Synthesis of new isoxazoles derivatives attached to sugar moieties

Article abstract of DOI:10.1002/jhet.5570410605

This work reports the synthesis of isoxazoles linked to sugar derivatives in different positions of furanosidic rings, by intramolecular oxidative cyclization of α,β-unsaturated oximes with iodine, potassium iodide and sodium hydrogen carbonate. These oxi

Full text of DOI:10.1002/jhet.5570410605

Nov-Dec 2004
877
Synthesis of New Isoxazoles Derivatives Attached to Sugar Moieties
1
1
1
2
Jorge M. Pinheiro , M. Isabel Ismael *, J. Albertino Figueiredo , Artur M. S. Silva
1
Departamento de Química, Unidade de Materiais Têxteis e Papeleiros, Universidade da Beira Interior,
Rua Marquês d'Ávila e Bolama, 6201-001 Covilhã, Portugal
2
Departamento de Química, Universidade de Aveiro, Campus Universitário de Santiago,
3810-193 Aveiro, Portugal
e-mail: iismael@ubista.ubi.pt; arturs@dq.ua.pt
Received February 19, 2004
This work reports the synthesis of isoxazoles linked to sugar derivatives in different positions of
furanosidic rings, by intramolecular oxidative cyclization of α,β-unsaturated oximes with iodine,
potassium iodide and sodium hydrogen carbonate. These oximes were obtained from aldehyde-sugar
derivatives.
J. Heterocyclic Chem., 41, 877 (2004).
Introduction.
carbohydrate portion/nature of the cell surface, which are
implicated in antigenicity, and the degree of differentiation
and behaviour of cells. The carbohydrate derivatives may
became incorporated as components into cell-surface gly-
coconjugates, or interfere as metabolites with its cellular
biosynthesis [14-17].
Taking into consideration the important biological appli-
cations of isoxazoles and some sugar derivatives, and our
interest on the preparation and molecular structure of sev-
eral types of nitrogen heterocyclic compounds [4-7],
prompted us to devote our attention to another type of
these compounds. In this work were synthesised new
isoxazoles derivatives linked to sugar moieties, which can
be regarded as pseudo-C-nucleosides and homopseudo-C-
nucleosides.
Nitrogen and oxygen heterocyclic compounds have
exhibited considerable biological applications, namely in
medicine and agriculture. Heterocyclic compounds having
an isoxazole ring have been used in the treatment of some
different health problems, like epilepsy, arteriosclerosis
[1], and more recently tested as potential anticonvulsant
agents and membrane muscle relaxants [2,3].
Isoxazole compounds have a five membered π-exces-
sive heterocycle ring with oxygen (furan-type) and nitro-
gen (pyridine-type) atoms and the partially reduced form
of isoxazoles (dihydroisoxazoles or isoxazolines) exists in
three isomeric forms, depending on the position of the
double bond. The isoxazole ring is considered to be an aro-
matic heterocycle as it exhibits electrophilic substitution
reactions and the NMR chemical shifts for ring protons are
consistent with an aromatic system. The ring heteroatoms,
however, modify appreciably the aromatic character of
isoxazole [8].
Several methods are available for the synthesis of isoxa-
zole compounds. The most widely used method consists of
1,3-dipolar cycloaddition reactions of nitrile oxides to acti-
vated acetylenes [9,10]. Isoxazoles can also be obtained by
thermolysis of (Z)-β-azido-α,β-unsaturated ketones and
esters [11,12,13]. In this communication we used the oxida-
tive cyclization of α,β-unsaturated oxime with iodine,
potassium iodide and sodium hydrogen carbonate, in water
[8,9]. An aldehyde derivative was treated with acetonyli-
denetriphenylphosphorane in chloroform at room tempera-
ture to give the corresponding α,β-unsaturated ketone,
which was converted into a ketoxime and then treated with
iodine to give the expected isoxazole derivative.
The search for new drugs with biological activity, high
selectivity, and lower toxicity is an important area in car-
bohydrate research [2]. Significant changes in plasma
membrane and function associated with malignant trans-
formations are evident from studies on the properties and
composition of the cell surfaces of normal and malignant
cells. Many of those differences are associated with the
Results and Discussion.
The synthesis of isoxazoles bearing sugar moieties
started from formylfuranosidic derivatives 1-3. These
formyl-compounds were prepared in several steps from
D-glucose, D-allose and D-galactose. Compounds 1 and 2
were obtained by oxidative cleavage of the corresponding
diol derivatives with NaIO [18,19]. The synthesis of com-
4
pound 3 has been reported by several methods [20,21], but
in this sequence the 6-OH oxidation of the commercially
available 1,2:3,4-di-O-isopropylidene-α-D-galactopyra-
nose was performed with PCC and molecular sieves, in
73% yield. In this way 3 was obtained in a smaller reaction
time, easy isolation process and better yield than that
reported in literature. The presence of the formyl group
1
13
1
was confirmed by H and C nmr spectra. In the H nmr
spectrum the resonance corresponding to the formyl pro-
ton was observed at δ 9.91 as doublet (J = 1.7 Hz), while in
13
C nmr the resonance of the formyl group appears at δ
199.4 as tertiary carbon. The structure can also be con-
firmed by the absence of hydroxyl group signals of
1,2:3,4-di-O-isopropylidene-α-D-galactopyranose.
The synthesis of formyl derivative 6 (Scheme 1)
started from the ketofuranoside 4, which was prepared

878
J. M. Pinheiro, M. I. Ismael, J. A. Figueiredo, A. M. S. Silva
Vol. 41
compound 5 with LiAlH leads to 6 in 67% yield
4
13
1
(Scheme 1). The H and C nmr spectra of 6 showed
the presence of the formyl group by the resonances at δ
9.93 and 201.4, respectively.
α,β-Unsaturated ketones 7-10 [22] were obtained by
Wittig reactions of the aldehydo-sugar derivatives 1-3
and 6 with the semi-stabilized ylide acetonylidenetriph-
enylphosphorane (Scheme 2). The relative stability of
this phosphorane is due to the presence of the carbonyl
group [14]. A mixture of the acetonylidenetriph-
enylphosphorane and the appropriate carbonyl deriva-
tive 1-3 or 6 in chloroform, at room temperature, during
five hours, gave the corresponding α ,β-unsaturated
ketones 7-10 [23-28] (Scheme 2). Compounds 1 and 3
lead to the formation of diastereomeric mixtures of
ketones 7 and 9, which were separated by flash chro-
matography. The E-isomers 7a and 9a were obtained in
72% and 82% yield, respectively and the Z forms 7b
and 9b were obtained in 8%, and 18% yield, respec-
tively. Compounds 8, and 10 were obtained in E-form in
80% and 78% yield, respectively. The pure E stereo-
by 3-OH oxidation of 1,2:5,6-di-O-isopropylidene-α-D-
glucofuranose, with PCC and molecular sieves [21].
The carbon chain elongation in position 3 of keto-com-
pound 4 was carried out by the Reformatsky reaction
with ethyl bromoacetate, to afford ester 5 in 67% yield.
The presence of the 3-C-ethoxycarbonylmethylene
1
13
group of 5 was assigned in their H and C nmr spec-
1
tra. In H nmr spectrum the resonances of the
methylenic protons (CH -1') appeared as an AB spin
2
system at δ 2.85 and 2.44 (J = 14.9 Hz) and the ethyl
group appeared at δ 4.22-4.05 (multiplet) and δ 1.26
13
(triplet). The C nmr spectrum showed the resonances
1
of the carbonyl group at δ 170.6, the C-3 (quaternary) at
δ 78.2, the ethyl group at δ 61.0 and 14.1 and also the
chemistry was confirmed by analysis of their H nmr
spectra, since the coupling constant of their vinylic
3
methylene group (CH -1') at δ 37.1 ppm. Reduction of
protons was J
~ 16 Hz.
2
Hα-Hβ

Nov-Dec 2004
Synthesis of New Isoxazoles Derivatives Attached to Sugar Moieties
879
α,β-Unsaturated ketones (E-isomer) 7a, 8, 9a and 10
were converted into the α,β-unsaturated ketoxime deriva-
tives 11-14 [22] by reaction with hydroxylamine
hydrochloride in a mixture of pyridine and methanol, at
room temperature, during 2 hours, in 93-98% yield
(Scheme 2). This method constitutes an improvement to
that reported in literature [9], since we used less excess of
hydroxylamine hydrochloride, smaller reaction times, and
compounds 11-14 were obtained in better yields. In our
propylidene-α-D-allo-furanos-3-yl)methyl]-3-methyl-
isoxazole (18) was reported. It involves an intramolecular
oxidative cyclization of the appropriate α,β-unsaturated
ketoxime derivative and was carried out using water as
solvent.
EXPERIMENTAL
General Methods.
1
case the reaction gave a single spot by tlc and their H and
NMR spectra were recorded on Bruker AC-P 250 spectrom-
13
C nmr spectra showed the presence of only one com-
1
13
eter (250 MHz for H and 62.9 MHz for C), with CDCl as
3
1
13
pound. The analysis of H and C nmr spectra of 7a, 8, 9a
and 10 and 11-14 supported the transformation of the keto
group 7a, 8, 9a and 10 into the oximes 11-14, since the β-
proton and carbon atoms of these functional groups were
shielded in the later compounds.
solvent with TMS as internal standard. Chemical shifts (δ) are
reported in ppm values and coupling constants (J) in Hertz.
High-resolution mass spectra (hrms) were performed on an
APEX III FT-ICR MS (Bruker Daltonics, Billerica, MA),
equipped with a 7T actively shielded magnet. Ions were gener-
ated using an Apollo API electrospray ionization (ESI) source.
Ionization was achieved by an electrospray ionization source
(Bruker Daltonics, Billerica, MA), with a voltage of between
1800 and 2200 V (to optimize ionization efficiency) applied to
the needle, and counter voltage of 450 V applied to capillary.
Samples were prepared by adding a spray solution of
50:49.5:0.5 (v/v/v) water/methanol/formic acid to the sample
at a v/v ratio of 1 to 5% to give best signal-to-noise ratio. Data
acquisition and data processing were performed using the
XMASS software version 6.1.2 (Bruker Daltonics). Infrared
(ir) spectra were obtained in a FT-IR Mattson Genesis II spec-
trophotometer. Optical rotations were determined on a
Bellingham+Stanley Ltd ADP 220. Melting point was deter-
mined on a Leitz-Biomed with platinum plate apparatus and is
uncorrected. Thin-layer chromatography (tlc) was carried out
on silica gel F-254 plates and the column chromatography in
silica gel 60 (230-400 mesh).
Isoxazole derivatives 15-18 were prepared by treatment
α,β-unsaturated oximes 11-14 with potassium iodide,
iodine and sodium hydrogen carbonate, at 100 ºC, during 4
hours. Intramolecular oxidative cyclization of 11-14 gave
the corresponding isoxazoles 15-18 in good yields (66-
69%) (Scheme 2). The obtained residue was purified by
flash chromatography using silica gel and a mixture of
ethyl acetate:toluene as eluent. This method constitutes an
improvement to the Moffatt method (oxidative cyclization
of unsaturated oxime) [9], since we have only used water
as solvent and smaller reaction times. This heterocycle
derivative was obtained as a single compound confirmed
1
13
by tlc, H and C nmr spectra.
1
In the H nmr spectra of 15-18 the isoxazole proton
resonance appears as a singlet near δ 6, while the C nmr
13
3-C-Ethoxycarbonylmethylene-1,2:5,6-di-O-isopropylidene-α-
D-allo-furanose (5).
spectra showed the resonances of O-C=C (C-5) at δ
168.3-167.4 and the C=N at δ 160.3-159.6 ppm as quater-
nary carbons. The resonance of C-4 appears at δ 105.1-
103.8 as CH.
A solution of ethyl bromoacetate (0.4 ml, 2.8 mmol) in dry
THF (1 ml) was added drop by drop with stirring, under nitro-
gen atmosphere at room temperature, to a mixture of granu-
lated zinc 20 mesh (0.095 g, 1.48 mmol) and 4 (0.258 g, 1
mmol) in dry THF (0.5 ml). The mixture was stirred for 1 hour
at 45 ºC, and then cooled to room temperature. A cold aqueous
solution of HCl (5%) (2 ml) was added, followed by extraction
with dichloromethane (3x15 ml). The organic layer was
washed with an aqueous solution of sodium bicarbonate (2.5%)
(15 ml), dried and the solvent evaporated. The obtained residue
was purified by column chromatography with ethyl
acetate:toluene (1:5 v/v) and 5 was obtained as syrup in 67%
1
yield (0.232 g). R = 0.69 (ethyl acetate:toluene 2:1). H nmr: δ
f
5.70 (d, 1H, H-1, J = 3.6 Hz), 4.76 (d, 1H, H-2, J = 3.6 Hz),
Conclusions.
4.29-4.05 (m, 4H, H-4, H-5, CH -6), 3.88-3.76 (m, 2H,
2
OCH CH ); 2.85 and 2.44 (AB system, 2H, CH -1', J = 14.9
2
3
2
In this work the synthesis of the new pseudo-C-nucleo-
sides 5-(3-O-Benzyl-1,2-O-isopropylidene-α-D-xylo-fura-
nos-4-yl)-3-methyl-isoxazole (15), 5-(3-O-Benzyl-1,2-O-
isopropylidene-α-D-ribo-furanos-4-yl)-3-methyl-isoxa-
zole (16) and 5-(1,2:3,4-Di-O-isopropylidene-α -D-
galacto-pyranos-5-yl)-3-methyl-isoxazole (17) and the
new homopseudo-C-nucleoside 5-[(1,2:5,6-di-O-iso-
Hz), 1.57, 1.43, 1.34 (3s, 4 x 3H, 4CH isopropylidene), 1.26
3
13
ppm (t, 3H, OCH CH , J = 6.3 Hz). C nmr: δ 170.6 (Cq,
2
3
CO Et), 112.6, 109.8 (Cq, isopropylidene), 103.3 (CH, C-1),
2
81.5 (2 x CH, C-2 and C-4), 78.3 (Cq, C-3), 73.2 (CH, C-5),
67.9 (CH , C-6), 61.0 (CH , OCH CH ), 37.1 (CH , C-1'),
2
2
2
3
2
26.6, 26.5, 26.4, 25.2 (4CH , isopropylidene), 14.1 ppm (CH ,
3
3
OCH CH ).
2
3

880
J. M. Pinheiro, M. I. Ismael, J. A. Figueiredo, A. M. S. Silva
Vol. 41
3-C-Formylmethylene-1,2:5,6-di-O-isopropylidene-α-D-allo-
furanose (6).
3-O-Benzyl-5,6,8-trideoxy-1,2-O-isopropylidene-α-D-ribo-oct-
5-(E)-enfuranos-7-ulose (8).
To a solution of 5 (0.346 mg, 1.0 mmol) in dry THF (20 ml)
This compound was obtained as syrup in 80% yield (0.254
at 0 ºC was added LiAlH (0.038 mg, 1 mmol) in small por-
tions. The reaction mixture was stirred at room temperature
g). R = 0.25 (ethyl acetate:n-hexane 1:3); ir: 1721 (C=O), 1641
(C=C) cm ; H nmr: δ 7.42-7.27 (m, 5H, Ph of benzyl), 6.68
4
f
-1
1
for 30 minutes. The excess of LiAlH was eliminated by addi-
(dd, 1H, H-5, J = 4.9, 16.1 Hz), 6.35 (d, 1H, H-6, J = 16.1 Hz),
4
tion of a solution THF/water (70%, 20ml). The mixture was
filtrated through celite and concentrated. The obtained residue
was purified by column chromatography with ethyl
acetate:toluene (1:2 v/v). 3-C-formylmethylene-1,2:5,6-di-O-
5.78 (d, 1H, H-1, J = 3.6 Hz), 4.77, 4.56 (AB system, CH ben-
zyl, 2H, J = 12.1 Hz), 4.67-4.60 (m, 2H, H-2 and H-4), 3.54 (q,
2
1H, H-3, J = 3.6, 9.2 Hz), 2.22 (s, 3H, CH -8), 1.62, 1.34 ppm
3
13
(2s, 2 x 3H, 2CH , isopropylidene); C nmr: δ 197.9 (Cq, C-7),
3
isopropylidene-α-D-allo-furanose (6) was obtained in 67%
142.1 (CH, C-6), 137.0 (Cq, Ph of benzyl), 130.9 (CH, C-5),
128.5, 128.2, 128.1 (CH, Ph of benzyl), 113.2 (Cq, isopropyli-
dene), 104.0 (CH, C-1), 81.8 (CH, C-3), 77.3 (CH, C-2), 76.9
1
yield (0.230 g). R = 0.58 (ethyl acetate:toluene 2:1); H nmr:
f
δ 9.93 (t, 1H, CHO, J = 1.7 Hz), 5.69 (d, 1H, H-1, J = 3.8 Hz),
4.37 (d, 1H, H-2, J = 3.8 Hz), 3.71-4.05 (m, 4H, H-4, H-5 and
(CH, C-4), 72.4 (CH , benzyl), 27.4 (CH -8), 26.7, 26.4 ppm
2 3
CH -6); 2.99-2.92 and 2.39-2.31 (2m, 2H, CH -1'), 1.55, 1.42,
(2CH , isopropylidene).
3
2
2
13
1.32, 1.31 ppm (4s, 4x3H, 4CH , isopropylidene); C nmr: δ
3
6,7,9-Trideoxy-1,2:3,4-di-O-isopropylidene-α-D-galacto-non-6-
(E)-enpyranos-8-ulose (9a).
201.4 (CH, CHO), 113.1, 110.2 (Cq, isopropylidene), 103.7
(CH, C-1), 82.0 (2 x CH, C-2 and C-4), 78.7 (Cq, C-3), 73.4
This compound was obtained as pellets (120-121 ºC) in 82%
(CH, C-5), 68.2 (CH , C-6), 61.9 (CH , OCH CH ), 45.3
2
2
2
3
yield (0.820 g). R = 0.48 (ethyl acetate:n-hexane 1:3); ir: 1722
(CH , C-1'), 26.8, 26.6, 26.5, 25.3 (4CH , isopropylidene),
f
2
3
-1 1
(C=O), 1635 (C=C) cm ; H nmr: δ 6.76 (dd, 1H, H-6, J = 16.0,
14.1 ppm (CH , OCH CH ).
3
2
3
4.8 Hz), 6.37 (d, 1H, H-7, J = 16.0 Hz), 5.69 (d, 1H, H-1, J = 5.0
Hz), 4.66 (dd, 1H, H-3, J = 7.7, 2.2 Hz), 4.49-4.47 (m, 1H, H-5),
4.37 (dd, 1H, H-2, J = 2.2, 5.0 Hz), 4.30 (dd, 1H, H-4, J = 7.7, 2.4
General Procedure for the Preparation of α,β-Unsaturated
Ketones 7-10.
Acetonylidenetriphenylphosphorane (0.35 g, 1.1 mmol) was
added to a solution of the appropriate formyl derivatives 1-3 or 6
(1.0 mmol) in chloroform (20 ml). The reaction mixture was
stirred at room temperature during 5 hours, then evaporated to
dryness and the obtained residue was purified by column chro-
matography using ethyl acetate:toluene (1:10 v/v).
Hz), 2.30 (s, 3H, CH -9), 1.59, 1.45, 1.36, 1.34 ppm (4s, 4 x 3H,
3
13
4CH , isopropylidene); C nmr: δ 198.6 (Cq, C-8), 142.0 (CH,
3
C-7), 131.3 (CH, C-6), 109.8, 108.9 (Cq, isopropylidene), 96.4
(CH, C-1), 72.8 (CH, C-4), 70.5 (CH, C-3), 69.2 (CH, C-5), 67.8
(CH, C-2), 27.4 (CH -9); 25.0, 24.9, 24.4, 24.2 ppm (4CH , iso-
3
3
propylidene).
3-O-Benzyl-5,6,8-trideoxy-1,2-O-isopropylidene-α-D-xylo-oct-
5-(E)-enfuranos-7-ulose (7a).
6,7,9-Trideoxy-1,2:3,4-di-O-isopropylidene-α-D-galacto-non-6-
(Z)-enpyranos-8-ulose (9b).
This compound was obtained as syrup in 72% yield (0.229 g).
This compound was obtained as syrup in 18% yield (0.021 g).
R = 0.38 (ethyl acetate:n-hexane 1:3); H nmr: δ 6.31 (d, 1H,
H-6, J = 11.5 Hz), 6.16 (dd, 1H, H-7, J = 11.5, 6.9 Hz), 5.55 (d,
1H, H-1, J = 5.1 Hz), 5.35 (d, 1H, H-5, J = 6.9 Hz), 4.66 (dd, 1H,
H-3, J = 2.5, 7.8 Hz), 4.51 (dd, 1H, H-4, J = 2.5, 7.8 Hz), 4.35 (t,
1
R = 0.38 (ethyl acetate:n-hexane 1:3); ir 1722 (C=O), 1638
f
f
-1 1
(C=C) cm ; H nmr: δ 7.39-7.16 (m, 5H, Ph of benzyl), 6.78 (dd,
1H, H-5, J = 5.3, 16.1 Hz), 6.38 (d, 1H, H-6, J = 16.1 Hz), 6.02
(d, 1H, H-1, J = 3.7 Hz), 4.84-4.80 (m, 1H, H-4), 4.69 (d, 1H, H-
2, J = 3.7 Hz), 4.58 and 4.49 (AB system, 2H, CH of benzyl, J =
1H, H-2, J = 2.5, 5.1 Hz), 2.02 (s, 3H, CH -9), 1.56, 1.48, 1.34,
2
3
13
12.1Hz), 4.02 (d, 1H, H-3, J = 3.2 Hz), 2.26 (s, 3H, CH -8), 1.51,
1.32 ppm (4s, 4 x 3H, 4CH , isopropylidene); C nmr: δ 198.6
3
3
13
1.35 ppm (2s, 2 x 3H, 2CH , isopropylidene); C NMR δ: 197.5
(Cq, C-8), 144.5 (CH, C-7), 126.6 (CH, C-6), 109.3, 109.0 (Cq,
isopropylidene), 96.5 (CH, C-1), 73.2 (CH, C-4), 71.1 (CH, C-3),
3
(Cq, C=O, C-7), 140.2 (CH, C-6), 136.9 (Cq, Ph of benzyl),
131.5 (CH, C-5), 128.8, 127.9, 127.5 (CH, Ph of benzyl), 111.7
(Cq, isopropylidene), 104.8 (CH, C-1), 82.9 (CH, C-3), 82.4
70.2 (CH, C-5), 65.9 (CH, C-2), 31.5 (CH -9); 26.0, 25.1, 24.4
3
ppm (4CH , isopropylidene).
3
(CH, C-2), 79.4 (CH, C-4), 72.2 (CH , benzyl), 27.2 (CH -8),
2
3
3-C-[4-Oxopent-2-(E)-enyl]-1,2:5,6-di-O-isopropylidene-α-D-
allo-furanose (10).
26.6, 27.0 ppm (2CH , isopropylidene).
3
3-O-Benzyl-5,6,8-trideoxy-1,2-O-isopropylidene-α-D-xylo-oct-
5-(Z)-enfuranos-7-ulose (7b).
This compound was obtained as syrup in 78% yield (0.267
g). R = 0.47 (ethyl acetate); ir: 1724 (C=O), 1633 (C=C),
f
-1
1
This compound was obtained as syrup in 8% yield (0.028 g).
cm ; H nmr: δ 7.05-6.93 (m, 1H, H-2'), 6.14 (d, 1H, H-3', J =
1
R = 0.25 (ethyl acetate:n-hexane 1:3); H nmr: δ 7.43-7.18 (m,
15.6 Hz), 5.68 (d, 1H, H-1, J = 3.8 Hz), 4.22 (d, 1H, H-2, J =
f
5H, Ph of benzyl), 6.33-6.23 (m, 2H, H-5, H-6), 6.00 (d, 1H,
H-1, J = 3.8 Hz), 5.48 (m, 1H, H-4), 4.63 (d, 1H, H-2, J = 3.8
3.8 Hz), 4.16-4.06 (m, 2H, CH -6), 4.04-4.00 (m, 1H, H-5),
3.95-3.77 (m, 1H, H-4), 2.97 (brs, 1H, OH-3), 2.75 (dd, 1H,
H-1', J = 6.1, 13.1 Hz), 2.23 (dd, 1H, H-1', J = 6.1, 13.1 Hz),
2
Hz), 4.57 and 4.43 (AB system, 2H, CH of benzyl, J = 12.0 Hz),
2
4.36 (d, 1H, H-3, J = 3.2 Hz), 2.19 (s, 3H, CH -8), 1.57, 1.32
1.99 (s, 3H, CH -5'), 1.56, 1.43, 1.34, 1.28 ppm (4s, 4 x 3H,
3
3
13
13
ppm (2s, 2 x 3H, 2CH , isopropylidene); C nmr: δ 198.4 (Cq,
4CH , isopropylidene); C-nmr: δ 197.9 (Cq, C-4'), 143.4
3
3
C-7), 143.5 (CH, C-6), 137.6 (Cq, Ph of benzyl), 128.4, 127.8,
127.7 (CH, Ph of benzyl), 127.6 (CH, C-5), 111.8 (Cq, isopropy-
lidene), 105.2 (CH, C-1), 84.3 (CH, C-3), 83.3 (CH, C-2), 78.8
(CH, C-3'), 125.3 (CH, C-2'), 112.6 (Cq, isopropylidene),
109.7 (Cq, isopropylidene), 104.7 (CH, C-1), 85.5 (CH, C-4),
83.1 (CH, C-5), 81.5 (Cq, C-3), 73.1 (CH, C-2), 67.8 (CH ,
2
(CH, C-4), 72.3 (CH , benzyl), 31.2 (CH -8), 26.93, 26.45 ppm
C-6), 36.0 (CH , C-1'), 27.6 (CH -5'), 27.1, 26.7, 26.5, 25.2
2
3
2 3
(2CH , isopropylidene).
ppm (4CH , isopropylidene).
3
3

Nov-Dec 2004
Synthesis of New Isoxazoles Derivatives Attached to Sugar Moieties
881
General Procedure to Prepare α,β-Unsaturated Oximes 11-14.
3,92-3,89 (m, 1H, H-5), 3.82 (d, 1H, H-4, J = 7.5 Hz), 2.82-2.74
(m, 2H, H-1', OH-3), 2.25 (dd, 1H, H-1', J = 7.3, 8.3 Hz), 2.01 (s,
A solution of α,β-unsaturated ketone 7a, 8, 9a or 10 (E iso-
mers) (1.0 mmol) and hydroxylamine hydrochloride (0.167 g, 2.4
mmol) in a mixture of pyridine (10 ml) and methanol (30 ml) was
stirred at room temperature for 2 hours and then evaporated to
dryness. The residue was co-evaporated twice with toluene and
purified by column chromatography using ethyl acetate:toluene
1:5 (v/v) to give the oxime derivatives 11-14 as pure compounds.
3H, CH C-5'), 1.56, 1.43, 1.34, 1.28 ppm (s, 3H, 4CH iso-
3,
3,
13
propylidene); C nmr: δ 155.9 (Cq, C-4'), 131.0 (CH, C-2'),
130.0 (CH, C-3'), 112.6, 109.7 (Cq, isopropylidene), 103.4 (CH,
C-1), 81.8 (CH, C-2), 81.3 (CH, C-4), 78.9 (Cq, C-3), 73.1 (CH,
C-5), 67.9 (CH , C-6), 35.5 (CH , C-1'), 27.1, 26.5, 26.3, 25.2
2
2
(CH , 4CH , isopropylidene), 9.6 ppm (CH , C-5').
3
3
3
General Procedure for the Preparation of Isoxazoles 15-18.
3-O-Benzyl-5,6,8-trideoxy-7-hydroxyimino-1,2-O-isopropyli-
dene-α-D-xylo-oct-5-(E)-enfuranose (11).
A solution of potassium iodide (0.581 g, 3.5 mmol) and iodine
(0.279 g, 1.1 mmol) in water (5 ml) was added in the dark to a
stirred solution of the appropriate oxime derivative 11-14 (1
mmol) and sodium bicarbonate (0.336 g, 4 mmol) in water (5
ml). The mixture was heated under reflux for 4 hours, cooled,
diluted with saturated aqueous sodium thiosulfate (3 ml), and
extracted with dichloromethane (3 x 20 ml). The organic phase
was dried and evaporated to dryness and the obtained residue was
purified by column chromatography with ethyl acetate:toluene
(1:4 v:v) to give the isoxazoles 15-18.
This compound was obtained as syrup in 93% yield (0.310 g);
R = 0,3 (ethyl acetate:toluene 1:3); ir: 3485 (OH), 1634 (C=C)
f
-1
1
cm ; H nmr: δ 9.45 (br s, 1H, NOH), 7.37-7.12 (m, 5H, Ph of
benzyl), 6.43 (d, 1H, H-6, J =16.1 Hz), 6.22, (dd, 1H, H-5, J =8.2,
16.1 Hz), 5.99 (d, 1H, H-1, J = 3.7 Hz), 4.78-4.64 (m, 3H, 1H of
CH of benzyl, H-2, H-4), 4.50 (part B from AB system, 1H, CH
2
2
of benzyl, J = 12.2 Hz), 3.92 (d, 1H, H-3 J =2.9 Hz), 2.35 (s, 3H,
13
CH -8), 1.51, 1.26 ppm (s, 3H, 2CH isopropylidene); C nmr:
3
3,
δ 155.8 (Cq, C-7), 137.4 (Cq, Ph of benzyl), 131.1 (CH, C-6),
129.0, 128.6, 128.1 (CH, Ph of benzyl), 127.7 (CH, C-5), 111.9
(Cq, isopropylidene), 105.1 (CH, C-1), 83.9 (CH, C-2), 83.7
5-(3-O-Benzyl-1,2-O-isopropylidene-α-D-xylo-furanos-4-yl)-3-
methylisoxazole (15).
(CH, C-4), 81.0 (CH, C-3), 72.3 (CH , benzyl), 26.9, 26.3 (2CH ,
2
3
This compound was obtained as syrup in 66% yield (0.218 g);
isopropylidene), 9.8 ppm (CH -8).
3
20
R =0,71 (ethyl acetate:n-hexane 2:1); α
= -23.33º (c 2.0,
f
D
-1
+
3-O-Benzyl-5,6,8-trideoxy-7-hydroxyimino-1,2-O-isopropyli-
dene-α-D-ribo-oct-5-(E)-enfuranose (12).
CHCl ); ir: 1618 (C=C) cm ; hrms: (M+Na) , found 354.1375,
3
+
C
C
H
NO Na, requires, 354.1318, (M+H) found 332.1502,
18 21
5
1
H
NO , requires 332.1498; H nmr: δ 7.38-7.18 (m, 5H, Ph
18 22
5
This compound was obtained as syrup in 98% yield (0.326 g);
of benzyl), 6.23 (s, 1H, H-4), 6.02 (d, 1H, H-1', J = 3.6 Hz), 5.33
(d, 1H, H-4', J = 3.1 Hz), 4.68 (d, 1H, H-2' J = 3.6 Hz), 4.57, 4.49
R = 0,5 (ethyl acetate:toluene 1:2); ir: 3500 (OH), 1630 (C=C)
f
-1
1
cm ; H nmr: δ 7.40-7.15 (m, 5H, Ph of benzyl), 6.48 (d, 1H,
(AB system CH of benzyl, J = 11.9 Hz), 4.02 (d, 1H, H-3' J = 3.1
2
H-6, J =16.1 Hz), 5.92 (dd, 1H, H-5, J =8.2, 16.1 Hz), 5.76 (d,
Hz), 2.29 (s, 3H, CH -3), 1.52, 1.33 ppm (2s, 2x3H, 2CH , iso-
3
3
1H, H-1, J =3.4 Hz), 4.76 (part A from AB system, 1H, CH of
2
13
propylidene); C nmr: δ: 167.4 (Cq, C-5), 159.8 (Cq, C-3),
136.9 (Cq, Ph of benzyl), 128.5, 128.0, 127.7 (CH, Ph of benzyl),
111.9 (Cq, isopropylidene), 105.0 (CH, C-4), 104.4 (CH, C-1'),
benzyl J =12.4 Hz), 4,68-4,48 (m, 3H, 1H of CH of benzyl, H-2,
2
H-4), 3.53 (dd, 1H, H-3 and J = 9.1, 4.3 Hz), 1.96 (s, 3H, CH -8),
3
13
1.63, 1.37 ppm (s, 3H, 2CH , isopropylidene); C nmr: δ 155.3
3
83.0 (CH, C-2'), 82.3 (CH,C-4'), 75.9 (CH, C-3'), 72.6 (CH , ben-
(Cq, C-7), 137.1 (Cq, Ph of benzyl), 130.8 (CH, C-6), 130.3 (CH,
C-5), 128.3, 128.1, 127.9 (CH, Ph of benzyl), 112.9 (Cq, iso-
propylidene), 103.6 (CH, C-1), 81.7 (CH, C-2), 78.1 (CH,C-4),
2
zyl), 26.9, 26.2 (2CH , isopropylidene), 11.4 ppm (CH -3).
3
3
5-(3-O-Benzyl-1,2-O-isopropylidene-α-D-ribo-furanos-4-yl)-3-
methylisoxazole (16).
77.3 (CH, C-3), 72.1 (CH , of benzyl), 26.6, 26.3 (2CH , iso-
2
3
propylidene), 9.5 ppm (CH -8).
3
This compound was obtained as syrup in 67% yield (0.222 g); R
f
6,7,9-Trideoxy-8-hydroxyimino-1,2:3,4-di-O-isopropylidene-α-
D-galacto-non-6-(E)-enpyranose (13).
20
= 0,68 (ethyl acetate:n-hexane 1:1); α = +47.78º (c 1.5, CHCl );
D
3
-1
+
ir: 1614 (C=C) cm ; hrms: (M+Na) , found 354.1327,
NO Na, requires, 354.1318, (M+H) found 332.1506,
C H NO , requires 332.1498; H nmr: δ 7.36-7.19 (m, 5H, Ph of
+
C
H
This compound was obtained as syrup in 97% yield (0.304 g); R
= 0,45 (ethyl acetate:toluene 1:2); ir: 3490 (OH), 1632 (C=C) cm ;
H nmr: δ 9.46 (br s, 1H, NOH), 6.39 (d, 1H, H-7, J = 16.1 Hz), 6.12
18 21
5
f
1
-1
18 22
5
1
benzyl), 6.08 (s, 1H, H-4), 5.84 (d, 1H, H-1', J = 3.5 Hz), 5.09 (d, 1H,
H-4', J = 9.1 Hz), 4.64-4.46 (m, 3H, CH benzyl, H-2'), 4.05 (dd, 1H,
(dd, 1H, H-6, J = 16.1, 8.2 Hz), 5.59 (d, 1H, H-1, J = 4.9 Hz), 4.64
(dd, 1H, H-4, J = 7.8, 6.5 Hz), 4.41 (d, 1H, H-5, J = 8.2, 6.5 Hz),
4.34 (q, 1H, H-2, J = 4.9, 2.3 Hz), 4.24 (dd, 1H, H-3, J = 7.8, 2.3
2
H-3' J = 9.1, 4.0 Hz), 2.29 (s, 3H CH -3), 1.70, 1.38 ppm (2s, 2x3H,
3
13
2CH , isopropylidene); C nmr: δ 168.1 (Cq, C-5), 159.7 (Cq, C-3),
3
137.0 (Cq, Ph of benzyl), 128.5, 128.1, 128.0 (CH, Ph of benzyl),
113.4 (Cq, isopropylidene), 104.5 (CH, C-4), 104.1 (CH, C-1'), 80.8
Hz), 2.02 (s, 3H, CH -9), 1.55, 1.48, 1.35 ppm (s, 3H, 4CH iso-
3
3,
13
propylidene); C nmr: δ 155.3 (Cq, C-8), 130.2 (CH, C-7), 130.1
(CH, C-6), 109.4, 108.7 (Cq, isopropylidene), 96.4 (CH, C-1), 73.3
(CH, C-4), 70.8 (CH, C-3), 70.3 (CH, C-5), 68.8 (CH, C-2), 26.1,
(CH, C-2'), 77.6 (CH, C-4'), 72.6 (CH , benzyl), 72.3 (CH, C-3'),
2
26.9 26.4 (2CH , isopropylidene), 11.4 ppm (CH -3).
3
3
25.9, 24.9, 24.3 (4CH , isopropylidene), 9.7 ppm (CH -9).
3
3
5-(1,2:3,4-Di-O-isopropylidene-α-D-galacto-pyranos-5-yl)-3-
methylisoxazole (17).
3-C-[4-Hydroxyiminopent-2-(E)-enyl]-1,2:5,6-di-O-isopropyli-
dene-α-D-allo-furanose (14).
This compound was obtained as syrup in 64% yield (0.199 g);
20
This compound was obtained as syrup in 96% yield (0.343 g);
R = 0,62 (ethyl acetate:n-hexane 1:2); α = -109.52º (c 1.4,
f
D
-1
1
-1
+
R = 0,47 (ethyl acetate); ir: 3490 (OH), 1631 (C=C) cm ; H
CHCl ); ir: 1615 (C=C) cm ; hrms: (M+Na) , found 334.1276,
f
3
+
nmr: δ 6.27-6.15 (m, 2H, H-3',H-2'), 5.67 (d, 1H, H-1, J = 3.4
Hz), 4.28 (d, 1H, H-2, J = 3.4 Hz), 4.14-4,09 (m, 2H, CH -6),
C
C
H
NO Na, requires, 334.1267, (M+H) found 312.1450,
15 21
6
1
H
NO , requires 312.1447; H nmr: δ 6.17 (s, 1H, H-4),
2
15 22
6

882
J. M. Pinheiro, M. I. Ismael, J. A. Figueiredo, A. M. S. Silva
Vol. 41
S. Cavaleiro and J. Elguero, Eur. J. Org. Chem., 3807 (2002).
[6] D. C. G. A. Pinto, A. M. S. Silva, J. A. S. Cavaleiro and J.
Elguero, Eur. J. Org. Chem., 747 (2003).
[7] A. I. R. N. A. Barros and A. M. S. Silva, Tetrahedron Lett.,
44, 5893 (2003).
5.59 (d, 1H, H-1', J = 4.9 Hz), 4.96 (d, 1H, H-5', J =1.1 Hz), 4.69
(dd, 1H, H-2' J = 7.8, 4.9 Hz), 4.49 (dd, 1H, H-3', J = 7.8, 1.9 Hz),
4.36 (dd, 1H, H-4' J =1.9, 1.1 Hz), 2.25 (s, 3H CH -3), 1.52, 1.40,
3
13
1.32, 1.29 ppm (s, 4x3H, 4CH , isopropylidene); C nmr: δ
3
168.3 (Cq, C-5), 159.6 (Cq, C-3), 109.8, 109.0 (Cq, isopropyli-
dene), 103.8 (CH, C-4), 96.5 (CH, C-1'), 71.6 (CH, C-2'), 70.6
(CH, C-3'), 70.5 (CH, C-5'), 64.5 (CH, C-4'), 26.1, 25.8, 24.8,
[8] R. R. Gupta, M. Kumar and V. Gupta, Heterocyclic
st
Chemistry, Springer, 1 Edition, Germany, 1999.
[9] H. P. Albrechet, D. B. Repke and J. Moffatt, J. Org. Chem.,
40, 2143 (1975).
24.3 (4CH , isopropylidene), 11.4 ppm (CH -3).
3
3
[10] G. Buchi and J. Vederas, J. Am. Chem. Soc., 94, 9128
(1972).
[11] T. P. Melo, C. S. Lopes, A. M. d'A. R. Gonsalves and R. C.
Storr, Synthesis, 5, 605 (2002).
[12] G. L'Abbé, J. P. Dekerk and Van Stappers, Bull. Soc. Chim.
Belg., 90, 1073 (1981).
[13] G. L'Abbé, Angew. Chem. Int. Ed. Engl., 14, 775 (1975).
[14] G. Nicolson and G. Poste, N. Engl. J. Med., 197, 253 (1976).
[15] G. Nicolson, Biochim. Biophys. Acta, 70, 1 (1972).
[16] A. Novogrodsky and E. Katchalski, Prod. Natl. Acad. Sci.
U.S.A., 70, 2515 (1973).
[17] L. Weiss, Front. Biol, 7, 257 (1967).
[18] A. P. Rauter, J. A. Figueiredo and M. I. Ismael, Carbohydr.
Res., 188, 19 (1989).
5-[(1,2:5,6-Di-O-isopropylidene-α-D-allo-furanos-3-yl)methyl]-
3-methylisoxazole (18).
This compound was obtained as syrup in 68% yield (0.245 g),
20
R = 0,63 (ethyl acetate:n-hexane 1:1), α
= +14.44º (c 2.0,
f
D
-1
+
CHCl ); ir: 3418 (OH), 1608 (C=C) cm ; hrms: (M+Na) , found
3
1
378.1523, C
H
NO Na, requires, 378.1529; H nmr: δ 6.17 (s,
17 25
7
1H, H-4), 5.76 (d, 1H, H-1', J = 3.8 Hz), 4.25 (d, 1H, H-2', J = 3.8
Hz), 4.21-4.15 (m, 2H, CH -6'), 3.98-3.85 (m, 1H, H-5'), 3.83 (d,
2
1H, H-4', J = 7.5 Hz), 3.28 (part A from AB system, 1 H of meth-
ylene, J = 15.3 Hz), 2.93-2.85 (m, 2 H, part B from AB system,
1H of methylene, OH-3') , 2.30 (s, 3H, CH -3), 1.58, 1.48, 1.38,
3
13
1.33 ppm (4s, 4x3H, 4CH , isopropylidene); C nmr: δ 167.9
3
(Cq, C-5), 160.3 (Cq, C-3), 112.8, 110.0 (Cq, isopropylidene),
105.1 (CH, C-4 ), 103.6 (CH, C-1'), 81.9 (CH, C-4'), 81.0 (CH,
[19] A. P. Rauter, J. A. Figueiredo, M. I. Ismael, M. S. Pais, A. G.
Gonzalez, J. Diaz and J. B. Barrera, J. Carbohydr. Chem., 6, 259
(1987).
C-2'), 78.8 (Cq, C-3'), 73.2 (CH, C-5'), 68.2 (CH , C-6'), 29.6
2
(CH , methylene), 26.9, 26.7, 26.5, 25.3 (4CH , isopropylidene),
[20] H. Lee, P. Hodgson, R. J. Bernacki, W. Kornytnyk and M.
Sharma, Carbohydr. Res., 176, 59 (1988).
2
3
11.5 ppm (CH -3).
3
[21] J. Ramza and A.Zamojski, Carbohydr. Res., 228, 205 (1992)
[22] In construction of the name of compounds synthesised in
this work, we used the carbohydrate nomenclature as the examples
shown in Figure 2.
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st
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