The behavior of two thiosugar thioglycosides towards oxidation

Article abstract of DOI:10.1016/S0957-4166(02)00034-4

Oxidation of 4-cyanophenyl 2,5-anhydro-1,6-dithio-α-D-glucoseptanoside with magnesium monoperoxyphthalate (MMPP) resulted in a mixture containing two endo- and two exo-monosulfoxides as well as two endo-exo bis-sulfoxides differing in the chirality of the sulfoxide groups. Besides the aforementioned six products a further endo-exo bis-sulfoxide isomer as well as an exo-sulfone was obtained via oxidation with NaIO₄. Oxidation of 4-nitrophenyl 1,5-dithio-β-D-ara binopyranoside with MMPP yielded only two endo-sulfoxides, while oxidation with NaIO₄ in turn led to cleavage of the carbohydrate ring. The formed dialdehyde was stabilized by cyclisation to a hemiacetal, which on further treatment with MMPP afforded an exo-monosulfoxide. The position of oxidation as well as the chirality of the respective sulfoxide groups was established by NMR spectroscopy and X-ray crystallography.

Full text of DOI:10.1016/S0957-4166(02)00034-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3423–3433
The behavior of two thiosugar thioglycosides towards oxidation†,‡
a
a
a
b,
´
´
Eva Bozo´, Ada´m Demeter, Attila Rill and Ja´nos Kuszmann *
aGedeon Richter Ltd., PO Box 27, H-1475 Budapest, Hungary
bInstitute for Drug Research, PO Box 82, H-1325 Budapest, Hungary
Received 7 January 2002; accepted 22 January 2002
Abstract—Oxidation of 4-cyanophenyl 2,5-anhydro-1,6-dithio-a-
D
-glucoseptanoside with magnesium monoperoxyphthalate
(MMPP) resulted in a mixture containing two endo- and two exo-monosulfoxides as well as two endo-exo bis-sulfoxides differing
in the chirality of the sulfoxide groups. Besides the aforementioned six products a further endo–exo bis-sulfoxide isomer as well
as an exo-sulfone was obtained via oxidation with NaIO4. Oxidation of 4-nitrophenyl 1,5-dithio-b-D-arabinopyranoside with
MMPP yielded only two endo-sulfoxides, while oxidation with NaIO4 in turn led to cleavage of the carbohydrate ring. The formed
dialdehyde was stabilized by cyclisation to a hemiacetal, which on further treatment with MMPP afforded an exo-monosulfoxide.
The position of oxidation as well as the chirality of the respective sulfoxide groups was established by NMR spectroscopy and
X-ray crystallography. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
sugar ring itself can also be oxidized due to the pres-
ence of two and three vicinal hydroxyl groups in 1 and
2, respectively (Scheme 1, B and D). To date only the
oxidation of one related compound, that of 4-
Some aromatic thioglycosides of thiosugars in which
the ring oxygen is substituted by sulfur are known
orally active anti-thrombotic agents.2 Although the
exact mechanism of their action is not yet fully under-
stood,3 the possibility that they may act via their
metabolites cannot be ruled out. As thioethers can
easily undergo in vivo oxidation to sulfoxides and
sulfones, we investigated the behavior of the thiosugar
thioglycosides 1 and 2 towards different oxidizing
agents in order to establish any structure–activity rela-
tionship of the products obtained. Both model com-
cyanophenyl 1,5-dithio-b-D-xylopyranoside has been
described in the literature5 and only a single endo-sulf-
oxide was isolated after oxidation with 3-chloroperben-
zoic acid (mCPBA). This was in agreement with the
findings of Hashimoto’s group, who oxidized the a- and
b-anomers of phenyl 1,5-dithio-D-glucopyranoside per-
acetate and established a rule,6,7 according to which the
a- anomer is oxidized predominantly at the exo, and
the b-anomer at the endo sulfur atom.
pounds, the 4-cyanophenyl 2,5-anhydro-1,6-dithio-a-
D-
glucoseptanoside 1 and the 4-nitrophenyl 1,5-dithio-
b- -arabinopyranoside 2, exhibit significant oral
D
2. Results and discussion
antithrombotic activity4 and they represent two distinct
structures. They can undergo oxidation at the endo
and/or at the exo sulfur atom§ thus resulting theoreti-
cally in 16 derivatives for both 1 and 2, that differ in
the oxidation state and/or chirality of the respective
sulfur atoms (Scheme 1, A and C). Furthermore, the
2.1. Oxidation of 4-cyanophenyl 2,5-anhydro-1,6-dithio-
a-D-glucoseptanoside 1
The oxidation of the glucoseptanoside 1 with one
equivalent of magnesium monoperoxyphthalate
(MMPP) (Scheme 2) resulted in a mixture of six com-
pounds 3, 4, 5, 7, 8 and 9, as shown by HPLC analysis.
They could be separated by concerted use of column
chromatography and preparative HPLC. Their struc-
ture was established by NMR spectroscopy (see Section
2.3).
* Corresponding author. E-mail: h13757kus@ella.hu
Orally active antithrombotic thioglycosides, Part XIV. For Part
†
XIII, see: Ref. 1.
‡
Dedicated to Professor Andras Messmer on the occasion of his 80th
birthday.
§ endo refers to the sulfur atom incorporated into the carbohydrate
ring and exo to the anomeric sulfur atom.
As shown in Table 1 the endo-(R) and exo-(R) mono-
sulfoxides 3 and 5 were formed as the main products in
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00034-4

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E. Bozo´ et al. / Tetrahedron: Asymmetry 12 (2001) 3423–3433
3424
Scheme 1.
almost equal amounts (44 and 38%), while all other
derivatives were only minor by-products in the oxida-
tion reaction of 1 with MMPP. Besides the aforemen-
tioned six products, a further endo–exo bis-sulfoxide
isomer 10 as well as a sulfone 11 could be isolated from
the complex reaction mixture (Fig. 1) by using one
equivalent of NaIO4 for the oxidation of 1 (Scheme 2).
In this case, however, the exo-(R)-sulfoxide 5 was the
main product (51%) and all other derivatives were
formed as by-products only (Table 1).
remained intact and only the carbohydrate moiety was
oxidized affording, after workup, a single product 15¶
which could be isolated in high yield (84%). This means
that, in accordance with the rule8 established for the
oxidation of methyl b-D-arabinopyranoside with
NaIO4, the thioarabinopyranoside 2 is also cleaved
selectively between the cis related vicinal hydroxyl
groups at C(3) and C(4). The first formed dialdehyde 14
rearranges via cyclisation to the isolated hemiacetal 15
which resisted further oxidation to the chain-shortened
dialdehyde D (Scheme 1). When the bicyclic thiogly-
coside 15 was subjected to oxidation with MMPP, in
contrast to 2 not the endo, but the exo-sulfur atom was
oxidized, affording the sulfoxide 16 as the sole product.
Scission of the sugar ring was not observed, which
might be attributed to the fact that the two vicinal
hydroxyl groups are in trans-arrangement and the ring-
system is too rigid to allow complexation with the
periodate anion.
2.3. Structure elucidation
While the configuration of the endo-sulfoxide group
could be determined unambiguously [3, 8, 9 endo-(R),
4, 10 endo-(S)] by NMR spectroscopy, the configura-
tion of the exo-sulfoxide group in 5 and 7 remained
uncertain (see below). Therefore 5 was converted into
its crystalline 3,4-di-O-4-nitrobenzoate derivative 6, the
X-ray analysis of which proved the exo-(R)-configura-
tion of the sulfoxide group (Fig. 2 and Table 2).
Accordingly, the parent compound 5 has exo-(R)-
configuration and 7 has exo-(S)-configuration. Further
oxidation of 5 resulted in 8 and 10, respectively, while
7 was converted into 9.
The chemical structure of the present compounds was
verified by standard high-resolution NMR methods as
outlined in Section 3. The position of oxidation (endo
and/or exo) as well as the chirality of the respective
sulfoxide groups was established by NMR spectroscopy
1
and X-ray crystallography. Complete H and 13C chem-
1
ical shifts assignments as well as the measured H–1H
coupling constants are given in Tables 3–5.
Comparison of the measured 13C NMR chemical shifts
of the starting compounds 1, 2 and 15 and the products
obtained on oxidation reveal clearly the position of
oxidation (see Table 5). Oxidation of the endo-sulfur to
sulfoxide leads to a ꢀ13–24 ppm downfield shift of the
C(1) and C(6) signals in 3 and 4 and the C(1) and C(5)
signals in 12, 13 and 16, while a ꢀ15–17 ppm
downfield shift of the C(1) carbon as well as a ꢀ6 ppm
downfield shift of the C(1%) aromatic quaternary carbon
was observed in the case of the exo-sulfoxides 5, 6 and
2.2. Oxidation of 4-nitrophenyl 1,5-dithio-b-D-
arabinopyranoside 2
Under the same conditions the behavior of the
arabinopyranoside 2 was quite different. On treatment
with MMPP only the two sulfoxides, endo-(R)-12 and
the endo-(S)-isomer, 13 could be detected and isolated
from the reaction mixture in yields of 30 and 33%,
respectively (Scheme 3). On the other hand, when
NaIO4 was used as the oxidant, both sulfur atoms
¶ The compound was numbered as a heterocyclic ring system.

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E. Bozo´ et al. / Tetrahedron: Asymmetry 12 (2001) 3423–3433
3425
Scheme 2.
Table 1. Yield of oxidation products obtained on treating 4-cyanophenyl 2,5-anhydro-1,6-dithio-a-D-glucoseptanoside 1 with
MMPP and NaIO4, respectively
Reagents
Oxidation products
3
4
5
7
8
9
10
11
endo/exoa
1+MMPP
1+NaIO4
R/−
44%
3%
S/−
2%
1%
−/R
38%
51%
−/S
7%
9%
R/R
1.4%
2%
R/S
1.2%
1.6%
S/R
−
3%
Sulfone
−
1.6%
a Configuration of the sulfoxide group; endo refers to the sulfur atom incorporated into the ring and exo to the anomeric sulfur atom.
7. The endo–exo bis-sulfoxides 8, 9 and 10 exert a
combined downfield (ꢀ28–32 ppm) effect on the C(1)
chemical shift, while the C(1) and C(1%) chemical shifts
of the exo-sulfone 11 show an upfield shift as compared
to the exo-sulfoxides 5, 6 and 7.
spectra it was evident that the arabinopyranoside ring
of the starting material 2 is not present (comparing the
chemical shifts and the coupling constants with those of
2, 12 and 13). The C(5)H proton and the C(5) carbon
resonate at 5.92 and 100.6 ppm, respectively. Further-
more, a singlet proton signal appears at 5.74 ppm and
its corresponding carbon signal at 97.4 ppm and there
is only one OH proton present. These carbon chemical
The structure of the bicyclic glycoside 15 needs to be
commented on here. From the 1H and 13C NMR

´
E. Bozo´ et al. / Tetrahedron: Asymmetry 12 (2001) 3423–3433
3426
Figure 1. HPLC of the mixture obtained by oxidation of 1 with sodium periodate.
Figure 2. ORTEP plot (using the program PLATON) of 6. Anisotropic displacement ellipsoids are represented at the 50%
probability level.

´
E. Bozo´ et al. / Tetrahedron: Asymmetry 12 (2001) 3423–3433
3427
1
shifts together with the measured H–13C HMBC corre-
lations (C(2)H–C(4), C(4)Ha–C(2), C(4)Ha–C(5),
C(7)H–C(2), C(7)H–C(5), C(5)H–C(7) and C(1)H–C(5))
are in full agreement with the rigid bicyclic hemiacetal
structure of 15. The lack of coupling between the C(1)H
and C(7)H protons (the calculated dihedral angle is
close to 90° in 15) and the observed strong NOE
between the C(7)H and C(2)H protons proved the
configuration at the C(7) stereogenic center.
Table 2. Crystal data and structure refinement of 6
Empirical formula
Formula weight
Temperature (K)
Radiation and wavelength
Crystal system
C27H19N3O10S2+C2H3N
650.63
293(2)
,
Cu-Ka, u=1.54180 A
Monoclinic
Space group
P21
Unit cell dimensions
,
a (A)
12.000(3)
6.870(1)
17.915(4)
91.07(2)
1476.7(5)
2
,
b (A)
,
c (A)
i (°)
Volume (A )
2.3.1. Determination of the configuration of the endo
sulfoxide group. According to literature data the sulfox-
ide configuration in relatively rigid six-membered rings,
where the SꢀO bond is in either an axial or equatorial
disposition, can be assigned on the basis of the follow-
ing spectral features: an axial sulfoxide is associated
with greater shielding of the carbon a to the sulfox-
ide,9–11 and a larger geminal coupling constant of the
a-methylene protons9,11–13 as compared to an equatorial
sulfoxide. Moreover, the significant deshielding of the
protons that are in syn-axial arrangement to an axial
sulfoxide can be used to assign the configuration of the
SꢀO centre.9,11,12,14
3
,
Z
Density (calculated) (Mg/m3)
Absorption coefficient, v
1.463
2.207
(mm−1
F(000)
)
672
Crystal colour
Colourless
Crystal description
Crystal size (mm)
Absorption correction
Max. and min. transmission
Theta range for data
collection
Block
0.40×0.25×0.04
psi-scans
0.9549 and 0.7939
4.40°5q574.68°
Index ranges
−145h514; −85k58;
−225l522
Due to the overbridging oxygen between C(2) and C(5),
the thioseptanoside ring of 1 adopts a considerably
rigid 34BS boat conformation with the 4-cyano-thio-
phenyl group in the axial position (see Scheme 2). In
this system the endo-sulfoxide oxygen can assume
quasi-axial (b) or quasi-equatorial (a) orientation. The
diagnostic greater shielding of the C(1) and C(6) car-
Reflections collected
Completeness to 2q
Number of standard
reflections
5976
0.987
3
Decay (%)
3
Independent reflections
Reflections I\2|(I)
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I\2|(I)]
R indices (all data)
Absolute structure parameter
Max. and mean shift/esd
5976 [Rint=0.0222]
4690
Full-matrix least-squares on F2
5976/75/425
2
bons as well as the larger geminal J6a,6b coupling could
be safely used to distinguish between the axial isomers
3, 8 and 9, and the equatorial isomers 4 and 10 (see
Tables 4 and 5). The observed ꢀ0.5–0.7 ppm upfield
shift of the C(4)H proton in the equatorial sulfoxides 4
and 10 as compared to the axial isomers 3, 8 and 9
might also be used to assign the sulfoxide configura-
tion. This difference in shift might be attributed to the
differences in shielding caused by the anisotropy of the
1.073
R1=0.0615, wR2=0.1478
R1=0.0777, wR2=0.1572
−0.02(2)
0.049, 0.003
0.468 and −0.368
Largest diff. peak and hole
−3
,
(e A
)
Scheme 3.

´
E. Bozo´ et al. / Tetrahedron: Asymmetry 12 (2001) 3423–3433
3428
Table 3. 1H NMR data for 1–16 as measured in DMSO-d6 at 30°C at 500 MHz
Compound
Chemical shifts (ppm) relative to TMS (lTMS=0.00 ppm)
H-1
H-2
H-3
H-4
H-5
H-6a
H-6b
2-OH
5.50
3-OH
4-OH
H-2%
H-3%
Others
1
2*
4.54
4.82
4.35
4.11
4.18
3.69
4.39
4.04
4.12
3.16
2.37
5.41
4.90
5.29
4.69
7.44
7.63
7.77
8.16
a 2.95
b 2.35
4.14
4.13
4.16
4.85
3.93
4.13
4.19
3
4
5
6
7
8
9
10
11
12*
4.84
4.98
3.39
4.01
3.70
4.34
4.20
4.90
4.89
4.87
5.40
4.78
4.77
5.25
4.29
4.18
4.60
3.91
4.28–4.34
5.94–6.00
4.24
3.41
2.64
3.10
3.38
2.73
3.21
3.08
3.34
2.50
3.09
3.05
2.39
2.75
2.22
3.07
3.19
3.84
2.26
4.95
5.78
5.49
5.52
5.48
5.38
7.70
7.62
8.00–8.07
8.10
7.92
7.97
8.03
8.00
8.13–8.17
7.73
7.85
7.71
8.05
8.01
8.09
8.12
8.07
4.12
4.13
4.26
4.09
4.19
3.79
5.51
5.04
4.83
5.70
5.65
5.20
5.27
5.45
5.52
5.49
5.33
5.05
4.38
4.47
3.88
4.24
4.55–4.59
3.97
4.28
3.97
4.91
4.27
4.83
4.46
4.28
4.69
4.40
a 3.29
b 3.10
a 3.12
b 3.37
5.92
5.39
6.00
8.14
8.14
8.18
8.42
13*
15
4.22
5.04
4.13
3.76
4.04
5.37
5.06
7.81
7.59
8.14
a 2.35
b 3.00
a 2.37
b 3.00
5.74 (H-7)
6.95 (7-OH)
5.71 (H-7)
7.08 (7-OH)
16
6.01
*Measured at 50°C.
Table 4. 1H–1H coupling constants (Hz) for 1–13a as measured in DMSO-d6 at 30°C at 500 MHz
Compound
1
2*
3
4
5
6
7
8
9
10
11
12*
13*
2J5a,5b
2J6a,6b
3J1,2
12.7
13.4
11.0
13.1
2.1
6.9
3.0
N.r.
15.3
2.1
7.2
2.0
12.4
2.7
7.2
2.1
N.r.
12.9
1.8
6.5
N.d.
N.r.
13.4
2.2
6.9
N.d.
N.r.
12.6
1.6
7.0
3.2
N.r.
14.8
1.6
7.6
2.7
N.r.
14.8
1.8
7.2
2.2
12.1
N.d.
6.9
2.3
N.r.
12.6
N.d.
7.3
3.3
N.r.
2.4
5.6
2.5
2.7
6.0
N.r.
2.0
4.5
2.8
3J2,3
3J3,4
3J4,5
N.r.
N.r.
3J4,5a
3J4,5b
3J5,6a
3J5,6b
3J2,2-OH
3J3,3-OH
3J4,4-OH
4J1,6b
4J2,5
10.2
3.8
9.5
2.9
12.4
3.4
2.7
2.6
4.5
2.2
2.9
3.2
3.0
2.4
3.0
2.4
3.1
2.3
5.6
2.5
4.7
2.1
3.3
3.0
2.9
2.6
5.7
4.3
5.8
7.2
4.6
5.4
4.9
N.r.
N.r.
4.9
4.8
1.1
0.8
0.8
11.8
4.3
2.2
ꢀ0.5
1.2
3.9
4.5
1.9
0.8
0.8
4.6
4.8
0.7
N.r.
0.9
4.9
4.9
1.0
0.8
0.8
N.r.
N.r.
1.5
N.d.
N.d.
10.8
4.4
1.9
ꢀ0.6
1.1
3.9
4.7
1.1
0.8
0.9
N.r.
N.r.
N.r.
N.d.
N.r.
N.r.
N.r.
0.8
4J3,5
4J1,5a
4J3,5b
5J2,6b
N.r.
N.r.
1.3
0.9
N.r.
0.9
0.9
1.1
0.8
1.1
0.9
N.r.
N.r.
1.1
1.1
1.1
a For coupling constants of 15 and 16 see Section 3.
*Measured at 50°C.
N.r.—not resolved.
N.d.—not determined.
sulfoxide group. One conspicuous conformational fea-
ture of the axial isomers is the observed intramolecular
H-bond between the endo sulfoxide oxygen and the
C(3)-hydroxyl proton (3-OH···OꢀS). This is reflected in
C(3)OH and C(3)H protons as well as in the observed
strong C(3)OHꢁC(1)H and C(3)OHꢁC(4)H NOE
interactions.
3
the large (ꢀ11 Hz) J3,3OH vicinal coupling constant,
The measured vicinal coupling constants (see Table 4)
indicate that the arabinopyranosides 2, 12 and 13 exist
indicating a predominantly trans-arrangement of the

´
E. Bozo´ et al. / Tetrahedron: Asymmetry 12 (2001) 3423–3433
3429
Table 5. 13C NMR data for 1–16 as measured in DMSO-d6 at 30°C at 125 MHz
Compound
Chemical shifts (ppm) relative to TMS (lTMS=0.00 ppm)
C-1
C-2
C-3
C-4
C-5
81.5
C-6
C-1%
C-2%
C-3%
C-4%
CN
Others
1
44.2
48.8
57.7
65.0
60.0
59.5
60.8
75.8
72.9
72.3
58.0
62.5
70.7
81.3
76.0
80.2
73.3
78.6
81.0
74.1
73.8
76.0
73.4
78.0
75.9
75.3
73.8
74.6
44.5
59.4
81.5
72.3
82.4
80.3
80.3
79.2
80.7
81.1
82.0
79.9
80.0
71.8
71.3
79.6
65.7
78.2
79.2
80.5
82.8
80.5
79.8
79.3
79.9
79.5
60.5
62.5
28.5
28.4
26.6
143.1
146.1
139.8
143.3
149.4
148.9
149.1
146.9
148.2
149.8
141.5
144.5
145.4
145.2
150.4
128.3
127.2
128.9
129.1
127.0
128.1
126.7
126.8
126.2
126.5
130.4
128.8
129.1
128.2
127.7
132.5
123.9
132.9
132.1
132.4
132.9
132.9
133.6
133.6
133.0
132.9
123.6
123.6
123.9
123.6
107.9
144.8
109.4
108.1
114.0
114.6
114.0
115.0
114.6
113.5
116.4
145.6
145.7
145.2
149.5
118.6
2a
3
29.2
79.0
81.6
80.9
78.7
81.4
79.1
79.1
81.5
80.8
47.9
51.0
100.6
100.3
43.2
50.3
26.7
26.7
27.3
48.6
48.8
52.2
26.2
118.3
118.6
118.0
118.5
118.6
118.4
118.4
118.1
117.5
4
5
6
7
8
9
10
11
12a
13a
15
16
97.4 (C-7)
96.9 (C-7)
a Measured at 50°C.
Scheme 4.
4
predominantly in the C1 conformation (see Scheme 4)
with the bulky 4-nitro-thiophenyl group oriented equa-
torially. It should be noted that 12 exhibited relatively
analysis of 12 (as well as 2 and 13) was accomplished at
1
50°C where the H signals became sharper.
1
broad H resonances at 30°C (the signals were beyond
In agreement with literature data, the 13C chemical shifts
2
the coalescence point at this temperature) due to confor-
mational exchange that is fast on the NMR chemical shift
timescale, as discussed below. Therefore, the NMR
of C(1) and C(5) are smaller, and the geminal J5a,5b
coupling is larger (see Tables 4 and 5) for 12 (axial
sulfoxide) as compared to 13 (equatorial sulfoxide). The

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E. Bozo´ et al. / Tetrahedron: Asymmetry 12 (2001) 3423–3433
3430
observed downfield shift of C(4)H in 12 relative to either
2 or 13 indicated the operation of the syn-axial effect. The
measured 5.2 ppm 12 and 3.2 ppm 13 upfield shift of C(4)
as compared to that of 2 can be attributed to the g-gauche
and g-anti effect of the sulfoxide oxygen in the 4C1
conformation. It is interesting to note that the presence
of the sulfoxide tends to increase long-range couplings:
W-coupling between C(3)H and C(5)Hb in 12 and 13 as
well as a long-range coupling between C(1)H and C(5)Ha
in 12 can be detected (see Table 4). These couplings are
absent in the starting 2.
2.3.2. Determination of the exo-sulfoxide configuration. In
contrast to the endo-sulfoxide, the configuration of the
exo-sulfoxide could not be established by NMR. There-
fore X-ray crystallographic analysis of 6 was completed
(Fig. 2) revealing the (R)-configuration of the sulfoxide
group. Accordingly the same configuration holds for the
parent compound 5, consequently the other endo sulfox-
ide must have (S)-configuration. The ꢀ2 and 5 ppm
upfield shift of the C(2) carbon observed for the exo-(R)-
sulfoxides 5 and 8 as compared with the exo-(S)-sulfox-
ides 7 and 9 (see Table 5) seems to be diagnostic of the
sulfoxide configuration.
The observed conformational exchange in 12 might be
attributed to a C1l4C1 equilibrium that is moderately
4
2.4. Conclusion
1
fast on the NMR chemical shift timescale. In the C4
conformation the bulkiest 4-nitro-thiophenyl group (as
well as the C(4)OH group) assumes the unfavorable axial
orientation, while the equatorial position of the 4-nitro-
The rules postulated in the literature6,7 for the site of the
oxidation of thiosugar thioglycosides are certainly not
generally valid. Contrary to their predictions the a-gly-
coside 1 gave predominantly the endo-sulfoxides, irre-
spective of the oxidising agent (MMPP or NaIO4),
whereas the b-glycoside 2 afforded exclusively exo-sulf-
oxides in the case of MMPP and the ring scission product
in the presence of NaIO4.
4
thiophenyl group in the C1 conformation comes at the
cost of three axial substituents (SꢀO, C(2)OH, C(3)OH).
Although in the 4C1 conformation there is an unfavorable
1,3-diaxial steric interaction between the oxygen of the
S-oxide and the C(2)OH group, this conformation could
be stabilized by C(2)OH···OꢀS hydrogen bonding. In a
fully H-bonded structure a value of ꢀ11 Hz would be
3
expected with vicinal J2,2-OH coupling (see below). The
2.5. Biological results
observed intermediate value (7.2 Hz) in 12 as compared
to the equatorial sulfoxide 13 (4.9 Hz) can be rationalized
The oral antithrombotic activity of 1, 2, 3, 5, 12, 13, 15
and 16 was determined on rats using Pescador’s model.15
All compounds were administered orally 3 h before
ligation.
4
in terms of the proposed H-bonded C1 conformation
1
and the C4l4C1 equilibrium that is fast on the NMR
chemical shift timescale. In the case of 2 and 13 we did
not observe spectral effects (minor resonances, conspic-
uous line-broadening or NOE effects), consequently the
From the data listed in Table 2 it can be seen that the
biological activity of the oxidation products depend on
both the location (endo/exo) as well as the chirality (R
or S) of the sulfoxide groups but no generally valid
structure–activity relationship could be established. Oxi-
dative cleavage of the sugar ring is accompanied by a
decrease in activity (compare 15 and 16 to the parent
compound 2) (Table 7).
4
1C4l4C1 equilibrium is shifted toward the C1 form.
From 13 a single crystal suitable for X-ray crystallo-
graphic analysis could be grown. The X-ray data showed
that in the solid phase 13 exists in the 4C1 conformation
(Fig. 3 and Table 6) and the sulfoxide oxygen is equato-
rial in agreement with the NMR data.
Figure 3. ORTEP plot (using the program PLATON) of 13. Anisotropic displacement ellipsoids are represented at the 50%
probability level.

´
E. Bozo´ et al. / Tetrahedron: Asymmetry 12 (2001) 3423–3433
3431
Table 6. Crystal data and structure refinement of 13
followed by heating at ca. 200°C. For column chro-
matography Kieselgel 60 was used. Melting points are
uncorrected. Analytical HPLC was carried out on a
SHIMADZU instrument, using WATERS Symmetry-
Shield RP-18 250×4.6 mm S-5 mm column, and the
following eluents: eluent A: 0.1% TFA in water and B:
0.1% TFA in 80% aq. acetonitrile over 35 min with a
gradient of 5–40% B in A. Preparative HPLC was
carried out on a SHIMADZU instrument, using a
WHATMAN Partisil M20 10/50 ODS-3; 22 mm I.D.,
Empirical formula
Formula weight
C11H13NO6S2
319.34
Temperature (K)
Radiation and wavelength
Crystal system
293(2)
Mo-Ka, u=0.71073 A
Monoclinic
,
Space group
P21
Unit cell dimensions
,
a (A)
8.932(1)
6.621(1)
11.556(1)
101.87(1)
668.79(14)
2
,
b (A)
,
c (A)
i (°)
Volume (A )
,
10 mm, 100 A column, eluent 0.1% TFA in water and
0.1% TFA in 80% aq acetonitrile. Optical rotations
were determined at 20°C. The NMR spectra were
recorded on a Varian INOVA™ spectrometer operating
at 500 MHz (1H) and 125 MHz (13C) by using a Varian
5-mm 1H{13C/15N} PFG Indirect NMR™ probe. 1H
and 13C NMR chemical shifts are given relative to TMS
(lTMS=0.00 ppm), as measured in DMSO-d6 at 30°C.
3
,
Z
Density (calculated) (Mg/m3)
Absorption coefficient, v
1.586
0.423
(mm−1
F(000)
)
332
Crystal colour
Yellow
1
Long range H–1H coupling constants were determined
Crystal description
Crystal size (mm)
Absorption correction
Max. and min. transmission
Theta range for data
collection
Prism
0.40×0.20×0.20
psi-scan
0.9826 and 0.9593
2.33°5q534.97°
1
from the resolution enhanced (sinebell apodization) H
1
NMR spectrum. H and 13C NMR assignments were
straightforward by a concerted use of standard high-
field one- and two-dimensional (2D) NMR methods:
1D DPFGSE-NOE (selective excitation by I-Burp2
Index ranges
−145h514; −105k510;
1
shaped pulses) and 2D H–1H as well as 13C–1H shift
−185l518
correlations (PFG-DQFCOSY, PFG-HSQC, PFG-
HMBC). The obtained scalar and NOE connectivities
provided abundant information to ensure unambiguous
spectral assignments.
Reflections collected
Completeness to 2q
Number of standard
reflections
5884
1
3
Decay (%)
10.00
Independent reflections
Reflections I\2|(I)
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I\2|(I)]
R indices (all data)
Absolute structure parameter
Max. and mean shift/esd
5884 [Rint=0.0133]
4500
3.2. Reaction of 1 with magnesium monoperoxyphtha-
late (MMPP)
Full-matrix least-squares on F2
5884/1/181
1.04
To a solution of 116 (1.7 g, 5.75 mmol) in ethanol (170
mL) was added a solution of MMPP (1.9 g, 3.8 mmol)
in water (20 mL) and the mixture was stirred at room
temperature for 1 h. Then the reaction mixture was
concentrated and the residue was submitted to column
chromatography (solvent A, then B). Concentration of
the first fraction gave 4-cyanophenyl 2,5-anhydro-1,6-
R1=0.0341, wR2=0.0815
R1=0.0540, wR2=0.0864
0.02(4)
0.001, 0.000
0.281 and −0.185
Largest diff. peak and hole
−3
,
(e A
)
dithio-a- -glucoseptanoside (6R)-S-oxide (3, 0.79 g,
D
44%): mp 212–215°C (EtOAc); [h]D +143 (c 0.5,
MeOH); Rf 0.6 (solvent B); anal. calcd for
C13H13NO4S2: C, 50.15; H, 4.21; N, 4.50; S, 20.59.
Found: C, 50.22; H, 4.18; N, 4.63; S, 20.67%.
3. Experimental
3.1. General methods
Organic solutions were dried over MgSO4 and concen-
trated under diminished pressure at or below 40°C.
TLC: Merck precoated silica gel 60 F254 plates, with
EtOAc (A), EtOAc–EtOH (B, 9:1), CHCl3–MeOH (C,
9:1) and toluene–acetone (D, 2:1) mixtures; detection
by spraying the plates with a 0.02 M solution of I2 and
a 0.30 M solution of KI in 10% aq. H2SO4 solution
Concentration of the second fraction and subsequent
recrystallization of the residue from acetone gave 4-
cyanophenyl
2,5-anhydro-1,6-dithio-a-D-glucosep-
tanoside (1R)-S-oxide (5, 0.68 g, 38%): mp 172–174°C
(acetone); [h]D +141 (c 0.5, MeOH); Rf 0.45 (solvent B);
anal. calcd for C13H13NO4S2: C, 50.15; H, 4.21; N, 4.50;
S, 20.59. Found: C, 50.06; H, 4.28; N, 4.61; S, 20.55%.
Table 7. Oral antithrombotic activity of 1, 2, 3, 5, 12, and 13 in rats using Pescador’s model15
Compound
1
2
3
5
12
13
15
16
S-Oxidea
–
37
–
43
endo (R)
25
exo (R)
47
endo (R)
43
endo (S)
27
–
34
exo (?)
20
Inhibitionb (%)
a Location and chirality of the sulfoxide group.
b Inhibition % at an oral dose of 2 mg/kg.

´
E. Bozo´ et al. / Tetrahedron: Asymmetry 12 (2001) 3423–3433
3432
The mother liquor was concentrated and separated by
acetone (30 mL) and the mixture was stirred at room
temperature for 1 h. The reaction mixture was filtered,
the filtrate was concentrated and the residue was sepa-
rated by HPLC. Concentration of the first fraction gave
HPLC (WHATMAN Partisil M20 10/50 ODS-3; 22
,
mm I.D., 10 mm, 100 A, eluent 0.1% TFA in water and
0.1% TFA in 80% aq. acetonitrile). Concentration of
the first fraction gave 4-cyanophenyl 2,5-anhydro-1,6-
4-cyanophenyl
2,5-anhydro-1,6-dithio-a-D-glucosep-
dithio-a-
D
-glucoseptanoside (1R)-S-oxide (6R)-S-oxide
tanoside (1R)-S-oxide (6S)-S-oxide (10, 50 mg, 3%):
mp 200–202°C (ether); [h]D −7 (c 0.5, pyridine); Rf 0.25
(solvent B); anal. calcd for C13H13NO5S2: C, 47.70; H,
4.00; N, 4.28; S, 19.59. Found: C, 47.78; H, 4.12; N,
4.35; S, 19.63%.
(8, 26 mg, 1.4%): mp 183–186°C (ether); [h]D −114 (c
0.39, pyridine); Rf 0.4 (solvent B); anal. calcd for
C13H13NO5S2: C, 47.70; H, 4.00; N, 4.28; S, 19.59.
Found: C, 47.82; H, 4.08; N, 4.33; S, 19.67%.
Concentration of the second fraction gave 4-cyanophenyl
Concentration of the subsequent fractions gave 8 (39
mg, 2%), 9 (26 mg, 1.6%), 7 (138 mg, 9%), 5 (780 mg,
51%) and 4 (17 mg, 1%): all of them identical to those
mentioned above.
2,5-anhydro-1,6-dithio-a-
D
-glucoseptanoside
(1S)-S-
oxide (6R)-S-oxide (9, 23 mg, 1.2%): mp 158–161°C
(ether); [h]D +125 (c 0.26, pyridine); Rf 0.45 (solvent B);
anal. calcd for C13H13NO5S2: C, 47.70; H, 4.00; N, 4.28;
S, 19.59. Found: C, 47.65; H, 4.13; N, 4.22; S, 19.50%.
Concentration of the seventh fraction gave 4-cyano-
phenyl 2,5-anhydro-1,6-dithio-a-D -glucoseptanoside
Concentration of the third fraction gave 4-cyanophenyl
1-S-dioxide (11, 26 mg, 1.6%) as an oil: [h]D +98.5
(c 0.26, MeOH); Rf 0.6 (solvent B); anal. calcd for
C13H13NO5S2: C, 47.70; H, 4.00; N, 4.28; S, 19.59.
Found: C, 47.82; H, 4.07; N, 4.35; S, 19.54%.
2,5-anhydro-1,6-dithio-a-
D
-glucoseptanoside
(1S)-S-
oxide (7, 125 mg, 7%): mp 87–91°C (ether); [h]D +311 (c
0.35, MeOH); Rf 0.4 (solvent B); anal. calcd for
C13H13NO4S2: C, 50.15; H, 4.21; N, 4.50; S, 20.59.
Found: C, 50.11; H, 4.13; N, 4.58; S, 20.63%.
Concentration of the eighth fraction gave 3 (46 mg,
3%): identical with the one prepared above.
Concentration of the fourth fraction gave 4-cyanophenyl
2,5-anhydro-1,6-dithio-a-
D
-glucoseptanoside
(6S)-S-
3.6. 4-Cyanophenyl 2,5-anhydro-3,4-di-O-(4-nitroben-
oxide (4, 35 mg, 2%): mp 189–193°C (ether); [h]D +468
(c 0.3, pyridine); Rf 0.3 (solvent B); anal. calcd for
C13H13NO4S2: C, 50.15; H, 4.21; N, 4.50; S, 20.59. Found:
C, 50.19; H, 4.17; N, 4.55; S, 20.54%.
zoyl)-1,6-dithio-a- -glucoseptanoside (1R)-S-oxide 6
D
A mixture of 5 (0.36 g, 1.16 mmol), pyridine (60 mL)
and 4-nitrobenzoyl chloride (3.65 g, 20 mmol) was
stirred at 80°C for 8 h, then cooled to room tempera-
ture and poured into ice-water. The precipitated crys-
tals were filtered off, washed with water and
recrystallized from acetonitrile to give 6 (0.58 g, 82%);
mp 172–175°C (acetonitrile); [h]D −45 (c 1, CHCl3); Rf
0.7 (solvent C); anal. calcd for C27H19N3O10S2: C,
53.20; H, 3.14; N, 6.89; S, 10.52. Found: C, 53.27; H,
3.12; N, 6.80; S, 10.61%.
3.3. Reaction of 5 with magnesium monoperoxyphtha-
late (MMPP)
To a solution of 5 (0.31 g, 1 mmol) in ethanol (30 mL)
was added a solution of MMPP (0.5 g, 1 mmol) in
water (6 mL) and the mixture was stirred at room
temperature overnight. The reaction mixture was con-
centrated and the residue was submitted to column
chromatography (solvent B). Concentration of the first
fraction gave 8 (170 mg, 52%): identical to that
obtained above.
3.7. Reaction of 2 with magnesium monoperoxyphtha-
late (MMPP)
To a solution of 217 (1.3 g, 4.3 mmol) in ethanol (210
mL) was added a solution of MMPP (1.44 g, 2.9 mmol)
in water (15 mL) and the mixture was stirred at room
temperature for 1 h. Then it was concentrated and
water (30 mL) was added to the residue. The precipi-
tated crystals were filtered off and washed with water to
Concentration of the second fraction gave 10 (110 mg,
34%): identical to that obtained above.
3.4. Reaction of 7 with magnesium monoperoxyphtha-
late (MMPP)
give 4-nitrophenyl 1,5-dithio-b-D-arabinopyranoside
To a solution of 7 (50 mg, 0.16 mmol) in ethanol (10
mL) was added a solution of MMPP (80 mg, 0.16
mmol) in water (1 mL) and the mixture was stirred at
room temperature overnight. Then the reaction mixture
was concentrated and the residue was submitted to
column chromatography (solvent B) to give 9 (33 mg,
63%): identical to that obtained above.
(5R)-S-oxide (12, 410 mg, 30%): mp 221–223°C
(water); [h]D −339 (c 0.5, pyridine); Rf 0.4 (solvent C);
anal. calcd for C11H13NO6S2: C, 41.37; H, 4.10; N, 4.39;
S, 20.08. Found: C, 41.29; H, 4.17; N, 4.33; S, 20.17%.
The filtrate was concentrated and the residue was sub-
mitted to column chromatography (solvent C) to give
4-nitrophenyl 1,5-dithio-b-D-arabinopyranoside (5S)-S-
3.5. Reaction of 1 with sodium periodate
oxide (13, 450 mg, 33%): mp 176–178°C (MeOH); [h]D
+131 (c 0.5, MeOH); Rf 0.3 (solvent C); anal. calcd for
C11H13NO6S2: C, 41.37; H, 4.10; N, 4.39; S, 20.08.
Found: C, 41.43; H, 4.18; N, 4.45; S, 20.01%.
To a solution of NaIO4 (1.15 g, 5.4 mmol) in water (35
mL) was added a solution of 1 (1.45 g, 4.9 mmol) in

´
E. Bozo´ et al. / Tetrahedron: Asymmetry 12 (2001) 3423–3433
3433
Acknowledgements
3.8. Reaction of 2 with sodium periodate
The authors are very much indebted to Dr. La´szlo´
Pa´rka´nyi and Dr. Gyula Argay for determining the
X-ray structures and to Dr. Gabriella Szabo´ for the
biological results.
To a solution of NaIO4 (1.15 g, 5.4 mmol) in water (35
mL) a solution of 2 (1.5 g, 5 mmol) in acetone (30 mL)
was added and the mixture was stirred at room temper-
ature for 1 h. Then the reaction mixture was filtered,
the filtrate was concentrated and water (30 mL) was
added to the residue. The precipitated crystals were
filtered off and washed with water to give
(1S,2S,5R,7S)-7-hydroxy-2-(4-nitrophenylthio)-6,8-
dioxa-3-thia-bicyclo[3,2,1]octane (15, 1.25 g, 84%): mp
127–130°C (water); [h]D −312 (c 1, MeOH); Rf 0.7
(solvent C); NMR coupling constants: J4a,4b 13.4, J1,2
2.4, 3J4a,5 2.5, 3J4b,5 1.1, 4J2,4a 1.0, 5J2,5 1.2, 5J1,4a 0.9 Hz.
Anal. calcd for C11H11NO5S2: C, 43.84; H, 3.68; N,
4.65; S, 21.28. Found: C, 43.90; H, 3.73; N, 4.55; S,
21.32%.
References
1. Bozo´, E.; Boros, S.; Kuszmann, J. Carbohydr. Res. 2001,
332, 325–333.
2. Bellamy, F.; Barberousse, V.; Martin, N.; Masson, P.;
Millet, J.; Samreth, S.; Sepulchre, Ch.; The´veniaux, J.;
Horton, D. Eur. J. Med. Chem. 1995, 30, 101–115.
3. Masson, P.; Theveniaux, J.; Coup, D.; Gregoire, T.;
Vaillot, M.; Dupouy, D.; Sie, P.; Boneu, B.; Millet, J.
Thromb. Haemost. 1999, 81, 945–950.
2
3
´
´
4. Szabo´, G.; Bozo´, E.; Baraba´s, E.; Kedves, R.; Csomor,
K.; Kuszmann, J. Drugs Future 1999, 24, 1241–1248.
5. Le Questel, J.-Y.; Mouhous-Riou, N.; Boubia, B.; Sam-
reth, S.; Barberousse, V.; Pe´rez, S. Carbohydr. Res. 1997,
302, 53–66.
3.9. Reaction of 15 with magnesium
monoperoxyphthalate
To a solution of 15 (0.90 g, 3 mmol) in EtOH (180 mL)
a solution of MMPP (1.0 g, 2 mmol) in water (10 mL)
was added and the mixture was stirred at room temper-
ature for 1 h. Then the reaction mixture was concen-
trated and the residue was submitted to column
chromatography (solvent D) to give (1S,2S,5R,7S)-7-
hydroxy - 2 - (4 - nitrophenylsulfinyl) - 6,8 - dioxa - 3 - thia-
bicyclo[3,2,1]octane (16, 0.5 g, 53%): mp 141–143°C
(ether); [h]D −78 (c 0.5, MeOH); Rf 0.4 (solvent D);
6. Yuasa, H.; Hashimoto, H. Tetrahedron 1993, 49, 8977–
8998.
7. Yuasa, H.; Kamata, Y.; Hashimoto, H. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 868–870.
8. Yu, R. J.; Bishop, C. T. Can. J. Chem. 1967, 45, 2195–
2203.
9. Buchanan, G. W.; Durst, T. Tetrahedron Lett. 1975, 21,
1683–1686.
10. Lambert, J. B.; Netzel, D. A.; Sun, H.; Lilianstrom, K.
K. J. Am. Chem. Soc. 1976, 98, 3778–3783.
11. Brunet, E.; Eliel, E. L. J. Org. Chem. 1986, 51, 677–686.
12. Foster, A. B.; Inch, T. D.; Qadir, M. H.; Webber, J. M.
Chem. Commun. 1968, 1086–1089.
2
3
3
NMR coupling constants: J4a,4b 13.3, J1,2 2.3, J4a,5
3
3
4
5
5
2.3, J4b,5 1.2, J7,7-OH 4.7, J2,4a 0.8, J2,5 1.3, J1,4a 0.8
Hz. Anal. calcd for C11H11NO6S2: C, 41.64; H, 3.49; N,
4.41; S, 20.21. Found: C, 41.43; H, 3.48; N, 4.20; S,
20.25%.
13. Allingham, Y.; Cookson, R. C.; Grant, T. A. Tetrahedron
1968, 24, 1989–1995.
Crystallographic data (excluding structure factors) for
the structures 6 and 13 in this paper have been
deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
175687 and CCDC 175688, respectively. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: +44(0)-1223-336033 or e-mail: deposit@ccdc.cam.
ac.uk].
14. Buck, K. W.; Foster, A. B.; Paradoe, W. D.; Dadir, M.
H.; Weber, J. M. J. Chem. Soc., Chem. Commun. 1966,
759–761.
´
15. Bagdy, D.; Szabo´, G.; Baraba´s, E.; Bajusz, S. Thromb.
Haemost. 1992, 68, 125–129.
´
16. Bozo´, E.; Medgyes, A.; Boros, S.; Kuszmann, J. Carbo-
hydr. Res. 2000, 329, 25–40.
´
17. Bozo´, E.; Boros, S.; Kuszmann, J. Carbohydr. Res. 1998,
311, 191–202.