Synthesis of some unusual (1,2,4-oxadiazole)-linked hexenopyranosides and mannopyranosides

Article abstract of DOI:10.1080/07328300802120901

A copper-catalyzed reaction of propargyl 4,6-di-O-acetyl-2,3-dideoxy- α-D-erythro-hex-2-enopyranoside with 3-(4-azidophenyl)-1,2,4-oxadiazoles gave the corresponding hexenopyranosides bearing an 1,2,4-oxadiazole subunit in the aglyconic part of the molecu

Full text of DOI:10.1080/07328300802120901

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Synthesis of Some Unusual
(1,2,4‐Oxadiazole)‐Linked
Hexenopyranosides and Mannopyranosides
Janaína Versiani dos Anjos a , Denis Sinou a , Rajendra M. Srivastava b
Silene Carneiro do Nascimento c & Sebastião J. de Melo c
,
a Laboratoire de Synthèse Asymétrique, UMR 5246‐ICBMS, CPE Lyon ,
Université de Lyon , 43 Boulevard du 11 Novembre 1918, 69622,
Villeurbanne Cedex, France
b Departamento de Química Fundamental , Universidade Federal de
Pernambuco, Cidade Universitária , Recife, PE, Brazil
c Departamento de Antibióticos , Universidade Federal de Pernambuco,
Cidade Universitária , Recife, PE, Brazil
Published online: 27 Jun 2008.
To cite this article: Janaína Versiani dos Anjos , Denis Sinou , Rajendra M. Srivastava , Silene Carneiro
do Nascimento & Sebastião J. de Melo (2008) Synthesis of Some Unusual (1,2,4‐Oxadiazole)‐Linked
Hexenopyranosides and Mannopyranosides, Journal of Carbohydrate Chemistry, 27:4, 258-277
To link to this article: http://dx.doi.org/10.1080/07328300802120901
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Journal of Carbohydrate Chemistry, 27:258–277, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300802120901
Synthesis of Some Unusual
(1,2,4-Oxadiazole)-Linked
Hexenopyranosides and
Mannopyranosides
Jana´ına Versiani dos Anjos,1 Denis Sinou,1
Rajendra M. Srivastava,2 Silene Carneiro do Nascimento,3
and Sebastiao J. de Melo3
˜
1
`
´
´
Laboratoire de Synthese Asymetrique, UMR 5246-ICBMS, CPE Lyon, Universite de
Lyon, Villeurbanne Cedex, France
2
´
Departamento de Quımica Fundamental, Universidade Federal de Pernambuco,
´
Cidade Universitaria, Recife, PE, Brazil
3
´
Departamento de Antibioticos, Universidade Federal de Pernambuco, Cidade
´
Universitaria, Recife, PE, Brazil
A copper-catalyzed reaction of propargyl 4,6-di-O-acetyl-2,3-dideoxy-a-D-erythro-hex-2-
enopyranoside with 3-(4-azidophenyl)-1,2,4-oxadiazoles gave the corresponding hexeno-
pyranosides bearing an 1,2,4-oxadiazole subunit in the aglyconic part of the molecule.
The same reaction between ethyl 4-azido-2,3,4-trideoxy-a-D-erythro-hex-2-enopyrano-
side and acetylenic 1,2,4-oxadiazoles afforded the corresponding hexenopyranosides
carrying a triazole and a 1,2,4-oxadiazole ring at C-4 of the carbohydrate. Combination
of the two sequences gave hexenopyranosides displaying two 1,2,4-oxadiazole subunits,
each one being embedded in the C-1 and C-4 frameworks, of the carbohydrate moiety. A
simple dihydroxylation reaction of these unsaturated carbohydrates yielded a series of
mannopyranosides bearing one or two 1,2,4-oxadiazole subunits at C-1 or C-4. These
new compounds were evaluated for their cytotoxic activities against two cell strains:
NCI-H292 (lung carcinoma) and Hep-2 (larynx carcinoma), some of them presenting
impressive cell growth inhibitions.
Keywords Cu-catalyst, [3 þ 2] Cycloaddition, Hexenopyranoside, Mannopyranoside,
1,2,4-Oxadiazole-based carbohydrate
Received January 14, 2008; accepted April 10, 2008.
`
´
Address correspondence to Denis Sinou, Laboratoire de Synthese Asymetrique, UMR
´
5246-ICBMS, CPE Lyon, Universite de Lyon, 43 Boulevard du 11 Novembre 1918,
Villeurbanne Cedex 69622, France. E-mail: sinou@univ-lyon1.fr
258

Synthesis of Hexenopyranosides and Mannopyranosides
259
INTRODUCTION
The 1,2,4-oxadiazole ring system is present in a large variety of compounds
possessing interesting biological activities, as well as in natural products.[1]
Substituted 1,2,4-oxadiazoles have been receiving considerable attention as
bioisosteres of amides and esters, and have been implicated in peptide chem-
istry and in the development of peptidomimetics.[2] Compounds containing
this heterocyclic subunit have been used as anti-inflammatory agents;[3] as
agonists of benzodiazepine,[4] muscarinic,[5] and sphingosine-1-phosphate-1
(S1P1) receptors;[6] as antagonists of integrin[7] and interleukin-8;[8] as antican-
cer agents;[9] and as antikinetoplastid parasites.[10]
Due to the above-mentioned important biological properties, it appeared
interesting to incorporate the oxadiazole units in the carbohydrate framework.
Effectively, tying of sugars to other simpler molecules is often employed to
deal with targeting mechanism of action and/or pharmacology.[11] Surprisingly,
only a few attempts have been made in order to synthesize oxadiazole-linked
carbohydrates. Oxadiazoles linked to a glycofuranose,[12] a glycopyranose,[2e,13]
and also an unsaturated glycopyranose[14] skeleton have been described. In a
program concerning the incorporation of heterocyclic moieties in carbohydrates,
we recently reported the incorporation of an 1,2,4-oxadiazole unit at position 1 of
various carbohydrates[15] using the copper-catalyzed procedure for the [3 þ 2]
cycloaddition (or “click chemistry”)[16] between a glycoside containing an
anomeric azide functionality and an oxadiazole bearing a terminal acetylenic
group, and at position 4 of ethyl a-D-mannopyranoside via the palladium-
catalyzed reaction of 5-(4-hydroxyphenyl)-1,2,4-oxadiazoles with ethyl a-O-D2-
glucopyranoside followed by a bishydroxylation of the later compounds.[17]
Here, we describe easy access to a new series of 2,3-dideoxy-a-D-erythro-
hex-2-enopyranoside and a-D-mannopyranoside derivatives carrying one oxa-
diazole moiety connected to other groups attached to C-1 or/and to C-4
positions using this [3 þ 2] cycloaddition reaction. Further, some preliminary
results concerning the biological activity of these compounds are reported.
RESULTS AND DISCUSSION
We chose to carry out the [3 þ 2] cycloaddition reaction between two sets of
1,2,4-oxadiazoles, one containing a terminal acetylenic group like 1 and 2,
and the other bearing an azido function like 3 (Fig. 1). The preparation of
1,2,4-oxadiazoles 1–2 has already been described by our group.[15] Azido
1,2,4-oxadiazoles 3 were prepared from nitro-oxadiazoles 4[18] by reduction
with tin chloride to afford the amino oxadiazoles 5; in situ transformation to
the diazo derivatives followed by substitution with sodium azide gave the
expected azido oxadiazoles 3a and 3b in an overall yield of 91% and 76%,
respectively (Sch. 1).

J. V. dos Anjos et al.
260
Figure 1: Structure of 1,2,4-oxadiazoles.
First we introduced the 1,2,4-oxadiazole subunit on the aglycon moiety.
For this purpose, the copper(I)-catalyzed 1,3-dipolar cycloaddition of azido
oxadiazoles 3a–b was performed with propargyl 4,6-di-O-acetyl-2,3-dideoxy-a-
D-erythro-hex-2-enopyranoside 6 using a 1:1 (v/v) mixture of dichloromethane
and water as the solvent in the presence of Cu(OAc)2 and sodium ascorbate
(Sch. 2).[19] The corresponding cycloadducts 7a and 7b were obtained in 91%
and 87% yield, respectively. The unsaturated carbohydrates 7a–b were sub-
jected to the dihydroxylation reaction under Upjohn conditions (catalytic
OsO4/NMO), followed by acetylation of the mixture, to afford the corresponding
f1-[4-(1,2,4-oxadiazol-3-yl)phenyl]-1H-1,2,3-triazol-4-ylgmethyl 2,3,4,6-tetra-O-
acetyl-a-D-mannopyranosides 8a and 8b in 67% and 72% yield, respectively
(Sch. 2). It should to be noticed that deacetylated mannopyranoside 9 could be
directly obtained from unsaturated carbohydrate 7a in 84% chemical yield
using the dihydroxylation reaction followed by deacetylation in the presence of
potassium carbonate (Sch. 2).
In order to introduce the 1,2,4-oxadiazole subunit at C-4 of the carbohydrate
scaffold, we used the sequence previously published by our group for the
preparation of unsaturated [1,2,3]-triazole-linked glycoconjugates.[20] The
copper(I)-catalyzed 1,3-dipolar cycloaddition of ethyl 4-azido-6-O-tert-butyldi-
methylsilyl-2,3,4-trideoxy-a-D-erythro-hex-2-enopyranoside 10[21] with acetylenic
oxadiazoles 1 and 2a–b was performed in a 1:1 (v/v) mixture of dichloromethane
Scheme 1: Synthesis of 1,2,4-oxadiazoles 5. Reagents and conditions: i) SnCl2, C2H5OH, reflux;
ii) aq. NaHCO3, rt; iii) CH2Cl2, aq. HCl, then NaNO2, 08C; iv) NaN3, 08C, then rt.

Synthesis of Hexenopyranosides and Mannopyranosides
261
Scheme 2: Synthesis of compounds 7, 8, and 9. Reagents and conditions: i) Cu(OAc)2
(20 mol%), sodium ascorbate (40 mol%), H2O/CH2Cl2 (1:1), rt; ii) OsO4 (1 mol%), NMO,
CH3COCH3/H2O (4:1), rt for compound 8a or K2OsO4. 2 H2O (1 mol%), NMO, citric acid, tert-
.
BuOH/H2O (1:1), rt for compound 8b; (iii) Ac2O, C5H5N, rt; iv) K2OsO4 2 H2O (1 mol%), NMO,
citric acid, tert-BuOH/H2O (1:1), then K2CO3, H2O, CH3OH, rt.
and water as the solvent in the presence of Cu(OAc)2 and sodium ascorbate
(Sch. 3)[19] to afford the corresponding cycloadducts 11 and 13a–b in 80%, 79%,
and 77% yield, respectively. Dihydroxylation of these unsaturated carbohydrates
11 and 13a–b under Upjohn conditions (catalytic OsO4/NMO), followed by acety-
lation of the mixture, afforded the corresponding ethyl 4-deoxy-2,3,6-tri-O-acetyl-
a-D-mannopyranosides 12, 14a, and 14b, bearing the oxadiazole subunit at
position 4, in 65%, 65%, and 84% yield, respectively (Sch. 3).
Finally, the introduction of two 1,2,4-oxadiazole subunits at the anomeric
position and at position 4 of the mannopyranose backbone was envisioned
using the two above-mentioned methodologies. Reaction of unsaturated
carbohydrates 7a–b, prepared as described before, with sodium azide in the
presence of a catalytic amount of Pd2(dba)3 þ dppb [or 1,4-bis(diphenylphosphino)-
butane] in tetrahydrofuran at 508C[21] afforded regio- and stereospecifically the

J. V. dos Anjos et al.
262
Scheme 3: Synthesis of compounds 11, 12, 13, and 14. Reagents and conditions: i) 1,2,4-
oxadiazole 1a, Cu(OAc)2 (20 mol%), sodium ascorbate (40 mol%), H2O/CH2Cl2 (1:1), rt;
ii) 1,2,4-oxadiazole 2, Cu(OAc)2 (20 mol%), sodium ascorbate (40 mol%), H2O/CH2Cl2 (1:1), rt;
iii) OsO4 (1 mol%), NMO, CH3COCH3/H2O (4:1), rt; iv) Ac2O, C5H5N, rt.
corresponding allylic azides 15a and 15b in 69% and 39% yield, respectively
(Sch. 4). As previously shown, the structures of compounds 15a–b were
assigned on the basis of the 1H NMR spectral analysis.[21] The vicinal
coupling constants J4,5 ¼ 10.0 Hz and 9.8 Hz for compounds 15a and 15b,
respectively, indicated a trans diaxial relationship between H-4 and H-5,
proving the erythro configuration. The copper(I)-catalyzed 1,3-dipolar cyclo-
addition of unsaturated azido carbohydrates 15a–b with 3-(4-ethynylphe-
nyl)-1,2,4-oxadiazoles 1a–b afforded the unsaturated carbohydrates 16a and
16b, bearing two oxadiazoles subunits at position 1 and 4, in 80% and 71%
yield, respectively. Finally dihydroxylation of unsaturated carbohydrate 16b
under Upjohn conditions (catalytic OsO4/NMO), followed by acetylation of
the obtained mixture, afforded the corresponding 2,3,6-tri-O-acetyl-4-deoxy-
a-D-mannopyranoside 17, bearing two oxadiazole subunits at the anomeric
position and at position 4, in 42% yield.

Synthesis of Hexenopyranosides and Mannopyranosides
263
Scheme 4: Synthesis of compounds 16 and 17. Reagents and conditions: i) NaN3, Pd2(dba)3,
dppb, THF/H2O (1.5:1), 508C; ii) 1b, Cu(OAc)2 (20 mol%), sodium ascorbate (40 mol%), H2O/
CH2Cl2 (1:1), rt; iii) K2OsO4. 2H2O (1 mol%), NMO, citric acid, tert-BuOH/H2O (1:1), rt; iv) Ac2O,
C5H5N, rt.
All the synthesized compounds have been evaluated for their cytotoxic
activities against two cell strains: NCI-H292 (lung carcinoma) and Hep-2
(larynx carcinoma) based on the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylte-
trazolium bromide (MTT) method.[22–24] The preliminary results showed
that these activities varied from 5% to 70% for NCI-H292 and from 3% to 61%
for Hep-2 of cell growth inhibition. The most potent compounds are 8a, 16a,
and 16b with 55%, 57%, and 61% of cell growth inhibition (NCI), respectively,
while compounds 16a, 16b, and 8a inhibited the cell growth by 44%, 50%, and
58% in the Hep-2 cell strain, respectively. Further tests are actually under
development and the results will be published in the future.
CONCLUSION
In conclusion, 4,6-di-O-acetyl-2,3-dideoxy-a-D-erythro-hex-2-enopyranosides
bearing an 1,2,4-oxadiazole subunit at the anomeric position were easily
obtained via a copper-catalyzed reaction of propargyl 2,3-dideoxy-a-D-
erythro-hex-2-enopyranoside with 3-(4-azidophenyl)-1,2,4-oxadiazoles. Ethyl
6-O-(tert-butyldimethylsilyl)-2,3,4-trideoxy-a-D-erythro-hex-2-enopyranosides
bearing an 1,2,4-oxadiazole unit at C-4 were obtained from ethyl 4-azido-

J. V. dos Anjos et al.
264
2,3,4-trideoxy-a-D-erythro-hex-2-enopyranoside and acetylenic 1,2,4-oxadia-
zoles in the presence of Cu(OAc)2 as the catalyst. The combination of these
two sequences gave the corresponding hexenopyranosides bearing two 1,2,4-
oxadiazole subunits at C-1 and at C-4 of the carbohydrate moiety. A series of
mannopyranosides bearing one or two 1,2,4-oxadiazole subunits at C-1 or C-4
of the carbohydrate moiety via a simple dihydroxylation reaction of these unsa-
turated carbohydrates were also synthesized. Some preliminary results
showed that there were some interesting cytotoxic activities against NCI-
H
292 and Hep-2 cell strains, compounds 8a, 16a, and 16b presenting impress-
ive cell growth inhibitions.
EXPERIMENTAL
General Procedure
All commercially available reagents were used as received. All reactions were
monitored by TLC analysis (TLC plates GF254 Merck). Air- and moisture-sensi-
tive reactions were performed under inert atmosphere. Melting points were
determined on a Bu¨chi apparatus and are uncorrected. Column chromatography
was performed on silica gel 60 (230–240 mesh, Merck). Optical rotations were
recorded using a Perkin-Elmer 241 polarimeter. NMR spectra were recorded
with a Bruker AMX 300 spectrometer and referenced as following: 1H
(300 MHz), internal SiMe4 at d 0.00 ppm, 13C (75 MHz), internal standard at d
77.23 ppm. Exact mass measurements of the molecular ions were obtained on
a Finnigan Mat 95 XL spectrometer. 3-(4-Ethynylphenyl)-5-phenyl-1,2,4-oxadia-
zole (1a),[25] 3-(4-ethynylphenyl)-5-methyl-1,2,4-oxadiazole (1b),[25] 3-(3-phenyl-
1,2,4-oxadiazol-5-yl)-N-(prop-2-yn-1-yl)propanamide (2a),[25] 3-[3-(4-bromophe-
nyl)-1,2,4-oxadiazol-5-yl]-N-(prop-2-yn-1-yl)propanamide (2b),[25] ethyl 4-azido-
2,3,4-trideoxy-a-D-erythro-hex-2-enopyranoside (10),[21] and 2-propynyl 4,6-
di-O-acetyl-2,3-dideoxy-a-D-erythro-hex-2-enopyranoside (6)[26] were prepared
according to the literature.
General Procedure for the Preparation of Oxadiazoles 3
A solution of nitro oxadiazole 4 (4.1 mmol) in ethanol (50 mL) was heated at
reflux in the presence of SnCl2 (3.1 g, 16.4 mmol). After total consumption of
the starting material, observed by TLC, the mixture was treated with an
aqueous NaHCO3 solution until pH 8.0. The resulting suspension was
extracted with ethyl acetate (3 ꢀ 100 mL). Evaporation of the solvent in
vacuo afforded the crude amino derivative 5, which was used in the next step
without further purification. This amino derivative 5 was dissolved in
CH2Cl2 (30 mL), and a 6 N aqueous solution of HCl (30 mL) was added at
08C. To this biphasic system was added dropwise a saturated aqueous

Synthesis of Hexenopyranosides and Mannopyranosides
265
solution of NaNO2 (10 mL). After stirring for 30 min at 08C, NaN3 (530 mg,
8.2 mmol) was added at 08C. Stirring was pursued for 30 min, and the
mixture was allowed to warm to rt. The two phases were separated, and the
aqueous phase was extracted with CH2Cl2 (3 ꢀ 50 mL). The combined
organic layers were washed with an aqueous solution of NaHCO3, then
brine, and dried (Na2SO4). Evaporation of the solvent in vacuo gave a
residue that was purified by column chromatography on silica gel to afford
pure oxadiazole 3.
3-(4-Azidophenyl)-5-phenyl-1,2,4-oxadiazole (3a)
Yield 91%; yellow solid; mp 1148C; Rf 0.76 (petroleum ether/EtOAc 3:2); 1H
NMR (CDCl3): 7.04 (br d, J ¼ 8.7 Hz, 2H, Harom), 7.38–7.50 (m, 4H, Harom),
7.99–8.09 (m, 3H, Harom); 13C NMR (CDCl3): 119.8, 124.0, 124.6, 127.9,
128.5, 129.5, 133.1, 143.2, 168.5, 176.1.
Anal. Calcd. for C14H9N5O (263.25): C, 63.87; H, 3.45. Found: C, 63.88; H,
3.56.
3-(4-Azidophenyl)-5-methyl-1,2,4-oxadiazole (3b)
Yield 76%; brown solid; mp 708C; Rf 0.71 (petroleum ether/EtOAc 3:2); 1H
NMR (CDCl3): 2.64 (s, 3H, CH3), 7.10 (br d, J ¼ 8.8 Hz, 2H, Harom), 8.04 (br d,
J ¼ 8.8 Hz, 2H, Harom); 13C NMR (CDCl3): 12.7, 119.8, 123.8, 129.3, 143.2,
168.0, 177.0.
EI-HRMS Calcd. for C9H7N5O [Mþ]: 201.0651. Found: 201.0660.
General Procedure for the Preparation of Carbohydrate–
triazole-Linked Oxadiazoles
The acetylenic compound (1.1 mmol) and the azido compound (1 mmol)
were suspended in 1:1 mixture of CH2Cl2 and water (4 mL). To this solution
was added a mixture of Cu(OAc)2 (36 mg, 0.2 mmol) and sodium ascorbate
(79 mg, 0.4 mmol). The resulting mixture was stirred under nitrogen at rt
until TLC analysis indicated complete consumption of the starting reagents.
The reaction contents were diluted with CH2Cl2 (5 mL) and water (5 mL).
The organic layer was separated, and the water phase was extracted again
with CH2Cl2 (5 mL). The combined organic layers were dried over Na2SO4
and filtered. Removal of the solvent in vacuo gave a residue that was
purified by column chromatography on silica gel using the indicated eluent
to give the corresponding carbohydrate–triazole-linked 1,2,4-oxadiazole.
f1-[4-(5-Phenyl-1,2,4-oxadiazol-3-yl)phenyl]-1H-1,2,3-triazol-4-ylgmethyl
4,6-di-O-acetyl-2,3-dideoxy-a-D-erythro-hex-2-enopyranoside (7a)
This compound was obtained by reacting acetylenic carbohydrate 6
(295 mg) and oxadiazole 3a (263.2 mg) for 24 h; yield 91%; colorless solid; mp

J. V. dos Anjos et al.
266
1
1808C; Rf 0.69 (EtOAc/petroleum ether 7:3); [a]2D0 þ25 (c ¼ 1.0, CH2Cl2); H
NMR (CDCl3): 2.09 (s, 3H, OAc), 2.12 (s, 3H, OAc), 4.15–4.32 (m, 3H, H-5,
H-6), 4.84 (d, J ¼ 12.4 Hz, 1H, CH2), 5.04 (d, J ¼ 12.4 Hz, 1H, CH2), 5.25 (br
s, 1H, H-1), 5.37 (br d, J ¼ 9.4 Hz, 1H, H-4), 5.88 (ddd, J ¼ 10.2, 2.1, 1.8 Hz,
1H, H-2), 5.95 (br d, J ¼ 10.2 Hz, 1H, H-3), 7.55–7.67 (m, 3H, Harom), 7.93
(br d, J ¼ 8.7 Hz, 2H, Harom), 8.11 (s, 1H, 55CH-N), 8.24 (br d, J ¼ 8.1 Hz,
2H, Harom), 8.37 (br d, J ¼ 8.9 Hz, 2H, Harom); 13C NMR (CDCl3): 21.2, 21.3,
61.8, 63.3, 65.6, 67.5, 94.3, 120.9, 121.1, 124.4, 127.7, 128.5, 129.4, 129.5,
130.0, 133.3, 139.1, 145.9, 168.2, 170.6, 171.2, 176.4.
Anal. Calcd. for C27H25N5O7 (531.52): C, 61.01; H, 4.74. Found: C, 61.11;
H, 4.80.
f1-[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenyl]-1H-1,2,3-triazol-4-ylgmethyl
4,6-di-O-acetyl-2,3-dideoxy-a-D-ERYTHRO-hex-2-enopyranoside (7b)
This compound was obtained by reacting acetylenic carbohydrate 6
(295 mg) and oxadiazole 3b (201.2 mg) for 23 h; yield 87%; colorless solid; mp
1768C; Rf 0.32 (petroleum ether/EtOAc 3:2); [a]2D0 þ29 (c ¼ 1.0, CH2Cl2); H
1
NMR (CDCl3): 2.09 (s, 3H, OAc), 2.12 (s, 3H, OAc), 2.69 (s, 3H, CH3), 4.17
(ddd, J ¼ 9.3, 4.9, 2.5 Hz, 1H, H-5), 4.21 (dd, J ¼ 12.2, 2.3 Hz, 1H, H-6), 4.29
(dd, J ¼ 12.2, 5.3 Hz, 1H, H-6), 4.83 (d, J ¼ 12.5 Hz, 1H, CH2), 5.02
(d, J ¼ 12.5 Hz, 1H, CH2), 5.25 (s, 1H, H-1), 5.36 (br d, J ¼ 9.3 Hz, 1H, H-4),
5.87 (ddd, J ¼ 10.2, 2.5, 1.7 Hz, 1H, H-2), 5.94 (br d, J ¼ 10.2 Hz, 1H, H-3),
7.89 (br d, J ¼ 8.7 Hz, 2H, Harom), 8.09 (s, 1H, 55CH-N), 8.24 (br d,
J ¼ 8.7 Hz, 2H, Harom); 13C NMR (CDCl3): 12.8, 21.2, 21.3, 61.8, 63.2, 65.7,
67.5, 94.3, 120.9, 121.1, 127.6, 127.7, 129.3, 130.0, 139.1, 145.9, 167.7, 170.6,
171.2, 177.3.
Anal. Calcd. for C22H23N5O7 (469.45): C, 56.29; H, 4.94. Found: C, 56.52;
H, 4.98.
Ethyl 6-O-(tert-butyldimethylsilyl)-2,3,4-trideoxy-4-f4-[4-(5-phenyl-1,2,4-
oxadiazol-3-yl)phenyl]-1H-1,2,3-triazol-1-ylg-a-D-erythro-hex-2-
enopyranoside (11)
This compound was obtained by reacting azido carbohydrate 10 (182 mg)
and oxadiazole 1a (271 mg) for 20 h; yield 80%; colorless solid; mp 58–598C;
Rf 0.24 (petroleum ether/EtOAc 9:1); [a]2D0 þ121.1 (c ¼ 1.0, CH2Cl2); H NMR
1
(CDCl3): 0.00 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3), 0.85 (s, 9H, CMe3), 1.26
(t, J ¼ 7.2 Hz, 3H, OCH2CH3), 3.60 (dq, J ¼ 9.5, 7.2 Hz, 1H, OCH2CH3), 3.62
(dd, J ¼ 11.7, 4.7 Hz, 1H, H-6), 3.71 (dd, J ¼ 11.7, 2.3 Hz, 1H, H-6), 3.89 (dq,
J ¼ 9.5, 7.2 Hz, 1H, OCH2CH3), 4.13 (ddd, J ¼ 9.6, 4.7, 2.1 Hz, 1H, H-5), 5.15
(br s, 1H, H-1), 5.42 (br d, J ¼ 9.6 Hz, 1H, H-4), 6.00 (br d, J ¼ 11.0 Hz, 1H,
H-2), 6.08 (ddd, J ¼ 10.0, 2.5, 2.5 Hz, 1H, H-3), 7.50–7.62 (m, 3H, Harom),
7.90 (s, 1H, 55CH-N), 7.96 (d, J ¼ 8.5 Hz, 2H, Harom), 8.10–8.25 (m, 4H,

Synthesis of Hexenopyranosides and Mannopyranosides
267
Harom); 13C NMR (CDCl3): 25.0, 15.7, 18.7, 26.3, 55.4, 62.8, 64.7, 71.6, 94.2,
119.4, 126.4, 128.1, 128.5, 128.5, 129.5, 129.9, 133.2, 133.5, 147.7, 169.0, 176.1.
Anal. Calcd. for C30H37N5O4Si (559.73): C, 64.37; H, 6.66. Found: C, 63.88;
H, 6.68.
N-(f1-[Ethyl 6-O-(tert-butyldimethylsilyl)-2,3,4-trideoxy-a-D-erythro-hex-2-
enopyranosid-4-yl]-1H-1,2,3-triazol-4-ylgmethyl)-3-(3-phenyl-1,2,4-
oxadiazol-5-yl)propanamide (13a)
This compound was obtained by reacting azido carbohydrate 10 (182 mg)
and oxadiazole 2a (281 mg) for 19 h; yield 79%; colorless oil; Rf 0.2 (CH2Cl2/
EtOAc 4:1); [a]2D0 þ61.2 (c ¼ 1.0, CH2Cl2); 1H NMR (CDCl3): 0.00 (s, 3H,
SiCH3), 0.01 (s, 3H, SiCH3), 0.87 (s, 9H, CMe3), 1.24 (t, J ¼ 7.1 Hz, 3H,
OCH2CH3), 2.81 (t, J ¼ 7.2 Hz, 2H, CH2), 3.30 (t, J ¼ 7.0 Hz, 2H, CH2), 3.53
(dd, J ¼ 11.7, 4.9 Hz, 1H, H-6), 3.57 (dq, J ¼ 9.6, 7.1 Hz, 1H, OCH2CH3), 3.64
(dd, J ¼ 11.7, 2.2 Hz, 1H, H-6), 3.86 (dq, J ¼ 9.6, 7.1 Hz, 1H, OCH2CH3), 4.06
(ddd, J ¼ 9.8, 4.9, 2.2 Hz, 1H, H-5), 4.51 (dd, J ¼ 15.2, 5.6 Hz, 1H, CH2N),
4.57 (dd, J ¼ 15.2, 5.6 Hz, 1H, CH2N), 5.11 (br s, 1H, H-1), 5.30 (br d,
J ¼ 9.8 Hz, 1H, H-4), 5.85 (br d, J ¼ 10.0 Hz, 1H, H-2), 6.00 (ddd, J ¼ 10.0,
2.8, 2.6 Hz, 1H, H-3), 6.64 (br t, J ¼ 5.6 Hz, 1H, NH), 7.43–7.52 (m, 3H,
H
arom), 7.57 (s, 1H, 55CH-N), 8.02 (dd, J ¼ 7.7, 2.2 Hz, 2H, Harom); 13C NMR
(CDCl3): –5.1 –5.0, 15.6, 18.7, 22.7, 26.2, 32.3, 35.2, 55.2, 62.7, 64.6, 71.2,
94.2, 121.9, 127.1, 127.7, 127.9, 129.2, 129.5, 131.5, 145.2, 168.5, 170.8, 179.2.
Anal. Calcd. for C28H40N6O5Si (568.74): C, 59.13; H, 7.09. Found: C, 59.51;
H, 7.20.
N-(f1-[Ethyl 6-O-(tert-butyldimethylsilyl)-2,3,4-trideoxy-a-D-erythro-hex-2-
enopyranosid-4-yl]-1H-1,2,3-triazol-4-ylgmethyl)-3-[3-(4-bromophenyl)-
1,2,4-oxadiazol-5-yl]propanamide (13b)
This compound was obtained by reacting azido carbohydrate 10 (182 mg)
and oxadiazole 2b (368 mg) for 17 h; yield 77%; colorless solid; mp 398C; Rf
1
0.1 (CH2Cl2/EtOAc 4:1); [a]D20 þ56.5 (c ¼ 1.0, CH2Cl2); H NMR (CDCl3): 0.00
(s, 6H, SiCH3), 0.87 (s, 9H, CMe3), 1.25 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 2.81
(t, J ¼ 7.0 Hz, 2H, CH2), 3.30 (t, J ¼ 7.0 Hz, 2H, CH2), 3.52 (dd, J ¼ 11.5,
4.7 Hz, 1H, H-6), 3.57 (dq, J ¼ 9.6, 7.1 Hz, 1H, OCH2CH3), 3.64 (dd, J ¼ 11.5,
2.2 Hz, 1H, H-6), 3.87 (dq, J ¼ 9.6, 7.1 Hz, 1H, OCH2CH3), 4.06 (ddd, J ¼ 9.8,
4.7, 2.2 Hz, 1H, H-5), 4.51 (dd, J ¼ 15.2, 5.6 Hz, 1H, CH2N), 4.57 (dd,
J ¼ 15.2, 5.6 Hz, 1H, CH2N), 5.11 (br s, 1H, H-1), 5.30 (br d, J ¼ 9.8 Hz, 1H,
H-4), 5.87 (br d, J ¼ 10.0 Hz, 1H, H-2), 6.02 (ddd, J ¼ 10.0, 2.8, 2.5 Hz, 1H,
H-3), 6.34 (br t, J ¼ 5.6 Hz, 1H, NH), 7.55 (s, 1H, 55CH-N), 7.61 (dd, J ¼ 8.7,
1.9 Hz, 2H, Harom), 7.91(dd, J ¼ 8.7, 1.9 Hz, 2H, Harom); 13C NMR (CDCl3):
–5.0, –5.1, 15.6, 18.7, 22.7, 26.2, 32.3, 35.2, 55.3, 62.7, 64.6, 71.2, 94.2, 121.9,
126.0, 126.1, 127.9, 129.3, 129.6, 132.5, 145.1, 167.8, 170.7, 179.5.

J. V. dos Anjos et al.
268
Anal. Calcd. for C28H39BrN6O5Si (647.64): C, 51.93; H, 6.07. Found: C,
52.02; H, 6.22.
f1-[4-(5-Phenyl-1,2,4-oxadiazol-3-yl)phenyl]-1H-1,2,3-triazol-4-ylgmethyl 6-O-
acetyl-2,3,4-trideoxy-4-f4-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-1H-
1,2,3-triazol-1-ylg-a-D-erythro-hex-2-enopyranoside (16a)
This compound was obtained by reacting 15a (566 mg) and acetylenic oxa-
diazole 1b (184 mg) for 24 h; yield 80%; colorless solid; mp 2078C; Rf 0.74
(EtOAc); [a]2D0 þ56 (c ¼ 1.0, CH2Cl2); 1H NMR (CDCl3): 2.09 (s, 3H, OAc),
2.66 (s, 3H, CH3), 4.13 (dd, J ¼ 12.2, 4.7 Hz, 1H, H-6), 4.29 (dd, J ¼ 12.2,
2.8 Hz, 1H, H-6), 4.44 (ddd, J ¼ 9.8, 4.7, 2.8 Hz, 1H, H-5), 4.90
(d, J ¼ 12.2 Hz, 1H, CH2), 5.05 (d, J ¼ 12.2 Hz, 1H, CH2), 5.41 (br s, 1H,
H-1), 5.50 (br d, J ¼ 9.8 Hz, 1H, H-4), 6.08 (br d, J ¼ 10.2 Hz, 1H, H-2), 6.18
(ddd, J ¼ 10.2, 2.6, 2.5 Hz, 1H, H-3), 7.55–7.67 (m, 3H, Harom), 7.90 (s, 1H,
55CH-N), 7.93 (d, J ¼ 8.7 Hz, 2H, Harom), 7.95 (d, J ¼ 8.6 Hz, 2H, Harom), 8.12
(d, J ¼ 8.5 Hz, 2H, Harom), 8.16 (s, 1H, 55CH-N), 8.24 (br d, J ¼ 8.2 Hz, 2H,
H
arom), 8.37 (br d, J ¼ 8.9 Hz, 2H, Harom); 13C NMR (CDCl3): 12.8, 21.1, 55.9,
61.9, 63.1, 69.0, 94.0, 119.3, 120.9, 121.4, 124.4, 126.4, 127.0, 127.9, 128.3,
128.6, 129.5, 129.6, 133.1, 133.4, 139.0, 145.5, 147.9, 168.2, 168.4, 170.9,
176.4, 177.0.
ESI-HRMS Calcd. for C36H30N10O6Na [M þ Na]þ: 721.2247. Found:
721.2244.
f1-[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenyl]-1H-1,2,3-triazol-4-ylgmethyl 6-O-
acetyl-2,3,4-trideoxy-4-f4-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-1H-
1,2,3-triazol-1-ylg-a-D-erythro-hex-2-enopyranoside (16b)
This compound was obtained by reacting 15b (497 mg) and acetylenic oxa-
diazole 1b (184 mg) for 18 h; yield 71%; colorless solid; mp 2038C; Rf 0.52
(EtOAc); [a]2D0 þ44 (c ¼ 0.5, CH2Cl2); 1H NMR (CDCl3): 2.09 (s, 3H, OAc),
2.67 (s, 3H, CH3), 2.69 (s, 3H, CH3), 4.12 (dd, J ¼ 12.2, 4.9 Hz, 1H, H-6), 4.28
(dd, J ¼ 12.2, 2.8 Hz, 1H, H-6), 4.43 (ddd, J ¼ 9.6, 4.9, 2.8 Hz, 1H, H-5), 4.89
(d, J ¼ 12.3 Hz, 1H, CH2), 5.04 (d, J ¼ 12.3 Hz, 1H, CH2), 5.40 (br s, 1H,
H-1), 5.50 (br d, J ¼ 9.6 Hz, 1H, H-4), 6.08 (br d, J ¼ 10.0 Hz, 1H, H-2), 6.17
(ddd, J ¼ 10.0, 2.5, 2.3 Hz, 1H, H-3), 7.91 (br d, J ¼ 8.5 Hz, 2H, Harom), 7.92
(br d, 2H, J ¼ 8.7 Hz, Harom), 7.96 (s, 1H, 55CH-Nl), 8.12 (br d, J ¼ 7.7 Hz,
2H, Harom), 8.14 (s, 1H, 55CH-N), 8.25 (br d, J ¼ 8.5 Hz, 2H, Harom); 13C
NMR (CDCl3): 12.8, 21.2, 55.8, 62.0, 63.0, 69.0, 94.0, 119.2, 121.0, 121.4,
126.5, 128.3, 129.4, 129.5, 133.1, 145.5, 162.7, 170.9, 177.0.
HRMS-ESI Calcd. for C31H28N10O6Na [M þ Na]þ: 659.2091. Found:
659.2074.

Synthesis of Hexenopyranosides and Mannopyranosides
269
General Procedure for the Preparation
of Azidocarbohydrates 15
The catalytic system was prepared by stirring for 1 h in a Schlenk tube
under argon Pd2(dba)3 (35 mg, 0.038 mmol) and 1,4-bis(diphenylphosphino)bu-
tane or dppb (64 mg, 0.15 mmol) in tetrahydrofuran (1.5 mL). This solution was
added under argon to a Schlenk tube containing the unsaturated carbohydrate
7 (0.38 mmol) and sodium azide (65 mg, 0.42 mmol) in a mixture of THF/water
(1.5 mL/2 mL). The mixture was stirred at 508C for 2 h. The solution was con-
centrated in vacuo, water (3 mL) was added, and the organic compound was
extracted with ether (3 ꢀ 10 mL). The combined extracts were washed succes-
sively with an aqueous 1 M solution of HCl (30 mL), saturated aqueous
NaHCO3 (30 mL), and brine (30 mL). The organic layer was dried over
Na2SO4. Removal of the solvent in vacuo gave a residue that was submitted
to column chromatography on silica gel using petroleum ether/EtOAc as the
eluent to afford the corresponding pure unsaturated azido carbohydrate 15.
f1-[4-(5-Phenyl-1,2,4-oxadiazol-3-yl)phenyl]-1H-1,2,3-triazol-4-ylgmethyl 6-O-
acetyl-4-azido-2,3,4-trideoxy-a-D-erythro-hex-2-enopyranoside (15a)
Yield 69%; colorless solid; mp 1468C; Rf 0.72 (EtOAc/petroleum ether 7:3);
1
[a]2D0 þ65 (c ¼ 1.0, CH2Cl2); H NMR (CDCl3): 2.14 (s, 3H, OAc), 3.95 (br d,
J ¼ 10.0 Hz, 1H, H-4), 4.01 (ddd, J ¼ 10.0, 4.7, 2.3 Hz, 1H, H-5), 4.31 (dd,
J ¼ 12.1, 4.7 Hz, 1H, H-6), 4.41 (dd, J ¼ 12.1, 2.3 Hz, 1H, H-6), 4.83
(d, J ¼ 12.4 Hz, 1H, CH2), 5.02 (d, J ¼ 12.4 Hz, 1H, CH2), 5.24 (br s, 1H,
H-1), 5.98 (ddd, J ¼ 10.0, 2.4, 2.0 Hz, 1H, H-2), 6.05 (br d, J ¼ 10.0 Hz, 1H,
H-3), 7.55–7.67 (m, 3H, Harom), 7.93 (d, J ¼ 8.6 Hz, 2H, Harom), 8.12 (s, 1H,
55CH-N), 8.23 (br d, J ¼ 8.3 Hz, 2H, Harom), 8.35 (br d, J ¼ 8.9 Hz, 2H,
H
arom); 13C NMR (CDCl3): 21.3, 54.8, 61.8, 63.7, 68.4, 94.0, 120.9, 121.2,
124.4, 127.7, 128.6, 128.7, 129.5, 129.6, 133.4, 139.1, 145.9, 168.2, 171.1, 176.4.
Anal. Calcd. for C25H22N8O5 (514.49): C, 58.36; H, 4.31. Found: C, 58.49; H,
4.34.
f1-[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenyl]-1H-1,2,3-triazol-4-ylgmethyl 6-O-
acetyl-4-azido-2,3,4-trideoxy-a-D-erythro-hex-2-enopyranoside (15b)
Yield 39%; colorless solid; mp 1248C; Rf 0.33 (EtOAc/CH2Cl2 3:7); [a]2D0 þ56
1
(c ¼ 0.5, CH2Cl2); H NMR (CDCl3): 2.13 (s, 3H, OAc), 2.69 (s, 3H, CH3), 3.94
(br d, J ¼ 9.8 Hz, 1H, H-4), 4.00 (ddd, J ¼ 9.8, 4.7, 2.3 Hz, 1H, H-5), 4.31 (dd,
J ¼ 12.1, 4.7 Hz, 1H, H-6), 4.40 (dd, J ¼ 12.1, 2.3 Hz, 1H, H-6), 4.82
(d, J ¼ 12.4 Hz, 1H, CH2), 5.00 (d, J ¼ 12.4 Hz, 1H, CH2), 5.23 (br s, 1H,
H-1), 5.97 (ddd, J ¼ 10.2, 2.3, 2.1 Hz, 1H, H-3), 6.04 (br d, J ¼ 10.2 Hz, 1H,
H-2), 7.90 (br d, J ¼ 8.9 Hz, 2H, Harom), 8.09 (s, 1H, 55CH-N), 8.25 (br d,
J ¼ 8.6 Hz, 2H, Harom); 13C NMR (CDCl3): 12.8, 21.2, 54.8. 61.8, 63.7, 68.4,
94.0, 121.0, 121.1, 127.7, 128.7, 129.3, 139.1, 145.9, 167.7, 171.1, 177.4.

J. V. dos Anjos et al.
270
HRMS-ESI Calcd. for C20H20N8O5Na [M þ Na]þ: 475.1454. Found:
475.1456.
General Procedure for the Bishydroxylation
of Unsaturated Carbohydrates
Method A
To a solution of unsaturated carbohydrate derivative (0.5 mmol) in a 4:1
mixture of acetone/water (10 mL) was added OsO4 (0.585 mg, 5 mmol) and
N-methylmorpholine-N-oxide (229 mg, 2 mmol) at 08C. The reaction mixture
was stirred overnight at rt, NaHSO3 (250 mg) was then added, and the
contents were stirred for 30 min at rt. The reaction mixture was diluted with
water (2.5 mL) and extracted with EtOAc (2 ꢀ 5 mL). The organic layer was
separated and dried over Na2SO4, and the solvent was evaporated in vacuo
to give the corresponding diol. The crude residue was directly acetylated
using Ac2O (153 mg, 1.5 mmol) in pyridine (3 mL) for 1 day. After removing
the solvent in vacuo, the residue was purified by column chromatography on
silica gel using the indicated eluent to afford the corresponding oxadiazole-
linked ethyl mannopyranoside.
Method B
To the unsaturated carbohydrate (0.5 mmol) and citric acid (96 mg,
0.5 mmol) dissolved in a 1:1 mixture of tert-butyl alcohol/water (6 mL) was
added potassium osmate dihydrate (1.84 mg, 5 mmol), followed by N-methyl-
morpholine N-oxide (117 mg, 1 mmol). The reaction mixture was stirred at rt
until disappearance of the starting material. The reaction mixture was
diluted with water (2.5 mL) and extracted with EtOAc (2 ꢀ 5 mL). The
organic layer was separated and dried over Na2SO4, and the solvent was evap-
orated in vacuo to give the corresponding diol. The crude residue was directly
acetylated using Ac2O (153 mg, 1.5 mmol) in pyridine (3 mL) for 1 day. After
removing the solvent in vacuo, the residue was purified by column chromato-
graphy on silica gel using the indicated eluent to afford the corresponding oxa-
diazole-linked ethyl mannopyranoside.
f1-[4-(5-Phenyl-1,2,4-oxadiazol-3-yl)phenyl]-1H-1,2,3-triazol-4-ylgmethyl
2,3,4,6-tetra-O-acetyl-a-D-mannopyranoside (8a)
This compound was obtained starting from 7a (266 mg) according to
method A in 67% yield; colorless solid; mp 718C; Rf 0.41 (petroleum ether/
EtOAc 3:2); [a]2D0 þ37 (c ¼ 1.0, CH2Cl2); H NMR (CDCl3): 2.00 (s, 3H, OAc),
1
2.05 (s, 3H, OAc), 2.14 (s, 3H, OAc), 2.17 (s, 3H, OAc), 4.07–4.16 (m, 1H,
H-5), 4.5 (dd, J ¼ 12.2, 2.2 Hz, 1H, H-6), 4.33 (dd, J ¼ 12.2, 5.2 Hz, 1H, H-6),
4.81 (d, J ¼ 12.6 Hz, 1H, CH2), 4.97 (d, J ¼ 12.6 Hz, 1H, CH2), 5.03 (br s, 1H,

Synthesis of Hexenopyranosides and Mannopyranosides
271
H-1), 5.30 (br d, J ¼ 3.1 Hz, 1H, H-2), 5.32 (dd, J ¼ 9.6, 9.6 Hz, 1H, H-4), 5.38
(dd, J ¼ 9.6, 3.1 Hz, 1H, H-3), 7.55–7.67 (m, 3 H, Harom), 7.95 (br d, J ¼ 8.9 Hz,
2H, Harom), 8.14 (s, 1H, 55CH-N), 8.24 (br d, J ¼ 8.3 Hz, 2H, Harom), 8.38 (br d,
J ¼ 8.7 Hz, 2H, Harom); 13C NMR (CDCl3): 21.0, 21.1, 21.2, 61.4, 62.8, 66.5, 69.2,
69.4, 69.8, 97.4, 121.0, 121.4, 124.4, 127.8, 128.5, 129.4, 129.5, 133.3, 139.0,
145.0, 168.2, 170.1, 170.3, 170.4, 171.0, 176.4.
HRMS-ESI Calcd. for C31H31N5O11Na [M þ Na]þ: 672.1918. Found:
672.1927.
f1-[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenyl]-1H-1,2,3-triazol-4-ylgmethyl
2,3,4,6-tetra-O-acetyl-a-D-mannopyranoside (8b)
This compound was obtained starting from 7b (235 mg) according to
method B in 72% yield; colorless solid; mp 618C; Rf 0.63 (EtOAc); [a]2D0 þ42
1
(c ¼ 1.0, CH2Cl2); H NMR (CDCl3): 2.00 (s, 3H, OAc), 2.04 (s, 3H, OAc), 2.13
(s, 3H, OAc), 2.17 (s, 3H, OAc), 2.69 (s. 3H, CH3), 4.11–4.17 (m, 2H, H-5,
H-6), 4.32 (dd, J ¼ 12.3, 5.4 Hz, 1H, H-6), 4.80 (d, J ¼ 12.5 Hz, 1H, CH2),
4.96 (d, J ¼ 12.5 Hz, 1H, CH2), 5.02 (br s, 1H, H-1), 5.29 (dd, J ¼ 4.7, 1.9 Hz,
1H, H-2), 5.35 (dd, J ¼ 9.4, 9.0 Hz, 1H, H-4), 5.38 (dd, J ¼ 9.4, 3.4 Hz, 1H,
H-3), 7.92 (dd, J ¼ 8.7, 1.7 Hz, 2H, Harom), 8.12 (s, 1H, 55CH-N), 8.26 (dd,
J ¼ 8.7, 1.9 Hz, 2H, Harom); 13C NMR (CDCl3): 12.8, 21.0, 21.1, 21.2, 61.3,
62.8, 66.4, 69.2, 69.4, 69.8, 97.3, 121.0, 121.4, 127.7, 129.3, 139.0, 144.9,
167.7, 170.0, 170.3, 170.4, 171.0, 177.3.
Anal. Calcd. for C26H29N5O11 (587.54): C, 53.15; H, 4.98. Found: C, 53.10;
H, 5.13.
Ethyl 2,3-di-O-acetyl-6-O-(tert-butyldimethylsilyl)-4-deoxy-4-f4-[4-(5-phenyl-
1,2,4-oxadiazol-3-yl)phenyl]-1H-1,2,3-triazol-1-ylg-a-D-mannopyranoside
(12)
This compound was obtained starting from 11 (214 mg) according to
method A in 65% yield; colorless solid; mp 748C; Rf 0.77 (CH2Cl2/EtOAc 9:1);
[a]2D0 þ59.5 (c ¼ 1.0, CH2Cl2); 1H NMR (CDCl3):–0.05 (s, 3H, SiCH3), 0.00
(s, 3H, SiCH3), 0.86 (s, 9H, CMe3), 1.23 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.79
(s, 3H, OAc), 2.11 (s, 3H, OAc), 3.34 (dd, J ¼ 11.9, 3.1 Hz, 1H, H-6), 3.53 (dq,
J ¼ 9.8, 7.1 Hz, 1H, OCH2CH3), 3.61 (dd, J ¼ 11.9, 1.5 Hz, 1H, H-6), 3.75 (dq,
J ¼ 9.8, 7.1 Hz, 1H, OCH2CH3), 4.32 (br d, J ¼ 10.7 Hz, 1H, H-5), 4.87
(d, J ¼ 1.7 Hz, 1H, H-1), 5.04 (dd, J ¼ 11.3, 10.7 Hz, 1H, H-4), 5.31 (dd,
J ¼ 3.4, 1.7 Hz, 1H, H-2), 5.91 (dd, J ¼ 11.3, 3.4 Hz, 1H, H-3), 7.47–7.59
(m, 3H, Harom), 7.85 (s, 1H, 55CH-N), 7.92 (d, J ¼ 8.3 Hz, 2H, Harom), 8.16
(dd, J ¼ 6.6, 1.7 Hz, 4H, Harom); 13C NMR (CDCl3): –5.1, –4.9, 15.4, 18.7,
20.9, 21.2, 26.2, 56.8, 62.1, 64.4, 69.1, 69.5, 71.8, 97.8, 121.5, 124.6, 126.4,
127.1, 128.5, 128.6, 129.5, 133.2, 133.4, 146.9, 169.0, 169.6, 170.3, 176.2.
HRMS-ESI Calcd. for C34H44N5O8Si [M þ H]þ: 678.2959. Found: 678.2979.

J. V. dos Anjos et al.
272
N-(f1-[Ethyl 2,3-di-O-acetyl-6-O-(tert-butyldimethylsilyl)-4-deoxy-a-D-
mannopyranosid-4-yl]-1H-1,2,3-triazol-4-ylgmethyl)-3-(3-phenyl-1,2,4-
oxadiazol-5-yl)propanamide (14a)
This compound was obtained starting from 13a (219 mg) according to method
A in 65% yield; colorless oil; Rf 0.2 (CH2Cl2/EtOAc 4:1); [a]2D0 þ44.4 (c ¼ 0.6,
CH2Cl2); 1H NMR (CDCl3): 0.00 (s, 3H, SiCH3), 0.10 (s, 3H, SiCH3), 0.93 (s, 9H,
CMe3), 1.30 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.85 (s, 3H, OAc), 2.18 (s, 3H, OAc),
2.84 (t, J ¼ 7.2 Hz, 2H, CH2), 3.28–3.35 (m, 3H, H-6, CH2), 3.52–3.66 (m, 2H,
OCH2CH3, H-6), 3.81 (dq, J ¼ 9.8, 7.2 Hz, 1H, OCH2CH3), 4.36 (br d,
J ¼ 10.0 Hz, 1H, H-5), 4.51 (d, J ¼ 5.5 Hz, 2H, CH2N), 4.93 (br s, 1H, H-1), 5.01
(dd, J ¼ 10.9, 10.6 Hz, 1H, H-4), 5.34 (dd, J ¼ 3.2, 1.8 Hz, 1H, H-2), 5.87 (dd,
J ¼ 11.3, 3.2 Hz, 1H, H-3), 6.56 (br t, J ¼ 5.5 Hz, 1H, NH), 7.47–7.52 (m, 3H,
H
arom), 7.60 (s, 1H, 55CH-N), 8.07 (dd, J ¼ 5.0, 1.8 Hz, 2H, Harom); 13C NMR
(CDCl3):–5.2, –4.9, 15.3, 18.6, 20.8, 21.2, 22.7, 26.2, 32.4, 35.4, 56.6, 61.9, 64.3,
69.2, 69.4, 71.4, 97.7, 127.1, 127.8, 129.2, 131.5, 168.6, 169.5, 170.3, 170.7, 179.1.
HRMS-ESI Calcd. for C32H46N6O9SiNa [M þ Na]þ: 709.2993. Found:
709.2992.
N-(f1-[Ethyl 2,3-di-O-acetyl-6-O-(tert-butyldimethylsilyl)-4-deoxy-a-D-
mannopyranosid-4-yl]-1H-1,2,3-triazol-4-ylgmethyl)-3-[3-(4-bromophenyl)-
1,2,4-oxadiazol-5-yl]propanamide (14b)
This compound was obtained starting from 13b (258 mg) according to method
A in 84% yield; colorless solid; mp 488C; Rf 0.2 (CH2Cl2/EtOAc 3:2); [a]2D0 þ37.0
1
(c ¼ 1.0. CH2Cl2); H NMR (CDCl3): 0.00 (s, 3H, SiCH3), 0.06 (s, 3H, SiCH3),
0.93 (s, 9H, CMe3), 1.29 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.85 (s, 3H, OAc), 2.18
(s, 3H, OAc), 2.84 (t, J ¼ 7.3 Hz, 2H, CH2), 3.31 (m, 3H, CH2, H-6), 3.59 (dq,
J ¼ 9.8, 7.1 Hz, 1H, OCH2CH3), 3.64 (br d, J ¼ 13.0 Hz, 1H, H-6), 3.81 (dq,
J ¼ 9.8, 7.1 Hz, 1H, OCH2CH3), 4.37 (br d, J ¼ 10.2 Hz, 1H, H-5), 4.51 (dd,
J ¼ 11.7, 5.8 Hz, 1H, CH2N), 4.58 (dd, J ¼ 11.7, 5.5 Hz, 1H, CH2N), 4.93 (br s,
1H, H-1), 5.01 (dd, J ¼ 11.2, 10.2 Hz, 1H, H-4), 5.33 (br d, J ¼ 3.2 Hz, 1H, H-2),
5.87 (dd, J ¼ 11.1, 3.2 Hz, 1H, H-3), 6.82 (br t, J ¼ 5.5 Hz, 1H, NH), 7.61 (s, 1H,
55CH-N), 7.64 (d, J ¼ 8.5 Hz, 2H, Harom), 7.95 (d, J ¼ 8.5 Hz, 2H, Harom); 13C
NMR (CDCl3): –5.2, –4.9, 15.3, 18.6, 20.8, 21.2, 22.6, 26.2, 32.3, 35.3, 56.6, 61.9,
64.3, 69.2, 69.4, 71.4, 97.7, 126.1, 129.3, 132.5, 167.9, 169.4, 170.3, 170.6, 179.4.
HRMS-ESI Calcd. for C32H45BrN6O9SiNa [M þ Na]þ: 787.2098. Found:
787.2093.
f1-[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenyl]-1H-1,2,3-triazol-4-ylgmethyl 2,3,6-
tri-O-acetyl-4-deoxy-4-f4-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-1H-
1,2,3-triazol-1-ylg-a-D-mannopyranoside (17)
This compound was obtained starting from 16b (318 mg) according to
method B in 42% yield; colorless solid; mp 2058C; Rf 0.58 (EtOAc); [a]2D0 þ18

Synthesis of Hexenopyranosides and Mannopyranosides
273
1
(c ¼ 0.5, CH2Cl2); H NMR (CDCl3): 1.86 (s, 3H, OAc), 2.06 (s, 3H, OAc), 2.22
(s, 3H, OAc), 2.67 (s, 3H, CH3), 2.70 (s, 3H, CH3), 3.99 (dd, J ¼ 12.2, 4.5 Hz,
1H, H-6), 4.19 (br d, J ¼ 12.2 Hz, 1H, H-6), 4.73 (br d, J ¼ 10.4 Hz, 1H, H-5),
4.89 (d, J ¼ 12.5 Hz, 1H, CH2), 5.02 (dd, J ¼ 10.4, 10.2 Hz, 1H, H-4), 5.04
(d, J ¼ 12.5 Hz, 1H, CH2), 5.17 (br s, 1H, H-1), 5.42 (br s, 1H, H-2), 6.17 (dd,
J ¼ 9.2, 2.1 Hz, 1H, H-3), 7.93–7.96 (m, 5H, Harom, 55CH-N), 8.13 (br d,
J ¼ 7.9 Hz, 2H, Harom), 8.20 (s, 1H, 55CH-N), 8.28 (br d, J ¼ 8.5 Hz, 2H,
H
arom); 13C NMR (CDCl3): 12.8, 20.8, 21.1, 21.3, 57.8, 61.6, 62.9, 68.7, 68.9,
69.4, 97.4, 120.4, 121.1, 121.6, 126.5, 127.1, 127.8, 128.3, 129.4, 132.9, 144.8,
147.6, 162.7, 169.6, 170.2, 170.7, 177.0, 177.4.
HRMS-ESI Calcd. for C35H34N10O10Na [M þ Na]þ: 777.2357. Found:
777.2352.
f1-[4-(5-Phenyl-1,2,4-oxadiazol-3-yl)phenyl]-1H-1,2,3-triazol-4-ylgmethyl-a-D-
mannopyranoside (9)
To the unsaturated carbohydrate 7a (700 mg, 1.3 mmol) and citric acid
(250 mg, 1.3 mmol) dissolved in a 1:1 mixture of tert-butyl alcohol/water
(60 mL) was added potassium osmate (5 mg, 13 mmol), followed by N-methyl-
morpholine N-oxide (305 mg, 2.6 mmol). The reaction mixture was stirred at
rt until disappearance of the starting material. Then the reaction mixture
was diluted with water (20 mL) and methanol (50 mL), and potassium carbon-
ate (540 mg, 3.9 mmol) was added. After 20 h, the precipitated solid was
filtered, and the solid was washed with EtOAc (5 mL) and water (5 mL).
Drying of the solid afforded compound 9 (400 mg, 60%). Colorless solid; mp
1
1908C; Rf 0.2 (EtOAc); [a]2D0 –72 (c ¼ 0.25, DMSO); H NMR (DMSO-d6): 3.40
(br d, J ¼ 10.0 Hz, 1H, H-4), 3.42–3.58 (m, 3H, H-5, H-6), 3.65–3.70 (m, 2H,
H-2, H-3), 4,67 (d, J ¼ 12.2 Hz, 1H, CH2), 4.80 (d, J ¼ 12.2 Hz, 1H, CH2),
4.82 (br s, 1H, H-1), 7.67–7.80 (m, 3H, Harom), 8.15 (br d, J ¼ 8.7 Hz, 2H,
H
arom), 8.22 (br d, J ¼ 7.7 Hz, 2H, Harom), 8.32 (br d, J ¼ 8.7 Hz, 2H, Harom),
8.91 (s, 1H, 55CH-N); 13C NMR (DMSO-d6): 59.4, 61.6, 67.4, 70.5, 71.2, 74.6,
99.6, 120.8, 122.7, 123.5, 126.3, 128.2, 129.0, 129.9, 133.8, 138.9, 145.4,
167.7, 175.9.
HRMS-ESI Calcd. for C23H23N5O7Na [M þ Na]þ: 504.1495. Found:
504.1487.
Cytotoxic Activity
The cytotoxic activity assays were based on the MTT method or the 3-(4,5-
dimethylazol-2-yl)-3,5-diphenyltetrazolium bromide method.[22–24] For the
cytotoxicity evaluation, the cell strains Hep-2 (larynx carcinoma) and NCI-
H292 (lung carcinoma) with proved viability were used. The cells were grown
in MEM (Minimal Essential Medium)[23] with 10% bovine fetal serum contain-
ing 1% antibiotics solution (penicillin 1000 UI/mL þ streptomycin 250 mg/mL)

J. V. dos Anjos et al.
274
and 1% glutamine (200 mM). A cellular suspension containing 5.104 cells/mL
was used and distributed in plates of 96 wells. The test samples containing
the drug in different concentrations (1.25, 2.5, 5.0, and 10.0 mg/mL) dissolved
in DMSO (0.1 mL) were added into each well. The plates were incubated for
72 h at 378C in an atmosphere containing 5% of CO2. After incubation, 15 mL
of MTT in phosphate-buffered saline solution (5 mg/mL) was added into each
well. After 2 h the culture medium was removed and 100 mL of DMSO was
added in each well in order to solubilize the formazan crystals.[27] The measure-
ments were performed in a Multskan ELX 800 cell reader at 595 nm.
ACKNOWLEDGMENTS
We are indebted to the CAPES/COFECUB program no. 334/01 for financial
support, and Brazilian National Research Council (CNPq) for providing a
fellowship to one of us (J. V. d. A.).
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