Conversion of 2,6-anhydro-D-altrose and -mannose derivatives with 4-substituted phenyl thiols to prepare compounds with potential antithrombotic activity

Article abstract of DOI:10.1016/S0008-6215(01)00102-1

Acetolysis of methyl 3,4-di-O-acetyl-2,6-anhydro-D-altropyranoside afforded a mixture containing, besides 1,3,4-tri-O-acetyl-2,6-anhydro-D-altropyranose, the (1R) and (1S) diastereomers of methyl 2,6-anhydro-D-altrose-tetraacetate. Treatment of this mixture with 4-cyanobenzenethiol in the presence of trimethylsilyl triflate resulted in a mixture containing the 3,4,5-tri-O-acetyl-2,6-anhydro-D-altrose bis(4-cyanophenyl) dithioacetal, the corresponding O-methyl S-aryl monothiohemiacetal diastereomers and the β-thiopyranoside, respectively. Acetolysis of methyl 3,4-di-O-acetyl-2,6-anhydro-D-mannopyranoside led to a mixture of the (1R) and (1S) diastereomers of methyl 2,6-anhydro-D-mannosetetraacetate, which was converted into the corresponding O-methyl S-aryl monothiohemiacetals. Treatment of 1,1,3,4,5-penta-O-acetyl-2,6-anhydro-aldehydo-D-altrose and -D-mannose with 4-cyano- and 4-nitrobenzenethiol, respectively, in the presence of trimethylsilyl triflate afforded the corresponding dithioacetal derivatives. All arylthio derivatives obtained after deacetylation were tested for their oral antithrombotic activity.

Full text of DOI:10.1016/S0008-6215(01)00102-1

www.elsevier.nl/locate/carres
Carbohydrate Research 332 (2001) 325–333
Note
Conversion of 2,6-anhydro-
D-altrose and -mannose
derivatives with 4-substituted phenyl thiols to prepare
compounds with potential 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 20 February 2001; accepted 29 March 2001
Abstract
Acetolysis of methyl 3,4-di-O-acetyl-2,6-anhydro-
D
-altropyranoside afforded a mixture containing, besides 1,3,4-
tri-O-acetyl-2,6-anhydro-
D
-altropyranose, the (1R) and (1S) diastereomers of methyl 2,6-anhydro-D-altrose-tetra-
acetate. Treatment of this mixture with 4-cyanobenzenethiol in the presence of trimethylsilyl triflate resulted in a
mixture containing the 3,4,5-tri-O-acetyl-2,6-anhydro- -altrose bis(4-cyanophenyl) dithioacetal, the corresponding
O-methyl S-aryl monothiohemiacetal diastereomers and the b-thiopyranoside, respectively. Acetolysis of methyl
3,4-di-O-acetyl-2,6-anhydro- -mannopyranoside led to a mixture of the (1R) and (1S) diastereomers of methyl
2,6-anhydro- -mannosetetraacetate, which was converted into the corresponding O-methyl S-aryl monothiohemiac-
etals. Treatment of 1,1,3,4,5-penta-O-acetyl-2,6-anhydro-aldehydo- -altrose and - -mannose with 4-cyano- and
D
D
D
D
D
4-nitrobenzenethiol, respectively, in the presence of trimethylsilyl triflate afforded the corresponding dithioacetal
derivatives. All arylthio derivatives obtained after deacetylation were tested for their oral antithrombotic activity.
© 2001 Elsevier Science Ltd. All rights reserved.
Keywords: O,S-Monothiohemiacetals; S,S-Dithioacetals; Thioglycosides; Oral antithrombotic activity
1. Introduction
cant antithrombotic activity.4 In the latter, the
ring oxygen is not replaced by sulfur, but an
additional sulfur atom is introduced into the
molecule via a 2,6-thioanhydro bridge. In or-
der to study the scope and limitations of this
alteration, the synthesis of thioglycosides
During our search for thioglycosides with
potential oral antithrombotic activity we
found, that not only 5-thio-b- -xylopyra-
D
nosides (1),2 but other 5-thio-pentopyrano-
sides3 and even glycosides with overbridged
tricyclic[2,2,2] structures like 2 possess signifi-
derived from 2,6-anhydro- -altrose (3a) and
D
-mannose (3b) was investigated (Scheme 1).
ꢀ Orally active antithrombotic thioglycosides, Part XIII.
For Part XII, see Ref. 1.
2. Results and discussion
* Corresponding author. Tel.: +36-1-3993300; fax: +36-
1-3993356.
E-mail address: kus13757@helka.iif.hu (J. Kuszmann).
Synthesis of the altrose deri6ati6es.—For
the synthesis of the corresponding thiogly-
0008-6215/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(01)00102-1

´
326
E. Bozo´ et al. / Carbohydrate Research 332 (2001) 325–333
Scheme 1.
Scheme 2.
That suggests that while the two diastereomers
of 5 afforded besides the dithioacetal 7 the
two diastereomers of the O-methyl S-aryl
monothioacetals 9a and 9b,† the triacetate 6
gave the b-thioglycoside 11 exclusively. The
stereoselectivity of the glycosidation reaction
is probably due to the presence of the two
cis-related acetoxy groups at C-3 and C-4,
which can either act as participating groups
during the glycosidation reaction or as steric
factors preventing the formation of the more
crowded a-glycoside (Scheme 2).
cosides, the bicyclic triacetate 6 was needed as
a donor which could be obtained theoretically
from the known5 methyl 3,4-di-O-acetyl-2,6-
anhydro-a- -altropyranoside (4) by acetolysis.
D
Treatment of 4 with acetic anhydride in the
presence of sulfuric acid resulted however in
an inseparable mixture containing, according
to NMR spectroscopy and subsequent reac-
tions, the two diastereomers of (1R) and (1S)
methyl 2,6-anhydro-
and 1,3,4-tri-O-acetyl-2,6-anhydro-b-
D
-altrose-tetraacetate (5)
-altro-
D
pyranose (6) in a ratio of 3:2. Reaction of the
above mixture of 5 and 6 with 4-cyanoben-
zenethiol in the presence of trimethylsilyl tri-
flate resulted in a mixture, which could be
partially separated by column chromatogra-
phy affording, besides a 2:1 mixture of 7+9a
(28%), 9b (14%) and 11 (18%), respectively.
† According to the NMR data, the anhydro ring of both
diastereomers had the same configuration and conformation
and differed only in the chirality of C-1. The configuration at
C-1 could not, however, be established by NMR spec-
troscopy.

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E. Bozo´ et al. / Carbohydrate Research 332 (2001) 325–333
327
Zemple´n deacetylation of 9b and 11 af-
forded 10b and 12, respectively, while the
mixture of 7+9a gave a mixture of 8+10a,
which was separated by column chromatogra-
phy. The configuration of C-1 in 10a and 10b
could not be established by NMR spec-
troscopy. The obtained compounds 8, 10a,
10b and 12 were submitted to biological test-
ing and all of them showed antithrombotic
activity. As among them the mercaptal type
compound (8) possessed the highest activity,
its large-scale synthesis became necessary. For
this reason, 4 was converted into the known6
pentaacetate (13) with acetic anhydride in the
presence of trifluoromethanesulfonic acid and
the resulting pentaacetate (13) was coupled
with 4-cyanobenzenethiol and 4-nitroben-
zenethiol in the presence of trimethylsilyl tri-
flate to give 7 and 14 in 85 and 92% yield,
respectively. Both dithioacetals were deacety-
lated according to Zemple´n affording 8 and
15, respectively. Compound 8, containing the
4%-cyano group, could be converted by stan-
dard methods7 into the 4%-aminothiocarbonyl
derivative 16.
Synthesis of the mannose deri6ati6es.—For
their synthesis, the methyl pyranoside (17)8
was used as starting material, but acetolysis of
this compound in acetic anhydride in the pres-
ence of sulfuric acid led to the cleavage of the
anhydro ring affording a 1:1 mixture of the
(1R) and (1S) methyl 2,6-anhydro- -man-
D
nose-tetraacetate (18). This inseparable mix-
ture was coupled with 4-cyanobenzenethiol in
the presence of trimethylsilyl triflate to give
the two diastereomers of the O-methyl S-aryl
acetals (20) in 95% yield containing the two
isomers in a 3:1 ratio. This inseparable mix-
ture was deacetylated according to Zemple´n to
furnish the mixture 21, which was submitted
to biological testing without separation. The
pentaacetate (19) was obtained according to
the literature6 by treating 17 with trifluoro-
methanesulfonic acid in acetic anhydride. This
pentaacetate (19) was coupled with 4-cyano-
benzenethiol and 4-nitrobenzenethiol in the
Scheme 3.

´
E. Bozo´ et al. / Carbohydrate Research 332 (2001) 325–333
328
presence of trimethylsilyl triflate to give 22
and 23 in 84 and 88% yield, respectively.
These compounds were deacetylated accord-
ing to Zemple´n to afford 24 and 27, and 24
could be converted by standard methods7 into
the 4%-aminothiocarbonyl derivative 25, which
gave 26 after methylation and subsequent
treatment with ammonium acetate (Scheme 3).
Biological results.—The oral antithrom-
botic activity of 8, 10a, 10b, 12, 15, 16, 21, 24,
25, 26 and 27 was determined on rats, using
Pescador’s model9 and 4-cyanophenyl 2,6-an-
followed by heating at ca. 200 °C. For column
chromatography, Kieselgel 60 was used. Melt-
ing points are uncorrected. Optical rotations
were determined at 20 °C. NMR spectra were
recorded with a Bruker AC 250 spectrometer
at 250 MHz (1H) and 62.9 MHz (13C) for
solutions in CDCl3 (internal Me4Si) unless
stated otherwise. Multiplicities of the 13C
NMR spectra were obtained from DEPT ex-
periments. The assignment of the protons was
based on homonuclear decoupling. Connectiv-
ities between identified protons and proto-
nated carbons were observed by means of
HETCOR experiments (Tables 2 and 3).
hydro - 1,2 - dithio - b - - mannopyranoside (2-
D
type compound)4 as reference. All compounds
were administered orally 3 h before ligation.
From the data listed in Table 1, it can be seen
that while 8, 10 and 15 were as active as the
reference compound, all other derivatives pos-
sessed a less pronounced biological activity. It
is worth mentioning that the altro derivatives
(8, 10, 15 and 16) were more active then the
corresponding manno ones (21, 24, 25 and
27). Furthermore, these results question the
general validity of the statement of the
literature2 that the presence of a ring-sulfur
atom in the carbohydrate moiety is essential
for the biological activity.
Acetolysis of 4.—To a solution of 45 (2.35
g, 9 mmol) in Ac2O (6 mL), concd H2SO4
(0.01 mL) was added at 0 °C. The mixture was
stirred at 0 °C for 30 min and NaOAc (0.1 g)
was added. The pH was adjusted to ꢀ6 with
ice-cold 6% aq NaHCO3 and stirring was con-
tinued at rt for 2 h. Then the mixture was
extracted with CH2Cl2, washed with water and
concentrated to yield a syrupy mixture con-
1
taining on the bases of H NMR spectroscopy
(1R and 1S) methyl 1,3,4,5-tetra-O-acetyl-2,6-
anhydro-
tri-O-acetyl-2,6-anhydro-b-
D
-altrose hemiacetal (5a,b) and 1,3,4-
-altropyranose
D
(6) in a ratio of 3:2 (2.6 g, 87%): Rf 0.4
(solvent A). When the reaction was carried
out at −10 °C, 4 was consumed after 90 min
only, but the ratio of the formed 5a,b and 6
remained unchanged.
Reaction of (5ab+6) with 4-cyanoben-
zenethiol.—Under Ar, to a stirred solution of
a 3:2 mixture of 5ab+6 (2.0 g, 6 mmol) and
4-cyanobenzenethiol (1.88 g, 13.9 mmol) in
1,2-dichloroethane (100 mL), TMSOTf (1.34
mL, 7.4 mmol) was added at −10 °C. After
stirring at −10 °C for 30 min, the reaction
was quenched with Et3N, concentrated and
3. Experimental
General methods.—Organic solutions were
dried over MgSO4 and concentrated under
diminished pressure at or below 40 °C. TLC:
E. Merck precoated Silica Gel 60 F254 plates,
with (A, 1:1; B, 2:1) hexane–EtOAc mixtures,
EtOAc (C), (D, 4:1) toluene–MeOH mixtures
and (E, 60:20:11:6) EtOAc–pyridine–water–
AcOH mixtures; detection by spraying the
plates with a 0.02 M solution of I2 and a 0.30
M solution of KI in a 10% aq H2SO4 solution
Table 1
Oral antithrombotic activity of 4-substituted phenyl S-acetals of 2,6-anhydro-D-altrose and -mannose in rats using Pescador’s
model9
a
Compound
Reference
8
10a 10b
12
15
16
21
24
25
26
27
C-4%-R
CN
50
CN CN CN CN NO2 CSNH2 CN CN CSNH2 C(NH)NH2 NO2
56 52 53 39 53 43 43 44 35 25 33
Inhibition b (%)
a 4-Cyanophenyl 2,6-anhydro-1,2-dithio-b-D-mannopyranoside4 was chosen as reference compound.
b Inhibition % at an oral dose of 2 mg/kg.

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E. Bozo´ et al. / Carbohydrate Research 332 (2001) 325–333
329
Table 2
1
Selected H NMR data for solutions in CDCl3
Compound Chemical shifts (l)
H-1 H-2
H-3
H-4
H-5
H-6a
H-6b
Others
5a
5b
6
5.80 3.50–4.40
5.90 3.50–4.40
6.27 4.00
4.75 3.60
5.35 3.50
5.30–5.50
5.30–5.50
5.39
5.72
3.47
5.05–5.25
5.05–5.25
5.10
5.04
4.03
3.50–4.40
3.50–4.40
3.91
3.68
3.50
3.41 (OMe)
3.52 (OMe)
4.14
5.14
3.67
5.10
5.12
4.35
4.20
3.86
4.20
4.15
2.10, 2.11, 2.19 (OAc)
2.03, 2.06, 2.17 (OAc)
4.85, 4.98, 5.06 (OH)
2.00, 2.08, 2.16 (OAc)
3.45 (OMe)
7
8a
9a
9b
4.82 3.58
4.66 3.35
5.60
5.46
4.92
4.99
3.66
3.50
1.96, 2.11, 2.12 (OAc)
3.37 (OMe)
4.68, 4.93, 5.30 (OH)
3.41 (OMe)
10a a
10b a
5.17 3.48
5.01 3.19
3.98
3.76
3.42
3.44
3.66
3.64
3.45
3.33
3.91
3.83
4.69, 4.86, 5.12 (OH)
2.12, 2.15 (OAc)
4.98, 5.40 (OH)
2.01, 2.09, 2.20 (OAc)
4.90, 5.03, 5.28 (OH)
4.80, 4.96, 5.24 (OH)
9.50, 9.85 (NH2)
3.47 (OMe)
11
5.81 4.16
5.95 3.87
4.87 3.71
5.48 3.60
5.14 3.42
5.39
4.04
5.76
3.55
3.52
5.12
3.87
5.09
4.08
4.08
4.14
3.87
5.17
3.72
3.68
3.95
3.82
3.75
3.52
3.50
4.69
4.33
4.22
3.90
3.90
12 a
14
15 a
16 a
20a
4.99 3.78
5.53
5.07
5.32
3.67
4.10
2.14, 2.08, 2.17 (OAc)
3.44 (OMe)
20b
4.90 3.65
5.48
5.06
5.29
3.59
4.05
2.05, 2.07, 2.18 (OAc)
3.35 (OMe)
4.56, 4.76, 5.04 (OH)
3.33 (OMe)
21a a
21b a
5.46 3.25–3.50
5.45 3.25–3.50
3.56–3.83
3.56–3.83
3.25–3.50
3.25–3.50
3.56–3.83
3.56–3.83
3.25–3.50
3.25–3.50
3.56–3.83
3.56–3.83
4.53, 4.78, 5.20 (OH)
2.04, 2.07, 2.20 (OAc)
2.05, 2.11, 2.20 (OAc)
4.65, 5.00, 5.60 (OH)
4.60, 4.84, 5.47 (OH)
22
23
4.57 3.85
4.69 3.92
5.47 3.55
5.30 3.50
5.44 3.35–3.52
5.56 3.55
5.72
5.75
3.85
3.86
3.82
3.81
5.07
5.08
3.40
3.38
3.35–3.52
3.38
5.30
5.32
3.73
3.72
3.68
3.70
3.64
3.68
3.48
3.50
3.35–3.52
3.46
4.10
4.10
3.86
3.84
3.82
3.83
24 a
25 a
26 a
27 a
4.65, 4.86, 5.56 (OH)
Coupling constants (Hz)
J1,2
J2,3
J3,4
J4,5
J5,6a
J5,6b
J6a,6b
5a
5b
6
7.9
8.1
1.8
8.7
9.4
8.2
8.7
9.1
9.0
1.2
ꢀ1
8.7
9.3
9.5
2.3
4.0
ꢀ1
nd b
nd
4.6
B1
ꢀ0
B1
1.4
B1
B1
4.4
ꢀ4.5
0.9
ꢀ0
ꢀ0
9.7
nd
nd
nd
nd
1.4
3.6
ꢀ3.5
3.7
3.8
3.6
3.1
1.1
nd
3.7
ꢀ3.5
ꢀ3.5
3.5
3.5
nd
nd
nd
nd
nd
nd
nd
8.5
3.6
ꢀ3
3.7
3.6
3.5
3.1
8.6
ꢀ8.8
3.7
ꢀ3
13
ꢀ1
1.0
ꢀ1
1.0
1.5
1.3
1.0
ꢀ1.5
ꢀ1
1.1
ꢀ1
ꢀ1
1.0
ꢀ1
nd
2.1
1.6
1.9
1.2
1.6
1.5
1.7
2.1
1.7
1.3
1.7
ꢀ1.5
ꢀ1.5
2.2
nd
10.4
13.3
12.2
13.6
13.4
12.1
12.0
10.5
10.0
13.4
12.0
12.0
12.1
12.0
nd
7
8 a
9a
9b
10a a
10b a
11
12 a
14
15 a
16 a
20a
20b
21a a
10.0
9.6
nd
9.6
nd

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E. Bozo´ et al. / Carbohydrate Research 332 (2001) 325–333
330
Table 2 (Continued)
Coupling constants (Hz)
J1,2
J2,3
J3,4
J4,5
J5,6a
J5,6b
J6a,6b
21b a
22
ꢀ3
1.4
1.2
ꢀ1
ꢀ1
ꢀ1
ꢀ1
nd
nd
nd
nd
nd
nd
9.5
9.3
9.0
ꢀ9
ꢀ9
9.3
9.8
9.8
9.3
9.0
ꢀ9
9.0
3.4
3.4
3.4
3.2
ꢀ3
3.1
ꢀ1
ꢀ1
B1
ꢀ1
ꢀ1
B1
1.4
1.5
ꢀ0
ꢀ1
ꢀ1
ꢀ0
13.1
13.2
12.0
ꢀ12
12.0
12.0
23
24 a
25 a
26 a
27 a
a Me2SO-d6.
b nd, not determined.
Table 3
Selected 13C NMR data for solutions in CDCl3
Compound
Chemical shifts (l)
C-1
C-2
C-3
C-4
C-5
C-6
Others
7
8 b
9a
56.7
54.9
88.3
87.9
89.4
89.0
83.8
82.7
56.2
88.0
88.5
57.4
57.0
54.2
78.4
79.6
78.3
76.5
78.6
78.1
65.6 a
65.1 a
78.4
81.8
84.9
80.4
80.5
82.4
66.2 a
68.4 a
66.2 a
66.2 a
68.5 a
68.3 a
67.4 a
70.8 a
66.1 a
66.6 a
67.8 a
67.8 a
67.9 a
68.2 a
68.1
70.0
68.1
76.8
66.3 a
69.2 a
66.3 a
66.5 a
69.3 a
69.6 a
69.4 a
65.6 a
66.3 a
71.7 a
74.7 a
71.4 a
71.3 a
73.7 a
69.4
71.5
69.3
69.0
71.0
71.2
66.4
66.4
69.4
68.4
71.2
68.0
68.1
70.7
118.1, 118.2 (CN)
118.8, 118.8 (CN)
56.4 (OMe); 118.2 (CN)
56.2 (OMe); 118.0 (CN)
55.0 (OMe); 118.8 (CN)
56.0 (OMe); 118.9 (CN)
118.1 (CN)
9b
10a b
10b b
11
70.3
69.7 a
68.4 a
71.8 a
68.4
12 b
14
119.0 (CN)
20a
21a b
22
68.2 a
69.5 a
68.2 a
68.2 a
68.8 a
56.2 (OMe); 118.4(CN)
56.0 (OMe); 118.5 (CN)
118.0, 118.1 (CN)
23
24 b
118.8, 118.8 (CN)
a Arbitrary assignment.
b Me2SO-d6.
submitted to column chromatography (solvent
B, then A). Concentration of the first fraction
gave 4-cyanophenyl 3,4-di-O-acetyl-2,6-anhy-
Concentration of the third fraction gave
3,4,5-tri-O-acetyl-2,6-anhydro- -altrose S-4-
D
cyanophenyl O-methyl monothiohemiacetal
(9b) (0.42 g, 14%): mp 138–143 °C (ether);
[h]D −34° (c 0.5, CHCl3); Rf 0.3 (solvent A);
Anal. Calcd for C20H23NO8S: C, 54.91; H,
5.30; N, 3.20; S, 7.33. Found: C, 54.87; H,
5.22; N, 3.27; S, 7.43.
dro-1-thio-b- -altropyranoside (11, 0.45 g,
D
18%): mp 165–167 °C (ether); [h]D −153° (c
0.4, CHCl3); Rf 0.6 (solvent A); Anal. Calcd
for C17H17NO6S: C, 56.19; H, 4.72; N, 3.85; S,
8.82. Found: C, 56.02; H, 4.58; N, 3.90; S,
8.73.
2,6-Anhydro-
D
-altrose
bis(4-cyanophenyl)
-altrose S-4-
Concentration of the second fraction gave
dithioacetal (8) and 2,6-anhydro-
D
1
on the basis of H NMR spectroscopy a 2:1
cyanophenyl O-methyl monothiohemiacetal
(10a).—To a solution of a 2:1 mixture of 7
and 9a (1.42 g, 2.8 mmol) in MeOH (20 mL)
and CH2Cl2 (10 mL), 3 M methanolic NaOMe
(0.1 mL) was added and the mixture was kept
at rt for 1 h. Thereafter it was neutralized with
mixture of 3,4,5-tri-O-acetyl-2,6-anhydro- -
D
altrose bis(4-cyanophenyl) dithioacetal (7) and
3,4,5-tri-O-acetyl-2,6-anhydro- -altrose S-4-
D
cyanophenyl O-methyl monothiohemiacetal
(9a) (1.0 g, 28%): Rf 0.5 (solvent A).

´
E. Bozo´ et al. / Carbohydrate Research 332 (2001) 325–333
331
mitted to column chromatography (solvent B)
to give 3,4,5-tri-O-acetyl-2,6-anhydro- -al-
solid CO2, concentrated and the residue was
submitted to column chromatography (solvent
C). Concentration of the first fraction gave 8
(0.7 g, 60%) as an oil: [h]D +4° (c 0.5,
MeOH); Rf 0.3 (solvent C); Anal. Calcd for
C20H18N2O4S2: C, 57.95; H, 4.38; N, 6.76; S,
15.47. Found: C, 57.88; H, 4.46; N, 6.82; S,
15.55.
D
trose bis(4-nitrophenyl) dithioacetal (14, 2.46
g, 92%) as an oil: [h]D +70° (c 0.58, CHCl3);
Rf 0.5 (solvent A); Anal. Calcd for
C24H24N2O11S2: C, 49.65; H, 4.17; N, 4.82; S,
11.05. Found: C, 49.74; H, 4.08; N, 4.90; S,
11.15.
Concentration of the second fraction gave
10a (0.25 g, 29%): mp 132–135 °C (ether); [h]D
−104° (c 0.5, MeOH); Rf 0.2 (solvent C);
Anal. Calcd for C14H17NO5S: C, 54.01; H,
5.50; N, 4.50; S, 10.30. Found: C, 54.13; H,
5.44; N, 4.61; S, 10.33.
2,6-Anhydro-
D
-altrose
bis(4-nitrophenyl)
dithioacetal (15).—Deacetylation of 14 (1.7 g,
2.9 mmol) was carried out as described for 8
to give 15 (0.97 g, 73%): mp 166–168 °C
(ether); [h]D +14° (c 0.5, pyridine); Rf 0.3
(solvent D); Anal. Calcd for C18H18N2O8S2: C,
47.57; H, 3.99; N, 6.16; S, 14.11. Found: C,
47.51; H, 4.01; N, 6.10; S, 14.22.
2,6-Anhydro- -altrose S-4-cyanophenyl O-
D
methyl monothiohemiacetal (10b).—Deacetyla-
tion of 9b (0.42 g, 0.96 mmol) was carried out
as described for 8 to give after column chro-
matography (solvent D) 10b (0.25 g, 83%) as
an oil: [h]D −21° (c 0.5, MeOH); Rf 0.3
(solvent D); Anal. Calcd for C14H17NO5S: C,
54.01; H, 5.50; N, 4.50; S, 10.30. Found: C,
54.07; H, 5.43; N, 4.55; S, 10.37.
2,6-Anhydro- -altrose bis[4-(aminothiocar-
D
bonyl)phenyl] dithioacetal (16).—A stirred so-
lution of 8 (0.4 g, 0.96 mmol) in dry pyridine
(10 mL) and Et3N (10 mL) was saturated with
a slow stream of dry H2S for 1 h. The mixture
was kept at rt overnight and was then concen-
trated. The residue was recrystallized from
MeOH to yield 16 (0.33 g, 72%): mp 112–
116 °C (MeOH); [h]D −15° (c 0.5, pyridine);
Rf 0.2 (solvent D); Anal. Calcd for
C20H22N2O4S4: C, 49.77; H, 4.59; N, 5.80; S,
26.57. Found: C, 49.85; H, 4.48; N, 5.91; S,
26.65.
4-Cyanophenyl 2,6-anhydro-1-thio-i- -al-
D
tropyranoside (12).—Deacetylation of 11 (0.45
g, 1.2 mmol) was carried out as described for
8 to give 12 (0.3 g, 87%): mp 125–130 °C
(ether); [h]D −211° (c 0.5, MeOH); Rf 0.3
(solvent D); Anal. Calcd for C13H13NO4S: C,
55.90; H, 4.69; N, 5.01; S, 11.48. Found: C,
55.83; H, 4.77; N, 5.11; S, 11.54.
Acetolysis of 17.—To a solution of 178 (1.0
g, 3.8 mmol) in Ac2O (5 mL), concd H2SO4
(0.01 mL) was added at 0 °C. The mixture was
stirred at 0 °C for 30 min and NaOAc (0.1g)
was added. The pH was adjusted to ꢀ6 with
ice-cold 6% aq NaHCO3 and stirring was con-
tinued at rt for 2 h. Then the mixture was
extracted with CH2Cl2, washed with water and
concentrated to yield a 1:1 diastereomeric
mixture of (1R and 1S) methyl 1,3,4,5-tetra-
Reaction of 13 with 4-cyanobenzenethiol.—
Under Ar, to a stirred solution of 136 (1.15 g,
2.9 mmol) and 4-cyanobenzenethiol (0.95 g, 7
mmol) in 1,2-dichloroethane (30 mL), TM-
SOTf (0.75 mL, 4 mmol) was added at 0 °C.
After stirring at rt for 24 h, the reaction was
quenched with Et3N, concentrated and sub-
mitted to column chromatography (solvent A)
to give 7 (1.35 g, 85%) as an oil: [h]D +65° (c
0.5, CHCl3); Rf 0.5 (solvent A); Anal. Calcd
for C26H24N2O7S2: C, 57.77; H, 4.47; N, 5.18;
S, 11.86. Found: C, 57.81; H, 4.38; N, 5.23; S,
11.90.
Reaction of 13 with 4-nitrobenzenethiol.—
Under Ar, to a stirred solution of 13 (1.8 g,
4.6 mmol) and 4-nitrobenzenethiol (2.2 g, 14
mmol) in 1,2-dichloroethane (40 mL), TM-
SOTf (1.2 mL, 6.4 mmol) was added at 0 °C.
After stirring at rt for 24 h, the reaction was
quenched with Et3N, concentrated and sub-
O-acetyl-2,6-anhydro- -mannose hemiacetal
D
(18, 1.08 g, 78%) as syrup: Rf 0.4 (solvent A),
identical with lit.6
Reaction of 18 with 4-cyanobenzenethiol.—
Condensation of 18 (0.4 g, 1.1 mmol) with
4-cyanobenzenethiol (0.3 g, 2.2 mmol) was
carried out as described for 13 to give after
column chromatography (solvent B) 3:1
diastereomeric mixture of 3,4,5-tri-O-acetyl-
2,6-anhydro- -mannose S-4-cyanophenyl O-
D
methyl monothiohemiacetal (20, 0.46 g, 95%)
as syrup: Rf 0.6 (solvent A); Anal. Calcd for

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E. Bozo´ et al. / Carbohydrate Research 332 (2001) 325–333
332
57.95; H, 4.38; N, 6.76; S, 15.47. Found: C,
57.88; H, 4.31; N, 6.82; S, 15.53.
C20H23NO8S: C, 54.91; H, 5.30; N, 3.20; S,
7.33. Found: C, 54.85; H, 5.28; N, 3.13; S,
7.41.
2,6-Anhydro- -mannose bis[4-(aminothio-
D
carbonyl)phenyl] dithioacetal (25).—A stirred
solution of 24 (0.4 g, 0.96 mmol) in dry pyri-
dine (10 mL) and Et3N (10 mL) was saturated
with a slow stream of dry H2S for 1 h. The
mixture was kept at rt overnight and was then
concentrated. The residue was recrystallized
from MeOH to yield 25 (0.34 g, 74%): mp
165–168 °C (MeOH); [h]D −282° (c 0.5, pyri-
dine); Rf 0.2 (solvent D); Anal. Calcd for
C20H22N2O4S4: C, 49.77; H, 4.59; N, 5.80; S,
26.57. Found: C, 49.83; H, 4.53; N, 5.87; S,
26.61.
2,6-Anhydro- -mannose S-4-cyanophenyl O-
D
methyl monothiohemiacetal (21).—To a solu-
tion of 20 (0.46 g, 1.0 mmol) in MeOH (15
mL), 3 M methanolic NaOMe (0.1 mL) was
added and the mixture was kept at rt for 1 h.
Thereafter it was neutralized with solid CO2,
concentrated and the residue was submitted to
column chromatography (solvent D) to give a
3:1 diastereomeric mixture of 21 (0.24 g, 74%)
as an oil: Rf 0.3 (solvent D); Anal. Calcd for
C14H17NO5S: C, 54.01; H, 5.50; N, 4.50; S,
10.30. Found: C, 53.96; H, 5.47; N, 4.44; S,
10.41.
2,6-Anhydro-
D
-mannose
bis(4-amidino-
phenyl) dithioacetal (26).—To a stirred solu-
tion of 25 (0.2 g, 0.4 mmol) in dry acetone (20
mL), MeI (0.2 mL) was added and the mix-
ture was refluxed for 2 h. After cooling to rt,
the precipitated crystals were filtered off and
3,4,5-Tri-O-acetyl-2,6-anhydro- -mannose
D
bis(4-cyanophenyl) dithioacetal (22).—Under
Ar, to a stirred solution of 196 (2.1 g, 5.4
mmol) and 4-cyanobenzenethiol (1.73 g, 12.8
mmol) in 1,2-dichloroethane (50 mL), TM-
SOTf (1.33 mL, 7.1 mmol) was added at 0 °C.
After stirring at rt for 24 h, the reaction was
quenched with Et3N, concentrated and sub-
mitted to column chromatography (solvent A)
to give 22 (2.45 g, 84%) as an oil: [h]D −145°
(c 0.5, CHCl3); Rf 0.6 (solvent A); Anal. Calcd
for C26H24N2O7S2: C, 57.77; H, 4.47; N, 5.18;
S, 11.86. Found: C, 57.69; H, 4.39; N, 5.26; S,
11.92.
washed with ether to give 2,6-anhydro- -man-
D
nose bis(4-[(imino)(methylthio)methyl]phenyl)
dithioacetal (0.25 g, 79%). The resulting com-
pound was dissolved in EtOH (25 mL),
NH4OAc (0.2 g) was added and the mixture
was stirred at 60 °C for 2 h. Then the reaction
mixture was concentrated, the residue was dis-
solved in 10% aq AcOH (20 mL) and purified
on an ion-exchange resin (Varion AD, H+
form) using 5% aq AcOH as eluent. The frac-
tions having the desired compound were
freeze dried to yield the diacetate of 26 (0.1 g,
54%) as a foam: [h]D −90° (c 0.34, MeOH);
Rf 0.6 (solvent E); Anal. Calcd for
C24H32N4O8S2: C, 50.69; H, 5.67; N, 9.85; S,
11.28. Found: C, 50.73; H, 5.59; N, 9.87; S,
11.33.
3,4,5-Tri-O-acetyl-2,6-anhydro- -mannose
D
bis(4-nitrophenyl) dithioacetal (23).—Under
Ar, to a stirred solution of 19 (1.3 g, 3.3
mmol) and 4-nitrobenzenethiol (1.28 g, 8.25
mmol) in 1,2-dichloroethane (25 mL), TM-
SOTf (0.85 mL, 4.5 mmol) was added at 0 °C.
After stirring at rt for 24 h, the reaction was
quenched with Et3N, concentrated and sub-
mitted to column chromatography (solvent B)
to give 23 (1.7 g, 88%) as an oil: [h]D −159°
(c 0.5, CHCl3); Rf 0.7 (solvent A); Anal. Calcd
for C24H24N2O11S2: C, 49.65; H, 4.17; N, 4.82;
S, 11.05. Found: C, 49.71; H, 4.12; N, 4.89; S,
11.10.
2,6-Anhydro- -mannose bis(4-nitrophenyl)
D
dithioacetal (27).—Deacetylation of 23 (1.7 g,
2.9 mmol) was carried out as described for 21
to give, after column chromatography (solvent
D), 27 (1.06 g, 80%): mp 197–199 °C (ether);
[h]D −271° (c 0.5, pyridine); Rf 0.3 (solvent
D); Anal. Calcd for C18H18N2O8S2: C, 47.57;
H, 3.99; N, 6.16; S, 14.11. Found: C, 47.59; H,
4.03; N, 6.11; S, 14.19.
2,6-Anhydro- -mannose bis(4-cyanophenyl)
D
dithioacetal (24).—Deacetylation of 22 (1.15
g, 2.1 mmol) was carried out as described for
21 to give, after column chromatography (sol-
vent D), 24 (0.67 g, 76%): mp 96–98 °C
(ether); [h]D −145° (c 0.5, MeOH); Rf 0.3
Acknowledgements
The authors are very much indebted to Dr
Gabriella Szabo´ for the biological results.
(solvent D); Anal. Calcd for C20H18N2O4S2
.
: C,

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E. Bozo´ et al. / Carbohydrate Research 332 (2001) 325–333
333
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