Synthesis of 4-acyl-1H-1,2,3-triazolic nucleosides

Article abstract of DOI:10.1081/NCN-100105247

Two simple regiospecific methodologies based on triazolic ring construction in the course of synthesis were applied for the synthesis of 1,2,3-triazolic nucleoside analogues. The cycloaddition reactions between diazomalonaldehyde and appropriate glycosylamine derivatives were rather effective, producing the desired nucleosides 11, 17 and 24. Diazotization of enamines 21a and 21b led to the corresponding triazolic ribonucleoside derivatives 22a and 22b, in good yields. Deprotection reaction of 22a, 22b and 24 was easily achieved by Lewis acid catalysis, producing the corresponding ribonucleosides 23a, 23b and 25.

Full text of DOI:10.1081/NCN-100105247

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SYNTHESIS OF 4-ACYL-1H-1,2,3-TRIAZOLIC
NUCLEOSIDES
Anna C. Cunha a , Letícia O. R. Pereira b , Rodrigo O. P. de Souza b , Maria Cecília B. V. de
Souza b & Vitor F. Ferreira c
a Universidade Federal do Rio de Janeiro, Núcleo de Pesquisas de Produtos Naturais, Rio de
Janeiro-RJ, 21941-590, Brazil
b Instituto de Química, Universidade Federal Fluminense, Niterói-RJ, 24210-150, Brazil
c Instituto de Química, Universidade Federal Fluminense, Niterói-RJ, 24210-150, Brazil
Published online: 17 Aug 2006.
To cite this article: Anna C. Cunha , Letícia O. R. Pereira , Rodrigo O. P. de Souza , Maria Cecília B. V. de Souza & Vitor F.
Ferreira (2001): SYNTHESIS OF 4-ACYL-1H-1,2,3-TRIAZOLIC NUCLEOSIDES, Nucleosides, Nucleotides and Nucleic Acids, 20:8,
1555-1569
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(8), 1555À1569 (2001)
SYNTHESIS OF 4-ACYL-1H-1,2,3-TRIAZOLIC
NUCLEOSIDES
Anna C. Cunha,1 Letõcia O. R. Pereira,2 Rodrigo O. P. de Souza,2
Maria Cecõlia B. V. de Souza,2 and Vitor F. Ferreira2,*
1Nucleo de Pesquisas de Produtos Naturais, Universidade Federal
do Rio de Janeiro, 21941-590, Rio de Janeiro-RJ, Brazil
2Instituto de Quõmica, Universidade Federal Fluminense,
24210-150, Niteroi-RJ, Brazil
ABSTRACT
Two simple regiospeci®c methodologies based on triazolic ring con-
struction in the course of synthesis were applied for the synthesis of 1,2,3-
triazolic nucleoside analogues. The cycloaddition reactions between
diazomalonaldehyde and appropriate glycosylamine derivatives were
rather e€ective, producing the desired nucleosides 11, 17 and 24. Dia-
zotization of enamines 21a and 21b led to the corresponding triazolic
ribonucleoside derivatives 22a and 22b, in good yields. Deprotection
reaction of 22a, 22b and 24 was easily achieved by Lewis acid catalysis,
producing the corresponding ribonucleosides 23a, 23b and 25.
The development of triazole-based compounds stimulated by their
pronounced biological activities brought about noticeable interest in the
synthetic manipulations of triazoles1.
Recently we reported a versatile and regioselective route for the
synthesis of 1,2,3-triazole derivatives presenting di€erent substituents at
positions 4 and 5. In all cases, only the isomer characterized by the presence
of alkyl or aryl moieties at position 5 and of acetyl or carboxylate groups at
position 4 was obtained. (Scheme 1: 1 !2)2.
*Corresponding author.
1555
Copyright # 2001 by Marcel Dekker, Inc.
www.dekker.com

1556
CUNHA ET AL.
Scheme 1. Methods for preparing triazoles by diazotization of enamines and by cycloaddi-
tion between diazocompounds and amines.
Another regioselective route based on the cycloaddition of amines to
a-diazocarbonyl compounds to produce substituted 1,2,3-triazoles was pre-
viously described by Arnold (Scheme 1: 3 ! 4)3.
Proceedingwithour researchwork4a on a-diazocarbonylcompounds4bÀ4f
and nucleoside derivatives4gÀ4k and grounded in the precedents above, we
herein report an extension of these two ecient methods to the nucleoside ®eld.
Advances in this area have indicated that changes in the carbohydrate or the
nitrogenated base moiety may be compatible with potent therapeutical com-
pounds5.
RESULTS AND DISCUSSION
Initially, triazolic gluconucleoside 11 was synthesized by the cycload-
dition between diazomalonaldehyde and aminoglucoside 10 (Scheme 2). The
treatment of D-glucosamine (7) with p-anisaldehyde in NaOH resulted in 2-
(4-methoxybenzylidene)imine-2-desoxy-D-glucopyranose (8) as a mixture of
two diastereoisomers, a and b, in 80% yield (Scheme 2). The reaction of this
mixture with acetic anhydride and pyridine in excess produced imine-tetra-
cetate 9 as the b-isomer. The stereospeci®city of this reaction at the anomeric
center is due to the bulky group at C-2. Selective acid hydrolysis of 9 led to
the desired glucosamine hydrochloride 10 in 82% yield6. Cycloaddition
reaction between 10 and diazomalonaldehyde in aqueous solution produced
the triazolic gluconucleoside 11 in 40% yield. All attempts to improve this
yield using an excess of D-glucosamine hydrochloride 10 in methanolic
solution led exclusively to bis-triazolic adduct 12.
In order to synthesize the triazolic gluconucleoside 17 presenting the
heterocyclic nucleus at the anomeric position, amine 16 was prepared

4-ACYL-1H-1,2,3-TRIAZOLIC NUCLEOSIDES
1557
Scheme 2. Synthetic route used for preparing triazolic gluconucleosides 11 and 12.
(Scheme 3) following the procedure described in the literature7. This involved
the selective protection of an amine group as the acetamide (13), followed by
the peracetylation of the hydroxy groups and the replacement of the acetyl
group at the anomeric position by a chlorine to form 147. The nucleophilic
Scheme 3. Synthesis of triazolic gluconucleoside 17.

1558
CUNHA ET AL.
Scheme 4. Anchimeric assistance responsible for the 1,2-trans stereochemistry in 15.
substitution of the chlorine group by the azide anion led to 15 in 90% yield.
The 1,2-trans stereochemistry of this compound may be explained by a SN2
attack by the azido anion at the anomeric carbon in the intermediate acy-
loxonium ion (II), which was formed from I by an anchimeric assistance of
the acetamide group at position 2 (Scheme 4). The catalytic hydrogenation of
15 led to the desired amine 16 in 85% yield. All attempts to form the triazole
derivative 17 by the reaction between this amine and diazomalonaldehyde, in
water or methanol, failed. However, a slightly modi®ed procedure using
acetic acid as co-solvent in methanol successfully gave 17 in 54% yield.
For the purpose of preparing the triazolic gluconucleoside 19, com-
pound 16 underwent a reaction with acetylacetone in the presence of Mon-
tmorillonite (K-10) clay8 resulting in enamine 18, in 80% yield. All attempts
to carry out the diazotization of 18 using mesyl azide failed to give 19
(Scheme 5). Since this reaction was rather e€ective with acyclic amines4 and
aminocarbohydrate 20, a compound where the amine group is not bonded to
the anomeric carbon but to C-5 instead, we speculated on the possible
elimination of the enamine group before the formation of the triazolic ring.
Ribonucleosides 22a and 22b were synthesized by constructing the
triazolic nucleus from 5-amino-5-deoxy-1,2-O-isopropylidene-b-D-ribofur-
anoside (20), which was prepared from commercially available D-ribose, in
four steps (Scheme 6)9. Amine 20 was readily condensed with acetylacetone
or ethyl acetoacetate forming 21a and 21b, respectively10. The diazotization
Scheme 5. Attempts to obtain 19 by direct diazotization of enamine 18.

4-ACYL-1H-1,2,3-TRIAZOLIC NUCLEOSIDES
1559
Scheme 6. Synthesis of triazolic ribonucleosides 23a, 23b and 25.
of enamines 21a or 21b with the diazo transfer reagent mesyl azide (MsN3)2
produced triazolic derivatives 22a and 22b, in 74 and 70% yield, respectively.
Finally, triazole derivative 24 was prepared from the reaction between 20
and diazomalonaldehyde, in 78% yield. Removal of the isopropylidene
group from the carbohydrate moiety of 22a and 22b as well as 24 can be
easily achieved by mild Lewis acid catalysis producing the corresponding
deprotected ribonucleoside derivatives 23a, 23b and 25, respectively, in good
yields (Scheme 6).
In conclusion, this work highlights the applicability of two simple
regioselective methodologies based on the triazolic ring construction in the
course of the synthesis for the synthesis of 1,2,3-triazolic nucleoside analo-
gues. Cycloaddition reactions between diazomalonaldehyde and appropriate
glycosylamine derivatives were e€ective for the preparation of nucleoside
derivatives 11 (Scheme 2), 17 (Scheme 3) and 24 (Scheme 6). Diazotization of
enamines 21a and 21b led to protected triazolic ribonucleosides 22a and 22b
in good yields (Scheme 6). On the other hand, the diazotization of enamine
18 (Scheme 5) failed to produce gluconucleoside 19, a compound which
presents the triazolic nucleus bonded to the anomeric carbon. Removal of the
isopropylidene group from the carbohydrate moiety of 22a, 22b and 24 was
easily achieved by Lewis acid catalysis producing the corresponding ribo-
nucleoside derivatives 23a, 23b and 25 (Scheme 6).
Since many substances containing triazolic nucleus have wide biological
activities11, the development of synthetic methods that grant access to tria-
zolic nucleoside analogues is decidedly important. Further studies including
the use of di€erent starting glycosylamine derivatives must be carried out to
verify the possibility of using both methods for preparing promising triazolic
nucleosides.

1560
CUNHA ET AL.
EXPERIMENTAL
General Procedures
Melting points were observed on a Fischer-John melting-point appa-
ratus and are uncorrected. Ultraviolet spectra were recorded on a Schimadzu
spectrophotometer; l in nm and e in moleÀ1 cmÀ1. 1H and 13C NMR spectra
were recorded with a Varian Unity Plus 300 spectrometer operating at 300
and 75 MHzrespectively, with tetramethylsilane as the internal standard.
Low resolution electron-impact mass spectra (12 eV) were obtained using a
Hewlett Packard 5985 instrument and high resolution fast atom bombard-
ment mass spectra (HRMS-FAB) were recorded in a 3-NBA (3-nitrobenzyl
alcohol) matrix in the positive ion mode on a VG ZAB-E mass spectrometer.
Infrared spectra were recorded on a Perkin-Elmer 1420 spectrophotometer.
Optical rotations were measured on a Perkin Elmer 24 B Polarimeter.
Column chromatography was performed using silica gel 60 (Merck 70À230
mesh). Merck silica gel F254 (0.2 mm) was used for TLC plates, detection
being carried out by spraying with aqueous ammonium sulfate solution
(25%, w=w), followed by heating. Solvents were dried over appropriate
agents and were immediately distilled before use12. Freshly puri®ed samples
were used to measure physical constants and spectral data.
2-Amino-2-deoxy-1,3,4,6-tetra-O-acetyl-b-D-glycopyranose Hydrochloride
(10)
A solution of 96 (1 g, 2.15 mmol) in acetone (16 mL) was heated in a
water bath and then an aqueous solution of HCl (0.5 N, 0.43 mL) was added
producing a gel. After adding diethyl ether (5 mL) the mixture was kept in the
refrigerator until complete crystallization. The solid was collected by ®ltra-
tion, washed with diethyl ether and dried in desiccator under P2O5. Hydro-
chloride 10 was obtained in 82% yield (676 mg). m.p 199 ꢀC (decomp.); ‰aŠ
25
D
1
‡ 39.7 (c 1.00, MeOH); H NMR (300.00 MHz, CDCl3) d 2.08; 2.11; 2.14;
2.29 (12H, s, 4 COCH3), 3.66 ꢁ1H; dd; J ˆ 10:2 and 9.0 Hz, H20), 5.04
(1H, dd, J ˆ 9:3 and 9.3 Hz, H40), 5.48 (1H, dd, J ˆ 10:3 and 9.0 Hz, H30),
4.08À4.17 (2H, m, H60 and H60), 4.30 (1H, dd, J ˆ 12:3 and 4.5 Hz, H600), 5.12
(2H, broad singlet, NH2) ppm; 13C NMR (75.0 MHz, CDCl3) d 20.5; 20.6;
20.9; 21.1 (4 COCH3), 52.3 (C20), 61.4 (C60), 67.9 (C40), 70.4 (C30), 71.4 (C50),
90.2 (C10), 168.8; 169.5; 169.9; 170.5 ( 4 CˆO) ppm.
2-(4-Formyl-1,2,3-triazo-1-yl)-1,3,4,6-tetra-O-acetyl-2-deoxy-a-D-
glucopyranose (11)
A solution of diazomalonaldehyde (91 mg, 0.93 mmol) and hydro-
chloride 10 (452 mg, 1.18 mmol) in water (7 mL) was stirred at room

4-ACYL-1H-1,2,3-TRIAZOLIC NUCLEOSIDES
1561
temperature for 24 hours. The white solid formed was collected by ®ltration,
washed with water and dried under vacuum leading to triazole 11 as a white
25
solid in 40% yield (158 mg). m.p. 141À142 ꢀC; ‰aŠ ‡ 38.9 (c 0.46, MeOH);
D
UV lmax (MeOH) 218 (e 3,847); IR (®lm) nmax (cmÀ1): 1702À1780 (CˆO); 1H
NMR (300.00 MHz, CDCl3) d 1.88, 1.99, 2.06 and 2.11 (12H, s, 4 COCH3),
4.09 (1H, ddd, J ˆ 10:1; 4:3 and 2.1 Hz, H50), 4.18 (1H, dd, J ˆ 12:3 and
2.1 Hz, H60), 4.41 (1H, dd, J ˆ 12:6 and 4.5 Hz, H60), 4.72 (1H, dd, J ˆ 10:5
and 8.7 Hz, H20), 5.24 (1H, dd, J ˆ 9:9 and 9.3 Hz, H40), 5.82 (1H, dd, J ˆ 10:8
and 9.3 Hz, H30), 6.24 (1H, d, J ˆ 8:7 Hz, H10); 8.14 (1H, s, H5), 10.14 (1H, s,
HCˆO) ppm; 13C NMR (75.0 MHz, CDCl3) d 20.0; 20.3; 20.4 and 20.5
(4 COCH3), 61.1 (C50), 63.1 (C20), 67.8 (C40), 71.8 (C30), 72.9 (C50), 91.3 (C10),
125.8 (C5), 147.4 (C4), 167.8; 168.9; 169.4 and 170.4 ( 4 CˆO), 184.7
(HCˆO) ppm; LRMS-FAB (m=z) (relative intensity): 428 (33), 154 (95), 136
‡
(87); HRMS-FAB: calcd for C17H22N3O10 (M ‡ H)
428.1305; found
428.1297.
2-Acetamido-3,4,6-tri-O-acetyl-1-chloro-2-deoxy-a-D-glucopyranose (14)
A solution of 13 (1.5 g, 6.80 mmol) in 5 mL of acetyl chloride was stirred
at room temperature under nitrogen atmosphere for 48 hours. Chloroform
(12 mL), ice (12 g) and water (10 mL) were added to this solution. The
organic phase was separated and washed with an aqueous solution of sodium
bicarbonate (15 mL). After drying over anhydrous sodium sulfate, the solvent
was removed under reduced pressure. The residue was puri®ed by column
chromatography on silica gel, using hexane-ethyl acetate (9 : 1) as the eluant,
and the resulting solid was crystallized out of diethyl ether. Nucleoside 14
was isolated as a white solid in 68% yield (1.59 mg). m.p. 119 ꢀC; 1H NMR
(300.00 MHz, CDCl3) 2.00, 2.06 and 2.11 (12H, s, 4 COCH3), 4.14 (1H, dd,
J ˆ 13:6 and 3.0 Hz, H60), 4.25À4.33 (2H, m, H50 and H60), 4.55 (1H, ddd,
J ˆ 10:6; 8.7 and 3.6 Hz, H20), 5.22 (1H, dd, J ˆ 9:6 and 9.6 Hz, H40), 5.35
(1H, dd, J ˆ 10:6 and 9.3 Hz, H30), 6.07 (1H, d, J ˆ 8:4, NHAc), 6.20 (1H, d,
J ˆ 3:9 Hz, H10) ppm; 13C NMR (75.0 MHz, CDCl3) d 20.3; 20.5 and 20.8
(4 COCH3), 53.2 (C20), 61.0 (C60), 66.8 (C40), 69.9 (C30), 70.7 (C50), 93.5 (C10),
168.9; 170.0; 170.4 and 171.2 (4 CˆO) ppm.
1-Azido-2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glucopyranose (15)
After being stirred, a solution of 14 (0.5 g, 1.66 mmol) and sodium azide
(0.15 g, 2.31 mmol) in dry DMF (3 mL) was heated under nitrogen atmo-
sphere at 75À80 ꢀC for 4 hours. The mixture was poured into cold water and
then extracted with ethyl acetate (4615 mL). The combined organic phases
were dried over anhydrous sodium sulfate and concentrated under reduced

1562
CUNHA ET AL.
pressure. The residue was puri®ed by column chromatography on silica gel
using a gradient from pure hexane to hexane-ethyl acetate (1 : 1) producing
1
15 as a white solid in 90% yield. m.p. 166À167 ꢀC; H NMR (300.00 MHz,
CDCl3) 1.99, 2.04, 2.05 and 2.11 (12H, s, 4 COCH3†, 3.92 (1H, m, H20), 3.80
(1H, ddd, J ˆ 9:9, 4.8 and 2.4 Hz, H50), 4.17 (1H, dd, J ˆ 12:5 and 2.4 Hz,
H60), 4.28 (1H, dd, J ˆ 12:5 and 4.8 Hz, H600), 4.77 (1H, d, J ˆ 9:3 Hz, H10),
5.11 (1H, dd, J ˆ 9:3 and 9.3 Hz, H40), 5.74 (1H, d, J ˆ 8:7 Hz, NHAc) ppm;
13C NMR (75.0 MHz, CDCl3) d 20.4; 20.5 and 20.6 and 23.1 (4 COCH3), 53.9
(C20), 61.7 (C60), 68.0 (C40), 72.0 (C30), 72.0 (C30), 73.7 (C50), 82.2 (C10),
169.2; 170.7, 170.5 and 170.6 (4 CˆO) ppm.
2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-glucopyranosylamine (16)
A mixture of 15 (1.50 g; 4.04 mmol) in ethyl acetate (50 mL) was
hydrogenated at room temperature and 2.5 atm pressure for 2 hours in the
presence of 0.63 g of Adam0s platinum oxide catalyst. The catalyst was
removed by ®ltration and washed with ethyl acetate. Activated charcoal
was added to the resulting mixture which was ®ltrated and the solution
was evaporated under reduced pressure producing a white solid. This
solid was re¯uxed in ethyl acetate-hexane (2 : 1, 30 mL) and then collected by
®ltration and washed with diethyl ether leading to 16 in 85% yield (1.19 mg).
1
m.p. 220À221 ꢀC (decomp.); H NMR (300.00 MHz, CD3OD) 2.01, 2.07,
2.09 and 2.13 (12H, s, 4 COCH3), 3.84 (1H, ddd, J ˆ 9:6, 4.8 and 2.4 Hz, H50),
3.90 (1H, dd, J ˆ 10:2 and 9.6 Hz, H20), 4.18 (1H, dd, J ˆ 12:0 and 2.4 Hz,
H60), 4.31 (1H, d, J ˆ 9:3 Hz, H10), 4.33 (1H, dd, J ˆ 12:0 and 4.8 Hz, H600),
5.05 (1H, dd, J ˆ 9:9 and 9.6 Hz, H40), 5.25 (1H, dd, J ˆ 10:5 and 9.3 Hz,
H30), 4.97 (3H, broad singlet, NHAc and NH2) ppm; 13C NMR (75.0 MHz,
CD3OD) d 11.2 and 11.3 (COCH3), 46.7 (C20), 54.3 (C60), 61.1 (C40), 64.4
(C50), 65.5 (C30), 76.7 (C10), 161.9, 162.5, 163.0 and 164.3 (4 CˆO) ppm.
1-(2-Acetamide-3,4,6-tri-O-acetyl-2-deoxy-b-D-glucopyranosyl)-4-formyl-
1,2,3-triazole (17)
A solution of diazomalonaldehyde (220 mg, 2.25 mmol) and 16 (152 mg,
0.44 mmol) in 3 mL of methanol and 0.2 mL of acetic acid was stirred at room
temperature for 24 hours. Concentration of the solution under reduced
pressure produced a residue which was puri®ed by column chromatography
on silica gel, using a gradient from pure hexane to hexane-acetone (1 : 1) as
the eluant. 17 was obtained as a yellow solid in 54% yield (101 mg). m.p.
25
228À229 ꢀC; ‰aŠ ‡ 6.3 (c 0.47, MeOH); UV lmax (MeOH) 217 (e 3,645); IR
D
(®lm) nmax (cmÀ 1): 1668À1747 (CˆO); 1H NMR (300.00 MHz, CDCl3) 1.80,
2.08, 2.09 and 2.10 (12H, s, 4 COCH3), 4.06 (1H, dd, J ˆ 10:1; 4.8 and 2.1 Hz,
H50), 4.17 (1H, dd, J ˆ 12:6 and 2.1 Hz, H60), 4.31 (1H, dd, J ˆ 12:6 and

4-ACYL-1H-1,2,3-TRIAZOLIC NUCLEOSIDES
1563
4.8 Hz, H60), 4.55 (1H, ddd, J ˆ 10:5, 9.9 and 9.9 Hz, H20), 5.28 (1H, dd,
J ˆ 10:2. and 9.3 Hz, H40), 5.45 (1H, dd, J ˆ 10:5 and 9.3 Hz, H30), 6.06 (1H,
d, J ˆ 9:9 Hz, H10); 8.50 ( 1H, s, H5), 10.14 (1H, s, HCˆO) ppm; 13C NMR
(75.0 MHz, CDCl3) d 20.4; 20.5; 20.6 and 20.7 (4 COCH3), 61.5 (C60), 57.3
(C20), 67.7 (C40), 74.9 (C50), 71.7 (C30), 86.1 (C10), 125.6 (C5), 147.3 (C4),
169.2, 170.4, 170.7 and 170.8 (4 CˆO), 184.2 (HCˆO) ppm; LRMS-FAB
(m=z) (relative intensity): 427 (4)168 (41), 154 (69), 136 (65); HRMS-FAB:
‡
calcd for C17H23N4O9ꢁM ‡ H† 427:1465; found 427.1459.
1-[N-2-(4-Oxopenten)]amino-2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-
glucopyranose (18)
A solution of 16 (301 mg, 0.87 mmol) in 2 mL dry methanol was slowly
added to a mixture of acetylacetone (683 mg, 6.82 mmol), Montmorillonite
K-10 (0.31 g) and 2 mL of dry methanol, under nitrogen atmosphere. After
stirring for 24 hours at room temperature, the mixture was ®ltrated and the
resulting solution was dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure and the remaining solid was puri®ed by
column chromatography on silica gel, using a gradient from hexane to
hexane-acetone (1 : 1) as the eluant. Enamine 18 was obtained in 80% yield
25
(298 mg). m.p. 188À190 ꢀC; ‰aŠ ‡ 5.2 (c 1.33, MeOH); UV lmax (MeOH)
D
1
301 (e 13.977); IR (®lm) nmax (cmÀ1): 3446 (N-H), 1746 (CˆO); H NMR
(300.00 MHz, CDCl3) d 1.91 (CH3C4), 2.02, 2.05 and 2.08 (12H, s, 4
CH3CˆO), 2.00 (CH3CˆO, enamine moiety), 3.68À3.76 (1H, m, H20), 3.78
(1H, ddd, J ˆ 10:1; 5:3 and 2.4 Hz, H50), 4.10 (1H, dd, J ˆ 12:3 and 2.1 Hz,
H60), 4.21 (1H, dd, J ˆ 12:3 and 5.1 Hz, H600), 5.04 (1H, dd, J ˆ 9:9 and
9.3 Hz, H40), 5.13 (1H, s, H3), 5.23 (1H, dd, J ˆ 9:0 and 9.0 Hz, H10), 5.51
(1H, dd, J ˆ 10:4 and 9.0 Hz, H30), 6.51 (1H, s, NHAc), 10.76 (1H, d,
J ˆ 8:7 Hz, N-H) ppm; 13C NMR (75.0 MHz, CDCl3) d 18.4, 20.4 and 20.5
(CH3CˆO, sugar moiety), 22.9 (CH3C4), 29.4 (CH3CˆO, enamine moiety),
54.5 (C20), 62.0 (C60), 68.7 (C40), 72.0 (C30), 72.6 (C50), 81.8 (C10), 98.6
(C3), 161.0 (C4), 169.8, 170.5 and 170.8 (CˆO, sugar moeity), 197.0 (CˆO,
enamine moiety) ppm; LRMS-FAB (m=z) (relative intensity): 429 (100), 168
‡
(38), 154 (53), 136 (48);); HRMS-FAB: calcd for C19H29N2O9ꢁM ‡ H†
428:1873; found 428.1864.
General procedure for the preparation of methyl 50-[N-2-(4-oxopenten)]amino-
5-deoxy-2,3-O-isopropylidene-b-D-ribofuranoside (21a) and methyl 3-[N-3-
ethyl-acryloyl]-amino-5-deoxy-2,3-O-isopropylidene-b-D-ribofuranoside (21b)
Compound 20 (500 mg, 2.46 mmol) was added either to a mixture of
acetylacetone (0.39 g, 3.90 mmol) or ethyl acetoacetate (0.28 g, 15.0 mmol),

1564
CUNHA ET AL.
montimorillonite K-10 (0.67 g) and 5 mL of dry dichloromethane at 0 ꢀC. The
reaction was kept under stirring for 6 h (acetylacetone) or 24 h (ethyl acet-
oacetate) at room temperature. The solid material was removed by ®ltration
and the resulting organic phase was dried over anhydrous sodium sulfate and
concentrated under reduced pressure leading to the crude product which was
chromatographed on a silica gel column eluted with a gradient from pure
hexane to hexane-ethyl acetate (3 : 7).
21a: obtained in 60% yield (214 mg) yield as a pale yellow solid: m.p.
49À50 ꢀC; IR (KBr) nmax(cmÀ1): 1613, 1573, 3427; 1H NMR (CDCl3) d: 1.32
(3H, s, H70), 1.48 (3H, s, H80), 1.94 (3H, s, C4), 2.01 (3H, s, CH3CˆO), 3.41
(3H, s, OCH3), 3.33À3.36 (2H, m, H50 and H500), 4.26 (1H, dd, J ˆ 7:5 and
7.5 Hz, H40), 4.60 (1H, d, J ˆ 6:6 Hz, H30), 4.63 (1H, d, J ˆ 6:0 Hz, H20), 5.0
or 5.02 (1H, s, H10), 5.0 or 5.02 (1H, s, H2), 8.76 (1H, broad singlet, N-H);
13C NMR (CDCl3) d: 18.7 (C4), 24.9 (C70), 26.3 (C80), 46.1 (C50), 55.3
(OCH3), 81.8 (C30), 85.1 (C20), 85.3 (C40), 95.9 (C2), 109.5 (C10), 112.5 (C60),
162.1 (C3), 195.2 (CˆO); LRMS-FAB (m=z) (relative intensity): 286 (100),
254 (43), 154 (47), 112 (59); HRMS-FAB: calcd for C14H24N1O5 ꢁM‡
‡
H† 286:1654; found 286.1643.
21bÀ: 1obtained in 50% yield (349 mg) as a yellow oil; IR (®lm)
1
n
max (cm ): 1613, 1573, 3427; H NMR (CDCl3) d: 1.32 (3H, s, C70), 1.48
(3H, s, C80), 1.94 (3H, s, C4), 2.01 (3H, s, CH3CˆO), 3.41 (3H, s, OCH3),
3.33À3.36 (2H, m, H50 and H500), 4.26 (1H, dd, J ˆ 7:5 and 7.5 Hz, H40), 4.60
(1H, d, J ˆ 6:6 Hz, H30), 4.63 (1H, d, J ˆ 6:0 Hz, H20), 5.00 or 5.02 (1H, s,
H10), 5.00 or 5.02 (1H, s, H2), 10.98 (1H, broad singlet, N-H); 13C NMR
(CDCl3) d: 18.7 (C4), 24.9 (C70), 26.3 (C80), 46.1 (C50), 55.3 (OCH3), 81.8 (C-
30), 85.1 (C20), 85.3 (C40), 95.9 (C2), 109.5 (C10), 112.5 (C60), 162.1 (C3), 195.2
‡
(CˆO); HRMS-FAB: calcd for C15H25N1O6ꢁM ‡ H† 315:1681; found
315.1674.
General procedure for the preparation of methyl 5-deoxy-5-C-(4-acetyl-5-
methyl-1,2,3-triazol-1-yl)-2,3-O-isopropylidene-(-D-ribofuranoside (22a) and
methyl 5-deoxy-5-C-(4-ethoxycarbonyl-5-methyl-1,2,3-triazol-1-yl)-2,3-O-
isopropylidene-b-D-ribofuranoside (22b)
A solution of b-amino-a,b-unsaturated ketone 21a (227 mg, 1.12 mmol)
or ester 21b (400 mg, 1.27 mmol) in 3 mL of acetonitrile was added to a
mixture of sodium hydride (2.83À6.67 mmol, oil free) in 1 mL of anhydrous
acetonitrile, under nitrogen, at room temperature. The mixture was stirred
for 0.5 h, followed by dropwise addition of a solution of methanesulfonyl
azide (3.31À6.61 mmol) in 1 mL of acetonitrile. After an additional stirring
for 24 h the reaction was quenched with an aqueous solution of sodium
hydroxide (10%, w=w). The separated organic layer was dried over anhy-
drous magnesium sulfate, and the solvent was removed under reduced

4-ACYL-1H-1,2,3-TRIAZOLIC NUCLEOSIDES
1565
pressure. The residue was extracted with methylene chloride (3610 mL).
After drying over anhydrous magnesium sulfate, the solvent was removed
under reduced pressure. Crude nucleosides 22a and 22b were puri®ed by
column chromatography on silica gel, using hexane-ethyl acetate (8 : 2) as the
eluant.
22a: the reaction using 0.068 g (2.83 mmol) of sodium hydride and
400 mg (3.31 mmol) of methanesulfonyl azide led to 183 mg of 22a (74%) as a
colorless oil; IR (®lm): 1683; 1H NMR (CDCl3) d: 1.30 (3H, s, C70), 1.46 (3H,
s, C80), 2.62 (3H, s, CH3C ˆ O), 2.69 (3H, s, CH3C2), 3.41 (3H, s, OCH3), 4.36
(1H, dd, J ˆ 16:8 and 9.3 Hz, H50), 4.46À4.54 (2H, m, H40 and H500), 4.69
(1H, dd, J ˆ 5:7 Hz, H20), 4.87 (1H, d, J ˆ 6:0 Hz, H30), 5.01 (1H, s, H10); 13C
NMR (CDCl3) d: 9.0 (CH3C2), 24.7 (C70), 26.2 (C80), 27.5 (CH3CˆO), 50.0
(C50), 55.6 (OCH3), 81.4 (C30), 84.2 (C40), 84.8 (C20), 110.0 (C10), 112.7 (C60),
136.8 (C5), 143.5 (C4), 194.1 (CˆO); LRMS-FAB (m=z) (relative intensity):
‡
312 (50), 154 (100), 136 (70); HRMS-FAB: calcd for C14H22N3O5:(M ‡ H)
312.1559; found 312.1556.
22b: the reaction using 160 mg (6.67 mmol) of sodium hydride and
800 mg (6.61 mmol) of methanesulfonyl azide led to 303 mg (70%) of 3b as a
yellow oil; IR (®lm) nmax (cmÀ1): 1716 (CˆO); 1H NMR (CDCl3) d 1.29 (3H,
s, C70), 1.45 (3H, s, C80), 1.43 (3H, t, J ˆ 7:2 Hz, OCH2CH3†, 2.63 (3H, s,
CH3C2), 3.40 (3H, s, OCH3), 4.42À4.51 (1H, m, H40), 4.36 (1H, dd, J ˆ 11:7
and 4.2 Hz, H50), 4.42À4.51 (3H, m, OCH2CH3 and H40), 4.55 (1H, dd,
J ˆ 11:7 and 8.1 Hz, H500), 4.68 (1H, d, J ˆ 5:7 Hz, H20), 4.86 (1H, d,
J ˆ 6:0 Hz, H30), 5.0 (1H, s, H10); 13C NMR (CDCl3) 8.9 (CH3C2), 24.6 (C70),
26.1 (C80), 50.2 (C50), 55.5 (OCH3), 81.3 (C30), 60.8 (OCH2CH3), 84.5
(C-40), 84.8 (C-20), 110.1 (C10), 112.6 (C60), 136.5 (C5), 138.2 (C4), 161.5
(CˆO); LRMS-FAB (m=z) (relative intensity): 342 (100), 154 (16); HRMS-
‡
FAB: calcd for C15H24N3O6: (M ‡ H) 342.1665; found: 342.1664.
Methyl 5-Deoxy-5-C-(4-formyl-1,2,3-triazol-1-yl)-2,3-O-isopropylidene-b-D-
ribofuranoside (24)
A solution of methyl 5-amino-5-deoxy-1,2-O-isopropylidene-b-D-ribo-
furanoside9 (20, 200 mg, 0.99 mmol) in methanol (5 mL) was slowly added to
a freshly prepared3a solution of diazomalonaldehyde (129 mg, 1.17 mmol) in
0.1 mL acid acetic and 4 mL of methanol-water (2 : 1) solution. The mixture
was stirred at room temperature for 24 hours and then concentrated under
reduced pressure. The oil produced was chromatographed on a silica gel
column, using chloroform-ethyl acetate (9 : 1) as the eluant, giving a pale
yellow solid in 78% yield (217 mg): m.p. 210À212 ꢀC (decomp.); IR (KBr)
1
nmax (cmÀ1): 1700; H NMR (CDCl3) d: 1.30 (3H, s, H80), 1.47 (3H, s,
H70), 3.39 (3H, s, OCH3), 4.50 (1H, dd, J ˆ 12.5 and 7.8 Hz, H50), 4.59
(1H, ddd, J ˆ 7.8, 4.7 and 0.9 Hz, H40), 4.68 (1H, d, J ˆ 6.0 Hz, H20), 4.67

1566
CUNHA ET AL.
(1H, dd, J ˆ 12.3 and 4.8, H500), 4.77 (1H, dd, J ˆ 6.0 and 0.9 Hz, H30), 5.03
(1H, s, H10), 10.16 (CHO); 13C NMR (CDCl3) d: 24.7 (C-70), 26.2 (C-80), 55.6
(OCH3), 53.4 (C- 50), 81.5 (C-30), 84.7 or 84.9 (C-20), 84.7 or 84.9 (C-40), 110.1
(C-10), 113.0 (C-60), 125.6 (C-5), 147.7 (C-4), 184.8 (CˆO); LRMS-FAB
(m=z) (relative intensity): 284 (100), 252 (39), 154 (62); HRMS-FAB: calcd
‡
for: C12H18N3O5 (M ‡ H) 284.1246; found: 284.1253.
General procedure for deprotection reaction with iodine in methanol
A solution of 22a (87 mg, 0.28 mmol), 22b (85 mg, 0.25 mmol) or 24
(82 mg, 0.29 mmol), iodine (30 mg) and methanol (3 mL) was stirred at
65À70 ꢀC for 10 hours. The excess of iodine was eliminated by adding aqu-
eous sodium thiosulfate solution (0.5 N). After ®ltration, the solvent was
evaporated under reduced pressure yielding a solid material, which was
chromatographed on a silica gel column using a gradient from pure hexane to
hexane-ethyl acetate (1 : 4).
Methyl 5-C-(4-Acetyl-5-methyl-1,2,3-triazole-1-yl)-5-deoxy-b-D-
ribofuranoside (23a)
Obtained in 70% yield (53 mg), m.p. 159À160 ꢀC; IR (®lm) nmax (cmÀ1):
1
3235À3502 (OH, br), 1674 (CˆO); H NMR (300.00 MHz, CDCl3) d 2.68
(3H, s, CH3C2 ), 2.67 (3H, s, CH3CˆO), 3.23 (3H, s, OCH3), 3.78 (1H,
dd, J ˆ 4.5 and 4.5 Hz, H20), 4.08 (1H, td, J ˆ 6.9 e 4.5 Hz, H30), 4.23 (1H,
td, J ˆ 7.2 e 3.6 Hz, H40), 4.53 (1H, dd, J ˆ 14.4 and 6.6 Hz, H50), 4.52 (1H, =
4:2 Hz; C2-OH†; 13C NMRꢁ75:0 MHz; CDCl3†d
9:0ꢁCH3C2†; 27:5 ꢁCH3
CˆO),49:8ꢁC50†; 54:9 ꢁOCH3; 71:8ꢁC30†; 73:9ꢁC20†; 80:2ꢁC40†; 108:7ꢁC10†;
135:4 ꢁC4†; 139:6ꢁC5†; 161:3ꢁCˆO) ppm; LRMS-FAB (m=z) (relative inten-
sity): 272 (75), 154 (100), 136 (67); HRMS-FAB: calcd for: C11H18N3O5
‡
(M ‡ H) 272.1246; found: 272.1210.
Methyl 5-C-(4-Carbethoxy-5-methyl-1,2,3-triazol-1-yl)-5-deoxy-b-D-
ribofuranoside (23b)
Obtained in 75% yield (56 mg); m.p. 97À98 ꢀC; IR (®lme) nmax ꢁcmÀ1†:
1
3324À3482 (br, OH), 1724 (CˆO); H NMR (300.00 MHz, CDCl3 d 1.42
(3H, t, J ˆ 7.2 Hz, OCH2CH3), 2.68 (3H, s, CH3C2), 3.25 (3H, s, OCH3), 4.42
(2H, q, J ˆ 7.2 Hz, OCH2CH3), 3.77 (1H, dd, J ˆ 4.2 and 4.2 Hz, H20),
4.03À4.09 (1H, m, H30), 4.22 (1H, td, J ˆ 6.6 e 4.2 Hz, H40), 4.53 (1H, dd,
J ˆ 14.7 and 6.6 Hz, H50), 4.73 (1H, dd, J ˆ 14.7 and 3.6 Hz, H500), 4.71
(1H, s, H10), 5.29 (1H, d, J ˆ 7.2 Hz, C3-OH), 5.32 (1H, d, J ˆ 4.2 Hz, C2-
OH) ppm; 13C NMR (75.0 MHz, CDCl3) d 9.1 (CH3C2), 50.1 (C50), 55.5

4-ACYL-1H-1,2,3-TRIAZOLIC NUCLEOSIDES
1567
(OCH3), 60.3 (OCH2CH3), 71.7 (C30), 73.9 (C20), 80.2 (C40), 108.7 (C10), 136.5
(C5), 138.2 (C4), 161.5 (CˆO) ppm; LRMS-FAB (m=z) (relative intensity):
302 (100); 154 (33); 136 (34); HRMS-FAB: calcd for: C12H20N3O6
‡
(M ‡ H) 302.1352; found: 302.1318.
Methyl 5-Deoxy-5-C-(4-formyl-5-methyl-1,2,3-triazol-1-yl)-b-D-
ribofuranoside (25)
Obtained in 81% yield (57 mg). IR (®lm) nmax ꢁcmÀ1): 3200À3500 (br,
OH); 1696 (CˆO); 1H NMR (300.00 MHz, CDCl3) d 3.28 (3H, s, OCH3), 3.81
(1H, d, J ˆ 4.5 Hz, H20), 4.01 (1H, dd, J ˆ 6.9 and 5.1 Hz, H30), 4.27 (1H, d,
J ˆ 6.9 and 3.9 Hz, H40), 4.73 (1H, s, H10), 4.63 (1H, dd, J ˆ 14.1 and 6.9 Hz,
H50), 4.85 (1H, dd, J ˆ 14.1 and 3.6 Hz, H500), 5.30 (2H, broad singlet, OH),
8.94 (1H, s, H5), 10.14 (HCˆO) ppm; 13C NMR (75.0 MHz, CDCl3) d 54.8
(OCH3), 52.8 (C50), 71.8 (C30), 74.2 (C20), 80.8 (C40), 108.6 (C10), 129.2 (C5),
146.9 (C4), 185.2 (HCˆO) ppm.
ACKNOWLEDGMENTS
Fellowships granted to A.C.C. and L.O.R.P from CNPq (Brazil) and
CAPES are gratefully acknowledged, respectively. M.C.B.V.S. and V.F.F.
are grateful to CNPq for the individual research fellowships. We thank
UNICAMP-IQ for MS spectra. We also thank Dr. Gilberto Alves Romeiro
(Universidade Federal Fluminense, Brazil) and Dr. Alice Maria Rolim Ber-
nardino (Universidade Federal Fluminense, Brazil) for useful advice. This
work was partially supported by CNPq (National Council of Research from
Brazil) and FAPERJ.
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Received July 6, 2000
Accepted February 7, 2001