
4/60 (d, 1H, J = 12.3 Hz), 4.54 (d, 1H, J = 12.3 Hz), 4.46 (d, 1H, J =
3.5 Hz), 4.28 (pt, 1H, J = 8.2, 7.7 Hz), 3.70–3.79 (m, 3H), 2.11 (s, 3H), 1.45,
1.32 (2s, 6H); FAB-MS m/z: 387[M+Na]+; Found: C 62.39, H 6.73. Calc. for
C19H24O7: C 62.63, H 6.64.
1,2,5-O-tri-acetyl-3,6-Anhydro-3-C-benzyloxymethyl-α-D-
glucofuranose (15)
A mixture of 14 (1.01 g, 2.77 mmol) in 88% formic acid (20 mL)
was stirred for 2 hours at 55◦C. The reaction mixture was cooled to room
temperature, evaporated and coevaporated with benzene. The residue was
dissolved in pyridine (20 mL) and acetic anhydride (3.4 mL, 36.03 mmol)
was added to this mixture. After being stirred overnight at room temper-
ature, the reaction mixture was evaporated. The residue was diluted with
EtOAc and washed with water. The organic layer was dried over MgSO4, and
evaporated. The residue was purified by silica gel column chromatography
(hexane/ethyl acetate = 2:1) to give 15 (1.02 g, 2.49 mmol, 90%). 1H NMR
(300 MHz, CDCl3) 7.26–7.39 (m, 5H), 6.11 (s, 1H), 5.07–5.24 (m, 2H), 4.89
(d, 1H, J = 5.3 Hz), 4.57 (s, 2H), 4.33 (pt, 1H, J = 8.1, 8.4 Hz), 4.00 (pt,
1H, J = 8.1, 8.3 Hz), 3.59–3.68 (m, 2H), 2.13, 2.09, 2.05 (3s, 9H); FAB-MS
m/z: 431[M+Na]+.
1-(2ꢁ,5ꢁ-di-O-acetyl-3ꢁ6ꢁ-anhydro-3ꢁ-C-benzyloxymethyl-β-D-
glucofuranosyl)-thymine (16a)
To a stirred mixture of 15 (950 mg, 2.33 mmol) and thymine (352 mg,
2.79 mmol) were added DBU (1.05 mL, 7.02 mmol) and TMSOTf (1.68 mL,

1104
M. J. Kim
9.30 mmol) at 0◦C. after being stirred for 3 hours at 60◦C, the reaction
mixture was poured into sat. NaHCO3 solution and extracted with CH2Cl2.
The organic layer was dried over MgSO4, and evaporated. The residue was
purified by silica gel column chromatography (hexane/ethyl acetate = 1:2)
to give 16 (779 mg, 1.63 mmol, 70%). IR (KBr): 3743, 1746, 1696, 1458,
1
1372, 1226, 1053, 754 cm−1; H NMR (300 MHz, CDCl3) 8.30 (s, 1H),
7.29–7.41 (m, 6H), 6.13 (d, 1H, J = 5.1 Hz), 5.27 (d, 1H, J = 5.1 Hz),
4.77 (d, 1H, J = 4.8 Hz), 4.54–4.67 (m, 3H), 4.38 (dd, 1H, J = 7.1, 9.2
Hz), 3.93 (dd, 1H, J = 6.4, 9.2 Hz), 3.66 (d, 1H, J = 10.2 Hz), 3.58 (d,
1H, J = 10.2 Hz), 2.13, 2.06 (2s, 6H), 1.96 (d, 3H, J = 1.1 Hz); FAB-MS
m/z: 497[M+Na]+; Found: C 58.08, H 5.72. N 5.84. Calc. for C23H26N2O9:
C 58.22, H 5.52, N 5.90.
6-Chloro-9-(2ꢁ,5ꢁ-di-O-acetyl-3ꢁ6ꢁ-anhydro-3ꢁ-C-benzyloxymethyl-
β-D-glucofuranosyl)-purine (16b)
Compound 15 (300 mg, 0.73 mmol) was condensed with 6-chloropurine
(136 mg, 0.88 mmol) to give compound 16b (hexane/ethyl acetate = 1:2,
277 mg, 0.55 mmol, 75%) according to the same procedure used in the
1
synthesis of compound 16a. H NMR (300 MHz, CDCl3) 8.77 (s, 1H), 8.31
(s, 1H), 7.30–7.44 (m, 5H), 6.37 (d, 1H, J = 2.7 Hz), 5.57 (d, J = 2.7 Hz),
5.37 (m, 1H), 4.89 (d, 1H, J = 5.0 Hz), 4.63 (m, 2H), 4.12 (m, 1H), 4.03 (m,
1H), 3.88 (m, 1H), 2.11, 2.05 (2s, 6H); FAB-MS m/z: 525[M+Na]+; Found:
C 54.65, H 4.58. N 11.04. Calc. for C23H23ClN4O7: C 54.93, H 4.61, N 11.24.
1-(2ꢁ,5ꢁ-di-O-acetyl-3ꢁ6ꢁ-anhydro-3ꢁ-C-hydroxymethyl-β-D-
glucofuranosyl)-thymine (17)
A mixture of 16 (580 mg, 1.21 mmol) and Pd/C (80 mg) in EtOH
(15 mL) was degassed and stirred overnight at room temperature under
hydrogen atmosphere. The reaction mixture was filtered through a silica
gel pad and washed with MeOH. The filtrate was evaporated and the
residue was purified by silica gel column chromatography (methylene
chloride/methanol = 10:1) to give 17 (397 mg, 1.03 mmol, 85%). 1H NMR
(300 MHz, CDCl3) 8.96 (s, 1H), 7.50 (d, 1H, J = 1.1 Hz), 5.86 (d, 1H,
J = 2.9 Hz), 4.85 (d, 1H, J = 4.8 Hz), 4.33–4.66 (m, 4H), 4.09 (m, 1H),
3.83 (m, 1H), 2.16, 2.12 (2s, 6H), 1.95 (d, 3H, J = 1.1 Hz); FAB-MS m/z:
407[M+Na]+; Found: C 49.88, H 5.36. N 7.24 Calc. for C16H20N2O9: C
50.00, H 5.25, N 7.29.
1-(3ꢁ6ꢁ-anhydro-3ꢁ-C-hydroxymethyl-β-D-glucofuranosyl)-thymine
(5a)
A solution of 17 (250 mg, 0.65 mmol) in saturated methanolic ammonia
(20 mL) was stirred overnight at room temperature and concentrated.

Synthesis of Novel Bicyclic Nucleosides
1105
The residue was purified by silica gel column chromatography (methylene
1
chloride/methanol = 6:1) to give 5a (166 mg, 0.55 mmol, 85%). H NMR
(300 MHz, DMSO-d6) 11.36 (s, 1H), 7.72 (s, 1H), 5.79 (d, 1H, J = 7.3 Hz),
5.64 (d, 1H, J = 5.3 Hz), 5.20 (d, 1H, J = 5.9 Hz), 4.73 (t, 1H, J = 5.6
Hz), 4.29 (d, 1H, J = 5.0 Hz), 4.08–4.17 (m, 2H), 3.87 (dd, 1H, J = 5.9,
10.7 Hz), 3.60–3.71 (m, 2H), 3.42 (m, 1H), 1.79 (s, 3H); 13C NMR (75 MHz,
DMSO-d6): 164.1, 151.2, 136.8, 110.0, 91.5, 89.2, 82.1, 79.0, 72.5, 71.3, 61.2,
12.6; FAB-MS m/z: 323[M+Na]+; Found: C 47.89, H, 5.25, N 9.23. Calc. for
C12H16N2O7: C 48.00, H 5.37, N 9.33.
6-Amino-(3ꢁ6ꢁ-anhydro-3ꢁ-C-hydroxymethyl-β-D-glucofuranosyl)-
purine (5b)
A solution of compound 16b (200 mg, 0.40 mmol) in methanolic
ammonia (20 mL) was heated in a sealed steal reaction vessel overnight at
80◦C, cooled to room temperature, and concentrated to give compound 18.
The residue was dissolved in EtOH (20 mL) and Pd/C (70 mg) was added.
This mixture was degassed and stirred overnight at room temperature
under hydrogen atmosphere. The reaction mixture was filtered through
a silica gel pad and washed with MeOH. The filtrate was evaporated and
the residue was purified by silica gel column chromatography (methylene
1
chloride/methanol = 5:1) to give 5b (74 mg, 0.24 mmol, 60%). H NMR
(300 MHz, CD3OD) 8.58 (s, 1H), 8.35 (s, 1H), 6.16 (d, 1H, J = 6.5 Hz),
4.18 (d, 1H, J = 5.1 Hz), 3.94–4.03 (m, 2H), 3.77 (m, 1H), 3.66–3.75 (m,
2H), 3.49 (m, 1H); 13C NMR (75 MHz, CD3OD): 156.1, 152.4, 149.8, 140.3,
119.4, 97.4, 91.6, 85.1, 75.1, 74.9, 74.8, 62.1; FAB-MS m/z: 332[M+Na]+;
Found: C 46.38, H, 4.96, N 22.58. Calc. for C12H15N5O5: C 46.60, H 4.89, N
22.64.
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