Synthesis of 4-substituted phenyl 3,6-anhydro-1,3-dithio-D-glucofuranosides and -pyranosides as well as 2,6-anhydro-1,2-dithio-α-D-altrofuranosides possessing antithrombotic activity

Article abstract of DOI:10.1016/S0008-6215(00)00218-4

1,2,5-Tri-O-acetyl-3,6-anhydro-3-thio-D-glucofuranose was synthesised starting from D-glucose and was used as a donor for the glycosidation of 4-cyano- and 4-nitrobenzenethiol. In the latter reaction, besides an anomeric mixture of the 4-nitrophenyl 2,5-di-O-acetyl-3,6-anhydro-1,3-dithio-D-glucofuranosides, the corresponding 2,6-anhydro-1,2-dithio-D-altrofuranosides were also obtained, formed via a rearrangement of the sugar moiety. A similar rearrangement could be observed during the hydrolysis of the glycosidic bond of methyl 3,6-anhydro-2,4-di-O-(4-nitrobenzoyl)-3-thio-α-D-glucopyranoside with aqueous trifluoroacetic acid, affording after acetylation besides 1-O-acetyl-3,6-anhydro-2,4-di-O-(4-nitrobenzoyl)-3-thio-α-D-glucopyranose (32α), 1,1,5-tri-O-acetyl-3,6-anhydro-2,4-di-O-(4-nitrobenzoyl)-3-thio-D-glucose, methyl 3,6-anhydro-2,4-di-O-(4-nitrobenzoyl)-3-thio-β-D-glucopyranoside and 1,5-di-O-acetyl-2,6-anhydro-3-O-(4-nitrobenzoyl)-2-thio-α-D-altrofuranose (40). Glycosidation of 4-cyanobenzethiol with 32α in the presence of trimethylsilyl triflate as promoter afforded 4-cyanophenyl 3,6-anhydro-2,4-di-O-(4-nitrobenzoyl)-1,3-dithio-β-D-glucopyranoside as a minor component only, besides 4-cyanophenyl 3,6-anhydro-2-S-(4-cyanophenyl)-4-O-(4-nitrobenzoyl)-1,2,3-trithio-β-D-gl ucopyranoside. When boron trifluoride etherate was used as promoter in the reaction of 32α with 4-cyano- and 4-nitrobenzenethiol, the corresponding β-thioglycosides were obtained, while 40 gave under identical conditions the α anomers exclusively. All thioglycosides obtained after deacylation were submitted to biological evaluation. Among these glycosides, the 4-cyanophenyl 3,6-thioanhydro-1,3-dithio-D-glucofuranoside possessed the strongest oral antithrombotic effect. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0008-6215(00)00218-4

www.elsevier.nl/locate/carres
Carbohydrate Research 329 (2000) 525–538
Synthesis of 4-substituted phenyl
3,6-anhydro-1,3-dithio-
D-glucofuranosides and
-pyranosides as well as
2,6-anhydro-1,2-dithio-a-
D
-altrofuranosides possessing
antithrombotic activityꢀ
a
b
b,
´
Eva Bozo´ , Sa´ndor Boros , Ja´nos Kuszmann *
aGedeon Richter Chemical Works Ltd., PO Box 17, H-1475 Budapest, Hungary
bInstitute for Drug Research, PO Box 82, H-1325 Budapest, Hungary
Received 1 June 2000; accepted 12 July 2000
Abstract
1,2,5-Tri-O-acetyl-3,6-anhydro-3-thio-
donor for the glycosidation of 4-cyano- and 4-nitrobenzenethiol. In the latter reaction, besides an anomeric mixture
of the 4-nitrophenyl 2,5-di-O-acetyl-3,6-anhydro-1,3-dithio- -glucofuranosides, the corresponding 2,6-anhydro-1,2-
dithio- -altrofuranosides were also obtained, formed via a rearrangement of the sugar moiety. A similar rearrange-
ment could be observed during the hydrolysis of the glycosidic bond of methyl 3,6-anhydro-
2,4-di-O-(4-nitrobenzoyl)-3-thio-a- -glucopyranoside with aqueous trifluoroacetic acid, affording after acetylation
besides 1-O-acetyl-3,6-anhydro-2,4-di-O-(4-nitrobenzoyl)-3-thio-a- -glucopyranose (32a), 1,1,5-tri-O-acetyl-3,6-an-
hydro-2,4-di-O-(4-nitrobenzoyl)-3-thio- -glucose, methyl 3,6-anhydro-2,4-di-O-(4-nitrobenzoyl)-3-thio-b- -gluco-
pyranoside and 1,5-di-O-acetyl-2,6-anhydro-3-O-(4-nitrobenzoyl)-2-thio-a- -altrofuranose (40). Glycosidation of
4-cyanobenzethiol with 32a in the presence of trimethylsilyl triflate as promoter afforded 4-cyanophenyl 3,6-anhydro-
2,4-di-O-(4-nitrobenzoyl)-1,3-dithio-b- -glucopyranoside as a minor component only, besides 4-cyanophenyl 3,6-an-
hydro-2-S-(4-cyanophenyl)-4-O-(4-nitrobenzoyl)-1,2,3-trithio-b- -glucopyranoside. When boron trifluoride etherate
D-glucofuranose was synthesised starting from D-glucose and was used as a
D
D
D
D
D
D
D
D
D
was used as promoter in the reaction of 32a with 4-cyano- and 4-nitrobenzenethiol, the corresponding b-thio-
glycosides were obtained, while 40 gave under identical conditions the a anomers exclusively. All thioglycosides
obtained after deacylation were submitted to biological evaluation. Among these glycosides, the 4-cyanophenyl
3,6-thioanhydro-1,3-dithio-D-glucofuranoside possessed the strongest oral antithrombotic effect. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: 3,6-Anhydro-3-thio- -glucofuranosides; 3,6-Anhydro-3-thio-D-glucopyranosides; Rearrangement reactions; Glycosida-
D
tion reactions; Thioglycosides; Oral antithrombotic activity
1. Introduction
ꢀ Orally active antithrombotic thioglycosides, Part XII. For
Part XI, see Ref. [1].
* Corresponding author. Tel.: +36-1-3993300; fax: +36-
1-3993356.
During our search for thioglycosides with
potential oral antithrombotic activity, we
found that some of the conclusions in the
literature, based on previous structure activity
E-mail address: kus13757@helka.iif.hu (J. Kuszmann).
0008-6215/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(00)00218-4

´
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 525–538
526
relationship studies [2] should be reconsidered.
In particular, the statement that the b- -xy-
out in a mixture of acetic acid and 0.1 M
hydrochloric acid at 100 °C. It afforded, after
subsequent acetylation, 12 in satisfactory yield
(72%), containing the a and b anomers in a
ratio of 1:2. Neither the yield, nor the
anomeric ratio was changed significantly
when, instead of 10 its acetylated derivative 11
was submitted to the same reaction condi-
tions. The pure 12a isomer could be separated
from the anomeric mixture by crystallisation,
but for the glycosidation reactions the mixture
was used as donor. The anomeric configura-
tion of 12a was deduced from the optical
rotation ([h]D +213°), which was in good
agreement with the value ([h]D +203°) re-
ported [8] for the corresponding oxygen ana-
logue. A further proof of the anomeric
structures was obtained from the NMR data
of both isomers, which were very similar to
those data [8] for the oxygen analogues, ex-
cept for the shift of H-3 and H-6 which, due
to the attached sulfur atom, appeared with an
expected upfield shift (H-3=4.75“3.75; H-
6= ꢀ3.9“ ꢀ3.0).
D
lopyranose configuration of the carbohydrate
moiety, as well as the presence of the ring
sulfur atom (1) is vital for biological activity.
According to our findings, other 5-thio-pen-
topyranosides [3] and even 5-thio-glucopyran-
osides 2 [4], as well as glycosides with over-
bridged bicyclic [2,2,2] structures like 3 pos-
sess significant antithrombotic activity [5]. In
the latter, the ring oxygen is not replaced by
sulfur, but an additional sulfur atom is intro-
duced into the molecule via a 2,6-thioanhydro
bridge. For studying the scope and limitations
of this alteration, the synthesis of thiogly-
cosides derived from 3,6-thioanhydro- -glu-
D
cose, which might form furanosides 4 as well
as pyranosides 5, was decided (Scheme 1).
2. Results and discussion
Synthesis of the furanosides.—For the syn-
thesis of the corresponding thioglycosides the
bicyclic triacetate 12 was needed as donor,
For the glycosidation reaction the furanose
triacetate 12 was used as donor, 4-cyanoben-
zenethiol as acceptor and trimethylsilyl triflate
as promoter. The mixture of the formed
anomeric thioglycosides was separated by
column chromatography affording 13a (8%)
and 13b (72%). When 4-nitrobenzenethiol was
used as aglycon and boron trifluoride etherate
as promoter, a complex mixture was formed
that contained according to NMR spec-
troscopy, besides the expected two anomers
14a and 14b, two further isomers, the anomers
which was obtained from
D
-glucose by con-
verting it according to the literature [6,7] in six
steps into the 3-O-mesyl-allofuranose deriva-
tive 6 (Scheme 2). The primary OH group of 6
was selectively tosylated, but attempts to ex-
change the tosyloxy group of the obtained
tosylate 7 by thioacetate resulted in a mixture,
due to the presence of the free 5-OH group,
which might interfere with the substitution
reaction. In order to avoid any unwanted
side-reaction, the OH group of 7 was pro-
tected by acetylation. The resulting mixed es-
ter 8 could be smoothly converted with
potassium thioacetate in N,N-dimethylfor-
mamide into the 6-S-acetate 9, which on treat-
ment with methanolic sodium methoxide
afforded the crystalline 3,6-thioanhydro
derivative 10 in high yield (82%). Hydrolysis
of the isopropylidene group of 10 was carried
of 3,5-di-O-acetyl-2,6-anhydro-2-thio- -altro-
D
furanoside (23a) and (23b). Despite the fact
that this mixture of isomers could only be
partly separated by column chromatography,
yielding a 2:1 mixture of 14a+23a (9%), a 2:3
mixture of 23a+23b (4%) and pure 14b
(68%), the structure of every component was
Scheme 1.

Table 1
1
Selected H NMR data for solutions in CDCl3
Compound Chemical shift l
H-1
5.68
5.80
H-2
4.71
H-3
4.65
H-4
4.12
H-5
5.12
5.21
H-6a
4.05
3.03
2.81
H-6b
4.18
3.37
2.91
Others
8
9
1.28; 1.48 (6 H, CMe2); 3.07(3 H, Ms); 1.94 (3 H, Ac); 2.38
(3 H, Ts-Me)
1.37; 1.58 (6 H, CMe2); 3.16 (3 H, Ms); 2.09 (3 H, OAc); 2.34
(3 H, SAc)
4.70–4.85 4.70–4.85 4.22
10
11
6.00
6.06
6.58
6.25
6.50
5.97
5.67
6.01
5.70
5.90
5.56
5.48
5.66
5.25
5.50
5.64
5.87
6.02
5.27
5.45
5.30
6.73
5.80
5.62
5.84
5.69
6.90
6.51
5.88
5.94
5.83
5.98
5.89
4.66
4.66
5.25
5.23
5.22
5.46
5.34
5.46
5.35
4.32
4.24
4.22
4.30
4.16
4.23
4.26
3.56
3.44
5.08
5.31
5.18
5.36
5.58
4.05
5.58
4.08
5.66
3.53
4.12
3.72
3.35
3.70
3.36
3.76
3.78
3.75
3.52
3.22
3.78
3.78
3.79
3.77
3.62
3.58
3.55
3.62
3.49
3.55
3.60
5.14
5.25
3.85
4.24
4.14
4.32
4.30
3.38
4.32
3.40
4.18
5.42
4.08
5.51
4.06
5.52
4.07
4.83
4.97
5.02
4.25
5.13
5.08
1.32; 1.52 (6 H, CMe2)
2.90–3.10 2.90–3.10 1.31; 1.50 (6 H, CMe2); 2.12(3 H, Ac)
2.92–3.08 2.92–3.08 2.08-2.15,3 (9 H, Ac)
12a
12b
12b b
13a
13b
14a
14b
16 a
17 a
18 a
19 a
20 a
21 a
22 a
23a
23b
25
5.03–5.14 5.03–5.14 2.95–3.15 2.95–3.15 2.08-2.15,3 (9 H, Ac)
4.80–5.00 4.80–5.00 3.13 2.68 1.51; 1.55; 1.63 (9 H, Ac)
2.90–3.12 2.90–3.12 2.08; 2.15 (6 H, Ac)
3.28 3.06 2.08; 2.11 (6 H, Ac)
5.10
5.06
5.12
5.10
/
5.05–5.18 5.05–5.18 2.95–3.10 2.95–3.10 2.10; 2.15 (6 H, Ac)
5.08
4.72
4.74
4.71
4.78
4.63
4.72
4.76
4.70
4.52
5.11
4.08
4.08
4.08
4.12
4.05
4.08
4.10
5.04
5.08
3.27
3.07
2.11; 2.12 (6 H, Ac)
2.65–2.85 2.65–2.85 6.18 (2-OH); 5.32 (5-OH)
2.90
2.94
2.88
2.96
2.94
2.90
2.67
2.76
2.75
2.75
2.77
2.78
6.02 (2-OH); 5.32 (5-OH)
6.00 (2-OH); 5.32 (5-OH); 3.79 (3 H, OMe); 8.95 (1 H, NH)
6.06 (2-OH); 5.33 (5-OH)
5.88 (2-OH); 5.25 (5-OH); 10.00 (1 H, NH); 2.04 (3 H, Ac)
6.00 (2-OH); 5.31 (5-OH); 9.47; 9.83 (2 H, NH2)
2.09 (3 H, SMe)
329
)
2.80–2.90 2.80–2.90 2.02; 2.15 (6 H, Ac)
3.28
2.86
3.05
3.21
3.11
3.22
3.15
2.96
3.15
2.98
2.05; 2.08 (6 H, Ac)
3.56 (3 H, OMe) 2.10; 2.18 (6 H, Ac)
3.61 (3 H, OMe)
3.59 (3 H, OMe)
2.08 (3 H, Ac)
2
4.65–4.78 4.65–4.78 2.97
26a
26b
32a
35
5.03
4.93
5.09
5.20
4.10
5.20
4.13
6.02
4.86
5.35
4.87
4.30
4.87
4.32
4.97
4.83
4.97
4.96
4.44
4.97
4.46
5.42
5.06
4.92
5.15
3.74
5.15
3.77
3.14
3.31
3.28
3.80
3.18
3.78
3.17
538
36 a
37
6.00–6.08 (2 H, OH-2,4)
6.03–6.13 (2 H, OH-2,4)
38 a
39
2.95–3.10 2.95–3.10 1.94; 1.94; 2.00 (9 H, Ac)
2.92
3.81
2.80–3.00 2.80–3.00 2.18 (3 H, Ac)
2.64 2.60 5.78; 5.35 (2 H, OH-3,5)
2.85–3.00 2.85–3.00 2.13 (3 H, Ac)
2.68 2.62 5.80; 5.36 (2 H, OH-3,5)
40
42
2.85
3.18
2.01; 2.09 (6 H, Ac)
43
44 a
45
46 a

Table 1 (Continued)
Coupling constants (Hz)
3J1,2
3J2,3
3J3,4
3J4,5
3J5,6a
3J5,6b
2J6a,6b
Others
8
9
10
11
3.4
3.6
3.2
3.4
4.4
ꢀ0
ꢀ0
4.1
ꢀ0
4.2
ꢀ0
3.3
ꢀ0
ꢀ0
ꢀ0
1.5
1.2
ꢀ0
ꢀ0
3.9
2.7
2.4
4.6
nd
0
8.3
8.0
4.4
3.9
5.6
5.0
5.6
4.9
4.6
4.9
4.6
4.6
4.6
4.6
4.6
4.9
4.6
4.6
ꢀ0
ꢀ0
3.7
3.7
ꢀ3.5
4.2
4.5
4.2
4.1
ꢀ4.5
4.4
ꢀ0
4.6
ꢀ0
ꢀ0
ꢀ0
ꢀ0
6.6
5.4
3.2
2.9
3.9
nd
nd
nd
nd
nd
5.9
8.5
3.7
3.9
6.6
(7.1)
(7.1)
nd
6.4
(6.8)
6.6
nd
6.5
(6.6)
6.3
6.4
6.3
6.3
6.1
(6.6)
(6.1)
5.8
4.4
4.4
4.9
4.4
4.4
3.9
4.4
3.9
(8.4)
6.1
4.4
(7.8)
(6.1)
(7.7)
(5.9)
11.2
14.4
10.3
ꢀ10.0
nd
10.3
(10.0)
(8.8)
nd
10.0
(10.2)
9.8
0
12a
12b
12b b
13a
13b
14a
14b
16 a
17 a
18 a
19 a
20 a
21 a
22 a
23a
23b
25
3.4
ꢀ0
ꢀ0
1.2
ꢀ0
1.7
ꢀ0
ꢀ1
ꢀ0
ꢀ0
ꢀ0
ꢀ0
ꢀ0
ꢀ0
1.0
0.7
3.6
3.6
nd
10.0
10.2
9.8
nd
9.8
ꢀ10
10.0
10.0
9.8
9.5
9.5
nd
nd
10.2
(9.7)
10.0
10.0
10.0
10.1
10.0
(9.8)
(8.3)
10.3
ꢀ0
ꢀ0
ꢀ0
ꢀ0
ꢀ0
ꢀ0
ꢀ0
ꢀ0
(8.4)
9.8
/
ꢀ4
3.5
3.5
3.4
3.4
3.4
3.7
ꢀ0
ꢀ0
nd
3.0
ꢀ3.5
2.1
3.2
2.9
3.2
ꢀ3.0
3.4
ꢀ0
2.2
ꢀ0
ꢀ0
ꢀ0
ꢀ0
J2,OH 5.4; J5,OH 6.6
J2,OH 4.2; J5,OH 5.9
J2,OH 4.2; J5,OH 5.9
J2,OH 4.2; J5,OH
6
J2,OH 3.9; J5,OH 5.8
ꢀ9.8
nd
329
12.5
12.5
12.5
11.7
12.6
12.2
11.7
12.2
11.7
nd
12.6
12.0
nd
12.7
nd
J1,3 1.0
(
26a
26b
32a
35
ꢀ3.0 3.5
2.9
ꢀ0
1.4
ꢀ0
1.2
5
3.4
2.7
2.5
2.7
ꢀ3.0
9.5
ꢀ0
1.5
ꢀ0
ꢀ0
ꢀ0
ꢀ0
J2,4 0.8; J3,5 1.0
J2,4 0.8
538
36 a
37
38 a
39
2.7
40
42
ꢀ0
ꢀ0
ꢀ0
ꢀ0
ꢀ0
ꢀ0
ꢀ0
J2,4 0.8
43
(7.8)
(9.3)
(7.7)
(9.3)
44 a
45
J3,OH 2.2; J5,OH 5.2
J2,4 0.8
J3,OH 2,4; J5,OH 4.8
46 a
12.7
a In Me2SO-d6.
b In benzene-d6; nd, not determined; values in parentheses, not first-order spin systems.

´
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 525–538
529
Table 2
Selected 13C NMR data for solutions in CDCl3
Compound Chemical shift l
C-1
C-2
C-3
C-4
C-5
C-6 Others
8
9
104.0 69.7 a 74.5 a 77.3 a 77.3 a 67.4 113.9; 26.5; 26.6 (CMe2); 38.9 (Ms); 169.9; 20.6 (Ac); 21.5 (Ts-Me)
104.0 70.5 a 77.0 a 77.2 a 77.3 a 29.6 113.8; 26.5; 26.6 (iCMe2); 39.0 (Ms); 170.0; 20.7 (OAc); 194.4; 30.4
(SAc)
10
11
106.4 77.3 a 49.6 84.6 a 88.0 a 34.1 113.1; 26.8; 27.3 (CMe2)
106.5 76.2 a 49.3 82.1 a 86.5 a 30.1 112.3; 26.3; 26.8 (CMe2); 169.8; 20.4 (Ac)
95.7 80.4 48.3 81.5 76.0 31.0 169.0; 169.4; 170.2; 20.4; 20.7; 20.8 (Ac)
101.1 83.1 48.0 83.1 76.4 30.8 169.1; 169.2; 170.1; 20.6; 20.7; 20.9 (Ac)
102.0 84.6 49.2 85.6 77.8 32.0 169.5; 169.7; 170.5; 20.8; 20.9; 21.1 (Ac)
89.5 81.2 a 49.6 82.2 a 76.6 31.0 169.4; 170.2; 20.5; 20.8 (Ac)
91.9 84.6 a 49.1 85.0 a 76.1 31.6 169.3; 170.1; 20.6; 20.7 (Ac)
89.3 81.3 a 49.7 82.3 a 76.7 31.1 169.4; 170.2; 20.5; 20.9 (Ac)
92.5 48.7 78.5 84.3 72.3 25.3 169.7; 169.8; 20.8; 20.9 (Ac)
89.8 47.4 79.5 84.2 72.0 27.4 169.7; 169.8; 20.8; 20.9 (Ac)
95.5 69.5 a 40.5 73.2 a 74.2 a 29.2 57.8, q (OMe) 169.8; 170.7; 20.8; 21.0 (Ac)
95.6 71.3 a 40.5 74.2 a 74.5 a 29.2 57.8, q (OMe)
12a d
12b
12b b,c
13a
13b
14a
23a
23b
25
26a
26b
32a d
35
99.8 75.3 a 39.2 72.7 a 73.9 a 31.1 56.8, q (OMe)
86.9 70.8 40.2 74.2 75.3 28.7 168.3; 20.6 (Ac)
82.8 76.5 a 39.4 73.7 74.6 a 30.6
36 b
37
85.4 76.2 43.3 73.7 76.2 31.8
82.5 76.4 a 39.4 73.7 74.6 a 30.6
38 b
39
85.2 76.3 a 43.2 73.7 76.0 a 31.8
86.9 75.0 a 44.4 73.7 72.3 a 29.4 168.0; 168.2; 169.9; 20.4; 20.5; 20.5 (Ac)
100.6 46.2 79.0 84.3 72.0 25.4 169.1; 169.7;20.8; 20.9 (Ac);
85.8 52.6 42.7 73.1 74.1 31.3
40 d
42 d
43
92.8 48.7 79.4 84.3 72.3 25.3
91.4 50.4 77.1 90.0 70.5 27.7
92.7 48.7 79.6 84.4 72.4 25.4
91.1 50.4 77.1 89.9 70.5 27.7
44 b
45
46 b
a Arbitrary assignment.
b In Me2SO-d6.
c In benzene-d6
d A heterocorrelation spectrum was recorded.
unambiguously established by NMR spec-
group attacks C-3 (15). This will result in the
formation of the 2,6-thioanhydro derivatives
with migration of the involved acetoxy group
from C-2 to C-3. As a consequence, the chiral-
ity of both C-2 and C-3 will be inverted,
consequently the configuration of the fura-
1
troscopy. From H NMR double resonance
experiments it was evident that in 23a and 23b
the thioanhydro bridge was shifted from C-3
to C-2 and an acetoxy group was attached to
C-3 (H-2=5.46“3.56 ppm, H-3=3.79“
5.14 ppm, for the corresponding 13C NMR
data see Table 2). Further NMR data (Tables
1–4), which proved the change in configura-
tion, will be discussed in detail later, together
with those of the 3-O-(4-nitrobenzoyl) ana-
logue 45.
The formation of 23 from 14 can be ex-
plained via a transannular participation reac-
tion of the sulfur atom of the 3,6-thioanhydro
bridge, which attacks C-2 while simulta-
neously the carbonyl group of the 2-O-acetyl
nosides changes from
(Scheme 2).
D
-gluco to
D
-altro
Zemple´n deacetylation of 13a afforded 16,
whereas 13b gave under the same conditions
besides 17 (58%) the corresponding 4-
(imino)(methoxy)phenyl glycoside (18) (15%).
The 4%-cyano group of 17 could be converted
by standard methods [9] into the 4%-aminothio-
carbonyl derivative 21, which on methylation
afforded 22. These transformations, by which
the antithrombotic activity of 1 could be in-

´
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 525–538
530
creased [9], had an opposite effect in the
present case (see Table 5).
Deacetylation of the 4-nitrophenyl analogue
14b gave 19, the nitro group of which was
reduced with sodium borohydride to give after
acetylation and selective O-deacetylation the
corresponding 4%-acetamidophenyl thioglyco-
side 20.
Table 3
NMR–NOE difference data
Compound
Saturated signal
Intensity enhancement (%)
H-1
H-2
H-3
H-4
H-5
H-6a
H-6b
Others
25
32a
35
37
38
39
40
H-1
H-1
H-1
H-1
H-1
H-3
H-1
H-2
H-3
H-4
H-1
H-1
H-2
H-3
H-4
8.2
10.7
4.2
4.5
5.0
5.0
6.0
3.56 ppm 3.4%
7.60 ppm 4.5%
7.68 ppm 4.8%
7.64 ppm 7.0%
2.2
3.3
2.4
4.3
9.9
2.5
4.0
4.5
4.1
4.0
2.4
3.5
6.4
2.0
42
43
6.0
4.1
7.58 ppm 9.0%
7.60 ppm 7.0%
4.2
5.6
3.3
5.5
3.2
7.7
3.9
Scheme 2.

´
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 525–538
531
Table 4
Long-range heteronuclear correlations determined by selective INEPT measurements a
1
Compound
Pulsed H signal
Signals that appeared in the selective INEPT spectrum
C-1
C-2
+
C-3
C-4
C-5
C-6
Others
32a
H-1
H-2
H-4
H-5
H-1
H-1
H-2
H-4
H-5
H-1
H-2
H-3
H-4
H-5
H-1
H-2
H-3
H-4
H-5
H-1
H-3
168.3
163.7
164.2
+
+
+
+
+
+
+
+
35
39
+
+
143.9
168.0; 168.2
163.4
+
+
163.5
+
+
+
+
169.9
169.1
40
42
43
+
+
+
+
+
+
+
163.4
+
+
+
+
+
169.7
143.7
142.6
+
+
+
+
+
+
+
+
+
+
+
+
164.1
+
+
+
+
142.6
163.3
a The pulse sequence was optimized for the 6 Hz heteronuclear coupling constant.
Table 5
Oral antithrombotic activity of 4-substituted phenyl 3,6-anhydro-1,6-dithio-
2,6-anhydro-1,6-dithio-a- -altrofuranosides in rats using Pescador’s model [15]
D
-glucofuranosides and pyranosides, as well as
D
a
Compound
Ref
17
19
20
21
22
36
38
44
46
C-4%ꢀR
CN
50
CN
51
NO2
26
NHAc
27
CSNH2
13
CNHSMe
38
CN
35
NO2
17
CN
39
NO2
24
b
Inhibition (%)
a 4-Cyanophenyl 2,6-anhydro-1,2-dithio-b-
D-mannopyranoside [5] was chosen as reference compound.
b Inhibition % at an oral dose of 2 mg/kg.
Synthesis of the pyranosides.—For their
synthesis, the triacetate 29 was needed as
donor. The corresponding methyl pyranoside
24 (Scheme 3), as well as its hydrolysis with
aqueous trifluoroacetic acid has already been
described in the literature [10]. Nevertheless,
the free sugar (27) was not characterised but
reduced immediately into the corresponding
thioanhydro-hexitol. When we converted this
free sugar into its peracetate, instead of 29, its
furanoside 12 was obtained. That means that
similarly to the oxygen analogues [11], the
thioanhydro pyranose 27 = furanose 33 equi-
librium is completely shifted towards the lat-
ter. In order to avoid this isomerisation, the
free hydroxyl groups of 24 were blocked by
acetylation, but hydrolysis of the glycosidic
bond of the resulting diacetate 25 was also
accompanied by isomerisation, affording, af-
ter acetylation, exclusively 12. That means
that the acetyl group at O-4 could not with-
stand the influence of the aqueous tri-
fluoroacetic acid. As the stability of ester
groups towards acids can be increased by
applying electron-withdrawing substituents
[12], the methyl pyranoside was converted into
the corresponding 2,4-di-O-(4-nitrobenzoate)
26. According to thin-layer chromatography
(TLC), a longer reaction time (24 h) was
needed for the complete hydrolysis of the
glycosidic bond of 26 compared with the ace-
tate 25 (4 h), and a mixture of several compo-

´
532
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 525–538
Scheme 3.
nents was obtained from which after acetyla-
tion three compounds, the rearranged 2,6-
thioanhydro-altrofuranose derivative 40, the
on C-3 with a simultaneous shift of the
thioanhydro bridge from C-3 to C-2, as sug-
gested for the formation of 23, yielding after
acetylation 40. The location of the O-(4-ni-
trobenzoyl) group at C-3 of 40 was proven by
NMR spectroscopy using HETCOR, as well
as selective INEPT and NOE measurements
(Tables 1–4). The latter also proved the a-po-
sition of the 1-O-acetyl group, as a strong
NOE intensity enhancement was detected on
H-6ax on irradiating H-1. The reaction time of
the hydrolysis of 26 could be shortened to 8 h
without influencing the ratio or the yield of
32a (38%), 39 (11%) and 40 (23%), but in
addition some of the b anomer 26b (12%) of
the starting methyl glycoside could be sepa-
rated. That means that the hydrolysis of the
glycosidic bond of 26 is accompanied by an
anomerisation process, and the corresponding
monocyclic 3,6-thioanhydro- -glucose deriva-
D
tive 39, as well as the 1-acetate 32a of the
needed pyranose donor molecule were isolated
by column chromatography in a ratio of 2:1:4.
The formation of the triacetate 39 means that
the hemiacetal ring of the intermediate 30 is
not stable and is at least partially opened
leading to the aldehyde-hydrate, which is then
acetylated. The formation of 40 can be ex-
plained in the following way. During the hy-
drolysis of the glycosidic bond of 26, the
4-O-(4-nitrobenzoyl) group of the intermedi-
ate 30 is partially split off affording 31, which
rearranges to the furanose derivative 34. This
latter undergoes a further rearrangement via
an attack of the 2-O-(4-nitrobenzoyl) group

´
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 525–538
533
b anomer is less prone to hydrolysis. The
chirality of C-1 in 26b as well as in 32a could
be established unambiguously by NMR spec-
troscopy, as in the former a long-range cou-
pling between H-1 and H-3 (4J1,3 1 Hz) proved
the equatorial arrangement of these protons,
while in 32a a strong NOE effect (6.0%) was
detected at H-6a on irradiating H-1.
products resulting from a Ritter reaction [14]
could be detected. Deacylation of 35 accord-
ing to Zemple´n afforded 36. When 4-nitroben-
zenethiol was glycosylated with 32a using
boron trifluoride etherate as promoter, the
corresponding b-thioglycoside 37 was ob-
tained in 57% yield and afforded after deacy-
lation 38. It should be mentioned that,
according to NMR spectroscopy, the bulky
aglycon is forced in a quasi equatorial posi-
tion, due to the presence of the 3,6-thioanhy-
dro bridge. As a consequence, the dihedral
angle between H-1 and H-2 approaches 90%,
resulting in the observed small coupling con-
stant (J1,2 1.2 Hz).
When the pyranose acetate 32a was used as
donor for the glycosidation of 4-cyanoben-
zenethiol in the presence of trimethylsilyl tri-
flate as promoter, the corresponding b-
thioglycoside 35 was formed in a very low
yield (15.5%) and a further product 42
(35.7%), containing
a
second 4-cyano-
phenylthio moiety attached to C-2 could be
separated by column chromatography. The
structure of 42 was evident comparing its
NMR data with that of 35, as in the 13C
spectra the signal of C-2 was shifted from 76.5
to 52.6 ppm, due to the change of the CꢀO
Condensation of the altrofuranose 1-acetate
40 with 4-cyano- and 4-nitrobenzenethiol in
the presence of boron trifluoride etherate af-
forded the corresponding a anomers 43 and
45 in high yield (85 and 87%), which gave 44
and 46, respectively, on deacetylation. The
exclusive formation of the a anomers is not
surprising, as the presence of the space-
demanding 2,6-thioanhydro bridge prevents
the approach of the bulky aglycon from the
b-side. The structure of these 2,6-thioanhydro
derivatives was established by NMR spec-
troscopy comparing the data of 43, 45 and the
diacetate anomers 23a and 23b with those of
the corresponding 3,6-thioanhydro derivatives
35 and 37. The shift of the thioether bridge
1
bond into a CꢀS one. As in the H spectra of
both 35 and 42, a long-range coupling be-
tween H-2 and H-4 could be detected (4J2,4 0.8
Hz), these protons are diequatorially ar-
ranged, consequently both compounds possess
the -gluco configuration. The retention of the
D
chirality at C-2 in 42 can be explained via a
cyclic sulfonium ion intermediate 41, which
can be formed from 35 via elimination of the
activated 2-O-(4-nitrobenzoyl) group with in-
version of configuration. The so formed
strained sulfonium ion 41 can be attacked
from the a-side only, leading to 42 with reten-
tion of the original configuration at C-2. An
attack of the thiolate moiety at C-3 of 41 is
less favoured because of the cis relation with
the bulky substituent at C-4 (Scheme 3). As
the yield of 35 could not be increased by
altering the reaction conditions, boron tri-
fluoride etherate was chosen as promoter,
which is a weaker Lewis acid than trimethylsi-
lyl triflate and should therefore not activate
the 2-O-(4-nitrobenzoyl) group. According to
the literature [13], this promoter afforded the
corresponding O-glucoside in low yield only
when 4-cyano phenol was the acceptor be-
cause of a Ritter reaction of the cyano group.
In our case, however, the reaction of acetate
32a with 4-cyanobenzenethiol yielded the thio-
glycoside 35 with a yield of 47%, and no
1
from C-3 to C-2 is evident from both the H
and the 13C spectra (Tables 1 and 2). The altro
configuration of the skeleton was proven by
the long-range (4J2,4 0.8 Hz) coupling existing
between H-2 and H-4 and the NOE difference
measurements, as in 43 the intensity of H-5
was enhanced by 7.7% on irradiating H-3
(Table 3).
Biological results.—The oral antithrom-
botic activity of 17, 19, 20, 21, 22, 36, 38, 44
and 46 was determined on rats using Pes-
cador’s model [15] and 4-cyanophenyl 2,6-
anhydro-1,2-dithio-b- -mannopyranoside (3-
D
type compound) [5] as reference. All com-
pounds were administered orally 3 h before
ligation. From the data listed in Table 5, it
can be seen that while 17 was as active as the
reference compound, all other derivatives pos-
sessed a less pronounced biological activity. It
is worthwhile mentioning that the 4-cyano-

´
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 525–538
534
5-O-Acetyl-1,2-O-isopropylidene-3-O-metha-
nesulfonyl-6-O-p-toluenesulfonyl-h- -allofura-
phenyl thioglycosides (17, 36 and 44) were
about twice as active as the correspond-
ing 4-nitrophenyl derivatives (19, 38 and 46,
respectively).
D
nose (8).—To a stirred soln of 6 (14.8 g, 50
mmol) in pyridine (150 mL), TsCl (11.4 g, 60
mmol), and after 1 h, Ac2O (15 mL) were
added at 0 °C. The mixture was kept at 20 °C
for 8 h and was then processed the usual way.
The residue, obtained on concentration of the
CH2Cl2 soln (22 g, 89%) was pure enough for
subsequent reactions. Pure 8 could be ob-
tained by column chromatography (solvent
B); [h]D +60°; Rf 0.5 (solvent B); Anal. Calcd
for C19H26O11S2: C, 46.15; H, 5.30; S, 12.97.
Found: C, 46.02; H, 5.44; S, 12.83.
3. Experimental
General methods.—Organic solns were
dried over MgSO4 and concd under dimin-
ished pressure at or below 40 °C. TLC: E.
Merck precoated Silica Gel 60 F254 plates,
with EtOAc (A), EtOAc–hexane mixtures (B,
1:1; C, 1:2; D, 1:3, E, 1:4, F, 2:1), EtOAc–
EtOH mixture (G, 19:1), and toluene–MeOH
mixture (H, 4:1); detection by spraying the
plates with a 0.02 M soln of I2 and a 0.30 M
soln of KI in 10% aq H2SO4 soln, followed by
heating at ca. 200 °C. For column chromatog-
raphy, Kieselgel 60 was used. Melting points
are uncorrected. Optical rotations were deter-
mined on 1.0% solns in CHCl3 at 20 °C unless
stated otherwise. NMR spectra were recorded
with a Bruker AC 250 at 250 MHz (1H) and
62.9 MHz (13C) or with a Varian XL-400
spectrometer MHz (1H) and 100 MHz (13C) or
for solns in CDCl3 (internal Me4Si) unless
stated otherwise. Multiplicities of the 13C
NMR spectra were obtained from DEPT ex-
periments. The assignment of the protons
were based on homonuclear decoupling. Con-
nectivities between identified protons and pro-
tonated carbons were observed by means of
HETCOR experiments. The ratio of a:b
anomeric mixtures was determined by 1H
NMR.
5-O-Acetyl-6-S-acetyl-1,2-O-isopropylidene-
3-O-methanesulfonyl-6-thio-h- -allofuranose
D
(9).—A stirred soln of crude 8 (22 g) and
KSAc (5.3 g) in DMF (100 mL) was heated at
100 °C for 1 h. The residue, obtained on con-
centration was dissolved in CH2Cl2, washed
with water, dried, filtered over charcoal and
concd. The residue was dissolved in ether (50
mL) and hexane (200 mL) was added gradu-
ally when crystallisation took place. The pre-
cipitate was filtered and washed with hexane
to give 9 (16 g, 90%); mp 132–134 °C; [h]D
+121°; Rf 0.6 (solvent B); Anal. Calcd for
C14H22O9S2: C, 42.20; H, 5.57; S, 16.09.
Found: C, 42.22; H, 5.54; S, 15.98.
3,6-Anhydro-1,2-O-isopropylidene-3-thio-h-
-glucofuranose (10).—To a stirred soln of 9
D
(8 g, 20 mmol) in CH2Cl2 (80 mL) and MeOH
(80 mL), 4.5 M methanolic NaOMe (5 mL
22.5 mmol) was added at 20 °C. The mixture
was concd after 30 min, the residue dissolved
in CH2Cl2, washed with water and concd. The
solid residue was filtered with ether–hexane to
give 10 (3.6 g, 82%); mp 116–118 °C; [h]D
+71°; Rf 0.4 (solvent C); Anal. Calcd for
C9H14O4S: C, 49.53; H, 6.47; S, 14.69. Found:
C, 49.48; H, 6.44; S, 14.55.
1,2-O-Isopropylidene-3-O-methanesulfonyl-
h-
D
-allofuranose (6).—To a soln of 1,2:5,6-di-
-allofuranose
O-isopropylidene-3-O-mesyl-
D
[6] (24 g) in MeOH (240 mL), 1 M HCl (24
mL) was added at 50 °C. The mixture was
kept at 50 °C for 30 min and was neutralized
after cooling with solid NaHCO3. The residue
obtained on concentration was dissolved in
acetone, filtered, and Silica Gel 60 (100 g) was
added to the filtrate. The slurry was concd to
dryness, and the residue was washed with
EtOAc to yield, after concentration, 6 (18 g,
85.7%) as a syrup. [h]D +81°; Lit. [7]: [h]D
+84° (c 0.28, CHCl3).
5-O-Acetyl-3,6-anhydro-1,2-O-isopropyli-
dene-3-thio-h- -glucofuranose (11).—Acetyla-
D
tion of 10 (4.4 g) with Ac2O (5 mL) in
pyridine (10 mL) afforded after usual process-
ing and column chromatography (solvent E)
11 (4.8 g, 93%) as a syrup; [h]D +107°; Rf 0.8
(solvent C); Anal. Calcd for C11H16O5S: C,
50.76; H, 6.20; S, 12.32. Found: C, 50.52; H,
6.34; S, 12.14.

´
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 525–538
535
phenyl 3,5-di-O-acetyl-2,6-anhydro-1,2-dithio-
-altrofuranoside (23).—To a stirred soln of
1,2,5-Tri-O-acetyl-3,6-anhydro-3-thio- -
D
D
glucofuranose (12).—(i) A soln of 10 (4.4 g) or
11 (5 g) in AcOH (16 mL) and 0.1 M HCl (16
mL) was kept at 100 °C for 10 min. The soln
was cooled, then NaHCO3 (0.6 g) was added
gradually to neutralise the HCl and was then
concd. The residue was dissolved in Ac2O (15
mL), heated at 100 °C for 10 min to give after
usual processing and column chromatography
(solvent C) of the residue 12 (4.4 g, 72%) as a
semi-solid residue, which according to NMR
spectroscopy contained 12a and 12b in a ratio
of ꢀ1:2; Rf 0.3 (solvent C). Anal. Calcd for
C12H16O7S: C, 47.36; H, 5.30; S, 10.54. Found:
C, 47.22; H, 5.44; S, 10.50.
12 (1.8 g, 5.9 mmol) and 4-nitrobenzenethiol
(1.2 g, 7.7 mmol) in dry 1,2-dichloroethane (60
mL), BF3·EtO2 (0.73 mL, 5.9 mmol) was
added. The mixture was kept at rt for 24 h
and then poured into an ice-cold 6% aq
NaHCO3 soln (100 mL). The separated or-
ganic layer was washed with water, 6% aq
NaHCO3 and concd. The residue was submit-
ted to column chromatography (solvent C).
Concentration of the first fraction gave, ac-
cording to NMR, a 2:1 mixture of 14a+23a
(210 mg, 9%); Rf 0.5 (solvent C).
Concentration of the second fraction gave a
2:3 mixture of 23a+23b (100 mg, 4%); Rf
0.45 (solvent C).
(ii) A soln of 24 (0.5 g) or 25 (0.7 g) in
CF3COOH (7.5 mL) and water (2.5 mL) was
kept at 20 °C for 5 h. The residue, obtained
after concentration was dissolved in pyridine
(5 mL) and Ac2O (3 mL) was added. The
mixture was kept at 20 °C for 24 h to give
after usual processing and column chromatog-
raphy (solvent C) 12 (0.55 g, 71%), which
according to NMR spectroscopy was a 3:2
mixture of 12a and 12b.
Concentration of the third fraction gave 14b
(1.6 g, 68%); [h]D −43 (c 0.34, CHCl3); Rf 0.4
(solvent C); Anal. Calcd for C16H17NO7S2: C,
48.11; H, 4.29; N, 3.51; S, 16.05. Found: C,
48.22; H, 4.33; N, 3.59; S, 16.11.
4-Cyanophenyl 3,6-anhydro-1,3-dithio-h- -
D
glucofuranoside (16).—Deacetylation of 13a
(240 mg, 0.6 mmol) with 1 M NaOMe (0.1
mL) in MeOH (10 mL) yielded, after neutral-
ization with solid CO2 and column chro-
matography (solvent H), 16 (150 mg, 80%):
mp 165–169 °C (ether); [h]D +315° (c 0.5,
MeOH); Rf 0.4 (solvent H); Anal. Calcd for
C13H13NO3S2: C, 52.86; H, 4.44; N, 4.74; S,
21.71. Found: C, 52.91; H, 4.33; N, 4.82; S,
21.79.
On recrystallisation from ether (80 mL)
pure 12a (1.7 g, 27.8%) can be obtained; mp
109–111 °C; [h]D +213°.
4-Cyanophenyl 2,5-di-O-acetyl-3,6-anhydro-
1,3-dithio- -glucofuranoside (13).—Under ar-
D
gon, to a stirred soln of 12 (0.5 g, 1.6 mmol)
and 4-cyanobenzenethiol (0.43 g, 3.2 mmol) in
dry 1,2-dichloroethane (20 mL), Me3SiOTf
(0.34 mL, 1.8 mmol) was added at −10 °C.
After stirring at rt for 30 min, the reaction
was quenched with Et3N, concd and the
residue submitted to column chromatography
(solvent C). Concentration of the first fraction
gave 13a (50 mg, 8%) as a syrup; [h]D +232°
(c 0.6, CHCl3); Rf 0.5 (solvent C); Anal. Calcd
for C17H17NO5S2: C, 53.81; H, 4.52; N, 3.69;
S, 16.90. Found: C, 53.75; H, 4.63; N, 3.61; S,
16.80.
4-Cyanophenyl 3,6-anhydro-1,3-dithio-i-
glucofuranoside (17) and 4-[(imino)(methoxy)-
methyl]phenyl 3,6-anhydro-1,3-dithio-i- -glu-
D
-
D
cofuranoside (18).—Deacetylation of 13b (300
mg, 0.8 mmol) with 1 M NaOMe (0.1 mL) in
MeOH (15 mL) yielded, after neutralization
with solid CO2 and column chromatography
(solvent H), 17 (135 mg, 58%): mp 192–
194 °C (ether); [h]D −138° (c 0.5, MeOH); Rf
0.4 (solvent H); Anal. Calcd for C13H13NO3S2:
C, 52.86; H, 4.44; N, 4.74; S, 21.71. Found: C,
52.81; H, 4.38; N, 4.72; S, 21.65.
Concentration of the second fraction gave
18 (40 mg, 15%): mp 148–153 °C (ether); [h]D
−104° (c 0.35, MeOH); Rf 0.3 (solvent H);
Calcd for C14H17NO4S2: C, 51.36; H, 5.23; N,
4.28; S, 19.58. Found: C, 51.41; H, 5.28; N,
4.33; S, 19.65.
Concentration of the second fraction gave
13b (0.45 g, 72%) as a syrup; [h]D +9° (c 0.5,
CHCl3); Rf 0.4 (solvent C); Calcd for
C17H17NO5S2: C, 53.81; H, 4.52; N, 3.69; S,
16.90. Found: C, 53.89; H, 4.61; N, 3.57; S,
16.93.
4-Nitrophenyl 2,5-di-O-acetyl-3,6-anhydro-
1,3-dithio- -glucofuranoside (14) and 4-nitro-
D

´
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 525–538
536
ether to give 22 (0.55 g, 74%): mp 110–114 °C
(ether); [h]D −85° (c 0.5, Me2SO); Rf 0.3
(solvent A); Anal. Calcd for C14H18INO3S3: C,
35.67; H, 3.85; I, 26.92; N, 2.97; S, 20.40.
Found: C, 35.72; H, 3.91; I, 26.81; N, 2.90; S,
20.47.
4-Nitrophenyl 3,6-anhydro-1,3-dithio-i- -
D
glucofuranoside (19).—Deacetylation of 14b
(1.6 g, 4 mmol) with 1 M NaOMe (0.2 mL) in
MeOH (30 mL) yielded, after neutralization
with solid CO2 and column chromatography
(solvent H), 19 (0.95 g, 75%): mp 188–190 °C
(MeOH); [h]D −193° (c 0.5, MeOH); Rf 0.3
(solvent H); Anal. Calcd for C12H13NO5S2: C,
45.70; H, 4.16; N, 4.44; S, 20.33. Found: C,
45.79; H, 4.28; N, 4.42; S, 20.40.
Methyl 3,6-anhydro-3-thio-h- -glucopyran-
D
oside (24).—To a soln of 25 (2.8 g) in CH2Cl2
(20 mL) and MeOH (10 mL), 3 M methanolic
NaOMe (0.1 mL) was added. After 20 h at
20 °C the mixture was neutralized with solid
CO2 to give after concentration and column
chromatography (solvent B), 24 (1.4 g, 77%);
mp 81–83 °C, lit. mp 83–84 °C [10]; Rf 0.3
(solvent B).
4-Acetamidophenyl 3,6-anhydro-1,3-dithio-
i- -glucofuranoside (20).—To a stirred soln
D
of 19 (0.44 g, 1.4 mmol) in EtOH (60 mL),
NaBH4 (330 mg) and NiCl2·6 H2O (30 mg)
were added. After 30 min at rt, the mixture
was neutralized with 4% aq HCl, filtered and
washed with EtOH. The filtrate was concd,
the residue was dissolved in pyridine (10 mL)
and Ac2O (10 mL) was added. The mixture
was kept at rt overnight and then processed in
the usual way. The residue was dissolved in
MeOH (30 mL) and methanolic 3 M NaOMe
(0.1 mL) was added. After 1 h at rt the
mixture was neutralized with solid CO2 and
concd. The residue was submitted to column
chromatography (solvent G) to yield 20 (300
mg, 66%): mp 178–183 °C (ether); [h]D −96°
(c 0.4, MeOH); Rf 0.5 (solvent G); Anal.
Calcd for C14H17NO4S2: C, 51.36; H, 5.23; N,
4.28; S, 19.58. Found: C, 51.40; H, 5.29; N,
4.22; S, 19.55.
Methyl 2,4-di-O-acetyl-3,6-anhydro-3-thio-
h- -glucopyranoside (25).—Under argon, 3 M
D
methanolic NaOMe (34 mL) was added to a
stirred soln of crude methyl-6-S-acetyl-2,4-di-
O-benzoyl-3-O-methanesulfonyl-6-thio-a- -
D
glucopyranoside [10] (38.7 g) in MeOH (580
mL) at 20 °C. The mixture was neutralised
with solid CO2 after 24 h and the residue
obtained after concentration was re-evapo-
rated with toluene (2×50 mL). The residue
was dissolved in pyridine (150 mL), and Ac2O
(85 mL) was added at 20 °C. After 20 h, the
mixture was processed in the usual way to
give, after concentration and column chro-
matography (solvent B), 25 (13.7 g, 69%) as a
solid residue; mp 106–109 °C (ether–hexane);
[h]D +64°; Rf 0.4 (solvent B); Anal. Calcd for
C11H16O6S: C, 47.82; H, 5.84; S, 11.60. Found:
C, 47.94; H, 5.99; S, 11.52.
4-(Aminothiocarbonyl)phenyl 3,6-anhydro-
1,3-dithio-i-
D
-glucofuranoside
(21).—A
stirred soln of 17 (0.75 g, 2.5 mmol) in dry
pyridine (20 mL) and Et3N (20 mL) was satu-
rated with a slow stream of dry H2S for 1 h.
The mixture was kept at rt overnight and was
then concd. The residue was recrystallized
from MeOH to yield 21 (0.79 g, 94%): mp
179–183 °C (MeOH); [h]D −149° (c 0.4,
Methyl 3,6-anhydro-2,4-di-O-(4-nitroben-
zoyl)-3-thio-h- -glucopyranoside (26).—To a
D
soln of 24 (1.92 g, 10 mmol) in pyridine (30
mL), 4-nitrobenzoyl chloride (5.6 g, 30 mmol)
was added and the slurry was stirred at 20 °C
for 24 h. Thereafter water (1.5 mL) was added
and after 30 min the mixture was poured into
water, extracted with CH2Cl2 and processed in
the usual way. The residue obtained on con-
centration was filtered with Et2O to give 26
(4.6 g, 94%); mp 199–202 °C (acetone–hex-
ane); [h]D +25°; Rf 0.6 (solvent B); Anal.
Calcd for C21H18N2O10S: C, 51.43; H, 3.70; N,
5.71; S, 6.54. Found: C, 51.40; H, 3.76; N,
5.67; S, 6.52.
1
Me2SO); Rf 0.4 (solvent A); H NMR: Anal.
Calcd for C13H15NO3S3: C, 47.40; H, 4.59; N,
4.25; S, 29.19. Found: C, 47.48; H, 4.48; N,
4.22; S, 29.25.
4-[(Imino)(methylthio)methyl]phenyl 3,6-an-
hydro-1,3-dithio-i- -glucofuranoside hydro-
D
iodide (22).—To a stirred soln of 21 (0.52 g,
1.6 mmol) in dry acetone (50 mL), MeI (0.7
mL) was added and the mixture was refluxed
for 2 h. After cooling to rt, the precipitated
crystals were filtered off and washed with
Hydrolysis of 26 with aq CF3COOH.—A
soln of 26 (980 mg, 1 mmol) in CF3COOH (10
mL) and water (2 mL) was kept at 25 °C for 8

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E. Bozo´ et al. / Carbohydrate Research 329 (2000) 525–538
537
(solvent C); Anal. Calcd for C27H19N3O5S3: C,
57.74; H, 3.41; N, 7.48; S, 17.12. Found: C,
57.65; H, 3.53; N, 7.43; S, 16.89.
Concentration of the second fraction gave
35 (40 mg, 13.5%); mp 106–111 °C (Et2O);
[h]D +18° (c 0.5, CHCl3); Rf 0.5 (solvent C);
Anal. Calcd for C27H19N3O9S2: C, 54.63; H,
3.23; N, 7.08; S, 10.80. Found: C, 54.58; H,
3.36; N, 6.95; S, 10.65.
The ratio, as well as the yield of 36b and 41
remained essentially unchanged when the
amount of 4-cyanobenezenethiol was dimin-
ished to 0.6 mmol. At −20 °C the reaction
was very sluggish, but gave no better results.
(ii) Under argon, to a stirred soln of 32a
(260 mg, 0.5 mmol) and 4-cyanobenzenethiol
(100 g, 0.75 mmol) in dry 1,2-dichloroethane
(10 mL), BF3·Et2O (0.1 mL, 0.8 mmol) was
added at 20 °C. After stirring at rt for 1.5 h,
the mixture was poured into water, and ex-
tracted with CH2Cl2. The combined organic
extracts were washed with 5% aq NaHCO3,
dried, concd and the residue purified by
column chromatography (solvent D) to give
35 (140 mg, 47.2%) identical with that de-
scribed above.
h. Thereafter toluene (2×5 mL) was evapo-
rated from the residue obtained on concentra-
tion. The residue was dissolved in pyridine (10
mL) and Ac2O (6 mL) was added at 20 °C.
The mixture was processed after 3 h in the
usual way and the residue submitted to
column chromatography (solvent C). The
fractions having Rf 0.6 gave on concentration
1,5-di-O-acetyl-2,6-anhydro-3-O-(4-nitroben-
zoyl)-2-thio-a- -altrofuranose (40) (190 mg,
D
23%); mp 182–184 °C (Et2O); [h]D +63°;
Anal. Calcd for C17H17NO9S: C, 49.63; H,
4.17; N, 3.40; S, 7.79. Found: C, 49.53; H,
4.15; N, 4.11; S, 7.66.
The fractions having Rf 0.5 gave on concen-
tration methyl 3,6-anhydro-2,4-di-O-(4-ni-
trobenzoyl)-3-thio-b- -glucopyranoside (26b)
D
(120 mg, 12%); mp 153–157 °C (Et2O); [h]D
−40 (c 0.5, CHCl3); Anal. Calcd for
C21H18N2O10S: C, 51.43; H, 3.70; N, 5.71; S,
6.54. Found: C, 51.38; H, 3.73; N, 5.65; S,
6.48.
The fractions having Rf 0.5 gave on concen-
tration 3,6-anhydro-1,1,5-tri-O-acetyl-2,4-di-
O-(4-nitrobenzoyl)-3-thio- -glucose (39) (102
D
mg, 11%); mp 64–66 °C (Et2O); [h]D +116°
(c 0.5, CHCl3); Anal. Calcd for C26H24N2O14S:
C, 50.32; H, 3.90; N, 4.51; S, 5.17. Found: C,
50.38; H, 3.73; N, 4.65; S, 5.02.
4-Cyanophenyl 3,6-anhydro-1,3-dithio-i- -
D
glucopyranoside (36).—To a stirred slurry of
35 (1 g) in CH2Cl2 (10 mL) and MeOH (15
mL), 3 M methanolic NaOMe was added at
20 °C. After 1 h, the clear soln was neutralized
with solid CO2 and the residue obtained on
concentration was purified by column chro-
matography (solvent C) to give 36 (330 mg,
66%) as a solid foam; mp 51–55 °C; [h]D
−147° (c 1, MeOH); Rf 0.45 (solvent B);
Anal. Calcd for C13H13NO3S2: C, 52.86; H,
4.44; N, 4.74; S, 21.71. Found: C, 52.99; H,
4.62; N, 4.56; S, 21.38.
The fractions having Rf 0.3 gave on concen-
tration 1-O-acetyl-3,6-anhydro-2,4-di-O-(4-ni-
trobenzoyl)-6-thio-a-
D
-glucopyranose
(32a)
(400 mg, 38.6%); mp 188–192 °C (Et2O); [h]D
−23°; Anal. Calcd for C22H18N2O11S: C,
50.97; H, 3.50; N, 5.40; S, 6.18. Found: C,
51.09; H, 3.68; N, 5.23; S, 6.09.
4-Cyanophenyl 3,6-anhydro-2,4-di-O-(4-ni-
trobenzoyl) - 1,6 - dithio - i -
D
- glucopyranoside
(35) and 4-cyanophenyl 3,6-anhydro-2-S-
(4-cyanophenyl)-4-O-(4-nitrobenzoyl)-1,2,6-
4-Nitrophenyl 3,6-anhydro-2,4-di-O-(4-ni-
trithio-i- -glucopyranoside (42).—(i) Under
D
trobenzoyl) - 1,3 - dithio - i -
D
- glucopyranoside
argon, to a stirred soln of 32a (260 mg, 0.5
mmol) and 4-cyanobenzenethiol (140 mg, 1
mmol) in dry 1,2-dichloroethane (10 mL),
Me2SiOTf (0.12 mL, 0.6 mmol) was added at
−10 °C. After stirring at −10 °C for 30 min,
the reaction was quenched with Et3N, concd
and the residue submitted to column chro-
matography (solvent C). Concentration of the
first fraction gave 42 (100 mg, 35.7%) as a
syrup; [h]D +277° (c 0.6, CHCl3); Rf 0.55
(37).—Under argon, to a stirred soln of 32a
(520 mg, 1 mmol) and 4-nitrobenzenethiol
(purity 80%) (250 mg, 1.25 mmol) in dry
1,2-dichloroethane (20 mL), BF3·Et2O (0.15
mL, 1.2 mmol) was added at 20 °C. After
stirring at rt for 30 min, the mixture was
poured into water, and extracted with CH2Cl2.
The combined organic extracts were washed
with 5% aq NaHCO3, dried, concd and the

´
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 525–538
538
residue purified by column chromatography
(solvent D) to give 37 (350 mg, 57.1%); mp
88–92 °C (Et2O); [h]D +32° (c 0.5, CHCl3);
Rf 0.5 (solvent C); Anal. Calcd for
C26H19N3O11S2: C, 50.89; H, 3.12; N, 6.85; S,
10.43. Found: C, 50.90; H, 3.16; N, 6.75; S,
10.35.
for C21H18N2O9S2: C, 49.80; H, 3.85; N, 5.53;
S, 12.66. Found: C, 49.77; H, 3.82; N, 5.48; S,
12.51.
4-Nitrophenyl 2,6-anhydro-2-thio-h- -altro-
D
furanoside (46).—A soln of 45 (970 mg, 2
mmol) was deacylated, as described for 36, to
give after column chromatography (solvent
F), 46 (210 mg, 64%); mp 204–208 °C (Et2O);
[h]D +404° (c 0.5, MeOH); Rf 0.4 (solvent F);
Anal. Calcd for C12H13NO5S2: C, 45.70; H,
4.16; N, 4.44; S, 20.33. Found: C, 45.62; H,
4.52; N, 4.37; S, 20.21.
4-Nitrophenyl 3,6-anhydro-1,3-dithio-i- -
D
glucopyranoside (38).—A soln of 37 (0.6 g)
was treated, as described for 36, to give after
column chromatography (solvent C), 38 (190
mg, 61%) as a solid foam; mp 63–66 °C; [h]D
−133° (c 1, MeOH); Rf 0.5 (solvent C); Anal.
Calcd for C12H13NO5S2: C, 45.70; H, 4.16; N,
4.44; S, 20.33. Found: C, 45.76; H, 4.22; N,
4.36; S, 20.18.
Acknowledgements
4-Cyanophenyl 5-O-acetyl-2,6-anhydro-3-
The authors are very much indebted to Dr
Gabriella Szabo´ for the biological results and
to Dr Eszter Ga´cs-Baitz (Central Research
Institute for Chemistry, Hungarian Academy
of Sciences) for the NMR data measured on
the Varian XL-400 instrument.
O-(4-nitrobenzoyl)-2-thio-h- -altrofuranoside
D
(43).—Under argon, to a stirred soln of 40
(0.97 g, 2 mmol) and 4-cyanobenzenethiol
(280 mg, 2.07 mmol) in dry 1,2-dichloroethane
(25 mL), BF3·Et2O (0.25 mL, 2 mmol) was
added at 20 °C. After stirring at rt for 1 h, the
mixture was poured into water, and extracted
with CH2Cl2. The combined organic extracts
were washed with 5% aq NaHCO3, dried,
concd and the residue purified by column
chromatography (solvent C) to give 43 (1 g,
85%) as a syrup; [h]D +162°; Rf 0.5 (solvent
C); Anal. Calcd for C22H18N2O7S2: C, 54.31;
H, 3.73; N, 5.76; S, 13.18. Found: C, 54.22; H,
3.78; N, 5.68; S, 13.02.
References
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[1] E. Bozo´, S. Boros, L. Pa´rka´nyi, J. Kuszmann, Carbo-
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give after column chromatography (solvent
F), 44 (260 mg, 44%); mp 156–160 °C (Et2O);
[h]D +311° (c 1, MeOH); Rf 0.4 (solvent F);
Anal. Calcd for C13H13NO3S2: C, 52.86; H,
4.44; N, 4.74; S, 21.71. Found: C, 52.88; H,
4.50; N, 4.66; S, 21.62.
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4-Nitrophenyl 5-O-acetyl-2,6-anhydro-3-O-
(4 - nitrobenzoyl) - 2 - thio - h -
D
- altrofuranoside
(45).—Under argon, to a stirred soln of 40
(410 mg, 1 mmol) and 4-nitrobenzenethiol
(purity 80%) (300 mg, 1.54 mmol) in dry
1,2-dichloroethane (20 mL), BF3·Et2O (0.2
mL, 1.5 mmol) was added at 20 °C and the
mixture was processed as described for 37 to
give 45 (440 mg, 87%); mp 83–86 °C (hexane);
´
[15] D. Bagdy, G. Szabo´, E. Baraba´s, S. Bajusz, Thromb.
[h]D +231°; Rf 0.4 (solvent C); Anal. Calcd
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.