Dynamic stereochemistry of Topiramate (anticonvulsant drug) in solution: Theoretical approaches and experimental validation

Article abstract of DOI:10.1016/j.carres.2011.11.010

Topiramate, an antiepileptic drug, was synthesized with an improved protocol and identified by ¹H NMR, ¹³C NMR, ¹H-¹H COSY, HMQC and HMBC spectrum. In parallel, density functional theory (DFT) using B3LYP functional and split-valance 6-311++G basis set has been used to optimize the structures and conformers of Topiramate. Also experimental and theoretical methods have been used to correlate the dependencies of ¹J and ²J involving ¹H and ¹³C on the C1-C2 (ω) and C1-O1 (θ) torsion angles in the glycosidic part of Topiramate. New Karplus equations are proposed to assist in the structural interpretation of these couplings. Importantly, due to the sensitivity of some couplings, most notably ²J_H1R,H1S, ²J_C2,H1R and ²J_C2,H1S values depend on both C-C (ω) and C-O (θ) torsion angles. Analyses of experimental coupling constants for protons on the pyranose ring of Topiramate indicate a twist boat structure for Topiramate in solution. In all calculations solvent effects were considered using a polarized continuum model (PCM).

Full text of DOI:10.1016/j.carres.2011.11.010

Carbohydrate Research 348 (2012) 47–54
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Dynamic stereochemistry of Topiramate (anticonvulsant drug) in solution:
theoretical approaches and experimental validation
Mina Ghiasi , Afsaneh Arefi Oskouie , Hamdollah Saeidian c
a,
⇑
b
a
Department of Chemistry, Faculty of Science, Alzahra University, PO Box: 19835-389, Vanak, Tehran, Iran
Department of Basic Science, Faculty of Paramedical, Shahid Beheshti University of Medical Science, Iran
Department of Science, Payame Noor University (PNU), Zanjan, Iran
b
c
a r t i c l e i n f o
a b s t r a c t
Topiramate, an antiepileptic drug, was synthesized with an improved protocol and identified by 1H NMR,
Article history:
Received 14 September 2011
Received in revised form 10 November 2011
Accepted 11 November 2011
Available online 19 November 2011
13
1
1
C NMR, H– H COSY, HMQC and HMBC spectrum. In parallel, density functional theory (DFT) using
⁄⁄
B3LYP functional and split-valance 6-311++G basis set has been used to optimize the structures and
conformers of Topiramate. Also experimental and theoretical methods have been used to correlate the
dependencies of 1J and J involving 1H and C on the C1–C2 (
2
13
x
) and C1–O1 (h) torsion angles in the gly-
cosidic part of Topiramate. New Karplus equations are proposed to assist in the structural interpretation
Keywords:
Topiramate
Karplus equation
Coupling constants
2
2
of these couplings. Importantly, due to the sensitivity of some couplings, most notably
and JC2,H1S values depend on both C–C (x) and C–O (h) torsion angles. Analyses of experimental coupling
H1R,H1S C2,H1R
J , J
2
constants for protons on the pyranose ring of Topiramate indicate a twist boat structure for Topiramate in
solution. In all calculations solvent effects were considered using a polarized continuum model (PCM).
Ó 2011 Elsevier Ltd. All rights reserved.
2
D NMR
QM calculation
1
. Introduction
NH2
O
S
Epilepsy is a chronic neurological disorder characterized by sei-
zures that result from the sudden, disorderly depolarization of
O
1
,2
O
neurons in the brain. Anticonvulsant drugs are estimated to be
3
4–9
useful in treating 90% of the epileptic patients. Topiramate,
sulfamate substituted monosaccharide: 2,3:4,5-bis-O-(1-methyle-
thylidene)-b- -fructopyranose sulfamate, Figure 1, is an anticon-
a
θ
1
O
ω
O
O
6
5
2
3
CH3
D
1
1
vulsant drug marketed worldwide for the treatment of epilepsy
and the prophylaxis of migraine. Recently, Topiramate is being
8
CH3
1
2
10
4
used in a growing number of other applications such as treat-
ment of bipolar disorders11 and post traumatic stress disorders
and is investigated for use in treating several other pathologies
such as bulimia nervosa,13 obsessive compulsive disorder,
O
12
O
9
H C
14
7
3
1
5
16
idiopathic intracranial hypertension, neuropathic pain , and
CH3
1
7
10
infantile spasms. This ability is attributed to both its primary
chemical structure and its conformation.
Figure 1. Chemical structure of Topiramate.
As Figure 1 shows Topiramate contains b-D-fructopyranose sul-
famate, the exocyclic sulfamatemethyl group which can exist in
three staggered orientations (gauch-gauche, gg; trans-gauche, tg;
and gauche-trans, gt), Scheme 1. Thus, because of the medical
and clinical properties of this compound, studying the conforma-
tion in solution is important, especially the interactions involving
the exocyclic hydroxymethyl substituted by sulfamate group at
this position.
2 2
So in this study we focused on the sulfamatemethyl (CH OSO -
NH ) fragment of fructopyranose in Topiramate to determine its
2
conformation details in solution. Determination of the conforma-
tion of biologically active molecules is often based on NMR spectral
data in combination with the computational methods.
In the present work, we are interested in extending the use of
J-coupling constants for the structural, stereo chemical and confor-
mational analysis of Topiramate, by definition of the dependences
2
2
1
1
13
⇑
Corresponding author. Tel.: +982188044051–9x2608; fax: +982188041344.
E-mail address: ghiasi@alzahra.ac.ir (M. Ghiasi).
of
J
HH
,
J
CH and
JCH coupling constants on the H/ C atomic
dihedral angles. So we present the results of the studies of
0
008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.11.010

4
8
M. Ghiasi et al. / Carbohydrate Research 348 (2012) 47–54
by TLC. The reaction mixture is washed with water (2 ꢁ 15 mL).
After separation of the organic layer, is dried over MgSO , evapo-
rated, and the crude product is used in the next step without fur-
ther purification.
O1
O3
H1S
H1R
O3
4
O2
O2
O2
O1
C3
C3
O1
C3
Step II: Preparation of Topiramate by the hydrolysis of N-[(diphen-
ylamino)
carbonyl]-2,3:4,5-bis-O-(1-methylethylidene)-b-D-fructo-
H1S
H1R
H1S
H1R
pyranose sulfamates
O3
The crude product obtained in step I is dissolved in acetone
7 mL) and sodium acetate–acetic acid buffer solution (pH 3.5).
(
gauche-gauche
gauche-trans
trans- gauche
gg (ω ≈ -60)
gt (ω ≈ 60)
tg (ω ≈ 180)
The reaction mixture is heated at 70 °C for 2 h. The cooled mixture
is diluted with water (7 mL) and the pH reached upto 13–14 by
Scheme 1. Idealized rotamers about the C1–C2 bond of Topiramate.
1
0 M NaOH. It is then extracted with t-butyl methyl ether
(
3 ꢁ 5 mL). The aqueous phase is treated with 85% phosphoric acid
to adjust the pH to 5.5–6 and white crystals precipitate on cooling
to 10 °C. The product is collected by filtration and washed with
cold water. The purity is increased by recrystallisation from a mix-
ture of acetone and water.
chemical shifts and a set of J-couplings about the C1–C2 (
C1–O1 (h) bonds,
x
) and
2
HH
J , J JCH, on b-D-fructopyranose, using
CH and 1
2
experimental and theoretical methods to determine the Karplus
equation.
2
.2. NMR measurements
2
2
. Experimental
1H NMR, 13C NMR, COSY, HMQC and HMBC spectra of Topira-
.1. Synthesis and characterization of Topiramate
The method of preparation involves a two step protocol involv-
mate were obtained at 298 K in CDCl3 (99.99% D) on a Bruker
1
DRX500 operating at 500.133 MHz for H and 125.770 MHz for
1
3
1
13
C, using 5 mm broad band inverse probe. H NMR and C NMR
ing in the first step reacting of 2,3:4,5-bis-O-(1-methylethylidene)-
b- -fructopyranose 1 with N-protected sulfamoyl chloride 2 in the
presence of triethylamine in toluene to produce N-substituted
spectra were acquired using a spectral width of 3255 and
22123 Hz, respectively, and a 90° pulse (10.3).
D
All 2D NMR spectra were acquired by pulsed field gradient-
selected methods. 2D correlation spectroscopy (COSY) was used
Topiramate 3. In the second step hydrolyzing of 3 in pH 3.5 to give
18
1
Topiramate as a white solid, mp 124–126 °C (Scheme 2).
Step I: Preparation of N-[(diphenylamino)carbonyl]-2,3:4,5-bis-
O-(1-methylethylidene)-b- -fructopyranose sulfamate (3)
Diphenylamine (1.2 g, 7.1 mmol) in toluene (10 mL) is added
dropwise to solution of chlorosulfonyl isocyanate (1.2 g,
.5 mmol) in toluene (10 mL) ꢀ10 °C under argon. The solution is
stirred for 30 min, after which the mixture of 2,3:4,5-bis-O-(1-
methylethylidene)-b- -fructopyranose (1.7 g, 6.5 mmol) and tri-
to confirm H assignments, Figure 2. Heteronuclear multiple
quantum correlation (HMQC) and heteronuclear multiple bond
1
3
D
correlation (HMBC) were used for C assignments, Figures 3 and
4. HMQC and HMBC spectra were recorded using 2048 ꢁ 1024 data
matrices; the number of scan and dummy scans were 48 and 16,
respectively, in all cases.
a
8
The HMQC and HMBC were recorded with 2 s inter pulse delay.
The spectral widths sw ꢁ sw = 3255 ꢁ 22123 Hz in all 2D exper-
D
1
2
ethylamine (1.4 mL, 10 mmol) in toluene is added dropwise. It is
then stirred at 5 °C and the progress of the reaction is monitored
iments. For Z-only gradients, the G1:G2:G3 = 50:30:40.1 gradient
ratios were used for both HMQC and HMBC spectra.
OH
O
O
O
O
O
1
O
O
O
S
Ph
Ph
Cl
S
N
C
O
+
HN
Ph
Cl
NH
N
O
O
Ph
2
O
Ph
NH2
HN
N
O
S
O
S
O
OPh
O
O
O
O
O
O
O
O
hydrolysis
O
O
O
O
3
Scheme 2. Synthesis of Topiramate.

M. Ghiasi et al. / Carbohydrate Research 348 (2012) 47–54
49
Figure 2. 1H– H COSY spectrum of Topiramate in CDCl
1
at 298 K.
3
3
3
. Computational details
4. Results and discussion
.1. Ab initio molecular orbital calculation
4.1. Geometry optimization of Topiramate
All calculations were carried out with GAUSSIAN program series
003 as the basic program and Gaussian viewer as a graphical
Topiramate structure was fully optimized in the B3LYP method
using 6-311++G basis set with no initial symmetry restrictions
1
9
⁄⁄
2
medium. The optimization of the geometry was performed by
employing a hybrid Hartree–Fock density functional scheme and
the adiabatic connection method Becke three parameter with
and assuming C
mate in gas phase was reoptimized by considering the solvent ef-
fect ( = 4.9) using the polarized continuum model (PCM). Tomasi’s
1
point group. The optimized geometry of Topira-
e
20
Lee–Yang–Parr (B3LYP) functional of density functional theory
polarized continuum model defines the cavity as the union of a ser-
2
1
⁄⁄
(
DFT) with the standard 6-311++G basis set. The initial struc-
ies of interlocking atomic spheres. The effect of polarization of the
2
5
ture of Topiramate was drowning on the basis of published crystal
solvent continuum is represented numerically. Figure 5 shows
the optimized structure of Topiramate in the CDCl solvent.
2
2,23
data of Topiramate.
Full optimizations were performed with-
3
out any symmetry constrains. This level of theory has been shown
A selection of calculated bond distances, bond angles, and dihe-
dral angles are compiled in Table 1. Calculation of vibrational fre-
quencies has confirmed the stationary point with no negative
eigenvalue observed in the force constant matrix.
to give reasonable potential energy surfaces for D-aldo and D-keto-
hexoses and reduces the basis superposition error.24 We computed
the harmonic vibrational frequencies to confirm that an optimized
geometry correctly corresponds to a local minimum that has only
real frequencies. The solvent effects on the conformational equilib-
4.2. Calculation of chemical shifts and NMR spin–spin coupling
constants
25
rium have been investigated with a PCM method at the B3LYP/6-
⁄⁄
3
11++G level. Solvation calculations were carried out for CDCl
3
with the geometries of optimization for this solvent. Conforma-
tional energy profiles around the C1–C2 bond in chloroform were
NMR computations of absolute shieldings were performed
2
6
using the GIAO method at the DFT optimized structure in the
1
13
calculated by driving the
x
dihedral angle from 0° to 360° in 30°
presence of solvent. The H and C chemical shifts were calculated
by using the corresponding absolute shielding calculated for Me Si
increments, while allowing the remaining geometrical parameters
4
to relax. In this report the orientations about the C2–C1 and C1–O1
at the same level of theory (Table 2). Good agreement between
experimental and theoretical chemical shifts shows the reliability
of DFT calculations for these series of molecules.
bonds are described by torsion angles (
h = C2–C1–O1–S) For the C2–C1 rotamers, we used the standard
nomenclature, Scheme 1. O2 and C3 are the reference atoms and
staggered conformers are designated as gt ( ꢂ 180)
ꢂ 60), tg (
and gg (
ꢂ ꢀ60).
x = O2–C2–C1–O1) and
(
Recent investigations have shown that density functional
theory (DFT) can be used to calculate reliable JCH, JHH and JCC values
x
x
2
7,28
x
in carbohydrates without scaling.
In the present work, we

5
0
M. Ghiasi et al. / Carbohydrate Research 348 (2012) 47–54
3
Figure 3. HMQC spectrum of Topiramate in CDCl at 298 K.
extend this approach to calculate the J-coupling constants using
DFT method.
dataset obtained in this work yielded an improved equation, (Eq.
1), with a substantially smaller rms error. According to Table 3
the following (Eq. 1) is yielded for Topiramate that related JH1R,H1S
1H and 13C NMR spin–spin coupling constants in the DFT opti-
mized structure in the presence of solvent were obtained by fi-
nite-field (Fermi-contact) double perturbation theory2 and
2
to
x and h.
9
2J
¼ ꢀ 10:82 þ 0:23 cosð
x
Þ ꢀ 0:70 cosð2
x
Þ ꢀ 0:71 cosðhÞ
⁄⁄
H1R;H1S
calculated at the B3LYP level using 6-311++G basis set. Appropri-
ate values for the perturbing fields imposed on the coupled nuclei
were chosen to ensure sufficient numerical precision, while still
allowing a satisfactory low-order finite-difference representation
of the effect of the perturbation. The result of recent study on hep-
þ 1:96 cosð2hÞðrms ¼ 0:41HzÞ
ð1Þ
show that 2JHH values in
and h, which
could be caused by the value of the H–C–H bond angle (this angle
3
2–34
The results of the previous study
unsubstituted CH OH fragment influenced both
2
x
ꢀ
ꢀ
2
arin, disaccharide with O- or N-sulfated (OSO3 or NSO3 ) residues,
show that the Fermi contact (FC) term was not always dominant
and that paramagnetic spin-orbit (PSO), diamagnetic spin-orbit
appears relatively constant despite changes in
the J values in the unsubstituted CH OH fragment appear to be
x
and h) on JHH. So
2
HH
2
influenced minimally by the H–C–H bond angle but whether O-
substitution affects the H–C–H bond angle significantly. Therefore,
this factor may be needed to be considered in the structural inter-
(
DSO), and spin-dipolar (SD) contributions considerably influenced
3
0
the magnitudes of proton–proton spin–spin coupling constants.
2
So we consider all the contributions to calculate the coupling con-
stants in the Topiramate molecule. All the equations describing the
pretation of JHH.
2
2
4.2.2. One bond 13C– H spin–spin coupling constants
1
dependencies of JCH and JHH on
x and h were parameterized from
3
5–37
the calculated couplings using a least-squares procedure. Specific
In previous studies
it was shown that one-bond proton–
staggered hydroxymethyl rotamers of Topiramate generated by
carbon couplings usually deviate from experimental data in both
directions: inaccuracy in the geometries and neglect of solvation
systematically rotating the (
x = O2–C2–C1–O2) and (h = C2–C1–
⁄⁄
O1–S) torsion, from 0° to 360° in 30° increments by holding both
the torsion angles at fixed values, were constructed in a Gaussian
viewer and subsequently geometrically optimized using B3LYP/6-
effects. So in this study we used the B3LYP/6-311++g by consid-
ering the solvent effect to decrease the effect of these two items.
3
7
Hircovíni et al. show that the calculated one bond proton–carbon
couplings even using MM2 level of theory are 6–10 Hz smaller
than the experimental values (the deviation is about 5% of the
experimental values). They show one-bond proton–carbon cou-
pling constants among anomeric protons, similarly the three-bond
proton–carbon depended on the torsion angle h. It seems that the
interaction of O atom electron lone pairs with MO of the C–H bond
causes this dependence; In particular, the C–H bond length
determines this dependence.
⁄
⁄
3
11++G . These structures were reoptimized taking solvent effects
into account.
1
1
4
.2.1. Geminal (two bond) H– H spin–spin coupling constants
2
J
H1R,H1S is affected by both
significantly greater than . The latter conclusion is supported by
previous studies of Stenutz et al.,
x and h, but its dependence on h is
x
31
which shown computed
2
J
H1R,H1S was related to both x and h. The additional hyper surface

M. Ghiasi et al. / Carbohydrate Research 348 (2012) 47–54
51
3
Figure 4. HMBC spectrum of Topiramate in CDCl at 298 K.
Table 1
Some structural details of Topiramate
s
optimized
⁄⁄
3
structure at B LYP/6-311++G level
Bond distance (Å)
O1–C1
O1–S
S–N1
1.43
1.65
1.66
1.44
1.54
1.53
1.40
1.41
1.51
S–O
C1–C2
C2–C3
C2–O2
C4–O5
C10–C11
Bond angles (degree)
N1–S–O1
S–O1–C1
O1–C1–C2
C2–O2–C6
105.36
119.93
111.45
114.33
109.03
106.32
C2–O–C10
C3–C4–C5
Dihedral angles (degree)
N1–S–O1–C1
S–O1–C1–C2
ꢀ90.29
92.75
O1–C1–C2–O2
C2–O2–C6–C5
50.69
ꢀ33.83
⁄
⁄
Figure 5. Optimized structure of Topiramate at B3LYP/6-311++G level in solvent.
pair effect39, and 1,4-lone pair effects. The shortest C1–H1 bond
31
1
and the largest JC1–H1 values, are expected for the C1–H1 bond that
C–H bond length is a key determinant of the 1
JCH value, with
shorter bond (greater S-character) yielding larger couplings. Sev-
does not experience bond-lengthening vicinal (anti) O1 lone-pair
interaction and experience bond-shortening 1,3-intraction with
3
2
1
eral structural factors influence C–H bond length: axial versus
an O2 lone-pair. A plot of calculated JC1,H1 versus rC1–H1 is linear,
equatorial bond orientation, vicinal lone pair effects,3
2,38
1,3-lone
Figure 6, indicating that the C–H bond length is highly correlated

5
2
M. Ghiasi et al. / Carbohydrate Research 348 (2012) 47–54
Table 2
Representation of some experimental (in CDCl
optimized Topiramate
3
at 298 K) and theoretical chemical shifts (ppm) and coupling constants (Hz) of Topiramate; DFT calculated J values in the DFT
Chemical shifts
Exp.
Coupling constant
Exp.
1H
13C
⁄
Calcd
Calcd
Calcd
Exp.
2
2
2
2
2
1
1
2
2
1
3
4
5
6
(H
R
, H
S
)
4.15–4.25
4.12
4.38
4.17
3.65, 3.85
4.58
4.27–4.37 a[4.5–4.7]
4.33 [4.28]
4.65 [4.4]
4.28 [4.24]
3.82, 3.94 [3.8]
4.92 [5.2]
1, 3, 4, 5
68.5–69.7
100.2
120.1
59.7
105.3
70–70.9
101.3
117.1
61.5
102.0
J
J
J
J
J
J
J
J
J
H1R,H1S
H3,H4
H4,H5
H5,H6
ꢀ11.05
2.6
7.9
0.80
2.0
146.2
151.5
3.9
ꢀ11.4
2.8
8.1
1.0
2.1
146.9
152.0
4.2
ꢀ4.4
2
3
6
(CH
2
)
H5,H6
0
NH
2
CH
3
25.9, 26.8
24.3, 25.5
C1,H1R
C1,H1S
C2,H1R
C2,H1S
CH
3
1.08
1.19 [1.32]
27.2, 28.1
26.1, 26.8
ꢀ4.1
a
Data in parentheses were taken from Abbate et al.44
1
3
1
Table 3
Torsion angles,
4.2.3. Two bond C– H spin–spin coupling constants
x
and h (°), and calculated 2JH1R,H1S, 2
J
C2,H1S and 2
J
C2,H1R values (Hz)
2
J
CCH values are useful structural constraints in biomolecules
such as saccharides and nucleosides and their derivatives
general rules have been proposed relating JCCH to specific patterns
of oxygen atom substitution on the coupled carbon and on the car-
40,41
2JH1R,H1S
2JC2,H1S
2JC2,H1R
and
x
h
C1–C2 rotamer
2
62
57
72
57
ꢀ12.4
ꢀ11.2
ꢀ8.9
+6.1
+2.0
+2.5
ꢀ5.2
ꢀ3.4
ꢀ5.8
ꢀ48
gt
gg
tg
192
bon bearing the coupled hydrogen. With respect to the CH
2
O-
CCH are expected to be sensitive to
x: JC2,H1R and JC2,H1S. Computed values of these coupling con-
2
2 2
SO NH conformation, two J
ꢀ
58
70
72
50
ꢀ72
171
ꢀ11.5
ꢀ12.9
ꢀ8.6
ꢀ2.2
ꢀ5.0
ꢀ5.2
+2.0
+6.3
+2.5
2
2
ꢀ
ꢀ
2
stants are given in Table 3. The dynamic range of
J
CCH is ꢃ+5 to
2
176
177
176
74
ꢀ69
176
ꢀ11.9
ꢀ12.0
ꢀ7.3
ꢀ2.2
ꢀ4.1
ꢀ4.5
ꢀ3.5
ꢀ1.6
ꢀ4.0
ꢀ5 Hz (
D
ꢂ 10 Hz), and the signs of JCH depend on
x.
2
2
The dependencies of JC5,H6R and JC5,H6S on
x
and h were param-
eterized using the complete dataset of 144 structures from the hy-
1
1
1
20
20
20
60
ꢀ60
180
ꢀ12.5
ꢀ12.4
ꢀ8.6
+4.0
+0.6
ꢀ0.3
+3.6
ꢀ0.5
ꢀ0.5
ꢀ4.0
ꢀ6.2
ꢀ5.8
ꢀ5.5
ꢀ3.5
ꢀ5.2
ꢀ2.0
+1.7
ꢀ2.0
+1.1
+4.8
+0.5
per surface, which yielded (Eqs. 2 and 3).
2J
2J
¼ ꢀ1:0845 þ 0:99 cosð
x
Þ ꢀ 4:15 sinð
ꢀ 1:03 cosð2hÞ ꢀ 1:61 sinð2hÞðrms ¼ 0:55HzÞ
¼ 1:12 þ 2:15 cosð Þ þ 3:78 sinð
ꢀ 0:95 cosð2hÞ þ 1:65 sinð2hÞðrms ¼ 0:36HzÞ
x
Þ
C2;H1R
C2;H1S
0
0
0
60
ꢀ60
180
ꢀ11.5
11.5
ð2Þ
ð3Þ
ꢀ7.4
x
x
Þ
ꢀ
ꢀ
ꢀ
120
120
120
60
ꢀ60
180
ꢀ13.5
ꢀ13.3
ꢀ9.6
4
.3. Conformational properties of pyranose ring in Topiramate
1
1
1
1
1
1
1
1
1
1
1
50
48
46
44
42
40
38
36
34
32
30
According to the Scheme 3 the pyranose ring in Topiramate
could exist in three conformations. The critical parameters are
the coupling constants of the proton on the pyranose ring:
2
2
2
2
J
H3,H4 = 2.7 Hz, JH4,H5 = 7.9 Hz, JH5,H6 = 0.8 Hz, and JH5,H6
0
= 1.9 Hz.
2
For the chair conformation, B, one would expect JH3,H4 to be a large
coupling about 10 Hz ‘anti coupling’ and
2
JH4,H5 to be small cou-
pling of 2–3 Hz ‘gauche coupling’, which is not the case for Topira-
mate. Alternative chair conformation, C, would exhibit a large
2
coupling for one of the
JH5,H6 values and a small coupling for
2
J
H4,H5. Neither situation is observed in the data for Topiramate. A
conformational averaging for Topiramate is probably excluded by
large values for the dihedral angle 0 and very small values for
0
1
.1
1.102
1.104
1.106
1.108
1.11
1.112
1.114
J
H5,H6 and JH5,H6 . To confirm twist boat conformation for Topira-
mate in solution, the geometry of three conformers A, B, and C
was optimized, Figure 7, and their coupling constants were calcu-
lated in solution. Table 4 indicates some structural details and
some calculated proton–proton spin–spin coupling constants in
the pyranose ring for these three conformers. Comparison between
experimental and calculated coupling constants for the three con-
formers shows good agreement between conformer A, twist boat,
and experimental data. Thus, Topiramate appears to assume a
twist boat structure in the solution. A single-crystal X-ray analysis
C
1
-H bond length (Å)
1
Figure 6. Computed 1
systematic rotations about
J
C1H1 versus C1–H1 bond lengths, data were generated from
and h.
x
with 1
constants. The above results relate the JCH to only two torsion an-
gles and h. Rotation of the C1–O1 bond modulates the stereo-
JCH magnitude, with shorter bonds yielding larger coupling
1
x
42
electronic effect of the O1 lone-pairs on the C1–H1R and C1–H1S
bond lengths, but other effects (1,3-lone pair interactions with
of Topiramate shows a similar twist structure in the solid state.
1
The results of previous H NMR study in cyclic diacetals of pyra-
0
0
43
44
O5 and bond orientation) also influence these bond lengths, so
nose with ‘cis–anti–cis’ arrangement and Topiramate tend to
adopt a twist-boat conformation, which is in agreement with our
results. It appears that the molecule is a combination of a large,
the Karplus equations for Topiramate that relate 1
JC1–H1 to x and
h, give relatively large rms errors.

M. Ghiasi et al. / Carbohydrate Research 348 (2012) 47–54
53
Me
Me
Me
H
Me
Me
O
Me
H
6
H
5
O
O
H
H
O
6
2
H
5
3
H
6
O
H
H
5
O
O
O
O
H
O
O
H
CH OR
2
2
4
H
3
2
3
1
4
O
Me
H
O
O
H
4
CH OR
2
H
1
Me
Me
CH OR
2
O
Me
1
Me
Me
A
B
C
2 2
Scheme 3. Presentation of different conformers of Topiramate (R: S(O )NH ), A: Twist boat conformer, B: Chair conformer, C: Alternative chair conformer.
Figure 7. Optimized structure of different conformers of Topiramate (R: S(O
2 2
)NH ), A: Twist boat conformer, B: Chair conformer, C: Alternative chair conformer.
Table 4
5. Conclusion
Presentation of torsion angles of intra-ring protons and proton–proton coupling
constants in pyranose ring for three conformers A, B and C
2 2 2
New structural constraints to assess exocyclic CH OSO NH
Conformer
A
B
C
group conformation in Topiramate based on multiple, redundant
J-couplings have been described in this report. Using theoretical
and experimental methods, equations were developed to correlate
Torsion angle (°)
H3C3C4H4
H4C4C5H5
H5C5C6H6
H5C5C6H6
ꢀ54.08
176.02
50.22
ꢀ86.74
Calcd
2.8
8.1
176.17
ꢀ58.33
54.50
ꢀ65.05
61.07
55.42
the magnitudes and signs of scalar couplings with the CH
SO NH conformation. Importantly, some of these couplings dis-
play dependence not only on but also on h. More importantly,
use of these equations allows assessments of correlated conforma-
tion about and h. The strategy was to obtain experimental chem-
2
O-
ꢀ174.10
0
2
2
ꢀ56.50
x
Coupling constant (Hz)
Exp.
2.2
1.7
9.6
2.0
2
J
J
J
J
H3,H4
H4,H5
H5,H6
H5,H6
9.7
2.6
1.4
2.1
2.6
7.9
0.80
1.9
2
2
2
x
1.0
2.0
ical shifts and coupling constants from Topiramate, and then these
data were used to test the ability of DFT methods to estimate the
chemical shifts and coupling constants. Good agreement between
experimental and theoretical data confirms the accuracy of
0
2 2
globular hydrophobic region and a small hydrophilic SO NH unit.
We suggest that the nature and disposition of these two segments
are important for the biological activity of Topiramate.
⁄⁄
B3LYP/6-311++G method for the calculation of chemical shifts
and coupling constants of saccharides.

5
4
M. Ghiasi et al. / Carbohydrate Research 348 (2012) 47–54
17. Zou, L. P.; Lin, Q.; Qin, J.; Cai, F. C.; Liu, Z. S.; Mix, E. Clin. Neuropharm. 2008, 31,
Notice that, the 2
JHH is determined mainly by the C–O torsion
86–92.
angle (h) in the absence of a hydroxyl proton on O6, when the hy-
droxyl group is substituted, (e.g., in a (1?6) glycosidic linkage).
In addition, this report generates new theoretical treatments in
drugs with the sugar part which makes the interpretation of sac-
charide conformational analysis more feasible. These results are
expected to be helpful for the understanding of conformational de-
tails of Topiramate in solution and give a clue to design binding of
Topiramate to DNA molecules and different enzymes. The present
findings have significant contribution not only for the studies of
Topiramate but also for the related studies of drugs with the sac-
charide part.
1
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The authors gratefully acknowledge partial financial support
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Tohoku University for his advice and suggestions for this work.
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