Synthesis of heterocyclic N-(β-d-glucopyranosyl)carboxamides for inhibition of glycogen phosphorylase

Article abstract of DOI:10.1016/j.carres.2012.01.020

In a DCC-mediated coupling 2,3,4,6-tetra-O-acetyl-β-d- glucopyranosylamine and propiolic acid gave N-propynoyl-2,3,4,6-tetra-O-acetyl- β-d-glucopyranosylamine which was transformed by 1,3-dipolar cycloadditions with aromatic azides and nitrile-oxides to t

Full text of DOI:10.1016/j.carres.2012.01.020

Carbohydrate Research 351 (2012) 56–63
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis of heterocyclic N-(b-D-glucopyranosyl)carboxamides for inhibition
of glycogen phosphorylase
Bálint Kónya a, Tibor Docsa b, Pál Gergely b,c, László Somsák a,
⇑
a Department of Organic Chemistry, University of Debrecen, PO Box 20, H-4010 Debrecen, Hungary
b Cell Biology and Signaling Research Group of the Hungarian Academy of Sciences at the Department of Medical Chemistry, Medical and Health Science Centre, University of Debrecen,
Egyetem tér 1, H-4032 Debrecen, Hungary
c Department of Medical Chemistry, Medical and Health Science Centre, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
In a DCC-mediated coupling 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosylamine and propiolic acid gave
Received 4 December 2011
Received in revised form 19 January 2012
Accepted 22 January 2012
Available online 31 January 2012
N-propynoyl-2,3,4,6-tetra-O-acetyl-b-
cycloadditions with aromatic azides and nitrile-oxides to the corresponding O-peracetylated N-(b-
copyranosyl)-1-substituted-1,2,3-triazole-4-carboxamides and N-(b- -glucopyranosyl)-3-substituted-
D
-glucopyranosylamine which was transformed by 1,3-dipolar
D-glu-
D
isoxazole-5-carboxamides, respectively. These compounds were O-deacetylated by Zemplén’s protocol
to be tested as inhibitors of rabbit muscle glycogen phosphorylase b. The best inhibitors of the two series
Keywords:
were N-(b-
D
-glucopyranosyl)-1-(3,5-dimethyl-phenyl)-1,2,3-triazole-4-carboxamide (Ki = 34
M).
lM) and
Azide–alkyne cycloaddition
Nitrile-oxide–alkyne cycloaddition
1,2,3-Triazole-4-carboxamide
Isoxazole-5-carboxamide
N-(b- -glucopyranosyl)-3-(indol-2-yl)-isoxazole-5-carboxamide (Ki = 164
D
l
Ó 2012 Elsevier Ltd. All rights reserved.
N-(b-D-Glucopyranosyl)carboxamide
Glycogen phosphorylase
1. Introduction
linker
lin ers
N
N
N
OH
H
N
Inhibitors of glycogen phosphorylase (GP) enzymes have been
considered as possible means for therapeutic intervention in first
of all type 2 diabetes but also other diseased states. For the bio-
chemical rationale behind these considerations the reader is kindly
referred to recent review articles.1–6 As part of an ongoing project
to synthesize new glucose derivatives7 for the inhibition of GP N-
O
A
B
C
HO
HO
R
HO
O
N
N
I
O
linker 2
linker 1
N O
N
OH
O
acyl-b-
Ki (against rabbit muscle GPb, RMGPb) 10
as N-acyl-N0-b- -glucopyranosyl urea derivatives4 II (R = 2-naph-
thyl: Ki (RMGPb) 0.35 M) have been taken as lead structures.
D
-glucopyranosylamines8 (Chart 1, I: e.g. for R = 2-naphthyl
H
N
H
HO
HO
N
R
l
M8 or 13 M9) as well
l
HO
O
N
D
O
O
O
II
D
E
F
l
N
Non-classical bioisosteric replacement of the NHCO moiety in I
by the heterocyclic linker A revealed high similarity of the amide
(see Ki of I above) and the 1,2,3-triazole type (for IA R = 2-naph-
linker
O
N
N
OH
O
H
H
N
HO
HO
N
R
thyl: Ki (RMGPb) 16 l
M9) inhibitors both in binding strength and
N
HO
structural features of the enzyme–inhibitor complexes.9,10
O
N
III
Applying the isomeric B, C, and D moieties as linkers resulted in
inhibitors of varying efficiency,11,12 whereby the 3-aryl-5-b-
D-
Chart 1.
glucopyranosyl-1,2,4-oxadiazole (ID type) derivatives proved to
be the most potent compounds (for the best inhibitor where
R = 2-naphthyl the Ki (RMGPb) was 2.4 l
M12). Very recently we
have reported on the synthesis and enzymatic evaluation of a
series of compounds of type II with linker 1 and linker 2 being
1,2,3-triazoles A and F as well as 1,3,4-oxadiazole B in various cou-
pling patterns.13 The best inhibitors against RMGPb were effective
in the upper micromolar range (linker 1 = A, linker 2 = B, R = Ph: Ki
⇑
Corresponding author. Tel.: +36 52 512 900x22348; fax: +36 52 512 744.
E-mail address: somsak@tigris.unideb.hu (L. Somsák).
854 lM; linker 1 = B, linker 2 = F, R = 2-naphthyl: Ki 745 lM).
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2012.01.020

B. Kónya et al. / Carbohydrate Research 351 (2012) 56–63
57
Herein we report on the synthesis and enzymatic test of some
compounds of type III with isoxazole E and 1,2,3-triazole F as
linkers.
Ac
O
H
AcO
AcO
N
OAc
O
3
2. Results and discussion
ArCH=NOH,
NaOCl, THF-H2O
For the preparation of compounds of type IIIE and IIIF construc-
tion of the heterocyclic parts by 1,3-dipolar cycloadditions14 of an
alkyne and nitrile-oxides15 as well as azides,16,17 respectively, was
envisaged. As the direct transformation of azide 118 by acylation of
an in situ generated iminophosphorane19 with propiolic acid failed,
N
O
OR
H
O
Ar
RO
RO
N
OR
the necessary protected N-propynoyl-b-D-glucopyranosylamine 3
O
was obtained from glucosylamine 220 and propiolic acid by a
DCC-mediated coupling in high yield (Scheme 1).
NaOMe
MeOH
21-27
14-20
The copper(I) catalyzed cycloaddition reaction (CuAAC) of 3
with aromatic azides was investigated first (Scheme 2). The non-
commercial azides were prepared either in situ from the corre-
sponding boronic acids following a recently published procedure21
or from the related aniline derivatives via diazonium salts.22 The
Ar
R = Ac
R = H
Ph
14 (55 %)
15 (52 %)
16 (50 %)
21 (97 %)
22 (91 %)
23 (88 %)
24 (95 %)
25 (90 %)
26 (76 %)
27 (70 %)
2-Naphthyl
Benzo-[b]-furan-2-yl
widely used system CuSO4–L-ascorbic acid was applied to generate
Benzo-[b]-thiophen-2-yl 17 (51 %)
the catalyst, and the cycloadducts 4–8 were obtained in high
Benzothiazol-2-yl
Indol-2-yl
18 (30 %)
19 (24 %)
20 (20 %)
23
yields. A trial with a recently published catalyst Cu(PPh3)2NO3
in 2 mol % loading under the same conditions did not significantly
improve the yield of 4 (93%).
Indol-3-yl
Scheme 3.
Alkyne 3 was next transformed with nitrile-oxides which were
oxidatively generated in situ from aromatic aldoximes by using
domestic bleach.24 The target compounds 14–20 were obtained
in modest to acceptable yields, among which the indole derivatives
19 and 20 having an NH group could be isolated in the lowest
yields.
O-Acetyl protecting groups were removed by the Zemplén pro-
tocol to give the test compounds 9–13 and 21–27 (Schemes 2 and
3, respectively) in high yields.
Proton and carbon NMR spectra of triazoles 4–13 and isoxazoles
14–27 contained resonances for the sugar part and the amide
moiety of the compounds as expected. In the 13C NMR spectra
signals for the triazole C-4 (quaternary) and C-5 (CH) appeared in
the 140–143 and 116–121 ppm range, respectively, thereby cor-
roborating the anticipated 1,4-disubstitution pattern of the 1,2,3-
triazole in analogy with previously reported compounds.10 The
isoxazole C(4)–H appeared in the 7.2–7.3 ppm range for the pro-
tected derivatives 14–20, and in the 7.5–7.9 ppm range for the
unprotected 21–27. HMBC spectra allowed to identify isoxazole
C3 (155–163 ppm) and C5 (162–166 ppm) resonances in the whole
series 14–27. Furthermore, detection of crosspeaks between isox-
azole C–H and both the amide CO and a quaternary carbon of the
aromatic substituent indicated the formation of 3-aryl-isoxazole-
5-carboxamides 14–20 (contrary to the possibility of 3-aryl-isox-
azole-4-carboxamide derivatives).
OAc
O
Ac
O
H2/Ra-Ni
AcO
AcO
AcO
AcO
N3
NH2
OAc
OAc
1
2
HC C COOH
DCC
88 %
1. PMe3
2.HC C COOH
The heterocyclic N-(b-D-glucopyranosyl) carboxamides were
OAc
H
tested for their inhibitory activity against rabbit muscle glycogen
phosphorylase b as described earlier,8 and the obtained data, to-
gether with some relevant literature values, are collected in Table
1. The triazole derivatives 9 and 11–13 had inhibitor constants in
the micromolar range. The inactivity of the 2-naphthyl compound
O
AcO
AcO
N
OAc
O
3
Scheme 1.
N
OAc
OR
N
CuSO4.5 H2O (5 mol%)
-ascorbic acid (15 mol%)
CH2Cl2-H2O 1:1, 50 °C
H
N
H
N
O
O
N
Ar
AcO
AcO
RO
RO
L
ArN3
+
OAc
OR
O
O
3
NaOMe
MeOH
9-13
R = H
4-8
1. NaNO2, HCl, 0 oC
2. NaN3
towards
7 and 8
NaN3
CuSO4.5 H2O (10 mol%)
Ar
R = Ac
MeOH
rt
Ph
4 (91 %)
5 (75 %)
9 (88 %)
10 (61 %)
11 (87 %)
12 (70 %)
13 (79 %)
towards
5 and 6
2-Naphthyl
3,5-di-Me-C6H3 6 (78%)
4-CF3-C6H4
4-tBu-C6H4
7 (79 %)
8 (85 %)
ArNH2
ArB(OH)2
Scheme 2.

58
B. Kónya et al. / Carbohydrate Research 351 (2012) 56–63
Table 1
Inhibition of rabbit muscle glycogen phosphorylase b (RMGPb, Ki [lM])
N
N
OH
OH
N
H
H
H
N
O
O
HO
HO
R
HO
HO
N
N
R
R
HO
OH
O
O
O
9
75
28
29
4.64
10
No inhibition
0.354
CH3
CH3
11
34
30
0.928
12
13
51
31
32
1.84
0.74
CF3
C(CH3)3
143
OH
O
H
N
HO
HO
N
17925
OH
O
N
N
33
R
N
OH
O
O
H
N
R
HO
HO
X
OH
O
21 172a
22 no inhibition
23 X = O no inhibition
24 X = S no inhibition
N
S
N
H
N
H
25 no inhibition
Calculated from the IC50 values by the Cheng–Prusoff equation29: Ki = IC50/(1 + [S]/Km).
26 164a
27 207a
a
10 was surprising especially in the light of very strong inhibition
by 2-naphthyl derivatives in other series of glucose based inhibi-
tors,7 for example, acyl ureas 28–32 from which 29 had the highest
affinity. While in these latter cases the inhibition became stronger
with increasing size of the aromatic part of the molecules, this ten-
dency seemed to be reversed among triazoles 9–13. The relatively
weak binding of a more or less similar triazole derivative 33 was
attributed to the diminished number of interactions of the inhibi-
tor with the protein as well as to the steric bulk of the aglycone
inducing unfavorable changes in the vicinity of the binding site
(more specifically the so-called 280s loop next to the catalytic
center).25 The present observations might have a similar origin.
In addition, the bioisosteric relationship of the amide and the
allosteric (or indole binding) site of the enzyme where some glu-
cose derivatives were also shown to be accommodated.4,26,27 These
points need further investigations.
In summary, 1,3-dipolar cycloadditions of aromatic azides and
nitrile-oxides were used as the key steps in the synthesis of N-
(b-
D-glucopyranosyl)-1-substituted-1,2,3-triazole-4-carboxamides
and N-(b-
D-glucopyranosyl)-3-substituted-isoxazole-5-carboxam-
ides, respectively. The new compounds inhibited rabbit muscle
glycogen phosphorylase b in the low micromolar range. The
amide-1,2,3-triazole bioisosterism could not be verified for the
‘second’ NHCO part of N-acyl-N0-b-
D-glucopyranosyl ureas.
3. Experimental
1,2,3-triazole moieties, which proved to be valid for N-acyl-b-
D-
3.1. General methods
glucopyranosylamines and 1-b- -glucopyranosyl-4-substituted-
D
1,2,3-triazoles9 outlined in the introduction, cannot be justified
for the case of the ‘second’ NHCO group of the N-acyl-N0-b-
D-gluco-
Melting points were measured in open capillary tubes or on a
Kofler hot-stage and are uncorrected. Optical rotations were deter-
mined on a Perkin–Elmer 241 polarimeter at room temperature.
NMR spectra were recorded with Bruker WP 360 SY (360/90 MHz
for 1H/13C) and Varian UNITYINOVA 400 WB (400/100 MHz for
1H/13C) spectrometers. Chemical shifts are referenced to Me4Si as
the internal reference (1H) or the residual solvent signal (13C).
Thin-layer chromatography (TLC) was carried out on aluminum
sheets coated with Silica Gel 60 F254 (Merck). TLC plates were in-
spected by UV light (k = 254 nm) and after gentle heating for the
carbohydrate derivatives. Silica gel column chromatography was
pyranosyl urea type GP inhibitors.
Inhibition of RMGPb by the isoxazoles 21–27 was even weaker.
Thus, phenyl-isoxazole 21 had a more than twice less affinity than
its triazole counterpart 9. An increase in the size of the aromatic
moiety as in compounds 22–25 resulted in a complete loss of activ-
ity. Interestingly, the indole derivatives 26 and 27, in which the
steric bulk of the rings must be essentially the same as in 23–25,
showed weak binding similar to that of 21. This might be due to
the hydrogen bond donor capacity of this ring system. It can also
be envisaged that these compounds bind to the so-called new

B. Kónya et al. / Carbohydrate Research 351 (2012) 56–63
59
performed with Silica Gel Si 60 (40–63
l
m) purchased from Merck
was washed with CH2Cl2 (2 ꢁ 10 mL/mmol). The combined organic
layer was dried, the solvent evaporated, and the residue purified by
column chromatography (eluent: 1:1 EtOAc–hexane).
(Darmstadt, Germany). Organic solutions were dried over anhy-
drous MgSO4, and concentrated at diminished pressure at 40–
50 °C (water bath). Aromatic aldoximes were prepared in the usual
way30 from the corresponding aldehydes purchased from Sigma-
Aldrich.
3.4.3. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-1-phenyl-
1,2,3-triazole-4-carboxamide (4)
Prepared by general procedure given in Section 3.4.1 from 3
(335 mg, 0.841 mmol) and PhN3 for 1 day. Yield: 396 mg (91%)
white crystals. Rf = 0.43 (1:1 EtOAc–hexane); Mp: 232–234 °C
3.2. N-Propynoyl-2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl-
amine (3)
[a
]
D
ꢀ6.9 (c 0.54, DMSO) 1H NMR (DMSO-d6, 360 MHz) d (ppm)
2,3,4,6-Tetra-O-acetyl-b-
2.882 mmol) was dissolved in dry CH2Cl2 (20 mL), propiolic acid
(355 L, 2 equiv) and DCC (0.565 g, 1.05 equiv) were added. The
D
-glucopyranosylamine20
(2,
1 g,
9.39 (s, 1H, triazole CH), 9.37 (br s, 1H, NH), 7.97 (d, 2H,
J = 7.6 Hz, ArH), 7.64–7.54 (m, 3H, ArH), 5.66 (t, 1H, J = 9.1,
9.1 Hz, H-1), 5.41, 5.24, 4.92 (3 pseudo t, J = 9.1, 10.6 Hz in each,
H-2, H-3, H-4), 4.19–4.44 (m, 2H, H-6a, H-5), 4.01 (dd, 1H,
J = 11.9, 3.0 Hz, H-6b), 2.01, 2.01, 1.95, 1.91 (4s, 12H, 4 ꢁ CH3);
13C NMR (DMSO-d6, 90 MHz) d (ppm) 171.0, 170.8, 169.9, 169.0
(CO), 157.3 (NHCO), 140.8 (triazole C-4), 129.2, 128.8, 128.8,
128.5, 125.5, 125.5 (Ar), 116.7 (triazole C-5), 78.1 (C-1), 73.9,
73.1, 70.6, 68.5 (C-2–C-5), 62.0 (C-6), 20.3, 20.2, 20.0 (CH3). Anal.
Calcd for C23H26N4O10 (518.47): C, 53.28; H, 5.05; N, 10.81. Found:
C, 52.88; H, 4.86; N, 10.94.
l
mixture was stirred at rt and monitored by TLC (1:1 EtOAc–hex-
ane). After consumption of the amine the solvent was evaporated
and the residue was purified by column chromatography (eluent:
1:1 EtOAc–hexane) to give 1.01 g (88%) yellow syrup. Rf = 0.5
(1:1 EtOAc–hexane); [
a
]
D
ꢀ31 (c 0.22, CHCl3); 1H NMR (CDCl3,
360 MHz) d (ppm) 7.27 (d, 1H, J = 9.0 Hz, NH), 5.20 (t, 1H, J = 9.4,
9.4 Hz, H-1), 5.03–4.80 (m, 2H, H-3, H-4), 4.19 (dd, 1H, J = 12.0,
3.3 Hz, H-6a), 4.00 (m, 2H, H-2, H-6b), 3.76 (ddd, 1H, J = 9.2, 5.0,
3.3 Hz, H-5), 2.97 (s, 1H, CH), 1.97, 1.95, 1.92, 1.91 (m, 12H,
4 ꢁ CH3); 13C NMR (CDCl3, 90 MHz) d (ppm) 171.4, 171.3, 170.6,
170.3 (4xOCOCH3), 153.0 (NHCO), 78.3 (C-1), 77.2 (CCH), 74.3,
73.6, 71.0, 68.7 (C-2–C-5), 61.1 (C-6), 49.7 (CCH), 21.7, 21.4 21.2,
21.2 (4 ꢁ OCOCH3). Anal. Calcd for C17H21NO10 (399.35): C, 51.13;
H, 5.30; N, 3.51. Found: C, 51.33; H, 5.12; N, 3.41.
3.4.4. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-1-(2-
naphthyl)-1,2,3-triazole-4-carboxamide (5)
Prepared by general procedure given in Section 3.4.2 from 3
(696 mg, 1.744 mmol) and 2-naphthylazide (prepared in situ from
naphthalene-2-boronic acid (300 mg, 1.744 mmol)). Yield: 743 mg
(75%) white crystals. Rf = 0.33 (1:1 EtOAc–hexane); Mp: 223–
3.3. General procedure for the Zemplén deacylation
225 °C [
a]
ꢀ1.1 (c 0.27, DMSO) 1H NMR (CDCl3, 360 MHz) d
D
(ppm) 8.61 (s, 1H, triazole CH), 8.14 (br s, 1H, NH), 7.89 (m, 5H,
ArH), 7.55–7.52 (m, 2H, ArH), 5.45 (t, 1H, J = 9.3, 9.3 Hz, H-1),
5.31, 5.11, 5.10 (3 pseudo t, 1H each, J = 9.5, 10.5 Hz in each, H-2,
H-3, H-4), 4.25 (dd, 1H, J = 12.2, 3.8 Hz, H-6a), 4.08 (dd, 1H,
J = 12.2, 1.9 Hz, H-6b), 3.85 (m, 1H, H-5), 2.03, 1.99, 1.98, 1.96
(4s, 12H, 4 ꢁ CH3); 13C NMR (CDCl3, 90 MHz) d (ppm) 170.8,
170.5, 170.2, 169.7 (CO), 160.3 (NHCO), 142.8 (triazole C-4),
133.9, 133.3, 130.5 128.5, 128.1, 127.9, 127.6, 119.2 (Ar), 118.8 (tri-
azole C-5), 78.1 (C-1), 73.8, 73.2, 70.6, 68.3 (C-2–C-5), 61.8 (C-6),
20.9, 20.7 (CH3). Anal. Calcd for C27H28N4O10 (568.53): C, 57.04;
H, 4.96; N, 9.85. Found: C, 56.64; H, 4.77; N, 9.98.
An O-peracylated compound (100 mg) was dissolved in dry
MeOH (1 mL) and a solution of NaOMe (1 M in MeOH) was added
to the solution in a catalytic amount. The reaction mixture was
kept at rt. When the reaction was complete (TLC, 7:3 CHCl3–MeOH)
the solution was neutralized with a cation exchange resin Amber-
lyst 15 (H+ form). Filtration and removal of the solvent resulted in
the corresponding deacetylated sugar derivative which, if neces-
sary, was purified by column chromatography.
3.4. General procedures for the Cu(I) catalyzed azide–alkyne
cycloaddition
3.4.5. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-1-(3,5-
3.4.1. In CH2Cl2–water mixtures with organic azides
dimethyl-phenyl)-1,2,3-triazole-4-carboxamide (6)
Equimolar amounts of N-propynoyl-2,3,4,6-tetra-O-acetyl-b-
glucopyranosylamine (3) and an azide were dissolved in CH2Cl2
(7 mL/mmol alkyne). Water (the same volume as that of CH2Cl2),
D
-
Prepared by general procedure given in Section 3.4.2 from 3
(798 mg, 2.00 mmol) and 3,5-dimethyl-phenyl-azide (prepared
in situ from 3,5-dimethyl-phenylboronic acid (300 mg,
2.00 mmol)). Yield: 852 mg (78%) yellow syrup. Rf = 0.48 (1:1
CuSO4ꢂ5H2O (5 mol %),
L-ascorbic-acid (15 mol %) were added and
the mixture was stirred at 50 °C and monitored by TLC (1:1
EtOAc–hexane). After disappearance of the starting materials the
reaction mixture was diluted with water and CH2Cl2, the phases
were separated, and the aqueous layer was washed with CH2Cl2
(2 ꢁ 10 mL/mmol). The combined organic layer was dried, the sol-
vent evaporated, and the residue purified by column chromatogra-
phy (eluent: 1:1 EtOAc–hexane).
EtOAc–hexane)
[a]
ꢀ29 (c 0.34, CHCl3) 1H NMR (CDCl3,
D
360 MHz) d (ppm) 8.49 (s, 1H, triazole CH), 7.94 (d, 1H, J = 9.5 Hz,
NH), 7.32 (s, 2H, ArH), 7.09 (s, 1H, ArH), 5.49 (t, 1H, J = 9.5,
9.5 Hz, H-1), 5.37, 5.16, 5.13 (3 pseudo t, 1H each, J = 9.5, 10.1 Hz
in each, H-2, H-3, H-4), 4.30 (dd, 1H, J = 11.9, 4.0 Hz, H-6a), 4.13
(dd, 1H, J = 11.9, 1.9 Hz, H-6b), 3.90 (m, 1H, H-5), 2.39 (s, 6H,
2 ꢁ CH3), 2.07, 2.03, 2.02, 1.99 (4s, 12H, 4 ꢁ CH3); 13C NMR (CDCl3,
90 MHz) d (ppm) 170.8, 170.4, 170.2, 169.6 (CO), 160.4 (NHCO),
142.4 (triazole C-4), 140.1, 136.4, 136.4, 131.2, 131.2, 124.3 (Ar),
118.8 (triazole C-5), 78.0 (C-1), 73.7, 73.1, 70.5, 68.2 (C-2–C-5),
61.8 (C-6), 21.4, 21.4 (CH3), 20.8, 20.7 (CH3). Anal. Calcd for
3.4.2. In CH2Cl2–water mixtures with organic azides prepared
in situ from boronic acids
Boronic acid (1 equiv) and NaN3 (1.2 equiv) were dissolved in
MeOH (5 mL/mmol of boronic acid). CuSO4ꢂ5H2O (0.10 equiv)
was added and the mixture was stirred overnight at rt. CH2Cl2
and water (10 mL of each/mmol of boronic acid), N-propynoyl-
C25H30N4O10 (546.53): C, 54.94; H, 5.53; N, 10.25. Found: C,
54.54; H, 5.34; N, 10.38.
2,3,4,6-tetra-O-acetyl-b-
D-glucopyranosylamine (3, 0.75 equiv)
3.4.6. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-1-(4-
and -ascorbic acid (0.5 equiv) were added and the reaction mix-
L
trifluoromethyl-phenyl)-1,2,3-triazole-4-carboxamide (7)
Prepared by general procedure given in Section 3.4.1 from 3
(426 mg, 1.069 mmol) and 4-CF3–C6H4–N3 for 1 day. Yield:
ture was heated to 50 °C. After consumption of the alkyne (TLC,
1:1 EtOAc–hexane) the reaction mixture was diluted with water
and CH2Cl2, the phases were separated and the aqueous layer
495 mg (79%) colorless oil. Rf = 0.48 (1:1 EtOAc–hexane) [a]
D

60
B. Kónya et al. / Carbohydrate Research 351 (2012) 56–63
ꢀ1.2 (c 0.30, DMSO) 1H NMR (CDCl3, 360 MHz) d (ppm) 8.77 (s, 1H,
triazole CH), 8.12 (d, 1H, J = 9.5 Hz, NH), 7.97 (d, 2H, J = 8.4 Hz,
ArH), 7.83 (d, 2H, J = 8.4 Hz, ArH), 5.56 (t, 1H, J = 9.4, 9.4 Hz, H-1),
5.40 (t, 1H, J = 9.7, 9.7 Hz, one of H-2, H-3, H-4), 5.18–5.05 (m,
2H, two of H-2, H-3, H-4), 4.30 (dd, 1H, J = 11.2, 4.0 Hz, H-6a),
4.10 (dd, 1H, J = 11.2, 4.0 Hz, H-6b), 3.96 (m, 1H, H-5), 2.05, 2.02,
2.00, 1.98 (4s, 12H, 4 ꢁ CH3); 13C NMR (CDCl3, 90 MHz) d (ppm)
170.7, 170.5, 170.0, 169.9 (CO), 160.0 (NHCO), 143.0 (triazole C-
4), 138.8, 131.2 (q, C–CF3, J = 34.9 Hz), 127.3, 126.0, 124.9, 124.4
(Ar), 121.9 (q, CF3, J = 277 Hz), 120.8 (triazole C-5), 77.9 (C-1),
73.7, 73.0, 70.5, 68.2 (C-2–C-5), 61.7 (C-6), 20.7, 20.6 (CH3). Anal.
Calcd for C24H25F3N4O10 (586.47): C, 49.15; H, 4.30; N, 9.55. Found:
C, 48.75; H, 4.11; N, 9.69.
3.4.10. N-(b-D-Glucopyranosyl)-1-(3,5-dimethyl-phenyl)-1,2,3-
triazole-4-carboxamide (11)
Prepared by general procedure given in Section 3.3 from 6
(180 mg, 0.317 mmol) for 1 h. Yield: 104 mg (87%) white crystals.
Rf = 0.74 (7:3 CHCl3–MeOH); Mp: 145–147 °C [
a]
+1.7 (c 0.33,
D
DMSO) 1H NMR (DMSO-d6 + D2O, 360 MHz) d (ppm) 9.15 (s, 1H,
triazole CH), 7.52 (s, 2H, ArH), 7.15 (s, 1H, ArH), 4.93 (d, 1H,
J = 9.0 Hz, H-1), 3.65 (dd, 1H, J = 11.0, 2.1 Hz, H-6a), 3.51–3.32 (m,
2H, H-3, H-6b), 3.31–3.12 (m, 3H, H-2, H-4, H-5), 2.34 (s, 6H,
2xCH3); 13C NMR (DMSO-d6 + D2O, 90 MHz) d (ppm) 160.7 (NHCO),
143.3 (triazole C-4), 140.2, 136.5, 133.2, 127.1, 126.4, 126.0 (Ar),
118.3 (triazole C-5), 80.0 (C-1), 72.7, 71.2, 70.3, 68.8 (C-2–C-5),
61.9 (C-6). Anal. Calcd for C17H22N4O6 (378.38): C, 53.96; H, 5.86;
N, 14.81. Found: C, 53.56; H, 5.73; N, 14.94.
3.4.7. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-1-(4-tbutyl-
phenyl)-1,2,3-triazole-4-carboxamide (8)
3.4.11. N-(b-D-Glucopyranosyl)-1-(4-trifluoromethyl-phenyl)-
1,2,3-triazole-4-carboxamide (12)
Prepared by general procedure given in Section 3.3 from 7
(200 mg, 0.341 mmol) for 2 h. Yield: 100 mg (70%) white crystals.
Prepared by general procedure given in Section 3.4.1 from 3
(456 mg, 1.143 mmol) and 4-tBu–C6H4–N3 for 1 day. Yield:
558 mg (85%) white crystals. Rf = 0.49 (1:1 EtOAc–hexane); Mp:
ꢀ5.4 (c 0.33, DMSO) 1H NMR (CDCl3, 360 MHz) d
Rf = 0.57 (7:3 CHCl3–MeOH); Mp: 241–243 °C [
a]
+4.5 (c 0.60,
D
194–196 °C [a]
D
DMSO) 1H NMR (DMSO-d6 + D2O, 360 MHz) d (ppm) 9.35 (s, 1H,
triazole CH), 8.16 (d, 2H, J = 8.3 Hz, ArH), 7.98 (d, 2H, J = 8.6 Hz,
ArH), 4.94 (d, 1H, J = 9.0 Hz, H-1), 3.64 (dd, 1H, J = 12.9, 2.4 Hz, H-
6a), 3.41–3.35 (m, 2H, H-3, H-6b), 3.29–3.06 (m, 3H, H-2, H-4, H-
5); 13C NMR (DMSO-d6 + D2O, 90 MHz) d (ppm) 160.5 (NHCO),
143.8 (triazole C-4), 139.4, 130.0, 129.7 (q, C–CF3, J = 30.4 Hz),
128.0, 127.7, (Ar), 122.7 (q, CF3, J = 273.2 Hz), 116.7 (triazole C-5),
80.0 (C-1), 72.4, 71.3, 70.4, 69.0 (C-2, C-3, C-4, C-5), 62.0 (C-6).
Anal. Calcd for C16H17F3N4O6 (418.32): C, 45.94; H, 4.10; N,
13.39. Found: C, 45.54; H, 3.91; N, 13.53.
(ppm) 8.55 (s, 1H, triazole CH), 8.00 (d, 1H, J = 9.5 Hz, NH), 7.64
(d, 2H, J = 8.6 Hz, ArH), 7.51 (d, 2H, J = 8.6 Hz, ArH), 5.52 (t, 1H,
J = 9.5, 9.5 Hz, H-1), 5.36, 5.16, 5.10 (3 pseudo t, 1H each, J = 9.5,
9.5 Hz in each, H-2, H-3, H-4), 4.26 (dd, 1H, J = 11.2, 4.0 Hz, H-
6a), 4.08 (dd, 1H, J = 11.2, 2.1 Hz, H-6b), 3.90 (m, 1H, H-5), 2.02,
1.99, 1.99, 1.96 (4s, 12H, 4 ꢁ CH3), 1.31 (s, 9H, C(CH3)3); 13C NMR
(CDCl3, 90 MHz) d (ppm) 170.7, 170.3, 170.1, 169.5 (CO), 160.4
(NHCO), 152.9 (Ar), 142.5 (triazole C-4), 134.0, 126.8, 126.8,
124.2, 124.2 (Ar), 120.4 (triazole C-5), 77.8 (C-1), 73.6, 73.1, 70.5,
68.2 (C-2–C-5), 61.8 (C-6), 34.9 (C(CH3)3), 31.2 (C(CH3)3), 20.7,
20.6 (CH3). Anal. Calcd for C27H34N4O10 (574.58): C, 56.44; H,
5.96; N, 9.75. Found: C, 56.20; H, 5.76; N, 9.94.
3.4.12. N-(b-D-Glucopyranosyl)-1-(4-tbutyl-phenyl)-1,2,3-
triazole-4-carboxamide (13)
Prepared by general procedure given in Section 3.3 from 8
(200 mg, 0.348 mmol) for 2 hour. Yield: 111 mg (79%) white crys-
tals. Rf = 0.62 (7:3 CHCl3–MeOH); Mp: 207–209 °C [a]D +1.9 (c 0.34,
3.4.8. N-(b-D-Glucopyranosyl)-1-phenyl-1,2,3-triazole-4-
carboxamide (9)
Prepared by general procedure given in Section 3.3 from 4
(200 mg, 0.386 mmol) for 1 h. Yield: 119 mg (88%) white crystals.
DMSO) 1H NMR (DMSO-d6 + D2O, 360 MHz) d (ppm) 9.06 (s, 1H,
triazol CH), 7.75 (d, 2H, J = 8.4 Hz, ArH), 7.58 (d, 2H, J = 8.5 Hz,
ArH), 4.94 (d, 1H, J = 8.9 Hz, H-1), 3.65 (dd, 1H, J = 11.4, 2.3 Hz, H-
6a), 3.51–3.34 (m, 2H, H-3, H-6b), 3.23 (m, 3H, H-2, H-4, H-5),
1.25 (s, 9H, C(CH3)3); 13C NMR (DMSO-d6 + D2O, 90 MHz) d (ppm)
161.5 (NHCO), 153.4 (Ar), 143.5 (triazole C-4), 134.5, 127.9,
127.6, 121.4, 121.1 (Ar), 120.2 (triazole C-5), 80.3 (C-1), 72.1,
71.2, 70.3, 69.1 (C-2–C-5), 61.9 (C-6), 35.4 (C(CH3)3), 31.8
(C(CH3)3). Anal. Calcd for C19H26N4O6 (406.43): C, 56.15; H, 6.45;
N, 13.79. Found: C, 55.78; H, 6.25; N, 13.95.
Rf = 0.53 (7:3 CHCl3–MeOH); Mp: 199–201 °C [
a]
+3.4 (c 0.15,
D
DMSO) 1H NMR (DMSO-d6 + D2O, 360 MHz) d (ppm) 9.38 (s, 1H,
triazole CH), 7.98 (d, 2H, J = 7.6 Hz, ArH), 7.58 (m, 3H, ArH), 4.89
(d, 1H, J = 8.9 Hz, H-1), 3.67 (dd, 1H, J = 12.3, 2.9 Hz, H-6a), 3.25–
3.09 (m, 5H, H-2, H-3, H-4, H-5, H-6b); 13C NMR (DMSO-
d6 + D2O, 90 MHz) d (ppm) 160.7 (NHCO), 143.4 (triazole C-4),
133.3, 131.7, 128.7, 127.9 (Ar), 118.4 (triazole C-5), 80.0 (C-1),
72.9, 71.2 70.1, 68.9 (C-2–C-5), 62.2 (C-6). Anal. Calcd for
C15H18N4O6 (350.33): C, 51.43; H, 5.18; N, 15.99. Found: C, 51.01;
H, 4.98; N, 16.05.
3.5. General procedure for the nitrile-oxide cycloaddition
3.4.9. N-(b-D-Glucopyranosyl)-1-(2-naphthyl)-1,2,3-triazole-4-
carboxamide (10)
Prepared by general procedure given in Section 3.3 from 5
(180 mg, 0.317 mmol) for 2 h. Yield: 77 mg (61%) white crystals.
A solution of N-propynoyl-2,3,4,6-tetra-O-acetyl-b-D-glucopyr-
anosylamine (0.5 mmol) and an arenecarbaldoxime (0.55 mmol,
1.1 equiv) in THF (4 mL) was stirred at rt under Argon. 0.2 M NaOCl
solution (20 mL) was slowly added dropwise in 5 h with a syringe
pump. The reaction was stirred at rt for an additional 12 h, then the
reaction mixture was diluted with water and EtOAc, the phases
were separated and the aqueous layer was washed with EtOAc
(2 ꢁ 30 mL/mmol). The combined organic layer was dried, the sol-
vent evaporated, and the residue purified by column chromatogra-
phy (eluent: 2:3 EtOAc–hexane).
Rf = 0.51 (7:3 CHCl3–MeOH); Mp: 275–277 °C (decomp.) [a] +4.4
D
(c 0.34, DMSO) 1H NMR (DMSO-d6 + D2O, 360 MHz) d (ppm) 9.35
(s, 1H, triazole CH), 8.50 (s, 1H, ArH), 8.17 (d, 1H, J = 8.9 Hz, ArH),
8.12–7.98 (m, 3H, ArH), 7.69–7.59 (m, 2H, ArH), 4.95 (d, 1H,
J = 9.0 Hz, H-1), 3.66 (dd, 1H, J = 10.9, 2.0 Hz, H-6a), 3.50–3.33 (m,
2H, H-3, H-6b), 3.29–3.10 (m, 3H, H-2, H-4, H-5); 13C NMR
(DMSO-d6 + D2O, 90 MHz) d (ppm) 160.3 (NHCO), 142.0 (triazole
C-4), 134.6, 131.9, 129.6, 129.4, 128.0, 127.7, 127.1, 124.4 (Ar),
119.1 (triazole C-5), 80.2 (C-1), 72.1, 71.3 70.1, 68.7 (C-2–C-5),
62.1 (C-6). Anal. Calcd for C19H20N4O6 (400.39): C, 57.00; H, 5.03;
N, 13.99. Found: C, 56.60; H, 4.86; N, 14.04.
3.5.1. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-3-phenyl-
isoxazole-5-carboxamide (14)
Prepared by general procedure given in Section 3.5 from 3
(248 mg, 0.621 mmol) and benzaldoxime (83 mg, 0.683 mmol).

B. Kónya et al. / Carbohydrate Research 351 (2012) 56–63
61
Yield: 177 mg (55%) white crystals. Rf = 0.31 (2:3 EtOAc–hexane);
1.96 (4s, 12H, 4 ꢁ CH3); 13C NMR (CDCl3, 90 MHz) d (ppm) 171.0,
170.8, 170.0, 169.6 (CO), 162.7 (isoxazole C-5), 159.0 (isoxazole
C-3), 155.9 (NHCO), 129.3, 126.2, 125.6, 125.0, 124.5, 122.6 (Ar),
106.4 (isoxazole CH), 78.2 (C-1), 73.9, 72.9, 70.6, 68.2 (C-2–C-5),
Mp: 212–214 °C
[
a]
ꢀ4 (c 0.21, CHCl3) 1H NMR (CDCl3,
D
360 MHz) d (ppm) 7.82–7.79 (m, 2H, ArH), 7.41 (d, 1H, J = 9.2 Hz,
NH), 7.40–7.35 (m, 3H, ArH), 7.20 (s, 1H, isoxazole CH), 5.37,
5.32, 5.07 (3 pseudo t, 4H, J = 9.5, 9.5 Hz in each, H-1, H-2, H-3,
H-4), 4.30 (dd, 1H, J = 11.9, 2.8 Hz, H-6a), 4.14 (dd, 1H, J = 12.6,
2.2 Hz, H-6b) 3.82 (ddd, 1H, J = 9.2, 4.0, 2.6 Hz, H-5), 2.01, 1.98
(2s, 12H, 4 ꢁ CH3); 13C NMR (CDCl3, 90 MHz) d (ppm) 170.9,
170.7, 170.0, 169.6 (CO), 165.5 (isoxazole C-5), 162.6 (isoxazole
C-3), 156.1 (NHCO), 130.8, 129.2, 129.2, 127.9, 127.0, 127.0 (Ar),
106.4 (isoxazole CH), 78.2 (C-1), 74.0, 72.8, 70.6, 68.2 (C-2–C-5),
61.7 (C-6), 20.8, 20.7 (OCOCH3). Anal. Calcd for C24H26N2O11
(518.47): C, 55.60; H, 5.05; N, 5.40. Found: C, 55.20; H, 4.87; N,
5.57.
61.8 (C-6), 20.8, 20.7, 20.6 (CH3). Anal. Calcd for C26H26N2O11
S
(574.56): C, 54.35; H, 4.56; N, 4.88. Found: C, 53.93; H, 4.36; N,
5.03.
3.5.5. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-3-
(benzothiazol-2-yl)-isoxazole-5-carboxamide (18)
Prepared by general procedure given in Section 3.5 from 3
(200 mg, 0.501 mmol) and benzothiazol-2-carbaldoxime (98 mg,
0.551 mmol). Yield: 86 mg (30%) white crystals. Rf = 0.39 (2:3
EtOAc–hexane); Mp: 179–181 °C [
a]
ꢀ7.6 (c 0.19, CHCl3) 1H
D
NMR (CDCl3, 360 MHz) d (ppm) 8.10 (d, 1H, J = 9.2 Hz, NH) 8.01
(m, 2H, ArH), 7.59–7.52 (m, 2H, ArH), 7.27 (s, 1H, isoxazole CH),
5.47, 5.39, 5.18, 5.14 (4 pseudo t, 4H, J = 9.2, 9.6 Hz each, H-1, H-
2, H-3, H-4), 4.38 (dd, 1H, J = 11.9, 5.3 Hz, H-6a), 4.17 (dd, 1H,
J = 11.9, 2.8 Hz, H-6b), 3.94 (ddd, 1H, J = 9.2, 5.3, 2.8 Hz, H-5),
2.06, 2.06, 2.04, 2.03 (4s, 12H, 4 ꢁ CH3); 13C NMR (CDCl3,
90 MHz) d (ppm) 171.0, 170.8, 170.0, 169.6 (CO), 162.4 (isoxazole
C-5), 161.1 (benzothiazole C-2), 158.3 (isoxazole C-3), 156.3
(NHCO), 152.5, 136.3, 126.9, 125.5, 123.7, 122.7 (Ar), 102.8 (isoxaz-
ole CH), 78.0 (C-1), 73.8, 72.6, 71.0, 68.8 (C-2–C-5), 61.8 (C-6), 20.8,
20.7, 20.6 (CH3). Anal. Calcd for C25H25N3O11S (575.54): C, 52.17; H,
4.38; N, 7.30. Found: C, 51.87; H, 4.20; N, 7.45.
3.5.2. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-3-(2-
naphthyl)-isoxazole-5-carboxamide (15)
Prepared by general procedure given in Section 3.5 from 3
(388 mg, 0.972 mmol) and naphthalene-2-carbaldoxime (200 mg,
1.069 mmol). Yield: 288 mg (52%) white crystals. Rf = 0.40 (2:3
EtOAc–hexane); Mp: 202–204 °C [
a]
D
ꢀ7.8 (c 0.24, CHCl3) 1H
NMR (CDCl3, 360 MHz) d (ppm) 8.12 (s, 1H, ArH), 7.83–7.76 (m,
4H, ArH), 7.62 (d, 1H, J = 9.2 Hz, NH), 7.46–7.43 (m, 2H, ArH),
7.31 (s, 1H, isoxazole CH), 5.42, 5.34, 5.12, 5.08 (4 pseudo t, 4H,
J = 9.2, 9.5 Hz in each, H-1, H-2, H-3, H-4), 4.32 (dd, 1H, J = 11.9,
5.1 Hz, H-6a), 4.14 (dd, 1H, J = 11.9, 2.8 Hz, H-6b) 3.89 (ddd, 1H,
J = 9.2, 5.1, 2.8 Hz, H-5), 2.00, 1.99, 1.98, 1.96 (4s, 12H, 4 ꢁ CH3);
13C NMR (CDCl3, 90 MHz) d (ppm) 171.2, 171.0, 170.4, 170.0
(CO), 163.7 (isoxazole C-5), 163.0 (isoxazole C-3), 156.5 (NHCO),
134.6, 133.5, 129.4, 128.9, 128.2, 127.8, 127.4, 127.3, 125.5, 124.0
(Ar), 106.8 (isoxazole CH), 78.5 (C-1), 74.2, 73.2, 70.9, 68.5 (C-2–
C-5), 62.1 (C-6), 21.1, 21.0 (CH3). Anal. Calcd for C28H28N2O11
(568.53): C, 59.15; H, 4.96; N, 4.93. Found: C, 58.85; H, 4.77; N,
5.07.
3.5.6. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-3-(indol-2-
yl)-isoxazole-5-carboxamide (19)
Prepared by general procedure given in Section 3.5 from 3
(300 mg, 0.752 mmol) and indol-2-carbaldoxime (132 mg,
0.827 mmol). Yield: 100 mg (24%) yellow oil. Rf = 0.44 (2:3
EtOAc–hexane)
[
a]
ꢀ8.1 (c 0.23, CHCl3) 1H NMR (CDCl3,
D
360 MHz) d (ppm) 8.24 (s, 1H, indol NH), 7.70–7.41 (m, 5H, ArH, in-
dol CH), 7.29 (s, 1H, isoxazole CH), 5.50, 5.42, 5.15, 5.11 (4 pseudo t,
4H, J = 9.2, 9.6 Hz each, H-1, H-2, H-3, H-4), 4.35 (dd, 1H, J = 11.9,
5.3 Hz, H-6a), 4.22 (dd, 1H, J = 11.9, 2.9 Hz, H-6b), 4.00 (ddd, 1H,
J = 9.2, 5.3, 2.9 Hz, H-5), 2.02, 2.00, 1.99, 1.98 (4s, 12H, 4 ꢁ CH3);
13C NMR (CDCl3, 90 MHz) d (ppm) 171.2, 170.8, 170.1, 169.5
(CO), 162.6 (isoxazole C-5), 158.8 (isoxazole C-3), 156.9 (NHCO),
137.1, 135.2, 128.4, 122.6, 121.9, 121.3 118.4 (Ar, indol C-2),
101.0, 100.2 (isoxazole CH, indol CH), 78.1 (C-1), 74.0, 72.7, 71.0,
68.4 (C-2–C-5), 61.9 (C-6), 20.5, 20.5, 20.4, 20.4 (CH3). Anal. Calcd
for C26H27N3O11 (557.51): C, 56.01; H, 4.88; N, 7.54. Found: C,
55.61; H, 4.69; N, 7.68.
3.5.3. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-3-(benzo-
[b]-furan-2-yl)-isoxazole-5-carboxamide (16)
Prepared by general procedure given in Section 3.5 from 3
(200 mg, 0.501 mmol) and benzo-[b]-furan-2-carbaldoxime
(89 mg, 1.551 mmol). Yield: 141 mg (50%) yellow oil. Rf = 0.39
(2:3 EtOAc–hexane) [
a
]
D
ꢀ6.7 (c 0.45, CHCl3) 1H NMR (CDCl3,
360 MHz) d (ppm) 7.62–7.55 (m, 2H, ArH), 7.47 (d, 1H, J = 9.2 Hz,
NH), 7.32–7.19 (m, 3H, ArH, isoxazole CH), 5.40, 5.33, 5.10, 5.08
(4 pseudo t, 4H, J = 9.2, 9.5 Hz in each, H-1, H-2, H-3, H-4), 4.27
(dd, 1H, J = 12.1, 5.2 Hz, H-6a), 4.06 (dd, 1H, J = 12.1, 2.8 Hz, H-
6b), 3.84 (ddd, 1H, J = 9.2, 5.2, 2.8 Hz, H-5), 2.01, 1.99, 1.98, 1.96
(4s, 12H, 4 ꢁ CH3); 13C NMR (CDCl3, 90 MHz) d (ppm) 170.9,
170.7, 170.0, 169.6 (CO), 162.6 (isoxazole C-5), 156.0 (isoxazole
C-3), 155.7 (NHCO), 155.4, 144.5, 127.8, 126.4, 123.8, 122.0 (Ar),
106.3 (isoxazole CH), 78.2 (C-1), 74.0, 72.9, 70.6, 68.2 (C-2–C-5),
61.7 (C-6), 20.8, 20.7 (CH3). Anal. Calcd for C26H26N2O12 (558.49):
C, 55.91; H, 4.69; N, 5.02. Found: C, 55.50; H, 4.50; N, 5.18.
3.5.7. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-3-(indol-3-
yl)-isoxazole-5-carboxamide (20)
Prepared by general procedure given in Section 3.5 from 3
(400 mg, 1.00 mmol) and indol-3-carbaldoxime (177 mg,
1.10 mmol). Yield: 110 mg (20%) yellow oil. Rf = 0.49 (2:3 EtOAc–
hexane) [
a]
ꢀ5.6 (c 0.15, CHCl3) 1H NMR (CDCl3, 360 MHz) d
D
3.5.4. N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-3-(benzo-
[b]-thiophen-2-yl)-isoxazole-5-carboxamide (17)
Prepared by general procedure given in Section 3.5 from 3
(204 mg, 0.513 mmol) and benzo-[b]-thiophen-2-carbaldoxime
(100 mg, 0.564 mmol). Yield: 151 mg (51%) yellow crystals.
(ppm) 7.75 (s, 1H, indol NH), 7.64–7.36 (m, 5H, ArH, indol CH),
7.28 (s, 1H, isoxazole CH), 5.49, 5.40, 5.17, 5.10 (4 pseudo t, 4H,
J = 9.2, 9.6 Hz each, H-1, H-2, H-3, H-4), 4.24 (dd, 1H, J = 11.9,
5.3 Hz, H-6a), 4.19 (dd, 1H, J = 11.9, 3.0 Hz, H-6b), 4.01 (ddd, 1H,
J = 9.2, 5.3, 3.0 Hz, H-5), 2.02, 2.00, 1.99, 1.98 (4s, 12H, 4 ꢁ CH3);
13C NMR (CDCl3, 90 MHz) d (ppm) 171.4, 171.2, 170.4, 170.0
(CO), 164.9 (isoxazole C-5), 160.0 (isoxazole C-3), 156.1 (NHCO),
139.1, 133.0, 125.5, 121.5, 120.0, 119.6 112.8 (Ar, indol C-2),
101.9, 101.0 (isoxazole CH, indol CH), 78.5 (C-1), 73.7, 73.0, 71.1,
68.2 (C-2–C-5), 61.5 (C-6), 20.7, 20.6 (CH3). Anal. Calcd for
Rf = 0.29 (2:3 EtOAc–hexane); Mp: 192–194 °C (decomp.) [
a
]
ꢀ7
D
(c 0.21, CHCl3) 1H NMR (CDCl3, 360 MHz) d (ppm) 7.77 (d, 1H,
J = 9.3 Hz, NH), 7.70–7.68 (m, 2H, ArH), 7.59 (s, 1H, ArH), 7.32–
7.29 (m, 2H, ArH), 7.21 (s, 1H, isoxazole CH), 5.40, 5.33, 5.11,
5.07 (4 pseudo t, 4H, J = 9.2, 9.5 Hz in each, H-1, H-2, H-3, H-4),
4.32 (dd, 1H, J = 12.0, 2.9 Hz, H-6a), 4.13 (dd, 1H, J = 12.0, 5.3 Hz,
H-6b), 3.90 (ddd, 1H, J = 9.2, 5.3, 2.9 Hz, H-5), 2.00, 1.99, 1.98,
C26H27N3O11 (557.51): C, 56.01; H, 4.88; N, 7.54. Found: C, 55.32;
H, 4.59; N, 7.64.

62
B. Kónya et al. / Carbohydrate Research 351 (2012) 56–63
3.5.8. N-(b-
D
-Glucopyranosyl)-3-phenyl-isoxazole-5-
3.5.12. N-(b-D-Glucopyranosyl)-3-(benzothiazol-2-yl)-isoxazole-
carboxamide (21)
5-carboxamide (25)
Prepared by general procedure given in Section 3.3 from 14
(80 mg, 0.154 mmol) for 1 hour. Yield: 52 mg (97%) white solid.
Prepared by general procedure given in Section 3.3 from 18
(80 mg, 0.139 mmol) for 1 h. Yield: 51 mg (90%) yellow solid.
Rf = 0.47 (7:3 CHCl3–MeOH); Mp: 215–217 °C (decomp.) [
a
]
+7.8
Rf = 0.55 (7:3 CHCl3–MeOH); Mp: 223–225 °C [
a
]
+5.8 (c 0.19,
D
D
(c 0.23, DMSO) 1H NMR (DMSO-d6 + D2O, 360 MHz) d (ppm)
7.92–7.90 (m, 2H, ArH), 7.80 (s, 1H, isoxazole CH), 7.55–7.53 (m,
3H, ArH), 4.88 (t, 1H, J = 9.3, 9.3 Hz, H-1), 3.68–3.35 (m, 3H, H-6a,
H-2, H-3), 3.27–3.08 (m, 3H, H-6b, H-5, H-4); 13C NMR (DMSO-
d6 + D2O, 90 MHz) d (ppm) 164.0 (isoxazole C-5), 162.5 (isoxazole
C-3), 156.2 (NHCO), 130.8, 130.7, 129.4, 129.3, 127.9, 126.7, (Ar),
105.0 (isoxazole CH), 80.1 (C-1), 79.0, 77.3, 71.6, 69.9 (C-2–C-5),
61.0 (C-6). Anal. Calcd for C16H18N2O7 (350.32): C, 54.86; H, 5.18;
N, 8.00. Found: C, 54.47; H, 5.00; N, 8.14.
DMSO) 1H NMR (DMSO-d6 + D2O, 360 MHz) d (ppm) 7.90–7.82
(m, 2H, ArH), 7.78 (s, 1H, isoxazole CH), 7.67–7.51 (m, 2H, ArH),
4.78 (t, 1H, J = 9.3, 9.3 Hz, H-1), 4.60–4.44 (m, 2H, H-2, H-3),
3.54–3.31 (m, 3H, H-6a, H-6b, H-4), 3.22 (ddd, 1H, J = 9.3, 4.0,
2.3 Hz, H-5); 13C NMR (DMSO-d6 + D2O, 90 MHz) d (ppm) 166.5
(isoxazole C-5), 161.9 (isoxazole C-3), 160.3 (benzothiazole C-2),
158.9 (NHCO), 150.4, 136.5, 127.3, 126.3, 125.5, 123.2 (Ar), 108.4
(isoxazole CH), 81.8 (C-1), 73.6, 71.5, 70.9, 69.7 (C-2–C-5), 62.5
(C-6). Anal. Calcd for C17H17N3O7S (407.40): C, 50.12; H, 4.21; N,
10.31. Found: C, 49.72; H, 4.03; N, 10.50.
3.5.9. N-(b-D-Glucopyranosyl)-3-(2-naphthyl)-isoxazole-5-
carboxamide (22)
3.5.13. N-(b-D-Glucopyranosyl)-3-(indol-2-yl)-isoxazole-5-
Prepared by general procedure given in Section 3.3 from 15
(160 mg, 0.281 mmol) for 1.5 h. Yield: 102 mg (91%) white solid.
carboxamide (26)
Prepared by general procedure given in Section 3.3 from 19
(100 mg, 0.179 mmol) for 2 h. Yield: 53 mg (76%) yellow oil.
Rf = 0.51 (7:3 CHCl3–MeOH); Mp: 218–220 °C (decomp.) [a] +6.0
D
(c 0.25, DMSO) 1H NMR (DMSO-d6 + D2O, 360 MHz) d (ppm) 8.54
(s, 1H, ArH), 8.10–7.99 (m, 4H, ArH), 7.88 (s, 1H, isoxazole CH),
7.65–7.62 (m, 2H, ArH), 5.12–4.93 (m, 4H, H-1, H-2, H-3, H-4),
3.70 (dd, 1H, J = 12.0, 5.0 Hz, H-6a), 3.22 (ddd, 1H, J = 9.0, 5.0,
3.0 Hz, H-5), 3.12 (dd, 1H, J = 12.0, 3.0 Hz, H-6b); 13C NMR
(DMSO-d6 + D2O, 90 MHz) d (ppm) 164.0 (isoxazole C-5), 162.2
(isoxazole C-3), 156.0 (NHCO), 133.8, 132.9, 129.0, 128.6, 128.6,
127.9, 127.6, 127.1, 127.0, 126.9, 125.2, 123.5 (Ar), 105.4 (isoxazole
CH), 79.8 (C-1), 79.0, 77.5, 71.9, 70.0 (C-2–C-5), 61.0 (C-6). Anal.
Calcd for C20H20N2O7 (400.38): C, 60.00; H, 5.03; N, 7.00. Found:
C, 59.64; H, 4.89; N, 7.20.
Rf = 0.45 (7:3 CHCl3–MeOH) [
a]
+1 (c 0.10, DMSO) 1H NMR
D
(DMSO-d6 + D2O, 360 MHz) d (ppm) 7.61–7.51 (m, 3H, ArH, isoxaz-
ole CH), 7.35–7.19 (m, 2H, ArH, indol CH), 4.97 (d, 1H, J = 10.6 Hz,
H-1), 3.50–3.07 (m, 6H, H-2, H-3, H-4, H-5, H-6a, H-6b); 13C NMR
(DMSO-d6 + D2O, 90 MHz) d (ppm) 164.0 (isoxazole C-5), 156.8
(isoxazole C-3), 155.4 (NHCO), 147.9, 136.0, 132.3, 125.9, 123.6,
121.5, 118.9 (Ar, indol C-2), 113.3, 110.2 (isoxazole CH, indol CH),
80.6 (C-1), 79.9, 77.7, 73.0, 70.3 (C-2–C-5), 61.6 (C-6). Anal. Calcd
for C18H19N3O7 (389.36): C, 55.53; H, 4.92; N, 10.79. Found: C,
55.13; H, 4.73; N, 10.93.
3.5.14. N-(b-D-Glucopyranosyl)-3-(indol-3-yl)-isoxazole-5-
3.5.10. N-(b-
D
-Glucopyranosyl)-3-(benzo-[b]-furan-2-yl)-
carboxamide (27)
isoxazole-5-carboxamide (23)
Prepared by general procedure given in Section 3.3 from 16
(120 mg, 0.215 mmol) for 1 h. Yield: 74 mg (88%) yellow solid.
Prepared by general procedure given in Section 3.3 from 20
(100 mg, 0.179 mmol) for 1.5 h. Yield: 49 mg (70%) yellow oil.
Rf = 0.40 (7:3 CHCl3–MeOH) [
a
]
D
+3 (c 0.10, DMSO) 1H NMR
Rf = 0.55 (7:3 CHCl3–MeOH); Mp: 196–198 °C [
a
]
+9 (c 0.18,
(DMSO-d6 + D2O, 360 MHz) d (ppm) 7.90 (s, 1H, isoxazole CH),
7.60–7.42 (m, 2H, ArH), 7.34–7.02 (m, 3H, ArH, indol CH), 4.96 (d,
1H, J = 9.2 Hz, H-1), 3.53–3.12 (m, 6H, H-2, H-3, H-4, H-5, H-6a,
H-6b); 13C NMR (DMSO-d6 + D2O, 90 MHz) d (ppm) 163.6 (isoxaz-
ole C-5), 157.2 (isoxazole C-3), 156.0 (NHCO), 139.1, 133.0, 129.8,
125.6, 124.0, 122.0, 119.1 (Ar, indol C-2), 111.9, 107.3 (isoxazole
CH, indol CH), 80.2 (C-1), 79.7, 78.2, 72.4, 69.9 (C-2–C-5), 61.0 (C-
6). Anal. Calcd for C18H19N3O7 (389.36): C, 55.53; H, 4.92; N,
10.79. Found: C, 55.25; H, 4.69; N, 10.88.
D
DMSO) 1H NMR (DMSO-d6 + D2O, 360 MHz) d (ppm) 7.79–7.72
(m, 4H, ArH, benzofuran CH, isoxazole CH), 7.48–7.33 (m, 2H,
ArH), 4.87 (d, 1H, J = 9.3 Hz, H-1), 3.46–3.10 (m, 6H, H-2, H-3, H-
4, H-5, H-6a, H-6b); 13C NMR (DMSO-d6 + D2O, 90 MHz) d (ppm)
164.0 (isoxazole C-5), 155.0 (isoxazole C-3), 154.9 (NHCO), 154.6
(benzofuran C-2), 145.6, 127.5, 126.6, 123.9, 123.0, 122.4 (Ar),
111.8 (benzofuran C-3), 108.9 (isoxazole CH), 79.9 (C-1), 79.0,
77.4, 71.9, 69.9 (C-2–C-5), 60.9 (C-6). Anal. Calcd for C18H18N2O8
(390.34): C, 55.39; H, 4.65; N, 7.18. Found: C, 54.89; H, 4.46; N,
7.32.
Acknowledgements
This work was supported by the Hungarian Scientific Research
Fund (OTKA CK77712, CNK80709) and TÁMOP 4.2.1./B-09/1/
KONV-2010-0007 project implemented through the New Hungary
Development Plan, co-financed by the European Social Fund. Some
compounds were made during a stay of BK at the University of
Lyon with J.-P. Praly supported by a joint program of French CNRS
and the Hungarian Academy of Sciences (PICS 4576). The authors
thank K. E. Kövér for her advice on HMBC spectra.
3.5.11. N-(b-D-Glucopyranosyl)-3-(benzo-[b]-thiophen-2-yl)-
isoxazole-5-carboxamide (24)
Prepared by general procedure given in Section 3.3 from 17
(120 mg, 0.209 mmol) for 1 h. Yield: 81 mg (95%) yellow solid.
Rf = 0.51 (7:3 CHCl3–MeOH); Mp: 234–236 °C [
a
]
D
+7.8 (c 0.25,
DMSO) 1H NMR (DMSO-d6 + D2O, 360 MHz) d (ppm) 8.16 (s, 1H,
benzothiophen CH), 8.08–7.95 (m, 2H, ArH), 7.83 (s, 1H, isoxazole
CH), 7.48–7.46 (m, 2H, ArH), 5.07 (d, 1H, J = 9.2 Hz, H-1), 4.97–
4.91 (m, 2H, H-2, H-3), 3.70 (ddd, 1H, J = 9.0, 3.7, 2.6 Hz, H-5),
3.46–3.17 (m, 3H, H-4, H-6a, H-6b); 13C NMR (DMSO-d6 + D2O,
90 MHz) d (ppm) 163.9 (isoxazole C-5), 155.7 (isoxazole C-3),
155.0 (NHCO), 154.8 (benzothiophen C-2), 144.6, 127.6, 126.6,
124.0, 122.3, 122.0 (Ar), 112.0 (benzothiophen C-3), 109.0 (isoxaz-
ole CH), 80.0 (C-1), 79.2, 77.4, 72.0, 70.0 (C-2–C-5), 61.0 (C-6). Anal.
Calcd for C18H18N2O7S (406.41): C, 53.20; H, 4.46; N, 6.89. Found:
C, 52.81; H, 4.28; N, 7.03.
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