Synthesis of 3′-deoxy-3′-C-methyl nucleoside derivatives

Article abstract of DOI:10.1016/j.bmc.2008.06.011

2′,3′-Dideoxy-3′-C-methyl nucleosides bearing the five naturally occurring nucleic acid bases were synthesized. Additionally, the 3′-deoxy-3′-C-methyl nucleoside analogues bearing 5-aminoimidazole-4-carboxamide as well as 1,2,4-triazole-3-carboxamide moieties were prepared. The synthesis of the corresponding 2′,3′-dideoxy-3′-C-methyl triazole derivative was also accomplished. The dideoxynucleoside derivatives were prepared by radical deoxygenation from their 3′-deoxy-3′-C-methyl parent ribonucleosides. When evaluated for their antiviral activity in cell culture experiments, none of these compounds showed any significant antiviral activity.

Full text of DOI:10.1016/j.bmc.2008.06.011

Bioorganic & Medicinal Chemistry 16 (2008) 7436–7442
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of 30-deoxy-30-C-methyl nucleoside derivatives
*
Mohamed Aljarah, Sarah Couturier, Christophe Mathé, Christian Périgaud
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-UM 1-UM 2, Université Montpellier 2, Case Courrier 1705, Place E. Bataillon, 34095 Montpellier cedex 05, France
a r t i c l e i n f o
a b s t r a c t
20,30-Dideoxy-30-C-methyl nucleosides bearing the five naturally occurring nucleic acid bases were syn-
thesized. Additionally, the 30-deoxy-30-C-methyl nucleoside analogues bearing 5-aminoimidazole-4-car-
boxamide as well as 1,2,4-triazole-3-carboxamide moieties were prepared. The synthesis of the
corresponding 20,30-dideoxy-30-C-methyl triazole derivative was also accomplished. The dideoxynucleo-
side derivatives were prepared by radical deoxygenation from their 30-deoxy-30-C-methyl parent ribonu-
cleosides. When evaluated for their antiviral activity in cell culture experiments, none of these
compounds showed any significant antiviral activity.
Article history:
Received 16 April 2008
Revised 2 June 2008
Accepted 6 June 2008
Available online 13 June 2008
Keywords:
Synthesis
Nucleoside analogues
30-C-Methyl group
Radical deoxygenation
Glycosylation
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
deoxy-3-C-methyl-b-
D-ribofuranose (1), which was obtained from
commercially available
D
-xylose following a procedure reported
Nucleoside analogues are an important class of biologically ac-
tive compounds. Currently, nucleoside analogues are prominent
drugs for the treatment of several viral infections.1 These nucleo-
side analogues share a common mechanism of action. They are
metabolized by cellular kinases to their 50-triphosphate forms,
which then exert their biological effect as virus-specific polymer-
ase competitive inhibitors or chain terminators because they lack
a hydroxyl group at the C-30 position. However, inherent drug
resistance2 and toxicity3 of the currently used antiviral drugs have
prompted the development of new agents possessing more potent
and broad antiviral activities. In order to discover new nucleoside
derivatives with antiviral activity, modifications of the base and/
or sugar moiety of natural nucleosides can be attempted. As a part
of our ongoing research on this topic, we have recently reported
the synthesis of 30-C-methyl nucleoside analogues incorporating
the five canonical bases of nucleic acids from a common sugar pre-
cursor.4 Herein, we report on the synthesis of the 20,30-dideoxy-30-
C-methyl counterparts (14–18) bearing the five naturally occurring
nucleic acid bases, all of them being hitherto unknown except for
15.5 Additionally, the synthesis of some nucleoside derivatives
bearing 5-aminoimidazole-4-carboxamide and 1,2,4-triazole-3-
carboxamide moieties was also undertaken.
by us. The syntheses of the protected 30-deoxy-30-C-methyl
nucleosides (2–5) were previously reported (Scheme 1).4 A glyco-
sylation reaction with heterocyclic bases, under Vorbrüggen con-
ditions6 using (trimethylsilyl)trifluoromethane sulfonate as
a
catalyst, afforded the target nucleosides. In order to prepare the
target compounds 14–18, regioselective 20-O-deacylation with
hydrazine hydrate7 was accomplished to give the key derivatives
6–9. The latter were then treated with O-phenyl chloro(thio)for-
mate (C6H5OC(S)Cl) and 4-dimethylaminopyridine (DMAP) in ace-
tonitrile. The corresponding 20-O-[phenoxy-(thiocarbonyl)]
intermediates were subsequently deoxygenated with tris(trimeth-
ylsilyl)silane8 in dry toluene in the presence of a0-azoisobutyro-
a,
nitrile (AIBN) to yield the protected 20,30-dideoxy-30-C-methyl
nucleoside derivatives 10–13. Removal of the benzoyl group with
methanolic ammonia afforded the desired dideoxynucleosides 14,
15 and 17, 18 after purification on silica gel column. Compound
10 was converted into the corresponding cytidine derivative 16
via the formation of a 4-thioamide intermediate followed by
aminolysis.9
The synthesis of the 5-aminoimidazole-4-carboxamide nucleo-
side 24 was envisioned from the 30-deoxy-30-C-methyl-adenosine
nucleoside 19 (Scheme 2).4 Indeed, a glycosylation reaction be-
tween 5-amino-4-carboxamide imidazole and a sugar precursor
usually lead to a mixture of different regioisomers.10 Thus, we
chose, as a synthetic strategy, a methodology based upon the
hydrolysis of a N1-alkyl inosine derivative under basic conditions.11
Conversion of adenine moiety of 19 to hypoxanthine moiety was
achieved following a treatment with sodium nitrite in acetic acid
to give the inosine derivative 20. Benzoylation of 20 with benzoyl
2. Results and discussions
The synthesis began with the preparation of an appropriate
methyl sugar precursor, namely, 1,2-di-O-acetyl-5-O-benzoyl-3-
* Corresponding author. Tel.: +33 (0) 467143855; fax: +33 (0) 467549610.
E-mail address: perigaud@univ-montp2.fr (C. Périgaud).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.06.011

M. Aljarah et al. / Bioorg. Med. Chem. 16 (2008) 7436–7442
7437
Scheme 3. Reagents and conditions: (a) methyl 1,2,4-triazole-carboxylate, bis-
PNPP, 165 °C; (b) NH3/MeOH, rt; (c) BzCl, pyridine, 0 °C ? rt; (d) i—1-methylim-
idazole, C6H5O(S)Cl, CH2Cl2, rt; ii—(Me3Si)3SiH, AIBN, toluene, reflux.
chloride in pyridine provided more lipophilic derivative 21, which
was easily handled in organic solvent. Next, compound 21 was
treated with 2-methoxyethoxymethyl chloride in the presence of
DBU in dichloromethane at 0 °C. The N1-substitution was carried
out regioselectively on 21 to give compound 22 in 52% yield. The
O6-substituted side product 23 was obtained in 23% yield. The
structure of compounds 22 and 23 was fully established from 1H,
13C and UV spectra according to literature data.12 Compound 22
was initially deprotected, to increase water solubility, and treated
with 0.2 M NaOH under reflux to give finally the target nucleoside
24.
Scheme 1. Reagents and conditions: (a) H2NNH2ꢀH2O, AcOH, pyridine, 100 °C (rt for
4 and 5); (b) i—DMAP, C6H5O(S)Cl, CH2Cl2 (1,4-dioxane for 8, 1,2-dichloroethane for
9), rt; ii—(Me3Si)3SiH, AIBN, toluene, reflux; (c) for compounds 10–13, NH3/MeOH,
rt; (d) for compound 16; i—Lawesson’s reagent, 1,2-dichloroethane, reflux; ii—NH3/
MeOH, 100 °C.
Thereafter, we were interested in the preparation of 30-deoxy-
30-C-methyl nucleosides bearing the 1,2,4,-triazole-3-carboxamide
moiety (Scheme 3). As in the case of the 5-aminoimidazole-4-car-
boxamide, a glycosylation reaction between a sugar precursor and
the triazole may give a mixture of N1- and N2-regioisomers.13 To
prepare in a regioselective way the N1-regioisomer, we used the
acid-catalyzed fusion procedure with methyl 1,2,4-triazole-3-car-
boxylate and sugar 1 in the presence of bis(p-nitrophenyl)phos-
phate as a catalyst.14 Under these conditions, the N1-regioisomer
25 was obtained in 81% yield as well as the N2-regioisomer 26 in
3% yield after purification on silica gel column chromatography.
Treatment of 25 with methanolic ammonia provided (3S)-1-(3-
deoxy-3-C-methyl-b-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide
(27). In order to prepare the 20,30-dideoxynucleoside counterpart, a
selective 50-O-benzoylation of 27 followed by a radical deoxygen-
ation at C-20 and removal of the protective group gave the target
nucleoside 30.
3. Conclusion
The syntheses of 20,30-dideoxy-30-C-methyl nucleosides bearing
the five canonical bases of nucleic acids were undertaken to dis-
cover new nucleoside derivatives as potential antiviral drugs. Addi-
tionally, the synthesis of some nucleoside derivatives bearing 5-
aminoimidazole-4-carboxamide and 1,2,4,-triazole-3-carboxamide
moieties was realized. However, when evaluated against HIV and
several RNA viruses in cell culture experiments, none of the nucle-
oside derivatives showed any antiretroviral activity nor cytotoxic-
Scheme 2. Reagents and conditions: (a) NaNO2, AcOH, H2O, rt; (b) BzCl, pyridine,
0 °C ? rt; (c) MEMCl, DBU, CH2Cl2, 0 °C ? rt; (d) i—NH3/MeOH, rt; ii—NaOH 0.2 M,
reflux.
ity at the highest concentration tested (usually 100 lM).

7438
M. Aljarah et al. / Bioorg. Med. Chem. 16 (2008) 7436–7442
(C-4), 150.8 (C-2), 139.4 (C-6), 133.7–128.7 (C arom.), 101.8 (C-
4. Experimental
4.1. General methods
5), 93.2 (C-10), 84.2 (C-40), 78.3 (C-20), 62.6 (C-50), 35.9 (C-30), 8.4
(CH3); m/z (FAB > 0) 347 (M+H)+, 235 (S)+; m/z (FAB < 0) 399
(MꢁH)ꢁ, 111 (B)ꢁ.
Evaporation of solvents was carried out on a rotary evaporator
under reduced pressure. Melting points were determined in open
capillary tubes on a Büchi-545 apparatus and are uncorrected. UV
spectra were recorded on an Uvikon 931 (Kontron) spectropho-
tometer. 1H NMR spectra were recorded at 300 or 400 MHz, 13C
NMR spectra at 100 MHz in CDCl3 or (CD3)2SO at ambient temper-
ature with a Brüker 300 Advance or DRX 400. Chemical shifts (d)
are quoted in parts per million (ppm) referenced to the residual
solvent peak, CHCl3 being set at d–H 7.26 and d–C 77 and
[(CD3)(CD2H)SO] being set at d–H 2.49 and d–C 39.5, relative to tet-
ramethylsilane (TMS). COSY experiments were performed in order
to confirm proton assignments. Coupling constants J are reported
in Hertz. 2D 1H–13C heteronuclear COSY experiments were re-
corded for the attribution of 13C signals. FAB mass spectra were
recorded in positive-ion or negative-ion mode on a JEOL JMS DX
300. The matrix was a mixture (50:50, v/v) of glycerol and thio-
glycerol (G-T). Specific rotations were measured on a Perkin-El-
mer Model 341 spectropolarimeter (path length 1 cm), and are
given in units of 10ꢁ1 deg cm2 gꢁ1. Elemental analyses were car-
ried out by the ‘Service de Microanalyses du CNRS, Division de
Vernaison (France)’. Thin layer chromatography was performed
on precoated aluminium sheets of Silica Gel 60 F254 (Merck, Art.
5554), visualization of products being accomplished by UV absor-
bency followed by charring with 5% ethanolic sulfuric acid and
heating. Column chromatography was carried out on Silica Gel
60 (Merck, Art. 9385). All moisture-sensitive reactions were car-
ried out under rigorous anhydrous conditions and under an argon
atmosphere using over-dried glassware. Solvents were dried and
distilled prior to use and solids were dried over P2O5 under re-
duced pressure.
4.2.2. 1-(5-O-Benzoyl-3-deoxy-3-C -methyl-b-D-ribofuranosyl)-
thymine (7)
The title compound 7 was obtained as a white foam (341.7 mg,
90%) and was crystallized from acetonitrile: mp 171–172 °C; ½a D20
ꢂ
ꢁ17.6 (c 1.02 in DMSO); UV kmax (EtOH)/nm 267 (
e 11,100), 225
(e 15,800), kmin (EtOH)/nm 245 (e
6100); 1H NMR (CDCl3) d 10.3
(1H, br s, NH), 7.97 (2H, m, 2H ortho), 7.51 (1H, s, H-6), 7.56–
7.36 (3H, m, 2H meta and 1H para), 5.64 (1H, s, H-10), 4.90 (1H,
br s, OH-20), 4.71 (1H, dd, J5 —4 ¼ 1:8 Hz and J5 —5 ¼ 12:9 Hz, H-
0
0
0
00
50), 4.51 (1H, dd, J5 —4 ¼ 3:9 Hz and J5
¼ 12:9 Hz, H-500), 4.34
0
0
00—50
(1H, m, H-40), 4.26 (1H, m, H-20), 2.09 (1H, m, H-30), 1.54 (3H, s,
CH3), 1.11 (3H, d, J
¼ 6:7 Hz, CH3); 13C NMR (CDCl3) d 164.8
CH3—3
0
(CO), 163.0 (C-4), 149.3 (C-2), 133.6 (C-6), 132.1–127.4 (C arom.),
108.9 (C-5), 91.9 (C-10), 82.6 (C-40), 76.8 (C-20), 61.6 (C-50), 34.8
(C-30), 10.9 (CH3), 7.1 (CH3); m/z (FAB > 0) 361 (M+H)+, 235 (S)+,
127 (BH2)+; m/z (FAB < 0) 359 (MꢁH)ꢁ, 125 (B)ꢁ. Anal. Calcd for
C
18H20N2O6: C, 59.99; H, 5.59; N, 7.77. Found: C, 59.72; H, 5.45;
N, 7.75.
4.2.3. 9-(5-O-Benzoyl-3-deoxy-3-C -methyl-b-D-ribofuranosyl)-
adenine (8)
The title compound 8 was obtained as a white foam (193 mg,
90%) and was crystallized from ethanol: mp 202 °C; ½a 20
ꢁ17.6
ꢂ
D
(c 1.01 in DMSO); UV kmax (EtOH)/nm 258 (
e 13,700), 230 (e
14,000), kmin (EtOH)/nm 244 (e
9600); 1H NMR (DMSO-d6) d 8.18
(1H, s, H-8), 8.07 (1H, s, H-2), 7.83–7.41 (5H, m, C6H5CO), 7.21
(2H, s, NH2), 5.88 (1H, d, J1 —2 ¼ 1:1 Hz, H-10), 5.71 (1H, d,
0
0
JOH-2 ¼ 5:0 Hz, OH-20), 4.51 (2H, m, H-20 and H-50), 4.42 (1H, dd,
0
J5 —4 ¼ 5:2 Hz and J5
¼ 12:4 Hz, H-500), 4.10 (1H, m, H-40), 2.60
0
0
00—50
(1H, m, H-30), 1.02 (3H, d, JCH
¼ 6:8 Hz, CH3); 13C NMR (DMSO-
0
3—3
d6) d 166.1 (CO), 156.5 (C-6), 153.1 (C-2), 149.3 (C-4), 139.5 (C-
8), 133.9–129.2 (C6H5CO), 119.5 (C-5), 91.1 (C-10), 83.2 (C-40),
76.7 (C-20), 64.9 (C-50), 37.8 (C-30), 9.9 (CH3); m/z (FAB > 0) 370
(M+H)+, 136 (BH2)+; m/z (FAB < 0) 368 (MꢁH)ꢁ, 134 (B)ꢁ; Anal.
Calcd for C18H19N5O4: C, 58.53; H, 5.18; N, 18.96. Found: C,
58.32; H, 5.11; N, 18.76.
4.2. General procedure for the preparation of compounds 6–9
Hydrazine hydrate (10 mmol) was added to a stirred solution of
nucleosides (2–5) (1.0 mmol) in a mixture of acetic acid/pyridine
(1:4, v/v, 10 ml). The reaction mixture was stirred at 100 °C for
90 min (3 days at room temperature for compound 4, 5 days at
room temperature for compound 5). After cooling to room temper-
ature, acetone (16 ml) was added and stirring continued for
30 min. The crude mixture was then diluted with a solution of sat-
urated sodium hydrogen carbonate and dichloromethane (50 ml).
The organic phase was washed with water (20 ml) and a solution
of saturated sodium chloride (20 ml), dried over sodium sulfate
and evaporated under reduced pressure and co-evaporated with
toluene. Column chromatography of the residue on silica gel using
as eluent a stepwise gradient of methanol (0–5%) in dichlorometh-
ane afforded the title compounds.
4.2.4. 9-(5-O-Benzoyl-3-deoxy-3-C-methyl-b-D-ribofuranosyl)-
N2-acetylguanine (9)
The title compound 9 (1.13 g, 90%) was precipitated from water:
+4.0 (c 1.01 in DMSO); UV kmax (EtOH)/nm 260 ( 12,600), 232
7900), kmin (EtOH)/nm 240 (
7300); 1H NMR (DMSO-d6) d 12.05
½
a 2D0
ꢂ
e
(e
e
(1H, s, NH), 11.63 (1H, s, NH), 8.13 (1H, s, H-8), 7.90–7.49 (5H, m,
C6H5CO), 5.83 (1H, d, J1 —2 ¼ 1:3 Hz, H-10), 5.75 (1H, d,
0
0
JOH-2 ¼ 5:3 Hz, OH-20), 4.51 (3H, m, H-20, H-50 and H-500), 4.15
0
(1H, m, H-40), 2.58 (1H, m, H-30), 2.18 (3H, s, CH3CO), 1.09 (3H, d,
JCH
¼ 6:8 Hz, CH3); 13C NMR (DMSO-d6) d 174.0 (CO), 166.1
0
3—3
(CO), 155.3 (C-6), 148.6 (C-4), 148.3 (C-2), 138.0 (C-8), 134.0–
129.2 (C6H5CO), 120.8 (C-5), 90.7 (C-10), 83.3 (C-40), 76.9 (C-20),
65.0 (C-50), 38.0 (C-30), 24.3 (CH3CO), 10.1 (CH3); m/z (FAB > 0)
428 (M+H)+, 194 (BH2)+, 105 (C6H5CO)+, 43 (CH3CO)+; m/z
(FAB < 0) 426 (MꢁH)ꢁ; Anal. Calcd for C20H21N5O9ꢀ1.3H2O: C,
53.28; H, 5.28; N, 15.53. Found: C, 52.87; H, 5.27; N, 15.91.
4.2.1. 1-(5-O-Benzoyl-3-deoxy-3-C -methyl-b-D-ribofuranosyl)-
uracile (6)
The title compound 6 was obtained as a white foam (923 mg,
90%) and was crystallized from acetonitrile: mp 155–156 °C; ½a D20
ꢂ
+16.5 (c 1.09 in DMSO); UV kmax (EtOH)/nm 263 (e 9500), 228 (e
13,900), kmin (EtOH)/nm 245 (e
6500); 1H NMR (CDCl3) d 10.34
(1H, s, NH), 7.95 (2H, m, 2H ortho), 7.83 (1H, d, J6–5 = 8.1 Hz, H-
6), 7.58–7.38 (3H, m, 2H meta and 1H para), 5.66 (1H, s, H-10),
5.41 (1H, dd, J5–6 = 8.1 Hz and J5-NH = 2.0 Hz, H-5), 4.81 (1H,
4.3. General procedure for the preparation of compounds 10–13
To a stirred solution of nucleosides (6–9) (1 mmol) in dichloro-
methane (30 ml) (1,4-dioxane for compound 8, 1,2-dichloroethane
for compound 9) were added successively DMAP (4 mmol) and
phenoxy(thiocarbonyl) chloride (2 mmol). After 30 min at room
temperature (24 h for compound 8), water was added (20 ml)
d, JOH-2 ¼ 2:3 Hz, OH-20), 4.66 (1H, dd, J5 —4 ¼ 2:2 Hz and J5 —5
¼
0
0
0
0
00
13:0 Hz, H-50), 4.60 (1H, dd, J5 —4 ¼ 3:1 Hz and J5
¼ 13:0 Hz, H-
0
0
00—50
500), 4.33 (1H, m, H-40), 4.21 (1H, m, H-20), 2.03 (1H, m, H-30), 1.10
(3H, d, JCH
¼ 6:7 Hz, CH3); 13C NMR (CDCl3) d 166.1 (CO), 163.9
0
3—3

M. Aljarah et al. / Bioorg. Med. Chem. 16 (2008) 7436–7442
7439
and the organic phase washed with hydrochloric acid 0.5 N (20 ml)
and water (20 ml), dried over sodium sulfate, and evaporated to
dryness. The resulting crude material was co-evaporated with
(2H, m, H-20 and H-30), 2.11 (1H, m, H-200), 2.05 (3H, s, CH3CO),
1.03 (3H, d, JCH
¼ 6:0 Hz, CH3); 13C NMR (DMSO-d6) d 174.0
0
3—3
(CO), 166.0 (CO), 155.3 (C-6), 148.5 (C-4), 148.2 (C-2), 137.9 (C-
8), 134.0-129.2 (C6H5CO), 121.0 (C-5), 85.0 (C-40), 83.7 (C-10),
64.8 (C-50), 39.9 (C-20), 33.7 (C-30), 24.3 (CH3CO), 16.3 (CH3); m/z
(FAB > 0) 412 (M+H)+, 219 (S)+, 194 (BH2)+, 43 (CH3CO)+; m/z
(FAB < 0) 410 (MꢁH)ꢁ, 192 (B)ꢁ.
dry toluene, then dissolved in the same solvent (20 ml) and
a, -
a0
azoisobutyronitrile (0.5 mmol) and tris(trimethylsilyl)silane
(2 mmol) were added. The reaction mixture was heated under re-
flux for 3 h. After cooling to room temperature, the solvent was re-
moved under reduced pressure. Chromatography of the residue on
a silica gel column using as eluent a stepwise gradient of methanol
(0–4%) in dichloromethane afforded the title compounds.
4.4. General procedure for the preparation of compounds 14,
15, 17, 18, 24, 27 and 30
4.3.1. 1-(5-O-Benzoyl-2,3-dideoxy-3-C-methyl-b-
pentofuranosyl)uracil (10)
The title compound 10 was obtained as a white foam (692 mg,
90%): 1H NMR (CDCl3) d 10.50 (1H, s, NH), 7.85 (2H, m, H ortho),
7.54 (1H, d, J6–5 = 8.1 Hz, H-6), 7.46–7.27 (3H, m, H meta and para),
D
-erythro-
A solution of nucleosides (10–13, 22, 25, 29) (1.0 mmol) in
methanolic ammonia (previously saturated at ꢁ10 °C and tightly
stoppered) (20 ml) was stirred for 12 h at room temperature, then
evaporated to dryness. The residue was subjected to silica gel col-
umn chromatography.
5.88 (1H, dd, J1 —2 ¼ 6:4 Hz and J1 ꢁ2 ¼ 1:8 Hz, H-10), 5.30 (1H, dd,
0
0
0
00
0
0
J5–6 = 8.1 Hz and J5-NH = 2.2 Hz, H-5), 4.48 (1H, dd, J5 —4 ¼ 2:9 Hz
4.4.1. 1-(2,3-Dideoxy-3-C-methyl-b-D-erythro-pentofuranosyl)-
uracile (14)
and J5 —5 ¼ 12:7 Hz, H-50), 4.43 (1H, dd, J5 —4 ¼ 3:6 Hz and
0
00
0
0
¼ 12:7 Hz, H-500), 3.75 (1H, m, H-40), 2.05 (3H, m, H-20, H-200
Purification using as eluent a stepwise gradient of methanol (0–
00—50
J5
and H-30), 0.99 (3H, d, JCH
¼ 5:9 Hz, CH3); 13C NMR (CDCl3) d
5%) in dichloromethane afforded the title compound 14 (275 mg,
0
3—3
166.2 (CO), 163.0 (C-4), 150.0 (C-2), 139.5 (C-6), 133.7–128.7 (C
arom.), 101.6 (C-5), 85.6 (C-10 and C-40), 62.9 (C-50), 41.4 (C-20),
32.4 (C-30), 15.6 (CH3); m/z (FAB > 0) 331 (M+H)+, 219 (S)+, 113
(BH2)+; m/z (FAB < 0) 329 (M–H)ꢁ, 111 (B)ꢁ.
91%), which was crystallized from ethanol: mp 173–174 °C; ½a D20
ꢂ
+45 (c 1.00 in DMSO); UV kmax (EtOH)/nm 262 (e 10,500), kmin
(EtOH)/nm 229 (e
2000); 1H NMR (CDCl3) d 11.25 (1H, s, NH),
0
0
8.03 (1H, d, J6–5 = 8.1 Hz, H-6), 5.93 (1H, dd, J1 —2 ¼ 7:1 Hz and
J1 —2 ¼ 2:3 Hz, H-10), 5.56 (1H, d, J5–6 = 8.1 Hz, H-5), 5.06 (1H, t,
0
00
4.3.2. 1-(5-O-Benzoyl-2,3-dideoxy-3-C-methyl-b-
D
-erythro-pen-
OH-50), 3.71 (1H, m, H-50), 3.54 (2H, m, H-500 and H-40), 2.17 (2H,
tofuranosyl)thymine (11)
m, H-20 and H-30), 1.99 (1H, m, H-200), 0.99 (3H, d, JCH
¼ 6:2 Hz,
0
3—3
The title compound 11 was obtained as a white foam (183.9 mg,
90%): 1H NMR (CDCl3) d 10.26 (1H, s, NH), 7.98 (2H, m, 2H ortho),
7.57–7.36 (3H, m, 2H meta and 1H para), 7.30 (1H, d, J6-CH3 = 1.2 Hz,
CH3); 13C NMR (CDCl3) d 163.2 (C-4), 150.3 (C-2), 140.6 (C-6),
100.7 (C-5), 87.8 (C-40), 84.1 (C-10), 59.9 (C-50), 40.4 (C-20), 30.9
(C-30), 15.6 (CH3); m/z (FAB > 0) 227 (M+H)+, 115 (S)+, 113 (BH2)+;
m/z (FAB < 0) 225 (MꢁH)ꢁ, 111 (B)ꢁ.
H-6), 6.03 (1H, dd, J1 —2 ¼ 7:0 Hz and J1 —2 ¼ 2:9 Hz, H-10), 4.60
0
0
0
00
(1H, dd, J5 —4 ¼ 2:6 Hz and J5 —5 ¼ 12:5 Hz, H-50), 4.49 (1H, dd,
0
0
0
00
¼ 12:5 Hz, H-500), 3.86 (1H, m, H-40), 2.22
4.4.2. 1-(2,3-Dideoxy-3-C-methyl-b-D-erythro-pentofuranosyl)-
thymine (15)
0
0
00—50
J5 —4 ¼ 4:4 Hz and J5
(2H, m, H-20 and H-30), 2.11 (1H, m, H-200), 1.62 (3H, s, CH ), 1.11
3
(3H, d, JCH
¼ 6:2 Hz, CH3); 13C NMR (CDCl3) d 166.3 (CO), 163.4
Purification using as eluent a stepwise gradient of methanol (0–
0
(C-4), 1503.0—3 (C-2), 135.2 (C-6), 133.5 ꢁ128.6 (C arom.), 110.5 (C-
5), 85.2 (C-10), 85.1 (C-40), 63.6 (C-50), 40.9 (C-20), 33.0 (C-30), 16.2
(CH3), 12.4 (CH3); m/z (FAB > 0) 345 (M+H)+, 219 (S)+, 127 (BH2)+;
m/z (FAB < 0) 343 (MꢁH)ꢁ, 125 (B)ꢁ.
5%) in dichloromethane afforded the title compound 15 (191.7 mg,
86%) which was lyophilized from water: ½a D20
ꢂ
+25.2 (c 1.03 in
DMSO); UV kmax (EtOH)/nm 267 (e 8000), kmin (EtOH)/nm 233 (e
1400); 1H NMR (CDCl3) d 11.24 (1H, s, NH), 7.90 (1H, d, J6-
0
0
0
00
= 1.1 Hz, H-6), 5.95 (1H, dd, J1 —2 ¼ 7:1 Hz and J1 —2 ¼ 2:5 Hz,
CH3
4.3.3. 9-(5-O-Benzoyl-2,3-dideoxy-3-C-methyl-b-
D
-erythro-pen-
H-10), 5.10 (1H, pt, OH-50), 3.73 (1H, m, H-50), 3.53 (2H, m, H-40
and H-500), 2.26 (1H, m, H-30), 2.11 (1H, m, H-20), 1.96 (1H, m, H-
tofuranosyl)adenine (12)
The title compound 12 was obtained as a white foam (158 mg,
200), 1.76 (3H, d, JCH = 1.1 Hz, CH3), 0.99 (3H, d, J
¼ 6:4 Hz,
CH3—3
0
56%): ½a 2D0
ꢂ
ꢁ8.6 (c 1.02 in DMSO); UV kmax (EtOH)/nm 259 (
e
CH3); 13C NMR (CD3C-5l3) d 163.8 (C-4), 150.3 (C-2), 136.4 (C-6),
108.3 (C-5), 87.6 (C-40), 83.7 (C-10), 60.0 (C-50), 40.3 (C-20), 31.0
(C-30), 15.8 (CH3), 12.2 (CH3); m/z (FAB > 0) 241 (M+H)+, 127
(BH2)+, 115 (S)+; m/z (FAB < 0) 239 (MꢁH)ꢁ, 125 (B)ꢁ.
13,300), 230 (
e
13,400); kmin (EtOH)/nm 244 (
e
9300); 1H NMR
(DMSO-d6) d 8.24 (1H, s, H-8), 8.09 (1H, s, H-2), 7.83–7.45 (5H,
m, C6H5CO), 7.21 (2H, s, NH2), 6.25 (1H, d, J1 —2 ¼ 7:2 Hz, H-10),
0
00
4.44 (2H, m, H-50 and H-500), 3.93 (1H, m, H-40), 2.69 (2H, m, H-20
and H-30), 2.22 (1H, m, H-200), 1.13 (3H, d, JCH
¼ 6:0 Hz, CH3);
4.4.3. 1-(2,3-Dideoxy-3-C-methyl-b-D-erythro-pentofuranosyl)-
cytosine (16)
0
13C NMR (DMSO-d6) d 166.1 (CO), 156.5 (C-6),31—353.0 (C-2), 149.3
(C-4), 139.6 (C-8), 133.9–129.2 (C6H5CO), 119.5 (C-5), 84.8 (C-40),
83.7 (C-10), 64.9 (C-50), 39.7 (C-20), 33.9 (C-30), 16.3 (CH3); m/z
(FAB > 0) 354 (M+H)+, 219 (S)+, 136 (BH2)+; m/z (FAB < 0) 352
(MꢁH)ꢁ, 134 (B)ꢁ; Anal. Calcd for C18H19N5O3ꢀ0.9CH3OH: C,
59.39; H, 5.96; N, 18.32. Found: C, 59.55; H, 5.46; N, 17.85.
To a solution of 10 (600 mg, 1.82 mmol) in 1,2-dichloroethane
(58 ml) was added Lawesson’s reagent (514 mg, 1.27 mmol). The
reaction mixture was heated under reflux for 90 min. The solvent
was then removed under reduced pressure and the residue purified
on silica gel column chromatography using as eluent a stepwise
gradient of methanol (0–0.5%) in dichloromethane to give the cor-
responding 4-thio intermediate as a yellow foam. A suspension of
this intermediate in methanolic ammonia (previously saturated at
ꢁ10 °C and tightly stoppered) (18.5 ml) was heated at 100 °C in a
stainless-steel bomb for 12 h, then cooled to room temperature
and evaporated to dryness. The residue was subjected to a silica
gel column chromatography using as eluent a stepwise gradient
of methanol (0–15%) in dichloromethane to afford the title com-
4.3.4. 9-(5-O-Benzoyl-2,3-dideoxy-3-C-methyl-b-D-erythro-pen-
tofuranosyl)-N2-acetylguanine (13)
The title compound 13 was obtained as a white foam (192 mg,
57%): UV kmax (EtOH)/nm 259 ( 8600), 236 ( 9200), kmin (EtOH)/
nm 245 (
7400); 1H NMR (DMSO-d6) d 11.91 (1H, s, NH), 11.51
e
e
e
(1H, s, NH), 8.03 (1H, s, H-8), 7.75–7.36 (5H, m, C6H5CO), 6.01
(1H, dd, J1 —2 ¼ 1:8 Hz and J1 —2 ¼ 7:0 Hz, H-10), 4.39 (1H, dd,
0
0
0
00
J5 —4 ¼ 3:1 Hz and J5 —5 ¼ 12:2 Hz, H-50), 4.33 (1H, dd,
pound 16 (377 mg, 91%) which was lyophilized from water: ½a D20
ꢂ
0
0
0
00
¼ 12:2 Hz, H-500), 3.83 (1H, m, H-40), 2.51
+69.7 (c 1.09 in DMSO); UV kmax (EtOH)/nm 272 (e 7500), kmin
0
0
00—50
J5 —4 ¼ 5:4 Hz and J5

7440
M. Aljarah et al. / Bioorg. Med. Chem. 16 (2008) 7436–7442
(EtOH)/nm 250 (
e
4900); 1H NMR (DMSO-d6) d 7.99 (1H, d,
4.4.7. 9-(2,5-Di-O-benzoyl-3-deoxy-3--Cmethyl-b-D-ribofuranosyl)-
0
0
J6–5 = 7.4 Hz, H-6), 7.04 (2H, pd, NH2), 5.90 (1H, dd, J1 —2 ¼ 6:1 Hz
hypoxanthine (21)
To a stirred solution of compound 20 (397 mg, 1.49 mmol) in
pyridine was added dropwise benzoyl chloride (692 l, 5.96 mmol)
and J1 —2 ¼ 2:8 Hz, H-10), 5.66 (1H, d, J5–6 = 7.4 Hz, H-5), 5.03 (1H,
br s, OH-50), 3.72 (1H, m, H-50), 3.53 (2H, m, H-500 and H-40), 2.11
(1H, m, H-30), 1.97 (2H, m, H-20 and H-200), 0.98 (3H, d,
0
00
l
at 0 °C. The reaction mixture was stirred at room temperature for
12 h, then diluted with water and dichloromethane. The organic
phase was washed with aqueous solution of sodium hydrogenocar-
bonate and water, dried over sodium sulfate, evaporated under re-
duced pressure and co-evaporated with toluene. The residue was
subjected to silica gel column chromatography using as eluent a
stepwise gradient of methanol (0–3%) in dichloromethane to afford
JCH
¼ 6:3 Hz, CH3); 13C NMR (DMSO-d6) d 163.8 (C-4), 153.3
0
3—3
(C-2), 139.2 (C-6), 91.1 (C-5), 85.9 (C-40), 82.8 (C-10), 58.3 (C-50),
39.3 (C-20), 29.0 (C-30), 13.8 (CH3); m/z (FAB > 0) 226 (M+H)+, 112
(BH2)+; m/z (FAB < 0) 224 (MꢁH)ꢁ.
4.4.4. 9-(2,3-Dideoxy-3-C-methyl-b-D-erythro-pentofuranosyl)-
adenine (17)
the title compound 21 as a white foam (452 mg, 64%): ½a D20
ꢁ34.4
ꢂ
Purification using as eluent a stepwise gradient of methanol
(0–10%) in dichloromethane to afford the title compound 12
(64.2 mg, 77%), which was lyophilized from water: UV kmax
(c 0.90 in DMSO); 1H NMR (DMSO-d6) d 12.44 (1H, s, NH), 8.30 (1H,
s, H-8), 8.10–7.50 (11H, m, H-2 and 2ꢃ C6H5CO), 6.27 (1H, d,
J1 —2 ¼ 1:1 Hz, H-10), 5.94 (1H, d, J2 —3 ¼ 5:9 Hz, H-20), 4.67 (1H,
0
0
0
0
e 13,400); kmin (EtOH)/nm 226 (e
2100); 1H
dd, J5 —4 ¼ 2:6 Hz and J5 —5 ¼ 12:5 Hz, H-50), 4.55 (1H, dd,
0
0
0
00
(EtOH)/nm 258 (
NMR (DMSO-d6) d 8.38 (1H, s, H-8), 8.13 (1H, s, H-2), 7.23 (2H,
J5 —4 ¼ 4:9 Hz and J5
¼ 12:5 Hz, H-500), 4.40 (1H, m, H-40), 3.22
0
0
00—50
s, NH2), 6.24 (1H, dd, J1 —2 ¼ 1:9 Hz) and (J1 —2 ¼ 7:1 Hz, H-10),
(1H, m, H-30), 1.19 (3H, d, JCH
¼ 6:8 Hz, CH3); 13C NMR (DMSO-
0
0
0
00
0
3—3
5.02 (1H, t, JOHꢁ5 ¼ JOH-5 ¼ 5:4Hz, OH-50), 3.62 (3H, m, H-50, H-40
d6) d 165.5 (CO), 165.1 (CO), 156.6 (C-6), 147.6 (C-4), 146.0 (C-2),
139.2 (C-8), 133.9–128.7 (2ꢃ C6H5CO), 124.6 (C-5), 88.4 (C-10),
83.1 (C-40), 79.5 (C-20), 63.6 (C-50), 36.6 (C-30), 9.2 (CH3); m/z
(FAB > 0) 475 (M+H)+, 339 (S)+, 137 (BH2)+; m/z (FAB < 0) 473
(MꢁH)ꢁ, 135 (B)ꢁ; Anal. Calcd for C25H22N4O6ꢀ0.4CH3OH: C,
62.61; H, 4.88; N, 11.50. Found: C, 62.67; H, 4.84; N, 11.42.
0
00
and H-500), 2.49 (2H, m, H-20 and H-30), 2.15 (1H, m, H-200), 1.07
(3H, d, JCH
¼ 6:0 Hz, CH3); 13C NMR (DMSO-d6) d 156.4 (C-6),
0
3—3
152.9 (C-2), 149.2 (C-4), 139.4 (C-8), 119.5 (C-5), 88.4 (C-40),
83.8 (C-10), 61.7 (C-50), 40.7 (C-20), 32.6 (C-30), 16.6 (CH3); m/z
(FAB > 0) 250 (M+H)+, 136 (BH2)+; m/z (FAB < 0) 248 (MꢁH)ꢁ,
134 (B)ꢁ.
4.4.8. 9-(2,5-Di-O-benzoyl-3-deoxy-3-C-methyl-b-
anosyl)-1-[(2-methoxyethoxy)-methyl]hypoxanthine (22) and
9-(2,5-di-O-benzoyl-3-deoxy-3-C-methyl-b- -ribofuranosyl)-6-
D-ribofur-
4.4.5. 9-(2,3-Dideoxy-3-C-methyl-b-D-erythro-pentofuranosyl)-
guanine (18)
D
Purification using as eluent a stepwise gradient of methanol (0–
O-[(2-methoxyethoxy)methyl]hypoxanthine (23)
15%) in dichloromethane afforded the title compound 18 (78.4 mg,
To a solution of compound 21 (369 mg, 0.78 mmol) in dichlo-
romethane (7.8 ml) were successively added dropwise DBU
(1.16 ml, 7.8 mmol) and (2-methoxyethoxy)methyl chloride
83%), which was lyophilized from water: ½a D20
ꢁ12.9 (c 1.03 in
ꢂ
DMSO); UV kmax (EtOH)/nm 255 (e
14,500); 1H NMR (DMSO-d6) d
10.58 (1H, s, NH), 7.97 (1H, s, H-8), 6.45 (1H, s, NH2), 6.00 (1H,
(445 ll, 3.9 mmol) at 0 °C. The reaction mixture was stirred at
dd, J1 —2 ¼ 1:9 Hz and J1 —2 ¼ 7:3 Hz, H-10), 4.95 (1H, t,
0
0
0
00
room temperature for 30 min, then diluted with water and dichlo-
romethane. After decantation, the organic phase was washed with
aqueous solution of sodium chloride and water, dried over sodium
sulfate and evaporated to dryness. The residue was subjected to
silica gel column chromatography using as eluent a mixture of
acetone and hexane (1:1, v/v) to afford in order of elution the title
compounds 23 (99.2 mg, 23%) and 22 (228 mg, 52%) as white
JOH-5 ¼ JOH-5 ¼ 5:5 HzHz, OH-50), 3.64 (1H, m, H-50), 3.54 (2H, m,
0
00
H-500 and H-40), 2.36 (2H, m, H-20 and H-30), 2.06 (1H, m, H-200),
1.05 (3H, d, JCH
¼ 6:3 Hz, CH3); 13C NMR (DMSO-d6) d 157.2 (C-
0
3—3
6), 154.0 (C-2), 150.9 (C-4), 135.6 (C-8), 117.1 (C-5), 88.3 (C-40),
83.1 (C-10), 61.5 (C-50), 40.4 (C-20), 32.5 (C-30), 16.5 (CH3); m/z
(FAB > 0) 266 (M+H)+, 152 (BH2)+, 115 (S)+; m/z (FAB < 0) 264
(MꢁH)ꢁ, 150 (B)ꢁ; Anal. Calcd for C11H15N5O3ꢀ0.4H2O: C, 48.49;
H, 5.84; N, 25.70. Found: C, 48.51; H, 5.79; N, 25.14.
foams: Compound 23: mp 68 °C; ½a D20
ꢁ26.2 (c 0.92 in DMSO);
ꢂ
1H NMR (DMSO-d6) d 8.61 (1H, s, H-8), 8.51 (1H, s, H-2), 8.11–
7.47 (10H, m, 2ꢃ C6H5CO), 6.38 (1H, d, J1 —2 ¼ 1:1 Hz, H-10), 6.06
0
0
4.4.6. 9-(3-Deoxy-3-C-methyl-b-D-ribofuranosyl)hypoxanthine
(20)
(1H, d, J2 —3 ¼ 5:9 Hz, H-20), 5.83 (2H, s, OCH2O), 4.67 (1H, m, H-
50), 4.56 (1H, m, H-500), 4.41 (1H, m, H-40), 3.85 (2H, m, OCH2-
CH2O), 3.50 (2H, m, OCH2CH2O), 3.32 (1H, m, H-30), 3.23 (3H, s,
0
0
To a stirred solution of compound 19 (1.0 g, 3.77 mmol) in gla-
cial acetic acid (56.9 ml) was added a solution of sodium nitrite
(2.7 g, 38.7 mmol) in water (19.4 ml). The reaction mixture was
stirred at room temperature for 3 days, then evaporated under re-
duced pressure and co-evaporated with toluene. The resulting
residue was subjected to silica gel column chromatography using
as eluent a stepwise gradient of methanol (0–20%) in dichloro-
methane to afford the title compound 20 (903 mg, 90%), which
OCH3), 1.22 (3H, d, J
¼ 6:8Hz, CH3); 13C NMR (DMSO-d6) d
CH3—3
0
165.5 (CO), 165.1 (CO), 159.1 (C-6), 151.6 (C-4 and C-2), 143.3
(C-8), 133.9–128.7 (2ꢃ C6H5CO), 121.2 (C-5), 91.3 (OCH2O), 88.7
(C-10), 83.2 (C-40), 79.2 (C-20), 70.9 (OCH2CH2O), 68.9 (OCH2CH2O),
63.5 (C-50), 58.0 (OCH3), 36.6 (C-30), 9.2 (CH3); m/z (FAB > 0) 475
(Mꢁ(CH3O(C2H4)OCH2)+H)+, 339 (S)+; m/z (FAB < 0) 473
(Mꢁ(CH3O(C2H4)OCH2)ꢁH)ꢁ; Anal. Calcd for C29H30N4O8: C,
61.91; H, 5.38; N, 9.96. Found: C, 61.46; H, 5.38; N, 9.64; Com-
was lyophilized from water: ½a D20
ꢂ
ꢁ42.1 (c 0.95 in DMSO); 1H
NMR (DMSO-d6) d 12.45 (1H, s, NH), 8.42 (1H, s, H-8), 8.07 (1H,
pound 22: mp 62 °C; ½a D20
ꢂ
ꢁ37.4 (c 0.88 in DMSO); 1H NMR
s, H-2), 5.90 (1H, d, J1 —2 ¼ 0:9 Hz, H-10), 5.76 (1H, br s, OH-20),
0
0
(DMSO-d6) d 8.42 (1H, s, H-8), 8.35 (1H, s, H-2), 8.10–7.51 (10H,
5.09 (1H, br s, OH-50), 4.27 (1H, d, J2 —3 ¼ 4:8 Hz, H-20), 3.86
0
0
m, 2ꢃ C6H5CO), 6.28 (1H, d, J1 —2 ¼ 1:1 Hz, H-10), 5.94 (1H, dd,
0
0
(1H, m, H-40), 3.77 (1H, dd, J5 —4 ¼ 2:2 Hz and J5 —5 ¼ 12:4 Hz,
0
0
0
00
J2 —1 ¼ 0:9Hz and J2 —3 ¼ 5:9 Hz, H-20), 5.42 (2H, 2ꢃ d,
J = 10.2 Hz, NCH2O), 4.66 (1H, m, H-50), 4.57 (1H, m, H-500), 4.42
(1H, m, H-40), 3.66 (2H, m, OCH2CH2O), 3.42 (2H, m, OCH2CH2O),
3.22 (1H, m, H-30), 3.20 (3H, s, OCH3), 1.20 (3H, d,
0
0
0
0
H-50), 3.56 (1H, dd, J5 —4 ¼ 3:4 Hz and J5
¼ 12:4 Hz, H-500),
0
0
00—50
2.38 (1H, m, H-30), 0.99 (3H, d, JCH
¼ 6:8 Hz, CH3); 13C NMR
(DMSO-d6) d 156.6 (C-6), 147.5 (C-34—)30, 145.7 (C-2), 138.1 (C-8),
124.3 (C-5), 90.3 (C-10), 86.2 (C-40), 77.3 (C-20), 60.4 (C-50), 35.4
(C-30), 9.4 (CH3); m/z (FAB > 0) 267 (M+H)+, 137 (BH2)+; m/z
J
¼ 6:8 Hz, CH3); 13C NMR (DMSO-d6) d 165.5 (CO), 165.1
CH3—3
0
(CO), 155.9 (C-6), 148.9 (C-2), 146.9 (C-4), 139.8 (C-8), 133.9–
128.7 (2ꢃ C6H5CO), 123.9 (C-5), 88.4 (C-10), 83.2 (C-40), 79.5
(C-20), 74.9 (NCH2O), 70.9 (OCH2CH2O), 68.3 (OCH2CH2O), 63.6
(FAB < 0)
265
(MꢁH)ꢁ,
135
(B)ꢁ;
Anal.
Calcd
for
C11H14N4O4ꢀ0.6H2O: C, 47.69; H, 5.53; N, 20.22. Found: C, 47.54;
H, 5.37; N, 19.98.

M. Aljarah et al. / Bioorg. Med. Chem. 16 (2008) 7436–7442
7441
(C-50), 58.0 (OCH3), 36.6 (C-30), 9.2 (CH3); m/z (FAB > 0) 563
4.4.11. 1-(3-Deoxy-3-C-methyl-b-D-ribofuranosyl)-1,2,
4-triazole-3-carboxamide (27)
(M+H)+, 339 (S)+, 225 (BH2)+; m/z (FAB < 0) 561 (MꢁH)ꢁ, 223
(B)ꢁ; Anal. Calcd for C29H30N4O8ꢀ0.4CH3OH: C, 61.37; H, 5.54; N,
9.74. Found: C, 61.33; H, 5.52; N, 9.68.
Purification using as eluent a stepwise gradient of methanol (0–
10%) in dichloromethane to afford the title compound 27 (481 mg,
86%) which was crystallized from acetonitrile: mp 157 °C; ½a D20
ꢂ
4.4.9. 1-(3-Deoxy-3-C-methyl-b-
D
-ribofuranosyl)-5-aminoimi-
ꢁ26.9 (c 0.97 in DMSO); 1H NMR (DMSO-d6) d 8.99 (1H, s, H-5),
7.83 and 7.62 (2H, 2ꢃ br s, NH2), 5.84 (1H, s, H-10), 5.77 (1H, br
dazole-4-carboxamide (24)
s, OH-20), 5.00 (1H, br s, OH-50), 4.24 (1H, d, J2 —3 ¼ 4:4 Hz, H-20),
0
0
A solution of compound 22 (264 mg, 0.47 mmol) in methanolic
ammonia (previously saturated at ꢁ10 °C and tightly stoppered)
(14.1 ml) was stirred at room temperature for 24 h, then evapo-
rated to dryness. A stirred solution of the resulting residue in
an aqueous solution of sodium hydroxide (0.2 M, 4.7 ml) was
heated under reflux for 4 h. After cooling to room temperature,
the reaction mixture was neutralized with hydrochloric acid 6 N
and evaporated under reduced pressure. The residue was sub-
jected to silica gel column chromatography using as eluent a
stepwise gradient of methanol (0–20%) in dichloromethane to af-
ford the title compound 24 (69.8 mg, 58%) which was lyophilized
3.89 (1H, m, H-40), 3.62 (2H, m, H-50 and H-500), 2.31 (1H, m, H-
30), 0.98 (3H, d, JCH
¼ 6:8 Hz, CH3); 13C NMR (DMSO-d6) d
0
3—3
160.5 (CO), 157.2 (C-3), 144.0 (C-5), 94.2 (C-10), 87.0 (C-40), 77.4
(C-20), 60.9 (C-50), 35.5 (C-30), 9.2 (CH3); m/z (FAB > 0) 243
(M+H)+, 131 (S)+, 113 (BH2)+; m/z (FAB < 0) 241 (MꢁH)ꢁ, 111
(B)ꢁ; Anal. Calcd for C9H14N4O4: C, 44.63; H, 5.83; N, 23.13. Found:
C, 44.77; H, 5.69; N, 23.10.
4.4.12. 1-(5-O-Benzoyl-3-deoxy-3-C-methyl-b-D-ribofuranosyl)-
1,2,4-triazole-3-carboxamide (28)
To a stirred solution of compound 27 (150 mg, 0.62 mmol) in
pyridine (3.1 ml) was added dropwise benzoyl chloride (108 l,
0.93 mmol) at 0 °C. The reaction mixture was stirred at room tem-
perature for 1 h, then diluted with water and dichloromethane. The
organic phase was washed with aqueous solution of sodium hydro-
genocarbonate and water, dried over sodium sulfate, evaporated
under reduced pressure and co-evaporated with toluene. The resi-
due was subjected to silica gel column chromatography using as
eluent a stepwise gradient of methanol [0–7%] in dichloromethane
to afford the title compound 28 as a white foam (142 mg, 66%):
from water: ½a 2D0
ꢂ
ꢁ40.0 (c 0.85 in DMSO); 1H NMR (DMSO-d6) d
7.45 (1H, s, H-2), 6.79 and 6,65 (2H, 2ꢃ br s, CONH2), 5.90 (2H,
l
s, NH2), 5.56 (1H, d, JOH-2 ¼ 4:1 Hz, OH-20), 5.47 (1H, d,
0
J1 —2 ¼ 1:5 Hz, H-10), 5.10 (1H, t, JOH-5 ¼ JOH-5 ¼ 5:2 Hz, OH-50),
0
0
0
00
0
0
0
0
0
4.12 (1H, t, J2 -OH ¼J2 —3 ¼3:9Hz, H-2 ), 3.78 (1H, m, H-4 ), 3.73
(1H, m, H-50), 3.53 (1H, m, H-500), 2.29 (1H, m, H-30), 0.97 (3H,
d, JCH
¼ 6:8 Hz, CH3); 13C NMR (DMSO-d6) d 167.3 (CONH2),
142.53—(30C-5), 128.0 (C-2), 113.2 (C-4), 90.5 (C-10), 86.2 (C-40),
77.0 (C-20), 60.9 (C-50), 35.7 (C-30), 10.1 (CH3); m/z (FAB > 0) 257
(M+H)+, 127 (BH2)+; m/z (FAB < 0) 255 (MꢁH)ꢁ, 125 (B)ꢁ; Anal.
Calcd for C10H16N4O4ꢀ0.7CH3OH: C, 46.11; H, 6.80; N, 20.10.
Found: C, 45.79; H, 6.28; N, 19.80.
½
a 20
ꢂ
ꢁ1.2 (c 0.85 in DMSO); 1H NMR (DMSO-d6) d 8.81 (1H, s, H-
D
5), 7.93–7.51 (7H, m, NH2and C6H5CO), 5.96 (1H, s, H-10),
5.84 (1H, br s, OH-20), 4.53 (1H, dd, J5 —4 ¼ 2:7 Hz and
0
0
4.4.10. 1-(2-O-Acetyl-5-O-benzoyl-3-deoxy-3-C-methyl-b-
furanosyl)-1,2,4-triazole-3-carboxylic acid methyl ester (25) and
2-(2-O-acetyl-5-O-benzoyl-3-deoxy-3-C-methyl-b- -ribofurano-
syl)-1,2,4-triazole-3-carboxylic acid methyl ester (26)
mixture of methyl 1,2,4-triazole-3-carboxylate (755 mg,
5.94 mmol) and 1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-3-C-methyl-
b- -ribofuranose 1 (1 g, 2.97 mmol) was heated at 160–165 °C until
D-ribo-
J5 —5 ¼ 12:3 Hz, H-50), 4.41 (2H, m, H-500 and H-20), 4.22 (1H, m,
0
00
H-40), 271 (1H, m, H-30), 1.09 (3H, d, JCH
¼ 6:8 Hz, CH3); 13C
NMR (DMSO-d6) d 165.6 (CO), 160.4 (CO),3—13057.5 (C-3), 145.0 (C-
5), 133.4–128.8 (C6H5CO), 93.3 (C-10), 83.5 (C-40), 76.8 (C-20), 64.5
(C-50), 37.2 (C-30), 9.2 (CH3); m/z (FAB > 0) 347 (M+H)+, 235 (S)+,
113 (BH2)+, 105 (C6H5CO)+; m/z (FAB < 0) 345 (MꢁH)ꢁ, 121
(C6H5CO2)ꢁ, 111 (B)ꢁ; Anal. Calcd for C16H18N4O5ꢀ0.6CH3OH: C,
54.54; H, 5.62; N, 15.33. Found: C, 54.22; H, 5.42; N, 15.75.
D
A
a,
D
the sugar had melted. Bis(p-nitrophenyl)phosphate (catalytic
amount) was added and heating at 160–165 °C was continued un-
der diminished pressure for 90 min. After cooling to room tempera-
ture, dichloromethane was added and the organic phase washed
with aqueous solution of sodium hydrogenocarbonate, dried over
sodium sulfate and evaporated to dryness. The residue was sub-
jected to silica gel column chromatography using as eluent a mix-
ture of petroleum ether/ethyl acetate (2:3, v/v) to afford in order
of elution the title compound 25 (977 mg, 81%), which was crystal-
4.4.13. 1-(5-O-Benzoyl-2,3-dideoxy-3-C-methyl-b-
D-erythro-
pentofuranosyl)-1,2,4-triazole-3-carboxamide (29)
To a stirred solution of compound 28 (100 mg, 0.29 mmol) in
dichloromethane (2.9 ml) were added successively 1-methylimid-
azole (138
ll, 1.74 mmol) and phenoxy(thiocarbonyl) chloride
(161 l, 1.16 mmol). The reaction mixture was stirred at room
l
lized from isopropanol: mp 92 °C; ½a D20
ꢂ
ꢁ13.0 (c 0.92 in DMSO); 1H
temperature for 24 h, then water was added. The organic phase
was washed with aqueous solution of hydrochloric acid (0.5 N)
and water, dried over sodium sulfate and evaporated to dryness.
The resulting residue was co-evaporated with dry toluene, then
NMR (DMSO-d6) d 8.90 (1H, s, H-5), 7.88–7.47 (5H, m, C6H5CO), 6.24
(1H, s, H-10), 5.52 (1H, d, J2 —3 ¼ 5:1 Hz, H-20), 4.58 (1H, dd,
0
0
J5 —4 ¼ 2:6 Hz and J5 —5 ¼ 12:5 Hz, H-50), 4.43 (1H, dd,
0
0
0
00
¼ 12:5 Hz, H-500), 4.26 (1H, m, H-40), 3.85
0
0
dissolved in the same solvent (4.4 ml) and
(32.8 mg, 0.20 mmol) and tris(trimethylsilyl)silane (179
a,
a0-azoisobutyronitrile
l,
00 —50
J5 —4 ¼ 4:6 Hz and J5
(3H, s, OCH3), 2.90 (1H, m, H-30), 2.16 (3H, s, CH3CO), 1.10 (3H, d,
l
¼ 6:8 Hz, CH3); 13C NMR (DMSO-d6) d 169.9 (CO), 165.5
0.58 mmol) were added. The reaction mixture was heated under
reflux for 4 h. After cooling to room temperature, the solvent was
removed under reduced pressure. Chromatography of the residue
on a silica gel column using as eluent a stepwise gradient of meth-
anol (0–5%) in dichloromethane afforded the title compound 29 as
JCH
0
3—3
(CO), 159.6 (CO), 154.4 (C-3), 146.1 (C-5), 133.4–128.7 (C6H5CO),
99.5 (C-10), 90.4 (C-40), 78.6 (C-20), 63.4 (C-50), 52.3 (OCH3), 36.1
(C-30), 20.5 (CH3CO), 8.9 (CH3); m/z (FAB > 0) 404 (M+H)+, 277 (S)+,
128 (BH2)+, 105 (C6H5CO)+, 43 (CH3CO)+; m/z (FAB < 0) 402 (MꢁH)ꢁ,
126 (B)ꢁ, 121 (C6H5CO2)ꢁ; Anal. Calcd for C19H21N3O7: C, 56.57; H,
5.25; N, 10.42. Found: C, 56.29; H, 5.27; N, 10.40. Compound 26
(48 mg, 3%): 1H NMR (DMSO-d6) d 8.21 (1H, s, H-5), 7.928–7.45
a white foam (56.3 mg, 59%): ½a D20
ꢂ
+13.2 (c 0.83 in DMSO); 1H NMR
(DMSO-d6) d 8.75 (1H, s, H-5), 7.89–7.48 (7H, m, NH2and C6H5CO),
6.21 (1H, d, J1 —2 ¼ 6:9 Hz, H-10), 4.46 (1H, dd, J5 —4 ¼ 2:9 Hz and
0
00
0
0
0
0
J5 —5 ¼ 12:2 Hz, H-50), 4.35 (1H, dd, J5 —4 ¼ 5:4 Hz and
(5H, m, C6H5CO), 6.65 (1H, s, H-10), 5.51 (1H, d, J2 —3 ¼ 5:1 Hz, H-
0
00
0
0
0
0
0
00
J5
¼ 12:2 Hz, H-500), 3.98 (1H, m, H-40), 2.70 (1H, m, H-30), 2.56
20), 4.54 (1H, dd, J5 —4 ¼ 2:7 Hz and J5 —5 ¼ 12:4 Hz, H-50), 4.38
00—50
0
0
(1H, m, H-20), 2.18 (1H, m, H-200), 1.13 (3H, d, JCH
¼ 6:5 Hz,
00 —50
(1H, dd, J5 —4 ¼ 4:6 Hz and J5
¼ 12:4 Hz, H-500), 4.23 (1H, m, H-
0
CH3); 13C NMR (DMSO-d6) d 165.6 (CO), 160.5 (CO), 31—357.2 (C-3),
144.7 (C-5), 133.4–128.8 (C6H5CO), 87.1 (C-10), 85.0 (C-40), 64.5
40), 3.90 (3H, s, OCH3), 3.03 (1H, m, H-30), 2.18 (3H, s, CH3CO),
1.07 (3H, d, JCH
¼ 6:8 Hz, CH3).
0
3—3

7442
M. Aljarah et al. / Bioorg. Med. Chem. 16 (2008) 7436–7442
(C-50), 39.6 (C-20), 33.2 (C-30), 15.5 (CH3); m/z (FAB > 0) 331 (M+H)+,
219 (S)+, 113 (BH2)+; m/z (FAB < 0)ꢁ, 111 (B)ꢁ; Anal. Calcd for
France, for a doctoral fellowship. We gratefully acknowledge Dr.
M. Liuzzi (Università degli Studi di Cagliari) for the biological re-
sults. This work was supported by Grants from the European Eco-
nomic Community program ‘Flaviterapeutics’ (QLK3-CT-2001-
00506).
C16H18N4O4: C, 58.17; H, 5.49; N, 16.96. Found: C, 58.05; H, 5.44;
N, 16.36.
4.4.14. 1-(2,3-Dideoxy-3-C-methyl-b-D-erythro-
pentofuranosyl)-1,2,4-triazole-3-carboxamide (30)
References and notes
Purification using as eluent a stepwise gradient of methanol (0–
10%) in dichloromethane afforded the title compound 30 (20.3 mg,
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74%) which was lyophilized from 1,4-dioxane: ½a 20
ꢁ4.7 (c 0.85 in
ꢂ
D
DMSO); 1H NMR (DMSO-d6) d 8.83 (1H, s, H-5), 7.81 and 7.51 (2H,
2ꢃ br s, NH2), 6.15 (1H, d, J1 —2 ¼ 6:4 Hz, H-10), 4.93 (1H, br s, OH-
0
00
50), 3.62 (3H, m, H-40, H-50 and H-500), 2.45 (2H, m, H-30 and H-20),
2.12 (1H, m, H-200), 1.07 (3H, d, JCH
¼ 6:3 Hz, CH3); 13C NMR
0
(DMSO-d6) d 160.6 (CO), 157.0 (C-3),31—344.0 (C-5), 88.7 (C-40), 87.9
(C-10), 61.4 (C-50), 40.2 (C-20), 32.1 (C-30), 15.8 (CH3); m/z
(FAB > 0) 227 (M+H)+, 115 (S)+, 113 (BH2)+; m/z (FAB < 0) 225
(MꢁH)ꢁ, 111 (B)ꢁ; Anal. Calcd for C9H14N4O3ꢀ0.21,4-dioxan: C,
48.27; H, 6.45; N, 22.98. Found: C, 48.19; H, 6.20; N, 23.00.
Acknowledgments
M.A and S.C. are particularly grateful to the Ministère de l’Edu-
cation Nationale, de l’Enseignement Supérieur et de la Recherche,