An economic synthesis of 1,2,3,4-tetra-O-acetyl-5-thio-D-xylopyranose and its transformation into 4-substituted-phenyl 1,5-dithio-D-xylopyranosides possessing antithrombotic activity

Article abstract of DOI:10.1016/S0008-6215(98)00088-3

D-Xylose was converted via 1,2-O-isopropylidene-α-D-xylofuranose (4) into 3-O-benzoyl-5-S-benzoyl- 1,2-O-isopropylidene-α-D-xylofuranose which, after methanolysis, acetylation and subsequent acetolysis afforded 1,2,3,4-tetra-O-acetyl-5-thio-α-D-xylopyranose (14) in an overall yield of 36%. Reaction of 4 with thionyl chloride gave a mixture of the diastereomeric cyclic sulfites, the structures of which were established by X-ray crystallography. Their oxidation with sodium periodate afforded the corresponding cyclic sulfate 23. Treatment of 23 with potassium thioacetate gave the potassium salt of 5-S-acetyl-1,2-O-isopropylidene-α-D-xylofuranose 3-O-sulfonic acid (26) which, after methanolysis, acetylation and subsequent acetolysis afforded 14 in an overall yield of 56%. Treatment of 4 with sulfuryl chloride gave a mixture containing 5-chloro-3-O-chlorosulfonyl-5-deoxy-1, 2-O-isopropylidene-α-D-xylofuranose, 3,7,9,11-tetraoxa-4-thia-10-dimethyl-tricyclo[6,3,0,0^2,6]undecane S-dioxide and 23 in a 2:3:7 ratio. Tetraacetate 14 was converted into the α-1-bromide 18 as well as into the α-1-O-trichloroacetimidate 17. These three compounds were used as donors for the glycosylation with 4-cyanothiophenol, affording the 4-cyanophenyl 2,3,4-tri-O-acctyl-1,5-dithio-α- (29) and β-D-xylopyranoside (30) in different ratios, depending on the reaction conditions, When donor 18 was used in the presence of potassium carbonate, besides 29 and 30 two aryl C-glycosylated-thioglycosides, i.e. 4-cyano-2-(2, 3,4-tri-O-acetyl-5-thio-β-D- xylopyranosyl)phenyl 2,3,4-tri-O-acetpy-1,5-dithio-α- and β-D-xylopyranoside (32 and 33) as well as 4-cyano-2-(2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranosyl)phenyl disulfide 34 could be isolated as byproducts. Deacetylation of 30 with sodium methoxide in methanol afforded, besides 4-cyanophenyl 1,5-dithio-β-D-xylopyranoside (1), the corresponding 4-[(methoxy)(imino)methyl]phenyl glycoside 2. The 4-cyano group of 1 was converted into the 4-aminothiocarbonyl, the 4-(methylthio)(imino)methyl, the 4-amidino and the 4-(imino)(hydrazino)methyl group. All of these glycosides showed a significant antithrombotic activity on rats.

Full text of DOI:10.1016/S0008-6215(98)00088-3

Carbohydrate Research 308 (1998) 297±310
An economic synthesis of 1,2,3,4-tetra-O-acetyl-
5-thio-d-xylopyranose and its transformation
into 4-substituted-phenyl 1,5-dithio-d-
xylopyranosides possessing antithrombotic
activity1,2
Eva Bozoa, Sandor Borosa, Janos Kuszmanna,*, Eszter Gacs-Baitzb,
Laszlo Parkanyib
a Institute for Drug Research, PO Box 82, H-1325-Budapest, Hungary
b Central Research Institute for Chemistry, Hungarian Academy of Sciences, PO Box 17, H-1525
Budapest, Hungary
Received 12 January 1998; accepted 29 March 1998
Abstract
d-Xylose was converted via 1,2-O-isopropylidene-ꢀ-d-xylofuranose (4) into 3-O-benzoyl-5-S-
benzoyl-1,2-O-isopropylidene-ꢀ-d-xylofuranose which, after methanolysis, acetylation and sub-
sequent acetolysis a€orded 1,2,3,4-tetra-O-acetyl-5-thio-ꢀ-d-xylopyranose (14) in an overall yield
of 36%. Reaction of 4 with thionyl chloride gave a mixture of the diastereomeric cyclic sul®tes, the
structures of which were established by X-ray crystallography. Their oxidation with sodium peri-
odate a€orded the corresponding cyclic sulfate 23. Treatment of 23 with potassium thioacetate
gave the potassium salt of 5-S-acetyl-1,2-O-isopropylidene-ꢀ-d-xylofuranose 3-O-sulfonic acid
(26) which, after methanolysis, acetylation and subsequent acetolysis a€orded 14 in an overall
yield of 56%. Treatment of 4 with sulfuryl chloride gave a mixture containing 5-chloro-3-O-
chlorosulfonyl-5-deoxy-1,2-O-isopropylidene-ꢀ-d-xylofuranose, 3,7,9,11-tetraoxa-4-thia-10-dime-
thyl-tricyclo[6,3,0,02,6]undecane S-dioxide and 23 in a 2:3:7 ratio. Tetraacetate 14 was converted
into the ꢀ-1-bromide 18 as well as into the ꢀ-1-O-trichloroacetimidate 17. These three compounds
were used as donors for the glycosylation with 4-cyanothiophenol, a€ording the 4-cyanophenyl
2,3,4-tri-O-acetyl-1,5-dithio-ꢀ- (29) and ꢁ-d-xylopyranoside (30) in di€erent ratios, depending on
the reaction conditions. When donor 18 was used in the presence of potassium carbonate, besides
29 and 30 two aryl C-glycosylated-thioglycosides, i.e. 4-cyano-2-(2,3,4-tri-O-acetyl-5-thio-ꢁ-d-
xylopyranosyl)phenyl 2,3,4-tri-O-acetyl-1,5-dithio-ꢀ- and ꢁ-d-xylopyranoside (32 and 33) as well
as 4-cyano-2-(2,3,4-tri-O-acetyl-5-thio-ꢁ-d-xylopyranosyl)phenyl disul®de 34 could be isolated as
byproducts. Deacetylation of 30 with sodium methoxide in methanol a€orded, besides 4-cyano-
phenyl 1,5-dithio-ꢁ-d-xylopyranoside (1), the corresponding 4-[(methoxy)(imino)methyl]phenyl
1
2
Orally active antithrombotic thioglycosides, Part V. For Part IV see [1].
Presented partly at the 9th European Carbohydrate Symposium, Utrecht, 6±11 July 1997, Abstr. A16.
* Corresponding author. Fax: 0036 13693229; e-mail: h13757kus@ella.hu
0008-6215/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved
PII S0008-6215(98)00088-3

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E. Bozo et al./Carbohydrate Research 308 (1998) 297±310
Â
298
glycoside 2. The 4-cyano group of 1 was converted into the 4-aminothiocarbonyl, the 4-(methyl-
thio)(imino)methyl, the 4-amidino and the 4-(imino)(hydrazino)methyl group. All of these glyco-
sides showed a signi®cant antithrombotic activity on rats. # 1998 Elsevier Science Ltd. All rights
reserved
Keywords: 1,2-O-Isopropylidene-ꢀ-d-xylofuranose cyclic sul®te and sulfate derivatives; 5-Thio-d-xylose deri-
vatives; Glycosidation reactions; Thioglycosides; C-Glycosides; Oral antithrombotic activity
1. Introduction
purity and containing only 2% of 5. According to
literature [5], the 5-thio group was introduced into
4 by the Whistler procedure [8] using the 5-O-tosyl
derivative 6 as the key intermediate which was
converted via the 5-S-benzyl derivative 7 into thiol
8, applying the reductive debenzylation with
sodium in liquid ammonia. For eluding this
unpleasant step, we introduced the thio group by a
modi®cation of Owen's procedure [9], using potas-
sium thiobenzoate instead of thioacetate as
reagent. However, depending on the reaction con-
ditions, a mixture of the S-benzoyl (11) and the
O,S-dibenzoyl 12 derivative, or a mixture of 12 and
the disul®de 16 was obtained. Formation of these
mixtures could be avoided by converting ®rst the
tosylate 6 into its 3-O-benzoate 10 [10], which gave
12 in a very clean reaction. Deacylation of 12 with
sodium methoxide in methanol a€orded, after
acidi®cation, methyl 5-thio-ꢀ-d-xylopyranoside
which was isolated as its triacetate 13. Acetolysis of
13 with acetic anhydride-sulfuric acid gave the tet-
raacetate 14 [9,11] which was converted into the
bromide 18 on treatment with hydrogen bromide
in acetic acid. A serious drawback of this reaction
sequence was the tosylation of 4, as the high yield
(90%) of 6 claimed in literature [5] (without giving
experimental details) could not be repeated by us.
Only the modest yield (60%) reported by Tipson
[12] was attained. On the other hand, the fact that
substitution of the 5-O-tosyl group by the thio-
benzoate could be carried out in satisfactory yield
only with the 3-O-protected derivative gave us the
idea to synthesize a cyclic 3,5-O-sulfate. It could be
presumed that a proper sulfur nucleophile could
attack this ester selectively at the less hindered
C-5 atom [13], and the resulting O-3-sulfate salt
could act as a protecting group which could be
selectively removed by hydrolysis [14]. As cyclic
sulfates are usually synthesized via the oxidation
of cyclic sul®tes [13±17], the reaction of diol 4
with thionyl chloride was investigated ®rst, using
dichloromethane as solvent and triethylamine ꢁas
base. The reaction was very fast even at 30 C
In the previous parts of this series of papers
[1±4], we have shown that the oral antithrombotic
activity of 4-cyanophenyl 1,5-dithio-ꢁ-d-xylopyr-
anoside (beciparcil, 1) [5] could be signi®cantly
increased by replacing the individual hydroxyl
groups of the pentose unit with azido groups or by
using the hexose congener (5-thio-d-glucopyr-
anose). During the synthesis of 1, which was nee-
ded as a reference compound for the biological
experiments, we isolated the corresponding 4-imi-
noether 2 as a byproduct. As the antithrombotic
activity of 2 superseded that of 1, a research pro-
gram was initiated, focusing on the structure-
activity relationships by transforming the cyano
group into di€erent carboxylic acid derivatives.
2. Results and discussion
An economic synthesis of 1,2,3,4-tetra-O-acetyl-
5-thio-d-xylopyranose.ÐIn the previous literature,
bromide 18 obtained from d-xylose (3) in an eight
step process [5] was used as glycosyl donor for the
synthesis of 1. For the conversion of 3 into the 1,2-
O-isopropylidene derivative 4, anhydrous copper
sulfate with sulfuric acid was used [6] a€ording a
mixture of 4 and the 1,2:3,5-di-O-isopropylidene
compound 5, which was converted in 70% yield
into 4 by partial hydrolysis with acetic acid. As,
according to the simple one pot synthesis of Mor-
avcova et al. [7], 4 can be obtained from 3 in a yield
of ꢀ90%, this method was applied by us. However
it turned out that the crude 4, obtained following
this procedure, had to be puri®ed by column chro-
matography before further use since the con-
taminants (ꢀ5% 3, ꢀ5% 5 and ꢀ10% inorganic
salts) decreased dramatically the yield of the next
step. This puri®cation could be avoided when the
mixture of 4 and 5 was partially hydrolysedꢁ in
methanol with 0.1 M hydrochloric acid at 40 C,
a€ording 4 in nearly quantitative yield and 98%

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E. Bozo et al./Carbohydrate Research 308 (1998) 297±310
Â
299
Scheme 1.
and two exo and endo3 isomers (19 and 20) were
formed respectively in a ratio of ꢀ2:1. They dif-
fered dramatically in almost all their properties and
reactivity, but their MS spectra both gave an
[M+H]+ ion at m/z 237, excluding a dimeric
structure.
lished by X-ray crystallography (see Figs. 1 and 2).
According to these data, the six membered ring of
the cyclic sul®te occupies an almost identical chair
conformation in both isomers, and the S!O bond
is in ``syn axial'' relation with the axially oriented
H-5a in 19.
The structures of 19 and 20 could not be
deduced from their NMR spectra, but were estab-
As cyclic sul®tes can undergo a selective ring
opening with strong nucleophiles via simultaneous
elimination of sulfur dioxide [18], the reaction of
potassium thiobenzoate with 19 and 20 in Nꢁ,N-
dimethyl formamide was investigated at 100 C.
While 20 was converted into the 5-S-benzoate 11
within 30 min, 5 h were needed for a complete
3
Exo and endo refers to the orientation of the S!O
bond in relation to the sugar furanose ring. The proper che-
mical name of 19 would be: 1R,2S,4R,7R,9R-3,5,8,10,12-pen-
taoxa-4-thia-11-dimethyl-tricyclo[7,3,0,02,7]-dodecane S-oxide
while in 20 the sulfur has the opposite con®guration (4S).

Â
Â
E. Bozo et al./Carbohydrate Research 308 (1998) 297±310
300
conversion of 19 and due to a partial 5-S!3-O
benzoyl migration a mixture of 11 and 12 was
formed. On the other hand, both 19 and 20 were
almost instantly oxidized by sodium periodate in
the presence of a catalytic amount of ruthenium(III)
chloride at room temperature a€ording the cyclic
sulfate 23 in excellent yield. The latter reacted
rapidly with potassium thioacetate in acetonitrile
to give the corresponding 5-S-acetate-3-O-sulfonic
acid potassium salt 26 in practically quantitative
yield. The sulfate ester could be hydrolyzed selec-
tively with aq sulfuric acid according [13,19] and
the resulting 3-OH derivative was isolated as its
acetate 27. However, this step was not necessary
for the conversion of 26 into 13, since all protecting
groups could be removed simultaneously by boil-
ing a methanolic solution of 26 in the presence of
hydrochloric acid, a€ording after acetylation 13 in
excellent yield (95%). The latter could be con-
verted by acetolysis in acetic anhydride-sulfuric
acid into 14 in 74% yield, consequently the overall
yield of the 3!4!19+20!23!26!13!14 reac-
tion sequence (Scheme 2) was 56%, making this
approach more economic than that published
(36.5%) [5].
(route a) yielding 21 and sulfur trioxide, or by a
substitution reaction with the chloride ion (route
b). The sultone 22 could be formed from 21 via
elimination of chlorine, which is a known reaction
under photochemical conditions [21]. Because of
the complex reaction and the low yield of 23, this
approach proved to be unsuitable for a large scale
synthesis of 14.
Synthesis of the 4-cyanophenyl 1,5-dithio-d-xylo-
pyranosides.ÐImidate 17 and bromide 18 have
been used [22] as 5-thio-d-xylopyranosyl donors
and reacted with 4-cyanothiophenol 28. The high-
est yield (64%) of the ꢁ-anomer 30 was obtained
using 18 in the presence of zinc oxide, but the for-
mation of the ꢀ-anomer 29 was not mentioned. In
order to check the in¯uence of the di€erent reac-
tion conditions on the yield and the anomeric ratio,
we applied acetate 14, imidate 17, as well as bro-
mide 18 as donors and used in the case of 18,
besides zinc oxide, potassium carbonate as pro-
moter too. From the data listed in Table 1, it can
be seen that although the yield was the highest
(90%) when acetate 14 was coupled with the agly-
con in the presence of trimethylsilyl tri¯ate, the ꢀ:ꢁ
ratio was 3:1. This might be the consequence of a
fast anomerisation of the primarily formed ꢁ-
anomer, catalysed by the presence of the strong
Lewis acid. The anomerisation was slower
(ꢀ:ꢁ=1:1) when imidate 17 was used as donor in
the presence of boron tri¯uoride diethyl etherate,
but the highest ꢁ-content (ꢀ:ꢁ ratio 1:4) was
obtained in the presence of zinc oxide, using bro-
mide 18 as donor. When the same reaction was
carried out in the presence of potassium carbonate,
besides 29 and 30 (3:7), their C-glycosylated
derivatives 32 and 33, as well as a C-glycosylated
disul®de 34 could be isolated in 5:2:1 ratio. As
proved earlier [1], the diglycosylated type deriva-
tives such as 32 and 33 are not formed via the
For shortening further the synthesis of 14, the
direct transformation of the diol 4 into the cyclic
sulfate 23 was considered. N,N-Sulfuryl diimida-
zole, which was used successfully [20] for a similar
reaction, is too expensive for an economic, large
scale synthesis. Therefore, the reaction of 4 with
sulfuryl chloride was investigated. When this reac-
tion was carried out in dichloromethane at 20 ꢁC in
the presence of triethylamine as base, a complex
.
mixture was formed containing besides SO3 Et3N
the 5-chloro-derivative 21, the sultone 22 and the
cyclosulfate 23 in a 2:3:7 ratio. The formation of 21
can be explained via 24 or 25, in which the terminal
ester group undergoes either a fragmentation
Fig. 1. ORTEP diagram of 19. Thermal ellipsoids represent
40% probabilities.
Fig. 2. ORTEP diagram of 20. Thermal ellipsoids represent
40% probabilities.

Â
E. Bozo et al./Carbohydrate Research 308 (1998) 297±310
Â
301
Scheme 2.
Table 1
Glycosydation of 4-cyanothiophenol with some 5-thio-d-xylopyranose donors under di€erent conditions
Donor
Promoter
Solvent
Time
Temperature
Yield (29+30)
ꢀ;ꢁ ratio (29:30)
14
17
18
18
TMSOTf
.
BF3 Et2O
ZnO
K2CO3
dichloroethane
dichloromethane
acetonitrile/toluene
acetone
1 h
0.5 h
0.5 h
1 h
r.t.
ꢁ
90%
60%
76%
45%
3:1
1:1
1:4
3:7
0 C
ꢁ
50 C
re¯.
corresponding S-glycosides 29 and 30. The forma-
tion of 34 strongly supported our earlier proposed
mechanism [1] according to which the C-glycosyl
type compound 31 is formed ®rst and is subse-
quently converted via S-glycosylation into the
diglycosylated derivatives (32 and 33). The inter-
mediate 31 is however air sensitive and is oxidized
during work up to 34 (Scheme 3).
Deacetylation of both S-glycosides 29 and 30
was carried out under Zemplen's conditions and
a€orded the crystalline ꢀ- 35 and ꢁ-anomer 1 in
excellent yield. However, when the reaction mix-
ture was not neutralized after completion, the slow
addition of methanol to the cyano group took
place and, in the case of 1, after 24 h at room tem-
perature the corresponding iminoether 2 could be

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E. Bozo et al./Carbohydrate Research 308 (1998) 297±310
Â
302
Scheme 3.
Scheme 4.
isolated in a 20% yield. This yield could not be
increased essentially by a prolonged reaction time,
or by a higher sodium methoxide concentration.
Attempts to convert the cyano group directly into
a carboxyl group failed, but it reacted readily in
pyridine±triethylamine solution with hydrogen sul-
®de and gave the corresponding thioamide 36 in
high yield. Methylation of 36 with methyl iodide in
acetone a€orded the highly crystalline methylthio-
imine 37 the methylthio group of which could be
easily exchanged by an amino or a hydrazino
group, a€ording amidine 38 and amidrazone 39,
respectively.
Biological results.ÐThe oral antithrombotic
activity of 1, 2, 36, 37, 38, and 39 was determined
in rats, using Pescador's model [23]. All com-
pounds were administered orally 3 h before liga-
tion. From the data listed in Table 2, it can be seen
that all beciparcil analogs in which the cyano
group of the aglycon was transformed into di€er-
ent carboxylic acid derivatives were more active
than beciparcil (1) itself. The most active com-
pound was the methylthio-derivative 37 which, in
contrary to the methoxy analogue 2, is stable only
as its hydroiodide salt and was selected for further
biological testing.
Table 2
Oral antithrombotic activity of 1, 2, 36, 37, 38 and 39 in rats
using Pescador's model [23]
Compound
1
2
36
37
38 39
ED50 (mg/kg)
25 10
5
1.5
5
2

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E. Bozo et al./Carbohydrate Research 308 (1998) 297±310
Â
303
3. Experimental
precoated Silica Gel 60 F254 plates, with hexane±
EtOAc mixtures (A, 1:1; B, 2:1; C, 3:1; D, 4:1; E,
5:1), toluene±MeOH mixture (F, 4:1), EtOAc±
EtOH mixture (G, 9:1) and EtOAc±pyridine±
water±AcOH mixture (H, 60:20:11:6); with
detection by spraying the plates with a 0.02 M soln
of I2 and a 0.3 M soln of KI in aꢁ10% aq H2SO4
soln followed by heating at ꢀ200 C. For column
chromatography, Kieselgel 60 was used. The mp
are uncorrected. Optical rotations were determined
General methods.ÐOrganic solns were dried
over MgSO4 and concentrated under diminished
pressure at or below 40 C. TLC used E. Merck
ꢁ
Table 3
Selected H NMR data for solutions in CDCl3
1
Compound
Chemical shift ꢂ
ꢁ
H-1
H-2
H-3
H-4
H-5a
H-5b
on 1.0% solns in CHCl3 at 20 C unless otherwise
1a
4.44
4.52
5.95
6.01
4.62
6.08
5.95
6.28
5.50
6.03
6.07
6.02
6.00
6.08
6.08
5.81
5.90
4.90
4.20
4.92
4.30
4.54
4.42
4.15
3.33 3.12
3.34 3.12
4.59 4.10
4.67 5.50
5.15 5.48
5.21 5.44
4.62 5.45
5.28 5.57
4.88 5.53
4.62 4.91
4.72 4.79
4.72 5.12
4.95 5.10
4.88 4.96
4.76 5.21
4.76 4.40
4.52 5.18
5.28 5.48
3.47
3.48
4.24
4.60
5.08
5.12
4.67
5.16
5.08
4.19
4.36
4.20
4.57
5.24
4.28
4.06
4.34
5.08
2.70
2.62
3.20
3.43
2.83
3.00
2.50
2.50
3.58
3.48
2.64
2.80
stated. NMR spectra were recorded with a Bruker
AC 250 spectrometer at 250 MHz (1H) and
62.9 MHz (13C) for solns in CDCl3 (internal
Me4Si) unless otherwise stated (Tables 3 and 4).
Multiplicities of the 13C NMR spectra were
obtained from DEPT experiments. The assignment
of the protons were based on homonuclear decou-
pling and NOE di€erence experiments. Con-
nectivities between identi®ed protons and
protonated carbons were observed by means of
HETCOR and selective INEPT experiments. The
ratio of ꢀ:ꢁ anomeric mixtures was determined by
1H NMR. Mass spectra were recorded with a Fin-
nigan MAT 8430 mass spectrometer/SS300 data
system. For the FAB mode, an Ion Tech FAB gun
(8 kV), and 4:1 glycerol±m-nitrobenzyl alcohol
matrix were used.
2a
11
12
13
14
16
17
18
19
20
20a
21
22
23
26
27
29
30
35a
36a
37a
38a
39a
3.00
3.06
3.13
4.16
4.57
4.56
3.66
2.82
2.93
4.96
4.57
4.80
3.75
3.46±3.64
4.86
3.01
3.14
3.14
2.75
2.73
2.64
2.72
2.65
2.58
5.00
3.06
3.17
2.80
2.87
2.60
2.48
2.52
2.50
2.46
5.20
5.02±5.16
3.86 3.34
3.28 3.06
3.36 3.12
3.35 3.12
3.24 3.05
3.48
3.44
3.48
3.45
3.40
Compound
Coupling constants (Hz)
Table 4
Selected 13C NMR data for solutions in CDCl3
J1,2
J2,3
J3,4
J4,5a
J4,5b
J5a,5b
Compound
Chemical shift ꢂ
1a
10.0
10.1
3.7 <1
3.8 <1
2.9
3.1
3.8 <1
9.8
8.6
8.8
8.6
2.2
2.9
9.9
9.9
2.5
10.0
10.94
4.3
4.3
4.3
10.0
7.3
4.7
4.6
nd
4.5
4.6
2.3
3.5
2.3
5.7
ꢀ1
2.0
5.9
6.9
4.6
4.0
3.4
4.6
4.1
4.2
4.6
13.2
13.3
14.2
13.6
13.0
13.1
nd
13.2
13.4
13.2
Ð
13.9
11.2
ꢀ14
12.9
13.7
13.6
13.4
14.0
13.4
13.3
13.0
13.2
13.2
2a
C-1
C-2 C-3 C-4 C-5
Others
11
12
13
14
16
17
18
19
20
20a
21
22
23
26
27
29
30
35a
36a
37a
38a
39a
6.7
1a
2a
50.6 78.9b 75.8b 73.0b 33.5
51.6 78.9b 75.8b 73.0b 33.6 164.9 (C=NH);
53.2 (OMe)
104.7 84.7b 80.8b 73.9b 25.4
104.8 83.5b 78.2b 77.0b 26.8
73.2b 72.4b 70.8b 69.9b 26.0
104.6 83.4b 77.9b 76.8b 36.2
76.0b 73.7b 72.4b 69.9b 26.2 160.7 (C=NH);
90.7 (CCl3)
10.2
10.2
11.2
11.3
ndb
11.3
11.2
11
12
14
16
17
3.1
3.4
10.2 10.0
9.8 9.8
3.7 <1
3.7 <1
3.8 <1
3.7 <1
3.3 <1
3.7 <1
3.7 <1
3.7 <1
4.4
10.3
3.9
10.1
11.1
9.9
2.1 ꢀ1
2.7
2.1
2.7
3.1
3.5
1.4
8.5
4.8
18
19
20
21
22
23
26
27
53.3 74.3b 72.2b 70.4b 27.6
104.5 83.2 69.0 70.8 55.3
105.5 83.6 79.8 72.0 63.4
104.8 86.8b 82.0b 78.7b 38.1
106.3 85.2b 82.3b 78.7b 52.0
104.4 82.4 87.3 69.2 73.6
104.4 83.4b 78.5b 78.4b 27.1
104.5 83.2b 77.7b 75.9b 26.3 30.2 (SAc);
20.5 (OAc)
2.1 ꢀ1
3.2
2.9
9.9
nd
7.6
7.2
11.2
10.2
9.9
10.6
11.0
9.8
10.2
9.9
8.8
8.6
9.5
8.6
8.6
8.8
8.6
9.5
8.6
8.6
30
38a
39a
50.6 73.7b 73.4b 72.0b 31.2 118.1 (CN)
51.0 73.0b 75.8b 79.0b 33.6 165.6 (C(NH2)2
52.4 73.0b 75.8b 79.0b 33.7 133.8 (C=NH)
+
)
10.1
10.7
a Me2SO-d6.
b nd, Not determined.
a Me2SO-d6.
b Arbitrary assignment.

Â
Â
E. Bozo et al./Carbohydrate Research 308 (1998) 297±310
304
Table 5
Crystal data and structure re®nement
Compound
19
20
Empirical formula
Formula weight
Crystal system
Space group
Unit cell dimensions, A
a (A)
C8H12O6S
236.24
tetragonal
P41212
orthorhombic
P212121
7.307(1)
6.704(1)
10.705(1)
14.279(2)
1024.8(2)
4
1.531
0.323 mm
496
b (A)
c (A)
39.572(8)
2112.8(6)
8
1.485
0.313
992
Volume A3
Z
Density (calc) (Mg/m3)
1
1
m (mm
F(000)
)
Crystal description
Crystal size (mm)
Re¯ections collected
Independent re¯ections
Data/restraints/parameters
Goodness-of-®t on F2
Final R indices [I>2ꢄ(I)]
R1
colourless blocks
0.50Â0.20Â0.15
0.30Â0.10Â0.10
4086
3480
2738/0/138
0.933
6852
2929
2455/0/138
0.931
0.0353
0.0834
0.0421
0.0841
wR2
R indices (all data)
R1
wR2
Weighting scheme used
k
0.0925
0.1144
0.1371
0.1137
w=1/[ꢄ2(Fo2)+(kP)2] where P=(Fo2+2Fo2)/3
0.462
0.06(11)
0.146, 0.164
0.463
0.07(10)
0.244±0.246
Absolute structure parameter
Largest di€. peak and hole (eA
3
)
X-ray data4: unit cell parameters were deter-
mined by least-squares of the setting angles of 25
(19: 15.08 ꢂꢃ ꢂ18.85ꢁ, 20: 13.14 ꢂꢃ ꢂ15.37ꢁ)
re¯ections. Intensity data were collected on an
Enraf±Nonius CAD4 di€ractometer (graphite
monochromator; Mo-Kꢀ radiation, l=0.71073 A)
at 293(2) K in the range 2.06 ꢂꢃ ꢂ29.45ꢁ (19, index
ranges: 10 ꢂ h ꢂ 10; 10 ꢂ k 10; 54 ꢂ l 54) and
2.38ꢂ ꢃ ꢂ32.40ꢁ (20, index ranges: 10 ꢂ h ꢂ 10;
16 ꢂ k ꢂ 16; 21 ꢂ l ꢂ 21) using !±ꢃ scans. The
intensities of three standard re¯ections were
monitored regularly every 60 min. The intensities
of the standard re¯ections indicated 2% (19) and
3% (20) decay. The structures were solved by
direct methods [24] and re®ned by anisotropic full
matrix least-squares on F2 [25]. Crystal data and
re®nement details are shown in Table 5. Hydrogen
atomic positions were calculated from assumed
geometries. Hydrogen atoms were included in
structure factor calculations but they were not
re®ned. The methyl hydrogen atoms were allowed
to rotate about the C±CH3 bonds. Neutral atomic
scattering factors and anomalous scattering factors
were taken from [26]. Final atomic parameters are
listed in Tables 6 and 7, bond lengths and angles
are given in Tables 8 and 9.
1,2-O-Isopropylidene-a-d-xylofuranose (4).ÐA
slurry of 3 (150 g) and anhyd CuSO4 (200 g) in
acetone (3 L) and H2SO4 (15 mL) was stirred at
20 ꢁC for 24 h and was then ®ltered. Concd
NH4OH (48 mL) was added and the ®ltered soln
was concentrated to yield a syrup containing
according to GLC [7] 4 and 5 in a ratio of ꢀ1:9.
This mixture was dissolved in MeOH (1.200 L),
ꢁ
warmed to 40 C, and then 0.1 M HCl (330 mL)
was added. After 100 min, when 5 (Rf 0.7, solvent
F) was completely converted into 4 (Rf 0.4, solvent
F) the mixture was neutralized with solid NaHCO3,
®ltered, concentrated and then coevaporated with
EtOH and toluene. The residue was dissolved in
CH2Cl2 (500 mL) dried, ®ltered and concentrated
to yield a syrup (190 g, ꢀ100%) containing,
according to GLC, 98% of 4 and 2% of 5.
4
Tables of atomic coordinates, bond lengths, and bond
angles have been deposited with the Cambridge Crystal-
lographic Data Centre. These tables may be obtained, on
request, from the Director, Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge, UK, CB2 1EZ.
Reaction of 6 with potassium thiobenzoate.Ð(a)
To a soln of 6 [11] (0.7 g) in DMF (10 mL), KSBz

Â
E. Bozo et al./Carbohydrate Research 308 (1998) 297±310
Â
305
Table 6
Table 7
Hydrogen coordinates (Â104) and isotropic displacement
Atomic coordinates (Â104) and equivalent isotropic displace-
ment parameters (A2Â103). U(eq) is de®ned as one third of the
trace of the orthogonalized Uij tensor
parameters (A2Â103)
19
19
x
y
z
U(iso)
Atom
x
y
z
U(eq)
Atom
H-1
H-2
H-3
H-4
H-6a
H-6b
H-14a
H-14b
H-14c
H-15a
H-15b
H-15c
9387
8726
9790
2970
1834
1535
1129
2464
3682
4935
5649
4535
1357
2243
3436
878
359
366
776
1286
971
250
294
30
60
60
56
58
75
75
104
104
104
114
114
114
C-1
C-2
C-3
C-4
O-5
C-6
O-7
S-8
O-9
O-10
C-11
O-12
O-13
C-14
C-15
10319(3)
9776(3)
9491(3)
10742(3)
10597(2)
10258(3)
8324(2)
6985(1)
7587(2)
11363(2)
12424(3)
11946(2)
7570(3)
11916(4)
14410(3)
2146(3)
1275(3)
726(3)
987(2)
707(2)
2553(3)
2595(2)
2724(1)
879(2)
1434(2)
2923(3)
3080(2)
4234(2)
4667(3)
2447(4)
800(1)
462(1)
549(1)
853(1)
1031(1)
1080(1)
1158(1)
843(2)
646(1)
262(1)
385(1)
733(1)
634(1)
209(1)
352(1)
47(1)
46(1)
43(1)
44(1)
52(1)
58(1)
66(1)
63(1)
56(1)
54(1)
49(1)
57(1)
75(1)
77(1)
84(1)
11981
10948
10584
10649
12658
12115
14663
14700
15141
479
118
437
20
H-1
H-2
H-3
H-4
H-6a
H-6b
H-14c
H-14b
H-14c
H-15a
H-15b
H-15c
235
85
807
2442
1705
215
1787
893
3376
3163
4134
1596
3033
2079
7539
6537
4999
5706
5320
4464
8060
8676
7855
6865
7063
7895
45
43
43
49
64
64
72
72
72
70
70
70
1708
3663
2383
2480
1755
3661
3707
6433
6601
6680
20
C-1
C-2
C-3
C-4
O-5
C-6
O-7
S-8
O-9
O-10
C-11
O-12
O-13
C-14
C-15
1394(4)
1206(4)
1116(3)
2260(3)
1643(3)
1837(4)
285(3)
851(2)
1904(2)
1232(2)
35(2)
7145(2)
6425(1)
5498(2)
5709(2)
6645(1)
5055(2)
4907(1)
4441(1)
5321(1)
6476(1)
7392(2)
7672(1)
4465(2)
8056(2)
7295(2)
35(1)
33(1)
33(1)
38(1)
43(1)
49(1)
46(1)
40(2)
38(1)
41(1)
36(1)
44(1)
65(1)
53(1)
52(1)
263(1)
1037(2)
1210(1)
14(1)
1304(1)
979(2)
966(1)
3055(3)
3871(4)
3101(3)
3406(3)
3186(5)
6097(4)
2530(2)
2332(2)
1146(2)
254(2)
3343(3)
2253(3)
110 ꢁC for 1.5 h. After concentration, the residue was
dissolved in CH2Cl2, washed with water, con-
centrated and submitted to column chromatography
(solvent D). Concentration of the ®rst fraction gave
12 (200 mg, 24%), identical with the compound
described above.
Concentration of the second fraction gave 5-S-
benzoyl-1,2-O-isopropylidene-ꢀ-d-xylofuranose
(11, 240 mg, 38%): mp 146±148 ꢁC (hexane);
[ꢀ]d+54ꢁ; Rf 0.3 (solvent D); Anal. Calcd for
C15H18O6S: C, 63.75; H, 5.35; S, 7.74. Found: C,
63.62; H, 5.18; S, 7.87.
(0.5 g) was added and the mixture was re¯uxed for
2 h. After concentration, the residue was dissolved
in CH2Cl2, washed with water, concentrated and
submitted to column chromatography (solvent D).
Concentration of the ®rst fraction gave 3-O-ben-
zoyl-5-S-benzoyl-1,2-O-isopropylidene-ꢀ-d-xylo-
furanose (12, 200 mg, 24%): mp 92±94 ꢁC
(hexane); [ꢀ]d 100ꢁ (c 0.5, CHCl3); Rf 0.6 (solvent
D); Anal. Calcd for C22H22O6S: C, 63.75; H, 5.35;
S, 7.74. Found: C, 63.62; H, 5.18; S, 7.87.
Concentration of the second fraction gave 3-O-
benzoyl-1,2-O-isopropylidene-5-thio-ꢀ-d-xylofur-
anose disul®de (16, 350 mg, 56%): [ꢀ]d+68ꢁ (c 0.5,
CHCl3); Rf 0.4 (solvent D); Anal. Calcd for
C30H34O10S2: C, 58.24; H, 5.54; S, 10.36. Found:
C, 58.19; H, 5.47; S, 10.35.
3-O-Benzoyl-5-S-benzoyl-1,2-O-isopropylidene-a-
d-xylofuranose (12).ÐTo a soln of 10 [10] (20.3 g)
in DMF (110 mL), KSBz (11.9 g) was added and
ꢁ
the mixture was stirred at 110 C for 1 h. After
concentration, the residue was dissolved in CH2Cl2,
washed with water and concentrated to yield 12
(17.8 g, 95%) identical with the compound described
above.
1,2-O-Isopropylidene-a-d-xylofuranose 3,5-cyclic
sul®tes (19 and 20).ÐTo a stirred soln of crude 4
(190 g) in CH2Cl2 (2 L) and Et3N (340 mL), thionyl
(b) To a soln of 6 (0.7 g) in DMF (10 mL), KSBz
(0.5 g) was added and the mixture was stirred at

Â
E. Bozo et al./Carbohydrate Research 308 (1998) 297±310
Â
306
Table 8
Bond distances and angles
Table 9
Ring torsion angles
Atom 1
Atom 2
Distance (A)
Atom 1 Atom 2 Atom 3 Atom 4
Torsion angle (ꢁ)
19
20
19
20
C-1
C-1
C-1
C-2
C-2
C-3
C-3
C-4
C-4
C-6
O-7
S-8
O-5
O-12
C-2
O-10
C-3
O-9
C-4
O-5
C-6
O-7
S-8
O-13
O-9
C-11
O-12
C-15
C-14
1.410(2)
1.395(2)
1.531(3)
1.410(2)
1.516(3)
1.447(2)
1.522(3)
1.429(2)
1.499(3)
1.447(3)
1.590(2)
1.442(2)
1.617(1)
1.421(2)
1.428(2)
1.498(3)
1.498(3)
1.400(3)
1.406(3)
1.531(3)
1.411(3)
1.508(3)
1.455(3)
1.523(3)
1.435(3)
1.506(3)
1.450(3)
1.620(2)
1.438(2)
1.632(2)
1.435(3)
1.428(3)
1.501(3)
1.510(3)
Pentafuranose ring O-5 C-1 C-2 C-3 C-4
O-5
O-12
O-12
O-5
O-10
C-1
C-1
C-1
C-1
C-1
C-2
C-2
C-2
C-2
C-3
C-3
C-3
C-3
C-1
C-1
C-4
C-4
C-2
C-2
C-2
C-2
C-3
C-3
C-3
C-3
C-4
C-4
C-4
C-4
O-5
O-5
O-5
O-5
O-10
O-10
C-3
C-3
O-9
O-9
C-4
C-4
O-5
O-5
C-6
C-6
C-4
C-4
C-1
C-1
104.8(2)
13.7(2)
127.4(2)
8.8(2)
105.9(2)
12.9(2)
125.7(2)
6.9(2)
160.5(1)
89.1(2)
83.2(2)
27.1(2)
75.9(2)
36.3(2)
44.8(2)
157.0(2)
99.5(2)
14.8(2)
156.5(2)
32.4(2)
160.9(2)
89.0(2)
82.8(2)
27.3(2)
74.7(2)
38.4(2)
45.8(3)
159.0(2)
96.3(2)
18.3(2)
159.4(2)
35.9(2)
O-10
C-1
O-9
C-2
O-9
C-2
O-12
C-2
C-6
S-8
O-10
C-11
C-11
C-11
C-3
Ring S-8 O-7 C-6 C-4 C-3 O-9
Atom 1
Atom 2
Atom 3
Angle (ꢁ)
O-5
C-3
C-4
C-6
C-6
C-2
C-4
O-13
O-7
C-4
C-4
C-6
O-7
O-7
C-3
C-3
S-8
C-6
C-6
O-7
S-8
O-7
O-7
S-8
O-13
O-9
S-8
S-8
C-3
C-3
70.5(2)
46.6(2)
57.9(2)
51.6(2)
59.1(2)
164.8(1)
54.5(2)
53.7(2)
58.4(2)
69.4(3)
47.0(3)
60.8(2)
172.4(2)
66.1(2)
169.3(1)
59.1(2)
172.6(2)
66.0(2)
19
20
O-12
O-12
O-5
O-10
O-10
C-3
O-9
O-9
C-2
O-5
C-1
C-1
C-1
C-2
C-2
C-2
C-3
C-3
C-3
C-4
C-4
C-4
O-5
C-6
O-7
S-8
O-5
C-2
C-2
C-3
C-1
C-1
C-2
C-4
C-4
C-6
C-3
C-3
C-4
C-4
S-8
O-7
O-9
O-9
S-8
C-11
O-12
C-15
C-15
C-14
C-14
C-14
C-11
111.4(2)
105.1(2)
107.1(2)
108.6(2)
104.1(2)
103.9(2)
105.5(2)
111.0(2)
102.5(1)
110.3(2)
103.7(1)
115.3(2)
109.6(1)
112.0(2)
115.7(1)
108.2(1)
106.4(1)
99.3(1)
117.0(1)
108.6(1)
105.0(2)
108.7(2)
109.9(2)
111.0(2)
108.6(2)
113.4(2)
110.5(1)
111.6(2)
105.1(2)
107.1(2)
107.9(2)
104.1(2)
104.0(2)
106.6(2)
110.8(2)
102.0(2)
110.7(2)
103.1(2)
115.1(2)
108.7(2)
111.9(2)
111.8(2)
104.0(1)
103.8(1)
97.61(9)
112.7(1)
108.1(2)
104.4(2)
107.7(2)
109.6(2)
110.5(2)
110.6(2)
113.6(2)
110.1(2)
S-8
O-9
O-9
O-9
O-9
S-8
Ring O-10 C-2 C-1 O-12 C-11
C-3
C-1
C-2
O-5
C-2
O-10
C-2
C-2
O-10
C-1
C-1
O-10
O-10
C-11
O-12
O-12
O-12
C-11
C-11
O-12
C-11
C-11
C-1
135.0(2)
24.7(2)
26.3(2)
117.7(2)
2.1(2)
136.0(2)
26.0(2)
29.2(2)
120.6(2)
4.9(2)
O-5
C-6
C-1
O-7
C-11
17.0(2)
20.5(2)
C-6
O-13
O-13
O-7
C-3
C-2
O-10
O-10
O-12
O-10
O-12
C-15
C-1
S-8
S-8
(50 ml) for 15 min to give, after cooling and ®ltra-
tionꢁthe endo isomer 20 (2.9 g, 29%); mp 132±
134 C (acetone±hexane); [ꢀ]d 10ꢁ; Rf 0.4 (solvent
C); MS: m/z 237 [M+H]+. The residue, obtained
on concentration of the ®ltrate, was submitted to
column chromatography (solvent C). The residue,
obtained on concentration of the fractions having
Rf 0.7, was crystallized with ether toꢁgive the exo
isomer 19 (6.1 g, 61%); mp 100±102 C (acetone±
hexane); [ꢀ]d+47ꢁ; MS: m/z 237 [M+H]+. Anal.
Calcd for C8H12O6S: C, 40.67; H, 5.12; S, 13.57.
Found for 19: C, 40.60; H, 5.08; S, 13.35. Found
for 20: C, 40.65; H, 5.15; S, 13.38.
O-9
O-10
C-11
C-11
C-11
C-11
C-11
C-11
O-12
chloride (78 mL) was added at 30 ꢁC. Stirring was
continued for 15 min, then water (40 mL) was
added gradually. The mixture was washed with
water, 6% aq NaHCO3, and water to give after
concentration a solid crude mixture (231 g, 98%)
containing 19 and 20 in a ratio of ꢀ2:1. An aliquot
part (10 g) of this mixture was boiled with ether
Reaction of 19 and 20 with potassium thiobenzo-
ate.Ð(a) A soln of 20 (0.5 g) and KSBz (0.4 g) in
DMF (10 mL) was stirred at 100 C. After 30 min,
when according to TLC the starting material
was consumed, the mixture was concentrated, the
ꢁ

Â
E. Bozo et al./Carbohydrate Research 308 (1998) 297±310
Â
307
residue dissolved in CH2Cl2 and washed with water
to give, after concn and ®ltration of the residue
with water, 11 (0.35 g, 53%) identical with the
compound described above.
Anal. Calcd for C12H18O6S: C, 49.64; H, 6.25; S,
11.04. Found: C, 49.60; H, 6.32; S, 10.95.
Methyl
2,3,4-tri-O-acetyl-5-thio-a-d-xylopy-
ranoside (13).Ð(a) A soln of 12 (2.0 g) in MeOH
(50 mL) and 3 M methanolic NaOMe (2.5 mL) was
stirred at room temperature for 1 h, then acidi®ed
with 10% aq HCl and re¯uxed for 1 h. After neu-
tralization with Et3N, the mixture was concentrated,
the residue was dissolved in pyridine (10 mL) and
Ac2O (10 mL) was added. The mixture was kept at
room temperature for 24 h, then processed the usual
way to give after column chromatography (solvent
B) 13 (0.95 g, 64%): [ꢀ]d+196ꢁ; Rf 0.6 (solvent B);
Anal. Calcd for C12H18O7S: C, 47.05; H, 5.93; S,
10.45. Found: C, 46.88; H, 5.90; S, 10.34.
(b) A soln of 26 (36.6 g) in MeOH (370 mL) and
concd HCl (37 mL) was boiled for 1.5 h. The
cooled mixture was neutralized with solid
NaHCO3, ®ltered and concentrated. Then, EtOH
and toluene were added and destilled o€ from the
residue which was thereafter dissolved in pyridine
(80 mL) and Ac2O (60 mL) was added. The mixture
was processed through the usual way after 24 h at
room temperature to give a syrup (29.5 g, 96.5%)
which, according to NMR contained >90% 13.
Column chromatography (solvent B) gave 13 iden-
tical with the compound described above.
(bꢁ) A similar mixture of 19 had to be heated to
100 C for 5 h, until the starting material was con-
sumed. The mixture was concentrated, the residue
dissolved in CH2Cl2 and washed with water. Col-
umn chromatography (solvent D) of the residue
obtained after concentration of the CH2Cl2 soln
a€orded 11 (0.25 g, 38%) and 12 (0.17 g, 19%)
identical with the compounds described above.
1,2-O-Isopropylidene-a-d-xylofuranose 3,5-O-
cyclic sulfate (23).ÐTo a stirred and ice cooled
soln of the crude mixture of 19 and 20 (120 g) in
EtOAc (600 mL) and CH3CN (600 mL), RuCl3
hydrate (50 mg) and subsequently a soln of NaIO4
(240 g) in water (2.4 L) was addedꢁat such a rate to
keep the temperature below 20 C. The formed
slurry was ®ltered after 30 min and the solid
material was washed with water (200 mL) and then
separately with EtOAc (3Â200 mL). The aq soln
was extracted with EtOAc (3Â200 mL), then the
combined organic solns were washed with 6% aq
NaHCO3, and wateꢁr to give after concn 23 (105 g,
82%); mp 151±155 C (acetone±hexane); [ꢀ]d+21ꢁ
(c 1, acetone); Rf 0.5 (solvent C); MS m/z 253
[M+H]+. The yields from 19 and 20 were 86 and
88%, respectively. Anal. Calcd for C8H12O7S: C,
38.09; H, 4.80; S, 12.71. Found: C, 38.12; H, 4.75;
S, 12.66.
1,2,3,4-Tetra-O-acetyl-5-thio-a-d-xylopyranose
(14).ÐTo a stirred soln of 13 (100 g) in Ac2O
ꢁ
(110 mL), concd H2SO4 (7 mL) was addeꢁd at 0 C
and stirring was continued for 1 h at 0 C. After
adding NaOAc (15 g), the pH was adjusted to ꢀ6
with ice-cold 6% aq NaHCO3 and stirring was
continued at room temperature for 2 h. Then, the
mixture was extracted with CH2Cl2, washed with
water, concentrated and submitted to column
chromatography (solvent B) to give 14 (80.8 g,
5-S-Acetyl-1,2-O-isopropylidene-a-d-xylofuranose
3-O-sulfonic acid potassium salt (26).ÐTo a stirred
soln of 23 (25.2 g) in CH3CN (250 mL), KSAc
(12 g) was added at room temperature. After 1 h,
the mixture was concentrated and the residue was
taken up in acetone±ether and the solids were
removed by ®ltration to give 26 (35.5 g, 97%); mp
ꢁ
74%); mp 98±100 C (ether±hexane); [ꢀ]d+204ꢁ (c
ꢁ
223 C dec.; [ꢀ]d 20ꢁ (c 1, water); Rf 0.4 (solvent
0.5); Rf 0.4 (solvent B); lit mp 98±100 ꢁC,
ꢁ
G); Anal. Calcd for C10H15O8S2K: C, 32.78; H,
4.13; S, 17.50; K, 10.67. Found: C, 32.55; H, 4.03;
S, 17.64; K, 10.89.
[ꢀ]d+210ꢁ (c 2.8) [9]; lit mp 99±100 C, [ꢀ]d+219ꢁ
(c 2.2) [11].
O-(2,3,4-Tri-O-acetyl-5-thio-a-d-xylopyranosyl)
trichloroacetimidate (17).ÐUnder argon, hydrazine
acetate (0.4 g) was added to a stirred soln of 14
(1.0 g) in DMF (30 mL) at room temperature. After
2 h, EtOAc (50 mL) and CH2Cl2 (50 mL) were
added, the organic layer was washed with brine,
concentrated and the residue submitted to column
chromatography (solvent A) to yield 15 (0.6 g,
69%): Rf 0.3 (solvent B). The resulting compound
was dissolved in CH2Cl2 (10 mL), CCl3CN
(2.05 mL) and K2CO3 (2.8 g) were added under
3-O-Acetyl-5-S-acetyl-1,2-O-isopropylidene-a-d-
xylofuranose (27).ÐTo a stirred soln of 26 (3.7 g)
in THF (100 mL), concd H2SO4 (5 mL) and water
(1.8 mL) were added. After 30 min at room tem-
perature, when hydrolysis of the sulfonic ester was
complete (Rf 0.4!0.7; solvent G), pyridine (20 mL)
and Ac2O (10 mL) were added. The mixture was
concentrated after 2 h and the residue puri®ed by
column chromatography (solvent E) to give 27
(1.8 g, 63%) as syrup; [ꢀ]d 17ꢁ; Rf 0.5 (solvent C);

Â
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E. Bozo et al./Carbohydrate Research 308 (1998) 297±310
308
argon and the mixture was stirred for 24 h at room
temperature. After diluting with ether, the mixture
was ®ltered through a bed of Celite, concentrated
and the residue submitted to column chromato-
graphy (solvent B) to yield 17 (0.6 g, 67%): mp
105±108 ꢁC (hexane±EtOAc); lit. [22] 110 ꢁC;
[ꢀ]d+221ꢁ (c 0.5, CHCl3); lit. [22] +227ꢁ (c 0.42,
CHCl3); Rf 0.7 (solvent B).
2,3,4-Tri-O-acetyl-a-d-xylopyranosyl bromide
(18).ÐTo a stirred soln of 15 (10 g) in CH2Cl2
(40 mL), 33% HBr in AcOH (20 mL) was added
and stirring was continued for 1 h at room tem-
perature. Then, the mixture was poured into ice-
water, extracted with CH2Cl2, washed with 6% aq
NaHCO3, water and concentrated to yield 18
temperature was allowed to raise and the mixture
was stirred at room temperature for 1 h, then
quenched with Et3N. The residue, obtained on
concentration, was submitted to column chroma-
tography (solvent A) to yield a 3:1 mixture of 29
and 30 (1.92 g, 90%).
Reaction of 17 with 4-cyanothiophenol.Ð4-Cya-
nothiophenol (95 mg) was added under argon to a
stirred soln of 17 (250 mg) in dry CH2Cl2 (10 mL)
and the mixture was cooled to 0 ꢁC. After addition
.
of 0.1 M BF3 OEt2 (1 mL) in CH2Cl2, the mixture
ꢁ
was stirred at 0 C for 30 min, then quenched with
Et3N. The residue, obtained on concentration, was
submitted to column chromatography (solvent A)
to yield a 1:1 mixture of 29 and 30 (140 mg, 60%).
Reaction of 18 with 4-cyanothiophenol.Ð(a) 4-
Cyanothiophenol (4.4 g) was added to a stirred
soln of 18 (10.5 g) in dry toluene (100 mL) and dry
MeCN (100 mL). After addition of ZnO (2.8 g), the
mixture was stirred at 50 ꢁC for 30 min, then
cooled to room temperature, ®ltered through Celite
and concentrated. The residue was submitted to
column chromatography (solvent A) to yield a 1:4
mixture of 29 and 30 (9.12 g, 76%).
(b) 4-Cyanothiophenol (2.6 g) and K2CO3 (2.6 g)
were added to a stirred soln of 18 (5 g) in dry
acetone (250 mL) and the mixture was re¯uxed
for 1 h. Then the reaction was cooled to room
temperature, ®ltered, the ®ltrate was concentrated,
and the residue was submitted to column chroma-
tography (solvent A) to yield on concentration of
the ®rst fraction a 3:7 mixture of 29 and 30 (2.67 g,
45%).
ꢁ
ꢁ
(10.5 g, 99%): mp 115 C (hexane), lit. 115 C [8];
[ꢀ]d +221ꢁ (c 0.5, CHCl3), lit. [8] +245ꢁ (c 1.75,
MeOH); Rf 0.7 (solvent B).
Reaction of 4 with sulfuryl chloride.ÐTo a
stirred soln of 4 (1.9 g, 10 mmol) in CH2Cl2
(30 mL), Et3N (3.4 mL, 25 mmol) and after cooling
ꢁ
to 0 C a soln of SO2Cl2 (0.9 mL, 11 mmol) in
CH2Cl2 (10 mL) was added. The mixture was kept
ꢁ
at 20 C for 24 h. The solid residue obtained on
concentration of the CH2Cl2 soln (2.5 g) contained
.
SO3 Et3N, 21, 22 and 23 in a 3:2:3:7 ratio. Column
chromatography (solvent E) a€orded 5-chloro-3-
O-chlorosulfonyl-5-deoxy-1,2-O-isopropylidene-d-
xylofuranose (21, 0.15 g, 5%); mp 82±84 ꢁC;
[ꢀ]d 74ꢁ; Rf 0.55 (solvent C); MS: m/z 308
[M+H]+; Anal. Calcd for C8H12Cl2O6S: C, 31.28;
H, 3.94; Cl, 23.09; S, 10.44. Found: C, 31.41; H,
4.03; Cl 22.88; S, 10.32.
Concentration of the fraction with Rf 0.5 gave a
1:2 mixture of 22 and 23 (1.6 g). This was dissolved
in CH3CN (20 mꢁL) and KSAc (0.8 g) was added.
After 20 h at 20 C the mixture was concentrated
and the residue was taken up in CH2Cl2. The solids
were removed by ®ltration to give crude 23 con-
taminated with KSAc. The organic soln was
washed with water to give on concentration
3,7,9,11-tetraoxa-4-thia-10-dimethyl-tricyclo[6,3,
0,02,6]undecane S-dioxide (22, 0.5 g, 21%); mp
150±152 ꢁC; [ꢀ]d +37ꢁ; Rf 0.5 (solvent C); MS m/z
237 [M+H]+; Anal. Calcd for C8H12O6S: C,
40.67; H, 5.12; S, 13.57. Found: C, 40.70; H, 5.18;
S, 13.55.
Concentration of the second fraction gave 4-
cyano-2-(2,3,4-tri-O-acetyl-5-thio-ꢁ-d-xylopyrano-
syl)phenyl 2,3,4-tri-O-acetyl-1,5-dithio-ꢀ-d-xylo-
ꢁ
pyranoside (32, 0.95 g, 20%): mp 97±102 C (hex-
ane); [ꢀ]d +164ꢁ (c 0.5, CHCl3); Rf 0.4 (solvent A);
1H NMR: ꢂ 5.63 (dd, 1 H, H-3), 5.44 (dd, 1 H, H-
200), 5.26 (dd, 1 H, H-300), 5.22 (dd, 1 H, H-2), 5.21
(ddd, 1 H, H-400), 5.07 (ddd, 1 H, H-4), 4.87 (d, 1
H, H-1), 4.86 (d, 1 H, H-100), 3.16 (dd, 1 H, H-5ax),
3.11 (dd, 1 H, H-500ax), 2.96 (dd, 1 H, H-500eq), 2.84
(dd, 1 H, H-5eq), 2.10±1.72 (m, 18 H, OAc); J1,2
4.5, J2,3 10.0, J3,4 9.6, J4,5ax 11.0, J4,5eq 4.9, J5ax,5eq
00 00
00 00
00 00
13.5, J1,5eq 1.4, J1 ,2 10.6, J2 ,3 9.6, J3 ,4 9.9,
J4 ,5 ax 10.5, J4 ,5 eq 4.2, J5 ax,5 eq 13.4 Hz; 13C
NMR: ꢂ 169.9, 169.8, 169.8, 169.7, 169.5, 168.7
(C=O), 140.3 (C-10), 139.3 (C-20), 134.5 (C-60),
132.0 (C-30), 131.7 (C-50), 117.4 (CN), 112.7 (C-40),
75.2 (C-2), 75.1 (C-200), 74.3 (C-300), 72.7 (C-400),
72.6 (C-4), 69.8 (C-3), 53.1 (C-1), 45.1 (C-100), 31.0
00 00
00 00
00
00
Reaction of 14 with 4-cyanothiophenol.Ð4-Cya-
nothiophenol (1.3 g) was added under argon to a
stirred soln of 14 (1.75 g) in dry 1,2-dichloroethane
ꢁ
(25 mL) and the mixture was cooled to 10 C.
After addition of Me3SiOTf (0.9 mL), the

Â
E. Bozo et al./Carbohydrate Research 308 (1998) 297±310
Â
309
(C-500), 26.9 (C-5), 20.8, 20.8, 20.6, 20.5, 20.3, 20.1
(OAc). Anal. Calcd for C29H33NO12S3: C, 50.94;
H, 4.86; N, 2.05; S, 14.07. Found: C, 50.99; H,
4.73; N, 2.11; S, 14.13.
[ꢀ]d+45ꢁ (c 0.5, CHCl3), lit.+37ꢁ (c 0.5, CHCl3)
[23]; Rf 0.4 (solvent B); Anal. Calcd for C18H19
NO6S2: C, 52.80; H, 4.68; N, 3.42; S, 15.66. Found:
C, 52.92; H, 4.75; N, 3.36; S, 15.59.
Concentration of the third fraction gave
4-cyano-2-(2,3,4-tri-O-acetyl-5-thio-ꢁ-d-xylopyr-
anosyl)phenyl disul®de (34, 0.23 g, 4%): mp 158±
Column chromatography (solvent B) of the
mother liquor gave 29 (1.1 g, 12%): mp 104±106 ꢁC
(hexane); [ꢀ]d+368ꢁ (c 0.5, CHCl3); Rf 0.45 (sol-
vent B); Anal. Calcd for C18H19NO6S2: C, 52.80;
H, 4.68; N, 3.42; S, 15.66. Found: C, 52.72; H,
4.65; N, 3.47; S, 15.70.
4-Cyanophenyl 1,5-dithio-b-d-xylopyranoside
(1).ÐA soln of 30 (6.0 g) in MeOH (240 mL) and
methanolic M NaOMe (0.1 mL) was stirred for
30 min at room temperature to yield, after deioni-
zation with Dowex 50 WX resin and concentra-
ꢁ
163 C (EtOAc-hexane); [ꢀ]d+26ꢁ (c 0.3, CHCl3);
Rf 0.35 (solvent A); 1H NMR: ꢂ 7.74 (d, 1 H, H-30),
7.72 (d, 1 H, H-60), 7.54 (dd, 1 H, H-50), 5.51 (dd, 1
H, H-2), 5.20 (ddd, 1 H, H-4), 5.17 (dd, 1 H, H-3),
4.59 (d, 1 H, H-1), 2.96 (dd, 1 H, H-5eq), 2.81 (dd,
1 H, H-5ax), 2.05±1.76 (m, 18 H, OAc); J1,2 10.6,
J2,3 9.6, J3,4 9.5, J4,5ax 10.1, J4,5eq 4.3, J5ax,5eq
13.5 Hz; 13C NMR: ꢂ 169.8, 169.7, 168.7 (C=O),
141.9 (C-10), 136.2 (C-20), 132.4 (C-50), 131.7 (C-30),
129.6 (C-60), 117.4 (CN), 112.6 (C-40), 74.5 (C-2),
74.1 (C-3), 72.3 (C-4), 44.8 (C-1), 31.3 (C-5), 20.8,
20.5, 20.2 (OAc); MS m/z 757 [M+H-AcOH]+.
Anal. Calcd for C36H36N2O12S4: C, 52.93; H, 4.44;
N, 3.43; S, 15.70. Found: C, 52.88; H, 4.33; N,
3.51; S, 15.62
ꢁ
ꢁ
tion, 1 (4.0 g, 96%): mp 173±175 C, lit. 175 C
[22]; [ꢀ]d+35ꢁ (c 0.5, MeOH), lit. [22] +36ꢁ (c 0.5,
MeOH); Rf 0.4 (solvent F).
4-[(Imino)(methoxy)methyl]phenyl 1,5-dithio-
b-d-xylopyranoside (2).ÐTo a soln of 1 (0.45 g), in
dry MeOH (10 mL), methanolic M NaOMe
(0.1 mL) was added. After 24 h at room tempera-
ture, the mixture was neutralized with solid CO2
and concentrated. The residue was submitted to
column chromatography (solvent F) to give, on
concentration of the ®rst fraction (Rf=0.4), the
unchanged starting material (350 mg).
Concentration of the fourth fraction gave
4-cyano-2-(2,3,4-tri-O-acetyl-5-thio-ꢁ-d-xylopyr-
anosyl)phenyl
2,3,4-tri-O-acetyl-1,5-dithio-ꢁ-d-
ꢁ
xylo-pyranoside (33, 0.43 g, 9%): mp 117±121 C
(hexane); [ꢀ]d+94ꢁ (c 0.5, CHCl3); Rf 0.3 (solvent
A); 1H NMR: ꢂ 7.76 (d, 1 H, H-30), 7.73 (d, 1 H, H-
60), 7.54 (dd, 1 H, H-50), 5.46 (dd, 1 H, H-200), 5.28
(dd, 1 H, H-2), 5.19 (ddd, 1 H, H-400), 5.17 (dd, 1
H, H-300), 5.10 (ddd, 1 H, H-4), 5.08 (dd, 1 H, H-3),
4.76 (d, 1 H, H-100), 4.18 (d, 1 H, H-1), 2.97 (dd, 1
H, H-500eq), 2.94 (dd, 1 H, H-500ax), 2.87 (dd, 1 H,
H-5eq), 2.69 (dd, 1 H, H-5ax), 2.01±1.71 (m, 18 H,
OAc); J1,2 10.5, J2,3 9.0, J3,4 9.5, J4,5ax 10.5, J4,5eq
Concentration of the second fraction yielded 2
ꢁ
(100 mg, 20%): mp 174±177 C; [ꢀ]d+28ꢁ (c 0.5,
MeOH); Rf 0.3 (solvent F); Anal. Calcd for
C13H17NO4S2: C, 49.51; H, 5.43; N, 4.44; S, 20.33.
Found: C, 49.59; H, 5.33; N, 4.37; S, 20.36.
4-Cyanophenyl 1,5-dithio-a-d-xylopyranoside
(35).ÐDeacetylation of 29 (0.6 g) with methanolic
M NaOMe (0.1 mL) in MeOH (20 mL) yielded,
after deionization with Dowex 50 WX resin and
00 00
00 00
00 00
4.1, J5ax,5eq 13.3, J1 ,2 10.7, J2 ,3 9.1, J3 ,4 9.2,
ꢁ
J4 ,5 ax 10.6, J4 ,5 eq 4.3, J5 ax,5 eq 13.5 Hz; 13C
NMR: ꢂ 169.7, 169.6, 169.6, 169.6, 169.3, 168.7
(C=O), 139.9 (C-10), 139.0 (C-20), 133.2 (C-60),
132.0 (C-50), 131.8 (C-30), 117.5 (CN), 112.9 (C-40),
74.8 (C-200), 74.2 (C-300), 73.9 (C-2), 73.8 (C-3), 72.6
(C-400), 72.0 (C-4), 52.9 (C-1), 45.0 (C-100), 31.4 (C-
5), 31.2 (C-500), 20.8, 20.7, 20.6, 20.5, 20.5, 20.1
(OAc). Anal. Calcd for C29H33NO12S3: C, 50.94;
H, 4.86; N, 2.05; S, 14.07. Found: C, 51.02; H,
4.77; N, 2.09; S, 14.11.
concentration, 35 (0.36 g, 87%): mp 136±138 C;
00 00
00 00
00
00
[ꢀ]d+626ꢁ (c 0.5, MeOH); Rf 0.4 (solvent F); Anal.
Calcd for C12H13NO3S2: C, 50.87; H, 4.62; N, 4.94;
S, 22.63. Found: C, 50.99; H, 4.73; N, 5.01; S,
22.57.
4-(Aminothiocarbonyl)phenyl
1,5-dithio-b-d-
xylopyranoside (36).ÐA stirred soln of 1 (4.0 g) in
dry pyridine (60 mL) and Et3N (60 mL) was satu-
rated with a slow stream of dry H2S for 2 h. The
mixture was kept at room temperature overnight
and was then concentrated. The residue was
recrystallized from MeOH to yield 36 (3.85 g,
86%): mp 174±179 ꢁC; [ꢀ]d+38ꢁ (c 0.5, MeOH); Rf
0.3 (solvent F); Anal. Calcd for C12H15NO3S3: C,
45.41; H, 4.76; N, 4.41; S, 30.30. Found: C, 45.43;
H, 4.76; N, 4.29; S, 30.37.
4-Cyanophenyl 2,3,4-tri-O-acetyl-1,5-dithio-a-d-
xylopyranoside (29) and 4-cyanophenyl 2,3,4-tri-O-
acetyl-1,5-dithio-b-d-xylopyranoside (30).ÐA 1:4
mixture of 29 and 30 (9.12 g) could be separated by
crystallization with diethyl ether to yield 30 (6.0 g,
66%): mp 159±162 ꢁC (Et2O), lit. 155 ꢁC [23];

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E. Bozo et al./Carbohydrate Research 308 (1998) 297±310
Â
310
4-[(Imino)(methylthio)methyl]phenyl 1,5-dithio-
[4] E. Bozo, S. Boros, and J. Kuszmann, Carbohydr.
Res., 299 (1997) 59±67.
[5] F. Bellamy, V. Barberousse, N. Martin, P. Masson,
J. Millet, S. Samreth, Ch. Sepulchre, J. Theve-
niaux, and D. Horton, Eur. J. Med. Chem., 30
(1995) 101±115.
[6] B.R. Baker and R.E. Schaub, J. Am. Chem. Soc.,
77 (1955) 5900±5905.
[7] J. Moravcova, J. Capkova, and J. Stanek, Carbo-
hydr. Res., 263 (1994) 61±66.
b-d-xylopyranoside (37).ÐTo a stirred soln of 36
(3.85 g) in dry acetone (385 mL), MeI (2.4 mL) was
added and the mixture was re¯uxed for 2 h. After
cooling to room temperature, the precipitated
crystals were ®ltered o€ and washed with ether to
give ꢁ37 (4.57 g, 82%) as its hydroiodide: mp 197±
200 C; [ꢀ]d+45ꢁ (c 0.5, Me2SO); Rf 0.4 (solvent
F); Anal. Calcd for C13H18INO3S3: C, 33.99; H,
3.95; I, 27.63; N, 3.05; S, 20.94. Found: C, 34.13;
H, 3.92; I, 27.74; N, 2.92; S, 20.87.
[8] D.L. Ingles and R.L. Whistler, J. Org. Chem., 27
(1962) 3896±3898.
4-Amidinophenyl 1,5-dithio-b-d-xylopyranoside
(38).ÐTo a soln of 37 (200 mg) in EtOH (10 mL),
NH4OAc (0.1ꢁg) was added and the mixture was
stirred at 60 C for 4 h. After cooling to room
temperature, the precipitated crystals were ®l-
tered o€ and washed with ether to give 38
[9] T.J. Adley and L.N. Owen, Proc. Chem. Soc.,
(1961) 418.
[10] P.A. Levene and A.L. Raymond, J. Biol. Chem.,
102 (1933) 317±325.
[11] J.C.P. Schwarz and K.C. Yule, Proc. Chem. Soc.,
(1961) 417.
[12] R.S. Tipson, Methods Carbohydr. Chem., 2 (1963)
246±250.
[13] P.A.M. Klein, G.J.P.H. Boons, G.H. Veeneman,
G.A. Marel, and J.H. van Boom, Tetrahedron
Lett., 30 (1989) 5477±5480.
[14] S.J. Kemp, J. Bao, and S.F. Pedersen, J. Org.
Chem., 61 (1996) 7162±7167.
[15] B.M. Kim and K.B. Sharpless, Tetrahedron Lett.,
30 (1989) 655±658.
[16] Y. Gao and K.B. Sharpless, J. Am. Chem. Soc.,
110 (1988) 7538±7539.
ꢁ
(120 mg, 55%) as its acetate salt: mp 195±199 C;
[ꢀ]d+30ꢁ (c 0.5, 50% aq AcOH); Rf 0.6 (solvent
H); Anal. Calcd for C14H20N2O5S2: C, 46.65; H,
5.59; N, 7.77; S, 17.79. Found: C, 46.82; H, 5.66;
N, 7.68; S, 17.65.
4-[(Hydrazino)(imino)methyl]phenyl 1,5-dithio-
b-d-xylopyranoside (39).ÐTo a stirred soln of 37
(200 mg) in EtOH (10 mL), 98% hydrazine hydrate
(0.7 mL) was added and stirring was continued at
room temperature for 5 h. The precipitated crystals
were ®ltered o€ and washed with EtOH to give 39
[17] B.B. Lohray, Y. Gao, and K.B. Sharpless, Tetra-
hedron Lett., 30 (1989) 2623±2626.
[18] V. Glacon, A.El Meslouti, R. Uzan, G. Demailly,
and D. Beaupere, Tetrahedron Lett., 37 (1996)
3683±3686.
ꢁ
(80 mg, 58%): mp 185±189 C; [ꢀ]d+12ꢁ (c 0.5,
pyridine); Rf 0.5 (solvent H); Anal. Calcd for
C12H17N3O3S2: C, 45.70; H, 5.43; N, 13.32; S,
20.33. Found: C, 45.56; H, 5.38; N, 13.17; S,
20.21.
[19] M.B. Goren and M.E. Kochansky, J. Org. Chem.,
38 (1973) 3510±3513.
[20] T.J. Tewson and M. Soderlind, J. Carbohydr.
Chem., 4 (1985) 529±543.
[21] M.S. Kharasch, T.H. Chao, and H.C. Brown, J.
Am. Chem. Soc., 62 (1940) 2393±2397.
[22] S. Samreth, J. Millet, F. Bellamy, J. Bajgrowicz, V.
Barberousse, and P. Renaut, EP-365397 A; Chem.
Abst., 114 (1991) P 122964k.
Acknowledgements
The authors are very much indebted to Dr.
Gabriella Szabo for the biological results and to
Dr. Gyula Horvath for the MS investigations.
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