Topiramate heterocyclic analogues: Synthesis and spectroscopic characterization

Article abstract of DOI:10.3998/ark.5550190.0012.712

Herein we describe the synthesis of a set of heterocyclic analogues of topiramate as possible therapeutic agents for epileptic seizure treatment. The new compounds and their precursors were characterized by physical, as well as spectroscopic techniques. W

Full text of DOI:10.3998/ark.5550190.0012.712

Regional Issue "Organic Chemistry in Argentina"
ARKIVOC 2011 (vii) 136-148
Topiramate heterocyclic analogues: synthesis and spectroscopic
characterization
Miriam A. Martins Alho and Norma D’Accorso*
Centro de Investigaciones en Hidratos de Carbono (CIHIDECAR-CONICET),
Departamento de Química Orgánica, FCEN, UBA, Intendente Güiraldes 2160,
Ciudad Universitaria, C1428EGA Buenos Aires, Argentina
E-mail: nbdac@yahoo.com, norma@qo.fcen.uba.ar
Regional Issue: Organic Chemistry in Argentina
Abstract
Herein we describe the synthesis of a set of heterocyclic analogues of topiramate as possible
therapeutic agents for epileptic seizure treatment. The new compounds and their precursors were
characterized by physical, as well as spectroscopic techniques. We verified that the preferential
conformation in solution of the carbohydrate ring is twist-boat. The stereochemistry of the new
asymmetric centre, generated during the heterocyclizations, was proposed using NOESY
experiment. These novel compounds could help to elucidate the mechanism of action of the
commercial drug used for this disease.
Keywords: Topiramate, D-fructose, heterocyclic rings, spectroscopic data
Introduction
Anticonvulsants are the primary drugs used for the treatment of epileptic disorders.1 A wide
diversity of chemical structures, including heterocycles, exhibits anticonvulsant activity.2 Bruce
E. Maryanoff et al.,3 reported the synthesis and biological activity studies of an anticonvulsant
called “topiramate”, a sulfamate monosaccharide derivative (Figure 1), which is used for
epilepsy treatment.
O
CH2OSO2NH2
O
O
O
O
Figure 1. Chemical structure of topiramate.
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Despite the fact that topiramate is structurally unrelated to other antiepileptic drugs and its
biological molecular mechanism of action is still unknown,4 several studies showed that this drug
acts by multiple neurostabilizing mechanisms, including the blockade of voltage-dependent
sodium channels, potentiation of γ-aminobutyric acid (GABA) derived neuroinhibition,
antagonistic effects on the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainite
receptor, which is a non-N-methyl-D-aspartic acid type receptor for glutamate and inhibition of
carbonic anhydrase.5-8 However, the pharmacology of topiramate appears to be complex and
some of its pharmacodynamic actions still remain to be further elucidated.9-11
In addition, this substance is currently being evaluated for its effectiveness in various
neurological and psychiatric disorders including alcohol dependence, body weight reduction and
smoking.12-14
Beyond these medical applications, in recent years cognitive effects in low-dose topiramate
treatments have been reported.15 On the other hand, Kockelmann et al.,16 reported that the
withdrawal of this drug caused significant improvement in frontal lobe associated measures like
verbal fluency and working memory. Very recently, Beer et al.,17 described a case of a fatal
topiramate poisoning, so it will be necessary to establish the potential lethal topiramate
concentrations.
Given the multiple etiologies of epilepsy, the limited understanding of the mechanisms
behind this disorder and the adverse effects of the topiramate, the search for less toxic, more
efficient agents for the treatment of seizure disorders is an ongoing endeavor. In this context, the
aim of this work was to synthesize novel derivatives of topiramate where the C-1 of fructose was
used to build heterocycles. We also proposed the preferential conformational in solution of the
1
carbohydrate moiety from measured coupling constants of H NMR spectra and determined the
configuration of the new stereocentres generated during the heterocyclization reactions.
Results and Discussion
To carry out this project we chose some heterocycles which were obtained by functionalizing
C-1 of 2,3:4,5-di-O-isopropylidene-β-D-fructopyranose 1. One of these heterocycles was
tetrazole, which is well known as a bioisoster of carboxylic acids18 and Hallberg et al. reported
the use of acylsulfonamide and tetrazole as isosteric groups.19 Since the mechanism of action of
topiramate is unknown, taking into account the diversity of structures with anticonvulsivant
properties, we synthesized a set other heterocyclic derivatives with potential biological
interest.20 In Scheme 1 we show the total synthetic pathway from compound 1 as the starting
material.
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Scheme 1. i. o-iodoxybenzoic acid (IBX)/EtOAc; ii. H2NOH.HCl/NaHCO3/EtOH; iii. Ac2O/Py;
iv. NaN3/NH4Cl/DMF; v. Ac2O; vi. BzCl/Py; vii. BzNHNH2/CH2Cl2; viii. phenyliodine
diacetate (PIDA)/NaOAc·3H2O/MeOH; ix. thiosemicarbazide/EtOH; x. FeCl3.6H2O/EtOH/Py.
To synthesize the heterocyclic derivatives we applied simple and efficient methods that we
have already used to prepare other carbohydrate products. Synthesis of compound 2 was
previously described by oxidation of 2,3:4,5-di-O-isopropylidene-β-D-fructopyranose, using
pyridinium chlorochromate (77.5% yield).21 Looking for an eco-friendly and a more efficient
oxidization we used o-iodoxybenzoic acid (IBX) as an oxidizing agent to replace the use of
chromium salts. We obtained quantitative recovering of the crude product (94% yield after
purification). 1,2:3,4-Di-O-isopropylidene-1-(tetrazol-5′-yl)-β-D-arabinopyranose
5
was
obtained by 1,3-dipolar cycloaddition using a methodology described in a previous paper.22
Other derivatives were the 2,5 disubstituted-1,3,4 oxadiazoles like 1,2:3,4-di-O-
isopropylidene-1-(2′-phenyl-1′,3′,4′-oxadiazol)-5′-yl-β-D-arabinopyranose 6 and the 2′-methyl-
1′,3′,4′-oxadiazole analogue 7 were synthesized by acylation of compound 5 (see Experimental
Section). Compound 6 was also obtained by oxidative cyclization of the corresponding benzoyl
hydrazone derivative 8 using phenyliodine diacetate (PIDA), but in this case the yield was
unsatisfactory. The acylation of compound 8 led to 1-(N-acetyl-2′-phenyl-4′,5′-dihydro-1′,3′,4′-
oxadiazol)-5′-yl-1,2:3,4-di-O-isopropylidene-β-D-arabinopyranose 9a and 9b.
On the other hand, the 1-(2′-amino-1′,3′,4′-thiadiazol)-5′-yl-1,2:3,4-di-O-isopropylidene-β-
D-arabinopyranose 11 and their non-aromatic analogues 12a and 12b were synthesized from the
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corresponding thiosemicarbazone 10 using the methodology previously described.23 In Structure
Block 1 we show the numbering applied for the carbohydrate and heterocyclic moieties.
Structure Block 1. Numbering of heterocyclic derivatives.
1H NMR data (chemical shifts, multiplicities and coupling constants) of compounds 5-7, 9a,
9b, 11, 12a and 12b are listed in Table 1, and meanwhile the spectroscopic data of the precursors
are reported in the Experimental Section.
Table 1. 1 H NMR data of heterocyclic derivatives 5-7, 9a, 9b, 11, 12a and 12b
H-2
H-3
H-4
H-5a
4.05
H-5b
3.94
H-5′ N-H
10.51
4.98
4.67
4.34
5a
6a
d, J2,3 2.2 dd, J3,4 7.9 dd, J4,5a 1.0 dd, J5a,5b 13.0 d, J4,5b 0.0
s (br)
5.11
4.72
4.33
d (br),
J4,5a 1.8
4.31
4.06
3.91
d, J2,3 2.5 dd, J3,4 8.0
dd, J5a,5b 13.0 d, J4,5b 0.6
5.03
4.69
4.02
3.91
7a
d, J2,3 2.4 dd, J3,4 8.0
ddd
dd, J5a,5b 13.0 d, J4,5b 0.9
J4,5a 1.6
4.22
4.75
4.61
3.82
3.77
6.46
s
9ab d, J2,3 2.5 dd, J3,4 7.8 dd, J4,5a 1.4 dd, J5a,5b 13.0 d, J4,5b 0.0
4.72
9bb d, J2,3 2.5 dd, J3,4 7.8 dd, J4,5a 1.8 dd, J5a,5b 13.0 d, J4,5b 0.0
4.99 4.65 4.27 4.02 3.91
11a d, J2,3 2.2 dd, J3,4 7.9 dd, J4,5a 0.0 dd, J5a,5b 13.0 d, J4,5b 0.0
4.89 4.49 4.15 3.79 3.71
12ab d, J2,3 2.5 dd, J3,4 7.9 dd, J4,5a 2.0 dd, J5a,5b 13.1 d, J4,5b 0.0
4.62
4.25
3.92
3.76
6.46
s
5.62
s (br)
6.19 8.48
s
s (br)
6.22 8.97
s (br)
4.68
4.62
4.22
4.22
3.76
12bb d, J2,3 2.9 dd, J3,4 7.8 dd, J4,5a 1.7 dd, J5a,5b 13.1 d, J4,5b 0.0
s
aPerformed at 200 MHz.
bPerformed at 500 MHz.
From the analysis of coupling constants listed in Table 1, we can conclude that in all
derivatives, the carbohydrate moiety have a twist-boat preferential conformation in solution.
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Maryanoff and col. reported the same conformation for the carbohydrate moiety of topiramate,
and they concluded that this conformation is very important for the pharmacologic activities.3 In
our cases, we observed that the presence of heterocyclic rings does not affect the carbohydrate
conformation, so these new compounds are very promising for future biological applications.
In a previous work,24 we studied the sensitivity to steric hindrance on the oxo- and thio-
heterocyclization reactions to synthesize spiro heterocycles. We found that the heterocyclizations
of pyranose and furanose thiosemicarbazones are more sensitive to a crowded environment, so a
single thiadiazoline ring was obtained. Cyclization of the corresponding benzoylhydrazone under
standard conditions (110 °C) demonstrated no diastereoselectivity, although the application of a
more energetic procedure (reflux) gave only one isomer.
The standard procedure performed on compound 8, gave a crude reaction mixture which
showed the presence of compound 9a and 9b (4:1 ratio) under spectroscopic analysis, meanwhile
the reaction carried out at reflux shows exclusively one isomer 9a. In order to determine the
configuration of the new stereocentre we performed a NOESY experiment on the isolated single
isomer. This allowed us to propose the S configuration for the main compound. Figure 2 shows
the spectroscopic correlations.
Figure 2. NOESY correlations for compound 9a.
For this reaction we did not expect any diastereoselection, because the cyclization takes place
on an exocyclic plane carbon, but the relative selectivity observed for cyclization of 8 at 110 °C
was unexpected. Because of this we calculated the minimized geometries of the two possible
diastereoisomers of 8, and found that the anti form was the less energetic. The conformation of
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the more stable rotamer is shown in Figure 3. It can be observed that the isopropylidene group, to
a certain extent, shields one side of the imine bond inhibiting the approach of the oxygen. If
oxygen attacks by the less sterically hindered side, the main compound resulting from the
heterocyclization reaction must be the S isomer, which is consistent with the configuration
obtained from NOESY spectrum.
Figure 3. Less energetic conformer for anti isomer of compound 8 and its main cyclization
product, compound 9a.
The application of standard procedure on compound 10, gave a crude reaction mixture which
showed the presence of both diastereoisomers 12a and 12b, and found that the relationship
between both isomers did not change when a higher temperature was used (62:38 or 61:39 ratio,
respectively). The NOESY experiment carried out on the mixture let us to propose the R
configuration for the main compound (Figure 4).
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Figure 4. NOESY correlations for compound 12a.
We tried to determine the reason of the slight preference for the R isomer and we found that
the conformation of the lower energy rotamer for anti configuration of 10 seem to be reactive on
both sides. However, a little steric hindrance on one side can be observed (Figure 5). This attack
generates a slight preference by the R isomer.
Figure 5. Less energetic conformer for anti isomer of compound 10 and its main cyclization
product, compound 12a.
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Conclusions
A new group of heterocyclic analogues of topiramate were efficiently synthesized from 2,3:4,5-
di-O-isopropylidene-β-D-fructopyrnose. These new derivatives were characterized physically
and spectroscopically using homo and heteronuclear techniques. From the conformational
analysis we can observe that in all cases the sugar ring has the required twist-boat conformation
to show biological activity. Therefore, we suppose that this set of compounds can help elucidate
the mechanism of action of this drug of clinical use.
Experimental Section
General. Synthesis of compounds 2-12 were carried out using all solvents and reagents as
purchased, without further purification. Analytical TLC was conducted on Silica Gel 60G
(Merck) on precoated plates and visualization was made by UV light and ethanol/sulfuric acid
(10:1) or cerium molybdate followed by heating. Flash-chromatographic separations were
performed on Silica Gel 60 G (Merck). Elemental analysis was performed on an Exeter
Analytical CE-440 elemental analyzer. Optical rotations were recorded at 20 °C on a Perkin
1
Elmer 343 polarimeter, and melting points were uncorrected. H, 13C NMR spectra were
recorded in deuterochloroform on a Bruker AC-200 spectrometer, operating at 200, 50 MHz
respectively; or a Bruker AMX-500 spectrometer, operating at 500, 125 MHz respectively.
1
13
Assignments of the H and C NMR spectra were confirmed with the aid of two dimensional
1
techniques H, 13C (COSY, HSQC). Chemical shifts (δ) are reported in parts per million
downfield from tetramethyl silane as internal standard. Minimum energy structures were founded
with HyperChem 8.0.3, using MM+ force field.
2,3:4,5-Di-O-isopropylidene-β-D-arabino-hexos-2-ulo-2,6-pyranose (2). 2,3:4,5-Di-O-isopro-
pylidene-β-D-fructopyranose (1.98 g, 7.5 mmol) was dissolved in ethyl acetate (40 mL), and IBX
(7.1 g) was added. The mixture was stirred and heated at reflux for 5 h, then, the solid was
filtered and crude 2 was obtained by evaporation, with a quantitative recovery. The syrup was
purified by dry flash chromatography, using mixtures of cyclohexane:acetone and was obtained
as a syrup (1.89 g; 96%) and their NMR signals are consistent with those reported in literature.21
2,3:4,5-Di-O-isopropylidene-β-D-arabino-hexos-2-ulo-2,6-pyranose oxime (3). Compound 2
(0.81 g, 3.1 mmol) was dissolved in ethanol (15 mL), and then hydroxylamine hydrochloride
(0.285 g, 4.1 mmol) and sodium bicarbonate (0.420 g, 5.0 mmol) were added with stirring and
left 3 h at room temperature. The salts were filtered and the solution was evaporated. The syrupy
residue was dissolved in CH2Cl2, filtered and purified by dry flash chromatography, using
mixtures of cyclohexane:acetone. Compound 3 crystallizes from cyclohexane:acetone as
20
1
colorless crystals (0.81 g). Yield 94%; mp 137-138 °C, [α]D -0.42 (1.1, CHCl3); H NMR δ
1.35, 1.38, 1.46, 1.55 (four s, 12 H, -C(CH3)2), 3.79 (dd, J = 1.0 Hz and 13.0 Hz, 1H, H-6b), 3.93
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(dd, J = 1.8 Hz and 13.0 Hz, 1H, H-6a), 4.27 (br d, J = 7.8 Hz, 1H, H-5), 4.63 (dd, J = 2.6 Hz
13
and 7.4 Hz, 1H, H-4), 4.66 (d, J = 2.2 Hz, 1H, H-3); C NMR δ 24.3, 24.7, 25.9, 26.1 (-
C(CH3)2), 61.1 (C-6), 70.1 (C-4), 70.5 (C-5), 71.7 (C-3), 100.4 (C-2), 109.1, 109.3 (-C(CH3)2),
149.5 (C-1). Anal. Calcd. for C12H19NO6: C, 52.7; H, 7.0; N, 5.1. Found: C, 53.0; H, 6.9; N,
5.3%.
2,3:4,5-Di-O-isopropylidene-β-D-arabino-hex-2-ulosonitrile (4). Compound 4 was prepared
dissolving compound 3 (0.60 g, 2.3 mmol) in pyridine (1 mL) and acetic anhydride (1 mL). The
mixture was heated at reflux, and the reaction was followed by TLC (cyclohexane:acetone 7:3),
and stopped by addition of ethanol. The reaction media was evaporated at reduced pressure and
the remains of acetic acid were removed by addition of toluene and evaporation. The syrup was
purified by dry flash chromatography, using mixtures of cyclohexane:acetone. Pure compound 4
1
was obtained as syrup (0.41 g). Yield 73%; [α]D20 -0.53 (1.2, CHCl3), H NMR δ 1.35, 1.48,
1.52, 1.54 (four s, 12 H, -C(CH3)2), 3.78 (dd, J = 1.8 Hz and 13.0 Hz, 1H, H-6b), 3.82 (dd, J =
1.2 Hz and 13.0 Hz, 1H, H-6a), 4.26 (dt, J = 7.9 Hz and 1.3 Hz, 1H, H-5), 4.61 (d, J = 2.0 Hz,
13
1H, H-3), 4.64 (dd, J = 2.3 Hz and 7.4 Hz, 1H, H-4); C NMR δ 23.9, 24.4, 25.7, 25.9 (-
C(CH3)2), 61.4 (C-6), 69.3 (C-4), 69.4 (C-5), 74.4 (C-3), 93.8 (C-2), 109.9, 111.5 (-C(CH3)2),
116.6 (C-1). Anal. Calcd. for C12H17NO5: C, 56.5; H, 6.7; N, 5.5. Found: C, 56.8; H, 6.7; N,
5.8%.
1,2:3,4-Di-O-isopropylidene-1-(tetrazol-5′-yl)-β-D-arabinopyranose (5). A mixture of
compound 4 (0.47 g, 1.8 mmol), NaN3 (0.24 g, 3.7 mmol) and NH4Cl (0.20 g, 3.7 mmol) was
suspended in DMF (10 mL) and heated at reflux with stirring for 1 h. The reaction media was
evaporated under reduced pressure; the residue was dissolved in CH2Cl2, filtered and evaporated.
The syrup was purified by dry flash chromatography using mixtures of cyclohexane:acetone.
20
Compound 5 crystallizes from cyclohexane:acetone (0.44 g). Yield 80%; mp 144-146 °C, [α]D
-0.51 (0.9, CHCl3), 1H NMR δ 1.20, 1.28, 1.57, 1.59 (four s, 12 H, -C(CH3)2); 13C NMR δ 23.7,
24.8, 25.6, 26.1 (-C(CH3)2), 61.1 (C-5), 68.6 (C-3), 70.0 (C-4), 74.5 (C-2), 100.4 (C-1), 109.4 ,
111.1 (-C(CH3)2), 156.8 (C-5′). Anal. Calcd. for C12H18N4O5: C, 48.3; H, 6.0; N, 18.8. Found: C,
48.4; H, 6.1; N, 18.8%.
1,2:3,4-Di-O-isopropylidene-1-(2′-phenyl-1′,3′,4′-oxadiazol)-5′-yl-β-D-arabinopyranose (6).
Compound 6 was synthesized by acylation of compound 5 and by oxidative cyclization of
compound 8.
Synthesis of (6) by benzoylation of compound (5)
Compound 5 (1.50 g, 5.03 mmol) was dissolved in pyridine (15 mL), and benzoyl chloride (2.5
mL) was added. The mixture was heated in a water bath (90 ºC ± 5) until disappearance of
compound 5 (3-4 h). The reaction was finished by adding water, and the mixture was evaporated
under reduced pressure. The residue was dissolved in CH2Cl2, extracted with NaHCO3 (sat),
washed with water, dried with anhydrous Na2SO4, filtered and concentrated. The residue was
purified by dry flash chromatography, using mixtures of cyclohexane:acetone. Compound 6 was
obtained as amorphous solid. Yield 81%; mp 111-113 °C, [α]D20 -0.38 (0.9, CHCl3), 1H NMR δ
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1.34, 1.39, 1.52, 1.62 (four s, 12 H, -C(CH3)2), 7.45-8.12 (m, 5H, aromatics); C NMR δ 24.3,
24.6, 25.9, 26.1 (-C(CH3)2), 61.6 (C-5), 70.0 (C-3), 70.2 (C-4), 73.2 (C-2), 98.0 (C-1), 109.5,
110.6 (-C(CH3)2), 123.6, 127.2, 129.0, 131.9 (aromatic carbons), 164.5, 165.4 (C-2 and C-5).
Anal. Calcd. for C19H22N2O6: C, 61.0; H, 5.9; N, 7.5. Found: C, 60.6; H, 6.0; N, 7.3%.
Synthesis of (6) by oxidative cyclization of compound (8)
2,3:4,5-Di-O-isopropylidene-β-D-arabino-hexos-2-ulo-2,6-pyranose benzoylhydrazone 8 (0.10 g,
0.26 mmol) was dissolved in methanol (3 mL). PIDA (0.14 g, 0.43 mmol) and NaOAc.3H2O
(0.11 g, 0.78 mmol) were added and left overnight at room temperature. The mixture was
evaporated at reduced pressure and the solid washed with hexane and then with water. The
residue was purified by dry flash chromatography, using mixtures of cyclohexane:acetone.
Compound 6 was obtained (0.04 g). Yield 40%.
1,2:3,4-Di-O-isopropylidene-1-(2′-methyl-1′,3′,4′-oxadiazol)-5′-yl-β-D-arabinopyranose (7).
Compound 7 was obtained by dissolving compound 5 (0.12 g, 0.4 mmol) in acetic anhydride (3
mL) and heated at reflux for 1.5 h. The reaction was stopped as described for compound 4.
Compound 7 was purified by dry flash chromatography, using mixtures of cyclohexane:acetone
(0.09 g). Yield 72%; mp 100-102 °C, [α]D20 -0.45 (1.0, CHCl3), 1H NMR δ 1.33, 1.37, 1.46, 1.59
13
(four s, 12 H, -C(CH3)2), 2.56 (s, 3H, heterocyclic -CH3); C NMR δ 11.1 (heterocyclic -CH3),
24.2, 24.6, 25.7, 26.0 (-C(CH3)2), 61.6 (C-5), 69.8 (C-3), 70.0 (C-4), 73.0 (C-2), 97.8 (C-1),
109.4, 110.5 (-C(CH3)2), 164.5, 164.6 (C-2′, C-5′). Anal. Calcd. for C14H20N2O6: C, 53.9; H, 6.4;
N, 9.0. Found: C, 53.6; H, 6.5; N, 8.9%.
2,3:4,5-Di-O-isopropylidene-β-D-arabino-hexos-2-ulo-2,6-pyranose benzoylhydrazone (8). A
mixture of compound 2 (0.333 g, 1.29 mmol) and benzoylhydrazine (0.203 g, 1.49 mmol) in 20
mL of CH2Cl2 was stirred overnight at room temperature. The solution was washed with HCl
1N, then with water, dried, filtered and evaporate under reduced pressure. The syrup was purified
by dry flash chromatography, using mixtures of cyclohexane:acetone. Pure compound 8 was
obtained as an amorphous solid (0.403 g). Yield 83%; mp 151-152 °C, [α]D20 -0.65 (0.9, CHCl3),
1H NMR δ 1.31, 1.40, 1.51 (three s, 12 H, -C(CH3)2), 3.67 (d, J = 13.0 Hz, 1H, H-6b), 3.86 (d, J
= 13.0 Hz, 1H, H-6a), 4.16 (d, J = 7.6 Hz, 1H, H-5), 4.52 (dd, J = 2.1 Hz and 7.9 Hz, 1H, H-4),
4.78 (br s, 1H, H-3), 7.34-7.90 (m, 5H, aromatic protons), 7.97 (s, 1H, H-1), 9.99 (s, 1H, NH);
13C NMR δ 24.3, 26.0, 26.1 (-C(CH3)2), 61.2 (C-6), 70.2 (C-4), 70.5 (C-5), 71.9 (C-3), 101.3 (C-
2), 109.3 (-C(CH3)2), 127.5, 128.5, 130.3, 131.9 (aromatic carbons), 149.2 (C-1), 165.0 (C=O).
Anal. Calcd. for C19H24N2O6: C, 60.6; H, 6.4; N, 7.4. Found: C, 60.3; H, 6.4; N, 7.5%.
Heterocyclization of compound (8). Cyclization was made by heating a mixture of
benzoylhydrazone 8 (0.022 g, 0.07 mmol) with of acetic anhydride (0.25 mL) and of pyridine
(0.6 mL) at 110 °C. Reaction was stopped after 1 h by addition of ethanol, and following the
same procedure used for compound 4. The crude was analyzed by NMR and it was a mixture of
compounds 9a and 9b in a 4:1 ratio as syrup.
5′S-1-(N-acetyl-2′-phenyl-4′,5′-dihydro-1′,3′,4′-oxadiazol)-5′-yl-1,2:3,4-di-O-isopropylidene-β-
D-arabinopyranose (9a). 1H NMR δ 1.32, 1.35, 1.52, 1.60 (four s, 12 H, -C(CH3)2), 2.33 (s, 3H,
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CH3-CO-), 7.39-7.90 (m, 5H, aromatic protons); C NMR δ 21.6 (CH3-CO-) 24.3, 25.3, 25.9,
26.4 (-C(CH3)2), 61.6 (C-5), 70.0 (C-3), 70.1 (C-4), 70.7 (C-2), 90.2 (C-5′), 103.1 (C-1), 109.3,
109.4 (-C(CH3)2), 124.5, 127.1, 128.5, 131.5 (aromatic carbons), 156.9 (C-5′), 172.2 (C=O).
5′R-1-(N-acetyl-2′-phenyl-4′,5′-dihydro-1′,3′,4′-oxadiazol)-5′-yl-1,2:3,4-di-O-isopropylidene-β-
D-arabinopyranose (9b). 1H NMR δ 1.32, 1.34, 1.37, 1.54 (four s, -C(CH3)2), 2.46 (s, 3H, CH3-
13
CO-), 7.39-7.90 (m, aromatic protons); C NMR δ 23.2 (CH3-CO-) 24.9, 26.0, 26.1, 26.3 (-
C(CH3)2), 61.2 (C-5), 69.4 (C-3), 70.1 (C-4), 70.4 (C-2), 91.4 (C-5′), 101.1 (C-1), 109.2, 109.3 (-
C(CH3)2), 127.4, 128.8, 129.7, 133.9 (aromatic carbons), 150.0 (C-5′), 172.9 (C=O).
Synthesis of 5′S-1-(N-acetyl-2′-phenyl-4′,5′-dihydro-1′,3′,4′-oxadiazol)-5′-yl-1,2:3,4-di-O-
isopropylidene-β-D-arabinopyranose (9a). Compound 9a was made by heating a mixture of
benzoylhydrazone 8 (0.144 g, 0.38 mmol) with acetic anhydride (1.5 mL) and of pyridine (2 mL)
at reflux. Reaction was stopped after 2 h by addition of ethanol, and following the same
procedure used for compound 4. The crude was purified by dry flash chromatography, using
mixtures of cyclohexane:acetone and compound 9a was obtained as a syrup (0.136 g). Yield 85
20
%, [α]D -2.28 (0.9, CHCl3). Anal. Calcd. for C19H23N2O6: C, 60.8; H, 6.1; N, 7.5. Found: C,
60.9; H, 6.3; N, 7.5%.
2,3:4,5-Di-O-isopropylidene-β-D-arabino-hexos-2-ulo-2,6-pyranose thiosemicarbazone (10).
To compound 2 (0.450 g, 1.74 mmol) dissolved in ethanol (10 mL), thiosemicarbazide (0.192 g)
was added with stirring. The mixture was heated at reflux and the reaction was followed by TLC
(cyclohexane:EtOAc 3:2). The solvent was evaporated and the syrup purified by dry flash
chromatography, using mixtures of cyclohexane:acetone. Compound 10 was obtained as an
20
1
amorphous solid (0.466 g). Yield 81%; mp 98-100 °C, [α]D -0.77 (1.2, CHCl3), H NMR δ
1.32, 1.37, 1.40, 1.53 (three s, 12 H, -C(CH3)2), 3.77 (d, J = 13.0 Hz, 1H, H-6b), 3.90 (dd, J = 1.7
Hz and 13.0 Hz, 1H, H-6a), 4.25 (br d, J = 1.8 Hz and 7.6 Hz, 1H, H-5), 4.60 (dd, J = 1.8 Hz and
7.6 Hz, 1H, H-4), 4.62 (d, J = 2.8 Hz, 1H, H-3), 6.81-7.19 (2 s, 2H, -NH2), 7.39 (s, 1H, H-1),
13
10.20 (s, 1H, -NH-); C NMR δ 24.3, 25.0, 26.1, 26.9 (-C(CH3)2), 61.1 (C-6), 70.0 (C-4), 70.3
(C-5), 72.2 (C-3), 100.8 (C-2), 109.2, 109.3 (-C(CH3)2), 143.4 (C-1), 179.3 (C=S). Anal. Calcd.
for 2(C13H21N3O5S).H2O: C, 45.9; H, 6.5; N, 12.4. Found: C, 46.2; H, 6.4; N, 12.2%.
1-(2′-Amino-1′,3′,4′-thiadiazol)-5′-yl-1,2:3,4-di-O-isopropylidene-β-D-arabinopyranose (11).
Compound 10 (0.298 g, 0.90 mmol) was dissolved in pyridine (30 mL) and FeCl3.6H2O (solution
2M in ethanol) (3.3 mL) was added with stirring. The mixture was heated for 10 min, then
evaporated, suspended in ethanol, filtered trough a silica pad, evaporated, suspended in acetone,
filtered and evaporated. The residue was purified by dry flash chromatography, using mixtures of
cyclohexane:acetone (0.153 g). Yield 51%; mp 185-187 °C, [α]D20 -0.56 (0.9, CHCl3), 1H NMR
13
δ 1.33, 1.37, 1.57 (three s, 12 H, -C(CH3)2, 5.62 (br s, 2H, -NH2); C NMR δ 24.1, 25.0, 25.9,
26.2 (-C(CH3)2), 61.8 (C-5), 70.2 (C-3), 70.4 (C-4), 73.9 (C-2), 100.7 (C-1), 109.3, 110.1 (-
C(CH3)2), 161.5, 169.5 (C-2′ and C-5′). Anal. Calcd. for C13H19N3O5S: C, 47.4; H, 5.8; N, 12.8.
Found: C, 47.4; H, 5.9; N, 12.7%.
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Heterocyclization of compound (10)
Compound 10 (0.394 g, 1.19 mmol) was dissolved in pyridine (3 mL) and then acetic anhydride
(3 mL) was added with stirring. The mixture was heated at 110 °C for 2 h and the reaction was
stopped and processed in the same way than for compound 4. The crude residue was
disaggregated with water and a greenish-yellow precipitate was obtained. Crystallization from
ethanol yields product 12 (0.272 g, 0.65 mmol) as a mixture of two diastereoisomers 12a and
1
12b in a 5:2 relationship, determined by H NMR Yield 55%; mp 244-248 °C. Anal. Calcd. for
C15H22N3O6S: C, 49.2; H, 6.0; N, 10.1. Found: C, 48.8; H, 6.0; N, 10.0%.
5′R-1-(N-acetyl-2′-acetamide-4′,5′-dihydro-1′,3′,4′-thiadiazol)-5′-yl-1,2:3,4-di-O-isopropylidene-
1
β-D-arabinopyranose (12a). H NMR δ 1.30, 1.45, 1.46, 1.50 (four s, 12 H, -C(CH3)2), 2.17,
2.18 (two s, 6 H, CH3CO-), 8.52 (br s, 1H, -NH-); 13C NMR δ 21.8, 23.3 (CH3CO-), 23.8, 25.3,
25.9, 26.0 (-C(CH3)2), 61.3 (C-5), 70.2 (C-5′), 70.3 (C-4), 70.4 (C-3), 71.6 (C-2), 104.2 (C-1),
108.2, 108.7 (-C(CH3)2), 149.0 (C-2′), 168.1, 171.0 (C=O).
5′S-1-(N-acetyl-2′-acetamide-4′,5′-dihydro-1′,3′,4′-thiadiazol)-5′-yl-1,2:3,4-di-O-isopropylidene-
1
β-D-arabinopyranose (12b). H NMR δ 1.33, 1.36, 1.51, 1.57 (four s, 12 H, -C(CH3)2), 2.21,
2.22 (two s, 6 H, CH3CO-), 8.97 (br s, 1H, -NH-); 13C NMR δ 22.1, 23.2 (CH3CO-), 24.2, 24.5,
26.1, 26.3 (-C(CH3)2), 62.1 (C-5), 68.0 (C-5′), 69.9 (C-2), 70.3 (C-3), 70.7 (C-4), 103.6 (C-1),
109.2, 109.5 (-C(CH3)2), 150.8 (C-2′), 168.1, 171.0 (C=O).
Acknowledgements
The authors acknowledged CONICET (PIP 5011), ANPCyT (PICT 13922) and UBA (X058) for
financial support. NBD is a Research Member of the CONICET.
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