Synthesis of 4-substituted phenyl 2,5-anhydro-1,6-dithio-α-D-gluco- and -α-L-guloseptanosides possessing antithrombotic activity

Article abstract of DOI:10.1016/S0008-6215(00)00156-7

Two independent approaches were investigated for the synthesis of 3,4-di-O-acetyl-1,6:2,5-dianhydro-1-thio-D-glucitol (18), a key intermediate in the synthesis of 1,3,4-tri-O-acetyl-2,5-anhydro-6-thio-α-D-glucoseptanose (13), needed as glycosyl donor. In the first approach 1,6-dibromo-1,6-dideoxy-D-mannitol was used as starting material and was converted via 2,5-anhydro-1,6-dibromo-1,6-dideoxy-4-O-methanesulfonyl-3-O-tetra hydropyranyl-D-glucitol into 18. The second approach started from 1,2:5,6-di-O-isopropylidene-D-mannitol and the allyl, 4-methoxybenzyl as well as the methoxyethoxymethyl groups were used, respectively, for the protection of the 3,4-OH groups. The resulting intermediates were converted via their 1,2:5,6-dianhydro derivatives into the corresponding 3,4-O-protected 2,5-anhydro-6-bromo-6-deoxy-D-glucitol derivatives. The 1,6-thioanhydro bridge was introduced into these compounds by exchanging the bromine with thioacetate, activating OH-1 by mesylation and treating these esters with sodium methoxide. Among these approaches, the 4-methoxybenzyl protection proved to be the most suitable for a large scale preparation of 18. Pummerer rearrangement of the sulfoxide, obtained via oxidation of 18 gave a 1:9 mixture of 1,3,4-tri-O-acetyl-2,5-anhydro-6-thio-α-L-gulo- (12) and -D-glucoseptanose 13. When 12 or 13 were used as donors and trimethylsilyl triflate as promoter for the glycosylation of 4-cyanobenzenethiol, a mixture of 4-cyanophenyl 3,4-di-O-acetyl-2,5-anhydro-1,6-dithio-α-L-gulo- (58) and -α-D-glucoseptanoside (61) was formed suggesting an isomerisation of the heteroallylic system of the intermediate. A similar mixture of 58 and 61 resulted when 18 was treated with N-chloro succinimide and the mixture of chlorides was used in the presence of zinc oxide for the condensation with 4-cyanobenzenethiol. When 4-nitrobenzenethiol was applied as aglycon and boron trifluoride etherate as promoter, a mixture of 4-nitrophenyl 3,4-di-O-acetyl-2,5-anhydro-1,6-dithio-α-L-gulo- (60) and -α-D-glucoseptanoside (62) was obtained. Deacetylation of 58, 61 and 62 according to Zemplen afforded 4-cyanophenyl 2,5-anhydro-1,6-dithio-α-L-guloseptanoside (59), 4-cyanophenyl 2,5-anhydro-1,6-dithio-α-D-glucoseptanoside (63) and 4-nitrophenyl 2,5-anhydro-1,6-dithio-α-D-glucoseptanoside (66), respectively. The 4-cyano group of 63 was transformed into the 4-aminothiocarbonyl, and the 4-(methylthio)(imino)methyl derivative and the 4-nitro group of 66 into the acetamido derivative. All of these thioglycosides displayed a stronger oral antithrombotic effect in rats compared with beciparcil, used as reference. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0008-6215(00)00156-7

www.elsevier.nl/locate/carres
Carbohydrate Research 329 (2000) 25–40
Synthesis of 4-substituted phenyl
2,5-anhydro-1,6-dithio-a-
D
-gluco- and
-a-L
-guloseptanosides possessing antithrombotic activityꢀ
1
´
Eva Bozo´ , Ade´l Medgyes, Sa´ndor Boros, Ja´nos Kuszmann *
Institute for Drug Research, PO Box 82, H-1325 Budapest, Hungary
Received 16 March 2000; accepted 12 May 2000
Abstract
Two independent approaches were investigated for the synthesis of 3,4-di-O-acetyl-1,6:2,5-dianhydro-1-thio-
citol (18), a key intermediate in the synthesis of 1,3,4-tri-O-acetyl-2,5-anhydro-6-thio-a- -glucoseptanose (13), needed
as glycosyl donor. In the first approach 1,6-dibromo-1,6-dideoxy- -mannitol was used as starting material and was
converted via 2,5-anhydro-1,6-dibromo-1,6-dideoxy-4-O-methanesulfonyl-3-O-tetrahydropyranyl- -glucitol into 18.
The second approach started from 1,2:5,6-di-O-isopropylidene- -mannitol and the allyl, 4-methoxybenzyl as well as
D-glu-
D
D
D
D
the methoxyethoxymethyl groups were used, respectively, for the protection of the 3,4-OH groups. The resulting
intermediates were converted via their 1,2:5,6-dianhydro derivatives into the corresponding 3,4-O-protected 2,5-anhy-
dro-6-bromo-6-deoxy-D-glucitol derivatives. The 1,6-thioanhydro bridge was introduced into these compounds by
exchanging the bromine with thioacetate, activating OH-1 by mesylation and treating these esters with sodium
methoxide. Among these approaches, the 4-methoxybenzyl protection proved to be the most suitable for a large scale
preparation of 18. Pummerer rearrangement of the sulfoxide, obtained via oxidation of 18 gave a 1:9 mixture of
1,3,4-tri-O-acetyl-2,5-anhydro-6-thio-a-
and trimethylsilyl triflate as promoter for the glycosylation of 4-cyanobenzenethiol, a mixture of 4-cyanophenyl
3,4-di-O-acetyl-2,5-anhydro-1,6-dithio-a- -gulo- (58) and -a- -glucoseptanoside (61) was formed suggesting an
L
-gulo- (12) and -
D
-glucoseptanose 13. When 12 or 13 were used as donors
L
D
isomerisation of the heteroallylic system of the intermediate. A similar mixture of 58 and 61 resulted when 18 was
treated with N-chloro succinimide and the mixture of chlorides was used in the presence of zinc oxide for the
condensation with 4-cyanobenzenethiol. When 4-nitrobenzenethiol was applied as aglycon and boron trifluoride
etherate as promoter, a mixture of 4-nitrophenyl 3,4-di-O-acetyl-2,5-anhydro-1,6-dithio-a-
coseptanoside (62) was obtained. Deacetylation of 58, 61 and 62 according to Zemple´n afforded 4-cyanophenyl
2,5-anhydro-1,6-dithio-a- -guloseptanoside (59), 4-cyanophenyl 2,5-anhydro-1,6-dithio-a- -glucoseptanoside (63)
and 4-nitrophenyl 2,5-anhydro-1,6-dithio-a- -glucoseptanoside (66), respectively. The 4-cyano group of 63 was
L
-gulo- (60) and -a-
D-glu-
L
D
D
transformed into the 4-aminothiocarbonyl, and the 4-(methylthio)(imino)methyl derivative and the 4-nitro group of
66 into the acetamido derivative. All of these thioglycosides displayed a stronger oral antithrombotic effect in rats
compared with beciparcil, used as reference. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: 2,5-Anhydro-
tions; Thioglycosides; Oral antithrombotic activity
D
-glucitol derivatives; 2,5-Anhydro-1,6-dithio-a-
L
-gulo- and -a-D-glucoseptanosides; Glycosidation reac-
ꢀ Orally active antithrombotic thioglycosides, Part X. For Part IX, see [1].
* Corresponding author. Tel.: +36-1-3993441; fax: +36-1-3993356.
E-mail address: h13757kus@ella.hu (J. Kuszmann).
1 Present address: Gedeon Richter Chemical Works Ltd., PO Box 17, H-1475 Budapest, Hungary.
0008-6215/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S 0008-6215(00)00156-7

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E. Bozo´ et al. / Carbohydrate Research 329 (2000) 25–40
26
1. Introduction
of 5. According to NMR spectroscopy the
ether 8, which was obtained in quantitative
yield, proved to be a mixture containing the
two tetrahydropyranyl diastereomers in a 1:1
ratio. Reaction of 8 with sodium sulfide af-
forded the 1,6-thioanhydro derivative 11 in
modest yield, which could be substantially
increased by applying a two step process. Ac-
cordingly 8 was treated with a slight excess
(1.2 equivalents) of the potassium salt of a
thioacid and the formed mixture was con-
verted without separation into 11 with an
excess of sodium methoxide in the presence of
methanol. When potassium thiobenzoate was
applied as reagent the yield of 11 was 50%,
while potassium thioacetate gave somewhat
lower yields. The 4-mesyloxy group of 11
could be exchanged with retention of configu-
ration with the acetoxy group on treatment
with sodium acetate in N,N-dimethylfor-
mamide. In this reaction a large excess of
sodium acetate had to be applied, otherwise
the reaction was sluggish, and besides 19
(route a) a relatively large amount (\10%) of
the rearranged 1,4-thioanhydro derivative 24
was formed, which could be isolated after
hydrolysis and acetylation as its diacetate 25.
Formation of 24 can be explained via the
attack of the acetoxy anion at C-6 of the
sulfonium intermediate 23 (route b). The tetra-
hydropyranyl group of the formed monoester
19 could be removed in methanol in the pres-
ence of an ion exchange resin (H+) and gave
diacetate 18 after subsequent acetylation in
crystalline state. In spite of the fact that the
overall yield of the conversion of 4 into 18 by
this approach was essentially the same as that
of the original reaction sequence [10], the ap-
plied reactions were much simpler and could
be easily scaled up (Scheme 2).
In a previous paper [2] we have shown that,
in contrast to the statement of the literature
[3], the oral antithrombotic effect of 4-
cyanophenyl 1,5-dithio-pentopyranosides is
not restricted to the b-D-xylo configuration as,
e.g., the corresponding 1,5-dithio-b-
D
-gluco-
pyranosides (1) and even the thioglycosides of
overbridged, 2,6 - thioanhydro - hexopyrano-
sides (2) [4], can exert significant biological
activity. Based on these facts the synthesis of
overbridged 2,5-anhydro-1,6-dithio- -gluco-
D
septanosides (3) was decided (Scheme 1).
2. Results and discussion
Synthesis of the donor molecules.—For the
synthesis of the aforementioned thioglyco-
sides, the tri-O-acetate 13, already described
in 1976, was needed as donor [5]. This 11 step
synthesis started from 1,6-dibromo-1,6-
dideoxy- -mannitol (4), but the overall yield
D
of the applied sequence 4“5“6“9“15“
18“14“13 [5–11] was ꢀ2%, making this
approach unsuitable for
preparation.
a
larger scale
To avoid the lowest yielding step of this
reaction sequence, i.e., the reductive splitting
of the mesyloxy groups (9“15), an alterna-
tive approach was applied by tosylating the
free 3-OH group of 5 and converting the
obtained 7 via 10“16“17 into 15 [10]. De-
spite the fact that the individual reactions of
this approach gave satisfactory yields, the
overall yield was not increased substantially
due to the increased number of steps.
To circumvent the reductive cleavage of the
3-O-sulfonic esters, the tetrahydropyranyl
blocking group was applied in the next ap-
proach for the protection of the 3-OH group
A further drawback of all these approaches
was that dibromide 4 was needed as starting
material, which is no longer available
Scheme 1.

´
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 25–40
27
Scheme 2.
commercially2 and the conversion of
-manni-
D
was chosen and subsequent hydrolysis of the
O-isopropylidene groups of the formed ether
27 led to 30 [15], which was converted via 33
into diepoxide 42 [16]. Treatment of the latter
with hydrogen bromide in acetone afforded
the key intermediate 38 [16], which was con-
verted into the 6-S-acetyl derivative 45. The
1-OH group of the latter was activated by
mesylation, and treatment of the obtained me-
sylate 48 with sodium methoxide in methanol
afforded thioanhydride 51. However, the con-
version of 51 into 15, i.e., the removal of the
allyl protecting groups proved to be problem-
atic, as neither basic [17] or acidic conditions
[18], nor the reductive cleavage with sodium
tol into 4 in a laboratory is quite cumbersome
[12,13], especially on a large scale. To over-
come these difficulties, another synthetic strat-
egy was considered by using a properly
substituted 2,5-anhydro-6-bromo-6-deoxy-
glucitol derivative as the key intermediate,
which can be prepared from -mannitol via its
D
-
D
easily obtainable 1,2:5,6-di-O-isopropylidene
derivative 26 [14]. For the protection of the
two hydroxyl groups of 26, the allyl group
2 Compound 4 had been produced by Chinoin (Budapest,
Hungary) and sold under the tradename Myelobromol as a
cytostatic.

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E. Bozo´ et al. / Carbohydrate Research 329 (2000) 25–40
28
Among the further reactions needed for the
conversion of the thioanhydro-glucitol deriva-
tive 15 into the desired glucothioseptanose
donor molecule 13, the acetylation and subse-
quent oxidation 15“18“14 caused no prob-
lems; however, the Pummerer rearrangement
of sulfoxide 14 led to a syrupy mixture con-
borohydride/iodide, described recently [19],
led to the desired result. Finally the boron
tribromide method, which was successfully
used [20] for the O-debenzylation of similar
1,6-thioanhydro-derivatives was applied, and
although according to thin-layer chromatogra-
phy (TLC) the deallylation took place, the
resulting dihydroxy derivative 15 could be sep-
arated in traces only.
To overcome these difficulties, the whole
reaction sequence was repeated using the more
easily removable 4-methoxybenzyl group for
the protection of the corresponding hydroxyl
groups. Accordingly, 26 was converted via the
28“31“34“43“39“46“49 reaction se-
quence into 52, the 4-methoxybenzyl blocking
groups of which could be removed either by
oxidation with 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone or by acidic hydrolysis
(MeOH–water–HCl). In both cases the dihy-
droxy derivative 15 had to be purified by
column chromatography. The overall yield of
this reaction sequence estimated from 26 was
ꢀ9%.
Finally, we tried to avoid this last purifica-
tion step by applying the 2-methoxyethoxy-
methyl group for the protection of the 3,4-OH
groups of 26 converting it via 29“32“35
into diepoxide 44. Treatment of this latter
with concentrated hydrogen bromide in ace-
tone — the usual conditions used for con-
verting the corresponding diepoxides into the
monobromo-2,5-anhydro compounds — led
to the simultaneous cleavage of the O-
methoxyethoxymethyl groups, and the trihy-
droxy derivative 41 formed was partially
converted into its 1,3-O-isopropylidene
derivative 36. This was isolated and character-
ised as its 6-S-acetate 37. To avoid this un-
timely cleavage of the O-protecting groups,
the addition of hydrobromic acid was carried
out in the presence of potassium bromide by
slowly adding one equivalent of sulfuric acid.
In this way the formed anhydro derivative 40
could be isolated in a yield of 58%. Its conver-
sion via the 40“47“50 reaction sequence
into the protected thioanhydride 53 caused no
problems. The protecting groups of 53 could
be split off easily by treatment with acid, but
the overall yield of the obtained dihydroxy
derivative 15 remained below 5% (Scheme 3).
taining the
L-gulo 12 and the
D-gluco 13 iso-
mer in a ratio of 1:9. Because of their very
similar Rf values, they could only be partially
separated by repeated column chromatogra-
phy, but for the synthesis of the corresponding
thioglucosides it was not necessary to separate
them, as the glycosides resulting after deacety-
lation could be easily purified by
crystallisation.
Glycosidation reactions.—For the synthesis
of the glucoseptanoside 61, the glucotriacetate
13 was used as donor, 4-cyanobenzenethiol as
acceptor and trimethylsilyl triflate as pro-
moter. Despite the fact that the isolated gly-
coside gave on TLC only one spot, according
to NMR spectroscopy it contained, besides
61, ꢀ10% of the corresponding gulo isomer
58. This fact led to the suppositions that dur-
ing the condensation reaction, the primarily
formed sulfonium ion 55 might undergo a
heteroallylic rearrangement, affording in an
equilibrium reaction the isomeric ion 54. Both
ions can be attacked by the bulky aglycon
only from the less hindered ‘exo’ side, yielding
the corresponding a anomers 58 and 61, re-
spectively. This supposition was backed by the
fact that when the pure gulo-triacetate 12 was
applied as donor, again both thioglycosides 58
and 61 were formed, but their ratio was 6:1.
That means that the rate of the isomerisation
cannot be faster than that of the glycosida-
tion, otherwise the same 1:9 ratio should have
been reached as in the first case. On the other
hand, the isomerisation made the tedious sep-
aration of the two triacetate donors 12 and 13
unnecessary, as when their 1:9 mixture —
obtained in the Pummerer reaction — was
used, the resulting thioglycoside mixture con-
tained the gulo 58 and the gluco 61 isomers in
the same 1:9 ratio, as in the first case when
pure 13 was applied as donor. As the acety-
lated thioglycosides possessed identical Rf val-
ues, they could not be separated by column
chromatography, but during deacetylation ac-

´
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 25–40
29
Scheme 3.
cording to Zemple´n the main component crys-
tallised spontaneously and could be purified
further by recrystallisation from methanol. In
this way, both 59 and 63 were obtained in
pure isomer-free form.
triflate. Accordingly, it could be assumed that
both chloro compounds 56 and 57 were
formed and reacted further via the sulfonium
intermediates 54 and 55, mentioned above.
For investigating the influence of the 4%-sub-
stituent of the aglycon on the biological activ-
ity, transformations of the 4%-cyano group of
63, which increased the biological activity in
the case of the corresponding thioxylopyra-
noside [22], were carried out. Accordingly, 63
was transformed into the thioamide 64 by
treatment with hydrogen sulfide in pyridine-
triethylamine solution. Methylation of 64 with
methyl iodide in acetone afforded the
methylthioimine 65.
As is known from the literature [21] that
cyclic thioethers, in which the sulfur atom is
flanked by methylene groups, can be con-
verted into a-chloro derivatives on treatment
with N-chlorosuccinimide, this reaction was
applied to the thioanhydro glucitol 18. Theo-
retically both the gulo 56 and the gluco-
acetochloro isomer 57 can be formed this way,
and although two distinct spots could be de-
tected on TLC, the individual compounds
could not be isolated because of their instabil-
ity. Nevertheless if their solution was used
directly for the glycosylation of the aglycon in
the presence of zinc oxide as promoter, the
two isomeric glycosides 58 and 61 were
formed in the same ratio (1:9) as in the case
when a 1:9 mixture of triacetates 12+13 was
used as donor in the presence of trimethylsilyl
When 4-nitrobenzenethiol was used as agly-
con in the glycosylation reaction and boron
trifluoride etherate as promoter, according to
NMR spectroscopy, a 1:4 mixture of the cor-
responding
L-gulo- 60 and
D
-glucothiohep-
tanoside 62 was obtained in a yield of 90%,
which could not be separated. Deacetylation
of this mixture afforded crystalline 66. The

´
30
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 25–40
Scheme 4.
Table 1
Oral antithrombotic activity of 4-substituted phenyl 2,5-anhydro-1,6-dithio-a-
L
-gulo- (59) and -a-D-glucoseptanosides (63–67) in
rats using Pescador’s model [23] compared with beciparcil
a
Compound
Ref
59
63
64
65
66
67
R b
CN
25
CN
3
CN
3.5
CSNH2
2
C(NH)SMe
3
NO2
2
NHAc
2
ED50 (mg/kg)
a Ref, reference compound (beciparcil=4-cyanophenyl 1,5-dithio-b-
b 4%-Sustituent of the aglycon.
D-xylopyranoside) [3].
4-nitro group of the latter was reduced with
sodium borohydride to give after acetylation
and subsequent O-deacetylation, according to
Zemple´n, the 4-acetamido derivative 67
(Scheme 4).
Biological results.—The oral antithrom-
botic activity of 59, 63, 64, 65, 66, and 67 was
determined in rats using Pescador’s model
[23]. All compounds were administered orally
3 h before ligation. From the data listed in
Table 1, it can be seen that all thioglycosides
were ꢀ10-fold active as beciparcil [3] used as
reference compound, but transformations of
the 4%-substituent of the aglycon had no sig-
nificant influence on the biological effect.
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 EtOAc (A), EtOAc–hexane mixtures (B,
1:1; C, 1:2; D, 1:3; E, 1:4; F, 2:1; G, 3:1; H,

´
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 25–40
31
2:3), EtOAc–EtOH mixture (I 9:1), toluene–
MeOH mixture (J, 4:1), CH2Cl2–MeOH mix-
tures (K, 9:1, L 95:5), CH2Cl2–acetone
mixture (M, 9:1) and CHCl3–MeOH mixture
(N, 95:5); detection by spraying the plates
with a 0.02 M solution of I2 and a 0.3 M
solution of KI in 10% aq H2SO4 soln, fol-
lowed by heating at ca. 200 °C. For column
chromatography Kieselgel 60 was used. The
melting points are uncorrected. Optical rota-
tions were determined on 1.0% solutions in
CHCl3 at 20 °C unless stated otherwise. 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
experiments. The assignment of the protons
were based on homonuclear decoupling exper-
iments. The ratio of a:b anomeric mixtures
centrated, the residue dissolved in CH2Cl2,
washed with 5% aq NaHCO3 and water, dried
and concentrated to a volume of ꢀ500 mL.
This solution contained according to TLC
(solvent C) and NMR measurements several
components, most probably the diastereomers
of 20, 21 and 22 [10] and afforded on evapora-
tion a syrup (33.9 g). As the individual com-
ponents could not be separated by column
chromatography, the original solution was
used in the further reaction. It was cooled
with ice, MeOH (100 mL) and subsequently 3
M NaOMe in MeOH (24.5 mL) was added
with stirring. The mixture was kept at 20 °C
for 3 h and was then neutralised with solid
CO2. The formed precipitate was filtered off
and washed with CHCl3 (50 mL). The residue,
obtained on concentration of the filtrate was
dissolved in CHCl3, washed with water, dried
and concentrated. The residue was purified by
column chromatography (solvent C contain-
ing 0.1% triethylamine) to give after concen-
tration of the fractions having Rf 0.5 (solvent
1
was determined by H NMR.
2,5-Anhydro-1,6-dibromo-1,6-dideoxy-4-O-
methanesulfonyl-3-O-tetrahydropyranyl- -glu-
D
1
citol (8).—To a stirred solution of 5 [6] (26.5
g, 72 mmol) in CH2Cl2 (240 mL), 3,4-dihydro-
2-H-pyran (8.45 mL, 93 mmol) and subse-
quently p-TsOH (70 mg) were added. The
solution was kept at 20 °C for 1 h during
which time it turned blue. Thereafter it was
washed with 5% aq NaHCO3 and water, dried
and concentrated to give 8 (32.5 g, 100%) as a
C) 11 (10.7g, 50%) as a syrup; H NMR: l
5.62–5.55 (m, 1 H, H-4), 4.75 (m, 1 H, H-2%),
4.65–4.35 (m, 3 H, H-2,3,5), 4.10, 3.80, 3.65–
3.45 (m, 2 H, H-6%), 3.25–3.05 (m, 2 H, H-
1ax,6ax), 3.13, 3.10 (2 s, 6 H, OMs) 2.50–2.30
(m, 2 H, H-1eq,6eq), 2.00–1.40 (m, 6 H, H-
13
3%,4%,5%); C NMR: l 100.1, 100.0 (C-2%), 87.8,
86.8, 84.1, 82.1, 80.1, 78.8, 76.9, 76.1 (C-
2,3,4,5), 63.8, 62.7 (C-6%), 39.1, 37.9 (OMs),
30.8, 30.6, 28.0, 27.8, 25.3, 25.0, 24.6, 24.5
(C-1,6,3%,5%), 20.1, 19.0 (C-4%). Anal. Calcd for
C12H20O6S2: C, 44.43; H, 6.21; S, 19.77.
Found: C, 44.48; H, 6.37; S, 19.56.
1
colourless oil. Rf 0.4+0.45 (solvent C); H
NMR: l 5.30 (m, 1 H, H-2%), 5.06, 4.86, 4.74,
4.52 (4m, 2 H, H-3,4), 4.50–4.25 (m, 2 H,
H-2,5), 3.92, 3.50 (m, 2 H, H-6%), 3.70–3.35
(m, 4 H, H-1a,1b,6a,6b), 3.13 (s, 3 H, OMs),
1.85–1.45 (m, 6 H, H-3%,4%,5%); 13C NMR: l
102.5, 96.7 (C-2%), 85.1, 84.2, 83.4, 83.0, 82.2,
81.8, 81.5, 77.8 (C-2,3,4,5), 63.8, 63.0 (C-6%),
38.8, 38.2 (OMs), 30.8, 30.5, 30.3, 28.0, 26.9,
25.0, 19.9, 19.2 (C-1,6,3%,4%,5%). Anal. Calcd for
Br2C12H20O6S: Br, 35.34; C, 31.88; H, 4.46; S,
7.09. Found: Br, 35.23; C, 31.57; H, 4.50; S,
7.00.
1,3,4-Tri-O-acetyl-2,5-anhydro-6-thio-h-
guloseptanose (12) and 1,3,4-tri-O-acetyl-2,5-
anhydro-6-thio-h- -glucoseptanose (13).—A
L
-
D
solution of sulfoxide 14 [5,11] in Ac2O was
kept at 100 °C for 8 h and was then concen-
trated. The residue was dissolved in EtOH
(100 mL), concentrated and this was repeated
once more. The residue was dissolved in
CH2Cl2, washed with 5% aq NaHCO3 and
water, dried and concentrated to give a syrup
(30 g, 100%) containing, according to NMR
spectroscopy, 12 and 13 in a ratio of 1:9. This
mixture could be partially separated by
column chromatography (solvent C). Concen-
tration of the first fraction yielded 12 (2 g);
[h]D −92° (c 0.4, CHCl3); Rf 0.45 (solvent C);
1,6:2,5-Dianhydro-4-O-methanesulfonyl-3-O-
tetrahydropyranyl-1-thio- -glucitol (11).—To
D
a stirred solution of 8 (30.1 g, 66.6 mmol) in
acetone (500 mL), potassium thiobenzoate (14
g, 79.4 mmol) was added and the reaction
mixture was boiled for 4 h. The formed slurry
was cooled, filtered and the salts were washed
with acetone (200 mL). The filtrate was con-

´
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 25–40
32
1H NMR: l 5.97 (d, 1 H, J1,2 3.4 Hz, H-1),
5.72 (d, J2,3 0, J3,4 2.9 Hz, H-3), 5.30 (dd, J4,5
6.4 Hz, H-4), 4.78 (ddd, 1 H, J5,6ax 3.2, J5,6eq
1.0 Hz, H-5), 4.29 (d, 1 H, H-2), 3.28 (dd, 1
H, J6ax,6eq 13.7 Hz, H-6ax), 2.35 (dd, 1 H,
was purified by column chromatography (sol-
vent K) to give 15 (0.24 g, 59%): mp 113–
1
115 °C (acetone); lit. mp 113–115 °C [10]; H
NMR: l 5.16 and 5.10 (2s, 2 H, OH-3,4), 4.35
(d,1 H, J3,4 2.9, J4,5 0 Hz, H-4), 4.28 (ddd,
J1eq,2 1, J1ax,2 1, J2,3 7.1 Hz, H-2), 3.96 (dd, 1
H, J4,5 0, J5,6eq 1, J5,6ax 2.7 Hz, H-5), 2.94 (dd,
1 H, J6eq,6ax 12.9 Hz, H-6ax), 2.86 (dd, 1 H,
J1ax,1eq 13 Hz, H-1ax), 2.35 (dd, 1 H, H-6eq),
13
H-6eq), 2.13, 2.12, 2.11 (3s, 9 H, COMe); C
NMR: l 170.3, 170.2, 169.3 (COMe), 80.1,
78.8, 78.2, 75.1 (C-2,3,4,5), 68.2 (C-1), 27.3
(C-6), 20.9, 20.7, 20.6 (COMe). Anal. Calcd
for C12H16O7S: C, 47.35; H, 5.30; S, 10.53.
Found: C, 47.16; H, 5.15; S, 10.32.
13
2.25 (dd, 1 H, H-1eq); C NMR: l 77.0, 80.4,
81.1, 81.3 (C-2,3,4,5), 23.7, 28.3 (C-1,6).
Concentration of the second fraction gave a
mixture of 12 and 13 (7 g), while concentra-
tion of the third fraction yielded 13 (19 g);
[h]D +112° (c 0.6, CHCl3); lit. [h]D +95° (c
(ii) A solution of 52 (250 mg) in MeOH (5
mL), water (4 mL) and concd HCl (1 mL) was
stirred at 60 °C for 6 h, cooled and neutralized
with NaHCO3. The residue obtained on con-
centration was submitted to column chro-
matography (solvent A) to give 15 (100 mg,
99%), identical with that described above.
(iii) A solution of 53 (0.78 g) in MeOH (8
mL), water (6 mL) and concd HCl (1.5 mL)
was stirred at 60 °C for 2 h and was worked
up as described in (ii) to give 15 (330 mg,
88%), identical with that described above.
1
1, CHCl3) [5]; Rf 0.4 (solvent C); H NMR: l
5.59 (d, 1 H, J3,4 3.2, J4,5 0 Hz, H-4), 5.36 (dd,
J2,3 7.3 Hz, H-3), 5.34 (d, J1,2 1.8 Hz, H-1),
4.68 (dd, 1 H, H-2), 4.38 (dd, 1 H, J5,6ax 2.9,
J5,6eq 2.2 Hz, H-5), 3.40 (dd, 1 H, J6ax,6eq 13.2
Hz, H-6ax), 2.51 (dd, 1 H, H-6eq), 2.16, 2.15,
2.10 (3s, 9 H, COMe); 13C NMR: l 170.8,
170.1, 169.7 (COMe), 80.5, 79.0, 77.8, 77.6
(C-2,3,4,5), 67.6 (C-1), 26.3 (C-6), 21.1, 20.7,
20.6 (COMe).
3,4-Di-O-acetyl-1,6:2,5-dianhydro-1-thio-
glucitol (18) and 3,6-di-O-acetyl-1,4:2,5-dian-
hydro-1-thio- -galactitol (25).—To a solution
D
-
3,4-Di-O-acetyl-1,6:2,5-dianhydro-1-thio-
D-
D
glucitol S-oxide (14).—To a solution of 18
(24.6 g, 0.1 mol) in AcOH (250 mL), 33% aq
H2O2 (10 mL) was added, the mixture was
kept at 20 °C for 20 h and concentrated. The
residue was dissolved in EtOH (100 mL), con-
centrated and this was repeated twice. The
residue was crystallised with ether to give 14
(24.4 g, 93%); mp 126–128 °C; lit. 126–127 °C
[10]; lit.128–130 °C [11]; Rf 0.3 (solvent A); 1H
NMR: l 5.12 (dd, 1 H, J2,3 6.9, J3,4 2.2 Hz,
H-3), 4.94 (d, J4,5 0 Hz, H-4), 4.86 (ddd, 1 H,
J1eq,2 ꢀ2, J1ax,2 2.9 Hz, H-2), 4.47 (dd, 1 H,
J5,6eq 1.5, J5,6ax 3.1 Hz, H-5), 3.75 (dd, 1 H,
J6eq,6ax 12.5 Hz, H-6eq), 3.50 (dd, 1 H, H-1eq),
2.66 (dd, 2 H, J1ax,1eq 12.5 Hz, H-1ax,6ax),
2.12, 2.05 (2s, 6 H, COMe); 13C NMR: l
170.0, 169.9 (COMe), 79.3 (C-4), 78.6 (C-3),
78.5 (C-5), 74.0 (C-2), 53.5 (C-6), 51.1 (C-1)
20.7, 20.6 (COMe).
of crude 19 (9.5 g, 33 mmol) in MeOH (290
mL), Dowex 50 WX2 (H+) (6 g) was added
and the mixture was stirred at 20 °C for 3 h.
The filtered solution was concentrated, the
residue dissolved in pyridine (50 mL) and
Ac2O (20 mL) was added at rt. After 3 h the
mixture was poured onto ice to give, after
extraction with CH2Cl2, and usual processing,
a semisolid residue. This was dissolved in
ether (20 mL) and gradually triturated with
hexane (50 mL) to give crystalline 18 (4.95 g,
61%). Concentration of the filtrate and
column chromatography (solvent C) of the
residue yielded a second crop of 18 (0.45 g,
5%); mp 76–77 °C, lit. mp 77–79 °C [10]; Rf
1
0.6 (solvent C); H NMR: l 5.62 (d, 1 H, J3,4
2.2, J4,5 0 Hz, H-4), 5.30 (dd, J2,3 6.8 Hz, H-3),
4.74 (ddd, 1 H, J1eq,2 1.5, J1ax,2 2.7 Hz, H-2),
4.25 (dd, 1 H, J5,6eq 1.5, J5,6ax 2.5 Hz, H-5),
3.16 (dd, 1 H, J6eq,6ax 13.9 Hz, H-6ax), 3.15
(dd, 1 H, J1ax,1eq 12.5 Hz H-1ax), 2.45 (dd, 1
H, H-6eq), 2.10 (dd, 1 H, H-1eq), 2.14, 2.12
(2s, 6 H, COMe); 13C NMR: l 170.9, 170.4
(COMe), 81.0, 79.2, 78.6, 75.4 (C-2,3,4,5),
28.2, 24.7 (C-1,6) 20.8, 20.6 (COMe).
1,6:2,5-Dianhydro-1-thio- -glucitol (15).—
D
(i) To a stirred solution of 52 (1 g, 2.5 mmol)
in CH2Cl2 (20 mL), water (1 mL) and subse-
quently DDQ (1.7 g, 7.5 mmol) was added.
The precipitated DDQH was filtered after 1 h
and the residue of the concentrated filtrate

´
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 25–40
33
chromatography (solvent E) to give 28 (1.3 g,
65%); [h]D +38° (c 0.5, CHCl3); Rf 0.4 (sol-
Concentration of the fractions having Rf 0.5
(solvent C) gave 25 (0.45 g, 5%) as a syrup;
1
1
vent E); H NMR: l 7.15 (d, 4 H, aromatic),
[h]D −33° (c 0.4, CHCl3); H NMR: l 5.17
6.76 (d, 4 H, aromatic), 4.52 (s, 4 H,
OꢀCH2ꢀAr), 4.11 (m, 2 H, H-2,5), 3.89 (dd, 2
H, J1a,2 6.4, J1a,1b 8.3 Hz, H-1a,6a), 3.73 (dd, 1
H, J1b,2 7.1 Hz, H-1b,6b), 3.66 (s, 6 H, OMe),
3.65 (m, 2 H, H-3,4), 1.20, 1.30 (2s, 12 H,
(m, 1 H, H-3), 4.45–4.33 (m, 4 H, H-
2,5,6a,6b), 3.66 (m, 1 H, H-4), 2.95–2.75 (m, 2
13
H, H-1a,1b), 2.08, 1.98 (2s, 6 H, COMe); C
NMR: l 170.2, 169.9 (COMe), 79.7, 76.3, 76.2
(C-2,3,5), 64.9 (C-6), 48.5 (C-4), 35.6 (C-1),
20.5, 20.5 (COMe). Anal. Calcd for
C10H14O5S: C, 48.77; H, 5.73; S, 13.02. Found:
C, 48.61; H, 5.87; S, 12.96.
13
CMe2); C NMR: l 159.2, 130.3, 129.6, 113.6
(C-aromatic), 108.4 (CMe2), 79.5 (C-3,4), 75.8
(C-2,5), 74.0 (OꢀCH2ꢀAr), 66.7 (C-1,6), 55.1
(OMe), 25.1, 26.6 (CMe2). Anal. Calcd for
C28H38O8: C, 66.92; H, 7.62. Found: C, 66.77;
H, 7.54.
4-O-Acetyl-1,6:2,5-dianhydro-3-O-tetra-
hydropyranyl-1-thio- -glucitol (19).—To a so-
D
lution of 11 (10.7 g, 33 mmol) in DMF (110
mL), sodium acetate (10.7 g, 130 mmol) was
added and the mixture was stirred at 100 °C
for 5 h. The cooled mixture was filtered and
the residue obtained on concentration was
dissolved in CH2Cl2, washed with water, dried
and concentrated to give 19 (9.5 g, 100%) as a
syrup, which contained less than 10% of 6-O-
acetyl-1,4:2,5-dianhydro-3-O-tetrahydropy-
1,2:5,6-Di-O-isopropylidene-3,4-di-O-(2-
methoxyethoxymethyl)- -mannitol (29).—To
D
a stirred suspension of NaH (50%, 10 g) in
DMF (40 mL), a solution of 26 (20 g, 76
mmol) in DMF (60 mL) and after 30 min
2-methoxyethoxymethyl chloride (20.7 mL,
182 mmol) were added. The mixture was
stirred at 20 °C for 1 h then poured onto ice
and extracted with CH2Cl2. The organic soln
was washed with 5% aq NaHCO3 and water,
dried and concentrated to give crude 29 (33.2
g, 99%). An aliquot part (2 g) was purified by
column chromatography (solvent B) to give 29
(1.4 g, 69%); [h]D +72° (c 0.5, CHCl3); Rf 0.4
ranyl-1-thio- -galactitol (24) and was pure
D
enough for the subsequent reaction. Purifica-
tion by column chromatography (solvent C)
1
yielded 19 (6 g, 63%), Rf 0.6+0.65; H NMR:
l 5.63, 5.53 (m, 1 H, H-4), 4.72 (m, H-2%),
4.60–4.40 (m, 1 H, H-3), 4.55 (m, 1 H, H-2),
4.02, 3.82, 3.60–3.45 (m, 2 H, H-6%), 3.20–
3.05 (m, 2 H, H-1ax,6ax), 2.55–2.33 (m, 2 H,
H-1eq,6eq), 2.08 (s, 3 H, COMe), 1.90–1.40
1
(solvent B); H NMR: l 4.97 and 4.80 (2d, 4
H, J 7.1 Hz, OꢀCH2ꢀO) 3.50–4.20 (m, 16 H,
H-1a,1b,2,3,4,5,6a,6b, OꢀCH2ꢀCH2ꢀO), 3.37
(s, 6 H, OMe), 1.28 and 1.36 (2s, 12 H,
CMe2); 13C NMR: l 108.8 (CMe2), 96.7
(OꢀCH2ꢀO), 79.3 (C-3,4), 73.9 (C-2,5), 71.4,
67.5 (O-CH2ꢀCH2ꢀO), 67.6 (C-1,6), 58.8
(OMe), 26.4, 25.2 (CMe2). Anal. Calcd for
C20H38O10: C, 54.78; H, 8.73. Found: C, 54.92;
H, 8.61.
13
(m, 6 H, H-3%,4%,5%); C NMR: l 171.1, 171.0
(COMe), 99.6, 99.1 (C-2%), 82.6, 82.2, 81.8,
81.7, 79.9, 79.5, 76.8, 75.9 (C-2,3,4,5), 63.4,
62.1 (C-6%), 30.6, 30.5, 28.2, 28.1, 25.3, 25.1,
24.8, 24.7 (C-1,6,3%,5%), 20.9, 20.8 (COMe),
19.9, 18.8 (C-4%). Anal. Calcd for C13H20O5S:
C, 54.15; H, 6.99; S, 11.12. Found: C, 54.10;
H, 6.92; S, 11.07.
3,4 - Di - O - (4 - methoxybenzyl) -
D
- mannitol
1,2:5,6-Di-O-isopropylidene-3,4-di-O-(4-
(31).—To a solution of crude 28 (12.3 g) in
MeOH (120 mL), water (36 mL) was added
and the pH of the mixture was adjusted to 4
by adding 1 M HCl (1.2 mL). The mixture
was boiled for 1.5 h and the resulting clear
solution was neutralised with NaHCO3 after
cooling. The residue obtained on concentra-
tion was dissolved in CHCl3, the insoluble
salts were filtered off and the residue of the
evaporated filtrate was recrystallized from
EtOH–Et2O to yield 31 (9.46 g, 91%); mp
91–92 °C; [h]D +38° (c 0.5, MeOH); Rf 0.5
methoxybenzyl)-
D
-mannitol
(28).—To
a
stirred suspension of NaH (50% in mineral oil,
20 g) in Me2SO (340 mL), a solution of 26
(52.4 g, 0.2 mol) in Me2SO (160 mL) and after
30 min 4-methoxybenzyl chloride (74 mL, 0.48
mol) were added. The mixture was stirred at
50 °C for 3 h, then cooled, diluted with water
and extracted with CH2Cl2. The organic soln
was washed with water, dried and concen-
trated to give crude 28 (110 g, 109%). An
aliquot part (2 g) was purified by column

´
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 25–40
34
1
and 19.1 (CMe2). Anal. Calcd for C11H18O5S:
C, 50.37; H, 6.92; S, 12.22. Found: C, 50.51;
H, 6.82; S, 6.85.
(solvent I); H NMR (Me2SO-d6): l 7.20 (d, 4
H, aromatic), 6.86 (d, 4 H, aromatic), 4.68 (d,
2 H, J 5.2 Hz, 2-OH and 5-OH), 4.56, 4.46
(2d, 4 H, J 10.5 Hz, OꢀCH2ꢀAr), 4.48 (t, 2 H,
J 5.7 Hz, 1-OH, 6-OH), 3.65 (s, 6 H, OMe),
3.40–3.80 (m, 8 H, H-1a,1b,2,3,4,5,6a,6b).
Anal. Calcd for C22H30O8: C, 62.55; H, 7.16.
Found: C, 62.48; H, 7.28.
2,5-Anhydro-6-bromo-6-deoxy-3,4-di-O-(4-
methoxybenzyl)- -glucitol (39).—A solution
D
of 43 (3.86 g, 10 mmol) in acetone (12 mL)
was added dropwise to a stirred, ice cooled
solution of HBr in AcOH (33%, 3 mL) and
acetone (10 mL). After 15 min the solution
was neutralised with solid NaHCO3, the pre-
cipitated salts were filtered off, washed with
acetone and the filtrate was concentrated. Eth-
anol and subsequently toluene were evapo-
rated from the residue, which was dissolved in
CH2Cl2, filtered and concentrated to give
crude 39 (4.6 g, 98.5%). Column chromatogra-
phy (solvent H) afforded 39 (3 g, 64%) as a
syrup: [h]D +8° (c 0.5, CHCl3); Rf 0.5 (sol-
3,4 - Di - O - (2 - methoxyethoxymethyl) - -
D
mannitol (32).—A solution of crude 29 (15 g)
in AcOH (120 mL) and water (60 mL) was
stirred at 50 °C for 4 h and was then concen-
trated. Ethanol (100 mL) and subsequently
toluene (100 mL) were evaporated from the
residue, which solidified. Recrystallisation
from EtOH–Et2O gave 32 (5.87 g, 48%): mp
77–79 °C; [h]D +30° (c 0.5, MeOH); Rf 0.3
1
(solvent J); H NMR (Me2SO-d6): l 4.70 (s, 4
1
vent H); H NMR: l 7.15–7.30 (m, 4 H,
H, OꢀCH2ꢀO), 4.54 (d, 2 H, J 5.6 Hz, 2-OH
and 5-OH), 4.37 (t, 2 H, J 5.4 Hz, 1-OH and
aromatic), 6.80–6.95 (m, 4 H, aromatic), 4.56,
4.48 (2d, 2 H, J 11.7 Hz, OꢀCH2ꢀAr), 4.51,
4.33 (2d, 2 H, J 11.5 Hz, OꢀCH2ꢀAr), 4.13–
4.32 (m, 2 H, H-2,5), 4.01–4.08 (m, 2 H,
H-3,4), 3.75–3.90 (m, 2 H, H-1a,1b), 3.82 (s, 6
H, OMe), 3.37–3.52 (m, 2 H, H-6a,6b); 13C
NMR: l 159.6, 159.5, 129.5, 129.4, 129.3,
129.1, 114.1, 113.9 (C-aromatic), 83.6, 83.2,
82.9, 81.4 (C-2,3,4,5), 71.8, 71.3 (OꢀCH2ꢀAr),
61.7 (C-1), 55.3 (OMe), 32.4 (C-6). Anal.
Calcd for BrC22H27O6: Br, 17.10; C, 56.54; H,
5.82. Found: Br, 17.00; C, 56.62; H, 6.05.
2,5-Anhydro-6-bromo-6-deoxy-3,4-di-O-(2-
6-OH),
3.25–3.70
(m,
16
H,
H-
1a,1b,2,3,4,5,6a,6b, OꢀCH2ꢀCH2ꢀO), 3.24 (s,
6 H, OMe); 13C NMR: l 96.4 (OꢀCH2ꢀO),
77.3,
70.8
(C-2,3,4,5),
71.4,
67.4
(OꢀCH2ꢀCH2ꢀO), 63.1 (C-1,6), 58.3 (OMe).
Anal. Calcd for C14H30O10: C, 46.92; H, 8.43.
Found: C, 46.73; H, 8.48.
2,5-Anhydro-6-S-acetyl-1,3-O-isopropyli-
dene-6-thio- -glucitol (37).—A solution of 44
D
(400 mg, 1.24 mmol) in acetone (2 mL) was
added dropwise to a stirred, ice cooled soln of
HBr in AcOH (33%, 0.5 mL) and acetone (2
mL). After 30 min the solution was neu-
tralised with solid NaHCO3, the precipitated
salts were filtered off, washed with acetone
and the filtrate was concentrated. The residue
containing 36 was dissolved in DMF (2 mL),
KSAc (170 mg) was added and the mixture
was stirred for 1 h at 80 °C. The residue
obtained on concentration was dissolved in
CH2Cl2, washed with water dried and concen-
trated to give after purification by column
chromatography (solvent L) 37 (70 mg,
21.5%) as a syrup: [h]D +13° (c 0.5, CHCl3);
methoxyethoxymethyl)-
D-glucitol
(40).—To
an ice cooled stirred soln of 44 (400 mg, 1.25
mmol) in acetone (10 mL) was added drop-
wise a soln of KBr (295 mg, 2.5 mmol) in
water (2 mL), and subsequently 1 M H2SO4
(2.5 mL) in acetone (10 mL). The mixture was
kept at 20 °C for 20 h and was then neu-
tralised with solid NaHCO3 and concentrated.
The residue gave after column chromato-
graphy (solvent M) 40 (292 mg, 58%) as a
syrup; [h]D +55° (c 0.5, CHCl3); Rf 0.4
1
(solvent M); H NMR: l 4.70–4.85 (m, 4 H,
OꢀCH2ꢀO), 4.05–4.30 (m, 4 H) 3.60–3.85
(m, 6 H) and 3.50–3.60 (m, 4 H) (H-
1a,1b,2,3,4,5, OꢀCH2ꢀCH2ꢀO), 3.40–3.50 (m,
2 H, H-6a,6b), 3.37 (s, 6 H, OꢀMe); 13C
NMR: l 94.8, 94.5 (OꢀCH2ꢀO), 83.6, 83.0,
81.6, 80.9 (C-2,3,4,5), 71.6, 71.5, 67.5, 67.2
(OꢀCH2ꢀCH2ꢀO), 60.3 (C-1), 58.9 (OMe),
1
Rf 0.5 (solvent L); H NMR: l 3.50–4.25 (m,
6 H, H1a,1b,2,3,4,5), 3.15–3.35 (m, 2 H, H-
6a,6b), 2.36 (s, 3 H, SAc), 1.38 and 1.43 (2s, 6
13
H, CMe2); C NMR: l 195.8 (SCOMe), 97.5
(CMe2), 85.4, 80.2, 76.2 and 73.1 (C-2,3,4,5),
60.6 (C-1), 32.0 (C-6), 30.5 (SCOMe), 28.6

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E. Bozo´ et al. / Carbohydrate Research 329 (2000) 25–40
35
3.55 (m, 4 H, OꢀCH2ꢀCH2ꢀO), 3.63 (d, 2 H,
J2,3 5.4 Hz, H-3,4), 3.38 (s, 6 H, OMe), 3.15
(m, 2 H, H-2,5), 2.86 (dd, 2 H, J1a,2 3.7, J1a,1b
5.4 Hz, H-1a,6a), 2.81 (dd, 2 H, J1b,2 2.7 Hz,
32.1 (C-6). Anal. Calcd for BrC14H27O8: Br,
19.80; C, 41.70; H, 6.75. Found: Br, 19.99; C,
41.99; H, 6.94.
1,2:5,6-Dianhydro-3,4-di-O-(4-methoxyben-
13
zyl)- -mannitol (43).—To a stirred solution of
D
H-1b,6b); C NMR: l 95.0 (OꢀCH2ꢀO), 76.3
31 (24.5 g, 58 mmol) in pyridine (170 mL), a
soln of tosyl chloride (30.2 g, 158 mmol) in a
mixture of CH2Cl2 (60 mL) and pyridine (15
mL) was added at 0 °C over a period of 30
min. The mixture was kept at 20 °C for 20 h
to give, after usual processing, crude 34 as a
syrup (47 g). This was dissolved in CH2Cl2
(100 mL) and MeOH (25 mL), cooled to 0 °C
and 4.3 M methanolic NaOMe (25 mL) was
added. After 30 min the mixture was diluted
with CH2Cl2, the organic soln was washed
with water, dried and concentrated. The
residue was purified by column chromatogra-
phy (solvent E) to give 43 (6 g, 27.6%) as a
syrup; [h]D −5° (c 0.5, CHCl3); Rf 0.3 (sol-
(C-3,4), 71.4, 67.1 (OꢀCH2ꢀCH2ꢀO), 58.8
(OMe), 49.8 (C-2,5), 46.4 (C-1,6). Anal. Calcd
for C14H26O8: C, 46.92; H, 8.43. Found: C,
47.14; H, 8.25.
2,5-Anhydro-6-S-acetyl-3,4-di-O-allyl-6-thio-
-glucitol (45).—A solution of crude 38 [15]
D
(24.5 g) and KSAc (8 g) in DMF (100 mL)
was stirred for 1 h at 80 °C. The residue
obtained on concentration was dissolved in
CH2Cl2, washed with water, dried and concen-
trated to give after purification by column
chromatography (solvent D) 45 (20.2 g, 84%)
1
as a syrup; [h]D +44°; Rf 0.4 (solvent C); H
NMR: l 5.85 (m, 2 H, OꢀCH2ꢀCHꢁCH2),
5.15–5.35 (m, 4 H, OꢀCH2ꢀCHꢁCH2), 3.70–
4.15 (m, 10 H, H-1a,1b, H-2, H-3, H-4, H-5,
OꢀCH2ꢀCHꢁCH2), 3.22 (dd, 1 H, J5,6a 6.1,
J6a,6b 13.7 Hz, H-6a), 3.10 (dd, 1 H, J5,6b 6.8
Hz, H-6b), 2.33 (s, 3 H, SAc); 13C NMR: l
194.9 (SCOMe), 133.9, 133.8 (OꢀCH2ꢀ
CHꢁCH2), 117.1 (OꢀCH2ꢀCHꢁCH2), 84.6,
83.1, 81.7, 80.8 (C-2,3,4,5), 70.4, 70.2
(OꢀCH2ꢀCHꢁCH2), 60.9 (C-1), 31.8 (C-6),
30.3 (SCOMe). Anal. Calcd for C14H22O5S: C,
55.61; H, 7.33; S, 10.60. Found: C, 55.66; H,
7.20; S, 10.44.
1
vent E); H NMR: l 7.20 (d, 4 H, aromatic),
6.83 (d, 4 H, aromatic), 4.63, 4.52 (2d, 4 H, J
11.5 Hz, OꢀCH2ꢀAr), 3.77 (s, 6 H, OMe), 3.40
(d, 2 H, J2,3 4.6 Hz, H-3,4), 3.13 (m, 2 H,
H-2,5), 2.76 (dd, 2 H, J1a,2 3.9, J1a,1b 5.4 Hz,
H-1a,6a), 2.63 (dd, 2 H, J1b,2 2.4 Hz, H-
13
1b,6b); C NMR: l 159.2, 130.0, 129.5, 113.6
(C-aromatic), 78.0 (C-3,4), 73.0 (OꢀCH2ꢀAr),
55.1 (OMe), 50.6 (C-2,5), 46.0 (C-1,6). Anal.
Calcd for C22H26O6: C, 68.38; H, 6.78. Found:
C, 62.39; H, 6.90.
1,2:5,6 - Dianhydro - 3,4 - di - O - (2 - methoxy-
2,5 - Anhydro - 6 - S - acetyl - 3,4 - di - O - (4-
ethoxymethyl)- -mannitol (44).—To a stirred
D
methoxybenzyl)-6-thio- -glucitol (46).—A so-
D
solution of 32 (6.1 g, 17 mmol) in pyridine (40
mL), a soln of tosyl chloride (7.7 g, 41 mmol)
in a mixture of CH2Cl2 (14 mL) and pyridine
(3 mL) was added at 0 °C over a period of 30
min. The mixture was kept at 20 °C for 20 h
to give, after usual processing, crude 35 as a
syrup (10 g); Rf 0.4 (solvent J). This was
dissolved in CH2Cl2 (50 mL) and MeOH (50
mL), cooled to 0 °C and 4.3 M methanolic
NaOMe (6.5 mL) was added. After 30 min the
mixture was diluted with CH2Cl2, the organic
soln was washed with water, dried and con-
centrated. The residue (6.2 g) was purified by
column chromatography (solvent A) to give
44 (2.8 g, 51%); mp 40–42 °C (ether–hexane);
[h]D −6° (c 0.5, CHCl3); Rf 0.5 (solvent A);
1H NMR: l 4.88, 4.78 (2d, 4 H, J 7.1 Hz,
OꢀCH2ꢀO), 3.74 (m, 4 H, OꢀCH2ꢀCH2ꢀO),
lution of crude 39 (3.5 g) and KSAc (1.02 g) in
DMF (15 mL) was stirred for 1 h at 80 °C.
The residue obtained on concentration was
dissolved in CH2Cl2, washed with water, dried
and concentrated to give after purification by
column chromatography (solvent H) 46 (3.2 g,
93%) as a syrup: [h]D +38° (c 0.5, CHCl3); Rf
1
0.4 (solvent H); H NMR: l 7.18–7.28 (m, 4
H, aromatic), 6.85–6.92 (m, 4 H, aromatic),
4.54, 4.26 (2d, 2 H, J 11.5 Hz, OꢀCH2ꢀAr),
4.48 (s, 2 H, OꢀCH2ꢀAr), 3.75–4.15 (m, 6 H,
H-1a,1b,2,3,4,5), 3.80, 3.79 (2s, 6 H, OMe),
3.22 (dd, 1 H, J5,6a 6.1, J6a,6b 13.7 Hz, H-6a),
3.10 (dd, 1 H, J5,6b 6.6 Hz, H-6b), 2.32 (s, 3 H,
SAc); 13C NMR: l 195.1 (SCOMe), 159.4,
159.3, 129.5, 129.3, 129.3, 129.2, 113.9, 113.8
(C-aromatic), 84.5, 83.4, 82.0 and 80.8 (C-

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E. Bozo´ et al. / Carbohydrate Research 329 (2000) 25–40
36
mL) was added at 0 °C, the solution was kept
for 1 h at 20 °C to give, after usual processing
and column chromatography, (solvent H) 49
(3.3 g, 89%) as a syrup: [h]D +21° (c 0.5,
2,3,4,5), 71.5 and 71.3 (OꢀCH2ꢀAr), 61.5 (C-
1), 55.2 (OMe), 32. (C-6), 30.4 (SCOMe).
Anal. Calcd for C24H30O7S: C, 62.32; H, 6.54;
S, 6.93. Found: C, 62.36; H, 6.78; S, 6.90.
2,5-Anhydro-6-S-acetyl-3,4-di-O-(2-meth-
1
CHCl3); Rf 0.6 (solvent H); H NMR: l 7.17–
oxyethoxymethyl)-6-thio- -glucitol (47).—A
D
7.27 (m, 4 H, aromatic), 6.85–6.93 (m, 4 H,
aromatic), 4.20–4.55 (m, 7 H, OꢀCH2ꢀAr,
H-1a,1b, H-2), 4.03 (m, 1 H, H-5), 3.95 (d, 1
H, J2,3 3.9 Hz, H-3), 3.81 (m, 1 H, H-4), 3.80
(s, 6 H, OMe), 3.20 (dd, 1 H, J5,6a 6.6, J6a,6b
13.7 Hz, H-6a), 3.06 (dd, 1 H, J5,6b 6.6 Hz,
H-6b), 3.00 (s, 3 H, OMs), 2.32 (s, 3 H, SAc);
13C NMR: l 194.9 (SCOMe), 159.4, 159.3,
129.5, 129.3, 129.2, 129.0, 113.9, 113.8 (C-aro-
matic), 83.6, 83.2, 81.9, 78.8 (C-2,3,4,5), 71.4,
71.2 (OꢀCH2ꢀAr), 68.6 (C-1), 55.2 (OMe),
37.4 (OMs), 31.8 (C-6), 30.4 (SCOMe). Anal.
Calcd for C25H32O9S2: C, 55.54; H, 5.97; S,
11.86. Found: C, 55.62; H, 5.63; S, 11.66.
2,5-Anhydro-6-S-acetyl-1-O-methanesul-
fonyl-3,4-di-O-(2-methoxyethoxymethyl)-6-
solution of crude 40 (2.4 g) and KSAc (0.82 g)
in acetone (50 mL) was stirred for 16 h at
20 °C. The residue obtained on concentration
was dissolved in CH2Cl2, washed with water,
dried and concentrated to give after purifica-
tion by column chromatography (solvent N)
47 (1.65 g, 70%) as a syrup: [h]D +81° (c 0.5,
1
CHCl3); Rf 0.5 (solvent N). H NMR: l 4.70–
4.85 (m, 4 H, OꢀCH2ꢀO), 3.50–4.25 (m, 14 H,
H-1a,1b,2,3,4,5, OꢀCH2ꢀCH2ꢀO), 3.39 (s, 6 H,
OMe), 3.25 (dd, 1 H, J5,6a 6.1, J6a,6b 13.7 Hz,
H-6a), 3.08 (dd, 1 H, J5,6b 7.1 Hz, H-6b); 13C
NMR:
l
195.1 (SCOMe), 94.6, 94.5
(OꢀCH2ꢀO), 83.7, 82.6, 81.1, 81.0 (C-2,3,4,5),
71.5, 71.5, 67.4, 67.1 (OꢀCH2ꢀCH2ꢀO), 60.2
(C-1), 58.9 (OMe), 31.8 (C-6), 30.3 (SCOMe).
Anal. Calcd for C16H30O9S: C, 48.23; H, 7.59;
S, 8.04. Found: C, 48.01; H, 7.60; S, 7.90.
2,5-Anhydro-6-S-acetyl-1-O-methanesul-
thio- -glucitol (50).—To a stirred solution of
D
47 (1.4 g) in pyridine (10 mL), mesyl chloride
(0.54 mL) was added at 0 °C. After 1 h at
20 °C, the mixture was processed the usual
way to give 50 (1.59 g, 95%) as a syrup; [h]D
fonyl-3,4-di-O-allyl-6-thio- -glucitol (48).—
D
To a stirred solution of 45 (4 g) in CH2Cl2 (20
mL) and pyridine (4 mL), mesyl chloride (1.5
mL) was added at 0 °C and was kept for 1 h
at 20 °C to give, after usual processing and
column chromatography, (solvent C) 48 (3.7
g, 73%) as a syrup: [h]D +39° (c 0.5, CHCl3);
1
+50°; Rf 0.3 (solvent F); H NMR: l 4.70–
4.90 (m, 4 H, OꢀCH2ꢀO), 4.35–4.50 (m, 2
H, H-1a,1b), 4.32 (m, 1 H, H-2), 4.24 (d, 1
H, J2,3 3.9 Hz, H-3), 4.05 (d, 1 H, J4,5 2.2
Hz, H-4), 3.96 (ddd, 1 H, J5,6a 6.3, J5,6b 7.3
Hz, H-5), 3.62–3.80 (m, 4 H) and 3.50–3.62
(m, 4 H) (OꢀCH2ꢀCH2ꢀO), 3.38 (s, 6 H,
OMe), 3.25 (dd, 1 H, J6a,6b 13.4 Hz, H-
6a), 3.09 (dd, 1 H, H-6b), 3.08 (s, 3 H, OMs),
2.35 (s, 3 H, SAc); 13C NMR: l 194.6
(SCOMe), 94.4, 94.6 (OꢀCH2ꢀO), 83.4, 82.8,
80.5, 78.6 (C-2,3,4,5), 68.4 (C-1), 71.4, 71.4,
67.5, 67.1 (OꢀCH2ꢀCH2ꢀO), 58.7, 58.8
(OMe), 37.4 (OMs), 31.5 (C-6), 30.3
(SCOMe). Anal. Calcd for C17H32O11S2: C,
42.85; H, 6.77; S, 13.45. Found: C, 42.90; H,
6.82; S, 13.28.
1
Rf 0.4 (solvent C); H NMR: l 5.80–6.00 (m,
2 H, OꢀCH2ꢀCHꢁCH2), 5.15–5.35 (m, 4 H,
OꢀCH2ꢀCHꢁCH2), 4.35–4.50 (m, 2 H, H-
1a,1b), 4.31 (m, 1 H, H-2), 3.75–4.25 (m, 7 H,
H-3, H-4, H-5, OꢀCH2ꢀCHꢁCH2), 3.22 (dd, 1
H, J5,6a 6.6, J6a,6b 13.7 Hz, H-6a), 3.08 (dd, 1
H, J5,6b 7.1 Hz, H-6b), 3.06 (s, 3 H, OMs),
2.35 (s, 3 H, SAc); 13C NMR: l 194.8
(SCOMe), 133.8, 133.7 (OꢀCH2ꢀCHꢁCH2),
117.6, 117.5 (OꢀCH2ꢀCHꢁCH2), 83.9, 83.0,
82.0,
78.7
(C-2,3,4,5),
70.6,
70.4
(OꢀCH2ꢀCHꢁCH2), 68.5 (C-1), 37.4 (OMs),
31.8 (C-6), 30.4 (SCOMe). Anal. Calcd for
C15H24O7S2: C, 47.35; H, 6.36; S, 16.85.
Found: C, 47.22; H, 6.43; S, 16.66.
1,6:2,5-Dianhydro-3,4-di-O-allyl-1-thio- -
D
glucitol (51).—To a stirred solution of 45
(15.1 g, 50 mmol) in CH2Cl2 (50 mL), pyridine
(10 mL) and mesyl chloride (6 mL) were
added at 0 °C and the mixture was processed
after 1 h at 20 °C in the usual way. The
CH2Cl2 soln containing 48 (Rf 0.5, solvent C)
2,5-Anhydro-6-S-acetyl-1-O-methanesul-
fonyl-3,4-di-O-(4-methoxybenzyl)-6-thio- -
D
glucitol (49).—To a stirred solution of 46 (3.2
g) in pyridine 20 (mL), mesyl chloride (1.1

´
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 25–40
37
was concentrated to 100 mL and 4.5 M
methanolic NaOMe (15 mL) was added at
0 °C. The mixture was neutralised with solid
CO2 after 1 h to give on concentration and
column chromatography (solvent D) 51 (8.8 g,
73%) as liquid; [h]D −5°; Rf 0.7 (solvent C).
1H NMR: l 5.85–6.05 (m, 2 H, OꢀCH2ꢀ
CHꢁCH2), 5.15–5.40 (m, 4 H, OꢀCH2ꢀ
CHꢁCH2), 4.45–4.55 (m, 2 H, H-2,4), 4.28
(br, 1 H, H-5), 3.95–4.25 (m, 5 H, H-3 and
OꢀCH2ꢀCHꢁCH2), 3.20 (dd, 1 H, J5,6ax 2.7,
J6ax,6eq 12.9 Hz, H-6ax), 3.12 (dd, J1ax,2 3.2,
J1ax,1eq 13.2 Hz, H-1ax), 2.30 (ddd, 1 H,
J1eq,6eqꢀ1, J1eq,2 ꢀ1 Hz, H-1eq), 2.20 (ddd,
J5,6eq 2.2 Hz, H-6eq); 13C NMR: l 134.3, 134.2
(OꢀCH2ꢀCHꢁCH2), 117.6, 117.4 (OꢀCH2ꢀ
CHꢁCH2), 86.5, 86.3, (C-3,4), 78.5 (C-5), 76.0
(C-2), 71.8, 70.6 (OꢀCH2ꢀCHꢁCH2), 29.0 (C-
6), 24.6 (C-1). Anal. Calcd for C12H18O3S: C,
59.48; H, 7.49; S, 13.23. Found: C, 59.51; H,
7.42; S, 13.12.
neutralised with solid CO2 to give after con-
centration and column chromatography (sol-
vent F) 53 (0.88 g, 83%) as a syrup; [h]D +44°
1
(c 0.5, CHCl3); Rf 0.4 (solvent F); H NMR: l
4.75–4.75 (m, 4 H, OꢀCH2ꢀO), 4.71 (d, 1 H,
J3,4 3.2, J4,5 ꢀ0 Hz, H-4), 4.52 (m, 1 H, H-2),
4.38 (dd, 1 H, J2,3 6.7 Hz, H-3), 4.31 (br, 1 H,
H-5), 3.65–3.85 and 3.50–3.60 (m, 8 H,
OꢀCH2ꢀCH2ꢀO), 3.38 (s, 6 H, OMe), 3.27
(dd, 1 H, J5,6ax 2.4, J6ax,6eq 12.5 Hz, H-6ax),
3.11 (dd, J1ax,2 3.2, J1ax,1eq 13.2 Hz, H-1ax),
2.33 (ddd, 1 H, J1eq,6eqꢀ1, J1eq,2ꢀ1 Hz, H-
1eq), 2.19 (ddd, J5,6eq 2.2 Hz, H-6eq); 13C
NMR: l 95.9, 95.4 (OꢀCH2ꢀO), 85.3 (C-4),
85.1 (C-3), 79.1 (C-5), 75.8 (C-5), 71.5, 71.4,
67.4, 67.1 (OꢀCH2ꢀCH2ꢀO), 58.7 (OMe), 28.5
(C-6), 24.6 (C-1). Anal. Calcd for C14H26O7S:
C, 49.69; H, 7.74; S, 9.47. Found: C, 49.71; H,
7.70; S, 9.40.
4-Cyanophenyl 3,4-di-O-acetyl-2,5-anhydro-
1,6-dithio-h-
L
-gulo- (58) and -h- -glucosep-
D
1,6:2,5-Dianhydro-3,4-di-O-(4-methoxyben-
tanoside (61).—(i) Under argon, a solution of
a 1:9 mixture of 12 and 13 (4.4 g, 14.5 mmol)
and 4-cyanobenzenethiol (3.9 g, 28.8 mmol) in
1,2-dichloroethane (100 mL) was cooled to
−10 °C. Thereafter Me3SiOTf (2.9 mL, 16
mmol) was added and the mixture was stirred
for 1 h at 20 °C. The reaction was quenched
with Et3N (4.5 mL), concentrated and the
residue purified by column chromatography
(solvent C). The syrup, obtained on concen-
tration of the fractions having Rf 0.5 (solvent
C) was, according to NMR spectroscopy, a
zyl)-1-thio- -glucitol (52).—To a stirred solu-
D
tion of 49 (3 g) in CH2Cl2 (10 mL), 1 M
methanolic NaOMe (20 mL) was added at
0 °C. After 5 h, the mixture was neutralised
with solid CO2 to give after concentration and
column chromatography (solvent C) 52 (1.5 g,
67%): mp 50–51 °C (ether–hexane); [h]D
+
1
10° (c 0.5, CHCl3); Rf 0.5 (solvent C). H
NMR (CDCl3): l 7.20–7.28 (m, 4 H, aro-
matic), 6.84–6.90 (m, 4 H, aromatic), 4.48–
4.62 (m, 3 H, OꢀCH2ꢀO and H-4), 4.35–4.45
(m, 3 H, OꢀCH2ꢀO and H-2), 4.20–4.28 (m, 2
H, H-3 and H-5), 3.78 (s, 6 H, OMe), 3.15
(dd, 1 H, J5,6ax ꢀ2.5, J6ax,6eq 12.9 Hz, H-6ax),
3.05 (dd, J1ax,2ꢀ3.0, J1ax,1eq 13.2 Hz, H-1ax),
2.25 (ddd, 1 H, J1eq,6eqꢀ1, J1eq,2 ꢀ1 Hz, H-
1eq), 2.12 (ddd, J5,6eq ꢀ2.0 Hz, H-6eq); 13C
NMR: l 159.3, 159.2, 129.8, 129.7, 129.5,
129., 113.7 (C-aromatic), 86.2 (C-4), 86.0 (C-
3), 78.5 (C-5), 75.9 (C-5), 72.4, 71.3
(OꢀCH2ꢀAr), 55.2 (OMe), 28.9 (C-6), 24.6
(C-1); Anal. Calcd for C22H26O5S: C, 65.65;
H, 6.51; S, 7.97. Found: C, 65.71; H, 6.77; S,
7.88.
1
1:9 mixture of 58+61 (5.48 g, ꢀ100%); H
NMR: l (58) 7.58–7.44 (m, 4 H, aromatic),
5.53 (d, 1 H, J2,3 0, J3,4 3.4 Hz, H-3), 5.33 (dd,
J4,5 6.8 Hz, H-4), 4.85 (dd, 1 H, J5,6eq 1.5, J5,6ax
3.2 Hz, H-5), 4.45 (dd, 1 H, J1,2 1.5, J1,6eq ꢀ1
Hz, H-1), 4.30 (d, 1 H, H-2), 3.43 (dd, 1 H,
J6ax,6eq 13.1 Hz, H-6ax), 2.15 (ddd, 1 H, H-
6eq), 2.12, 2.09 (2s, 6 H, OAc); (61) 7.60–7.45
(m, 4 H, aromatic) 5.61 (d, 1 H, J3,4 3.2, J4,5
0
Hz, H-4), 5.33 (dd, J2,3 7.1 Hz, H-3), 4.80 (dd,
1 H, J1,2 2.4, H-2), 4.37 (dd, 1 H, J5,6eq 2.6,
J5,6ax 2.4 Hz, H-5), 4.04 (dd, 1 H, J1,6eq ꢀ1 Hz,
H-1), 3.45 (dd, 1 H, J6ax,6eq 13.2 Hz, H-6ax),
2.51 (ddd, 1 H, H-6eq), 2.16, 2.10 (2s, 6 H,
COMe); 13C NMR: l (58) 171.3, 170.3
(COMe), 141.9 (C-1%), 132.4, 129.4 (C-
2%,3%,5%,6%), 118.5 (CN), 110.0 (C-4%), 81.8 (C-2),
81.4 (C-3), 77.6 (C-4), 75.6 (C-5), 47.6 (C-1),
1,6:2,5 - Dianhydro - 3,4 - di - O - (2 - methoxy-
ethoxymethyl)-1-thio- -glucitol (53).—To a
D
stirred solution of 50 (1.5 g) in CH2Cl2 (10
mL) 4 M methanolic NaOMe (4 mL) was
added at 0 °C. After 5 h, the mixture was

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E. Bozo´ et al. / Carbohydrate Research 329 (2000) 25–40
38
22.9 (C-6) 20.7, 20.6 (COMe); (61) 170.9,
170.3 (COMe), 141.8 (C-1%), 136.1, 132.4 (C-
2%,3%,5%,6%), 118.4 (CN), 110.3 (C-4%), 80.5 (C-4),
79.6 (C-5), 78.9 (C-3), 78.6 (C-2), 45.8 (C-1),
26.5 (C-6) 20.8, 20.7 (COMe). Anal. Calcd for
C17H17NO5S2: C, 53.81; H, 4.52; N, 3.69; S,
16.90. Found: C, 53.90; H, 4.63; N, 3.58; S,
16.85.
(ii) The ratio of 58:61 remained unchanged
when pure 13 was used as donor.
(iii) When pure 12 was used as donor, the
ratio of 58:61 was 6:1.
The mother liquor gave on concentration a
2:1 mixture of 59+61 (120 mg, 34.5%).
4-Nitrophenyl 3,4-di-O-acetyl-2,5-anhydro-
1,6-dithio-h-
L
-gulo- (60) and -h- -glucosep-
D
tanoside (62).—Under argon, to a solution of
a 1:9 mixture of 12 and 13 (0.9 g, 2.96 mmol)
and 4-nitrobenzenethiol (0.48 g, 3.1 mmol) in
1,2-dichloroethane (15 mL) BF3·Et2O (0.35
mL, 2.9 mmol) was added, and the mixture
was stirred for 24 h at 20 °C. It was then
poured into ice cooled 6% aq NaHCO3 (25
mL) and extracted with 1,2-dichloroethane (15
mL). The organic solution was washed with
water, dried, concentrated and the residue
purified by column chromatography (solvent
C). Concentration of the fractions having Rf
0.6 afforded, according to NMR spec-
troscopy, a 1:4 mixture of 60+62 (1.05 g,
(iv) To a slurry of 18 (6.6 g, 26.8 mmol) in
toluene (100 mL), NCS (3.5 g, 26.2 mmol) was
added and the mixture was stirred for 1 h at
20 °C. During this period 18 was gradually
dissolved and succinimide precipitated. This
was filtered off and was washed with toluene
(50 mL). The filtrate, containing 56 and 57 (Rf
0.7 solvent C) was added dropwise over a
period of 30 min to a stirred slurry of freshly
fused ZnO (2.8 g, 34.4 mmol) and 4-
cyanobenzenethiol (4.4 g, 32.5 mmol) in
MeCN (150 mL). Stirring was continued for
30 min at 20 °C, then the mixture was filtered
through Celite. The residue obtained on con-
centration of the filtrate was freed from 4-
cyanobenzenethiol disulfide (Rf 0.8) by
column chromatography (solvent C) to give
after concentration of the fractions having Rf
0.5, a mixture of 58+61 (8 g, 79%), identical
to that obtained according to method (i).
1
89%). H NMR: l (60) 8.12 (d, 2 H, aro-
matic), 7.45 (d, 2 H, aromatic), 5.50 (d, 1 H,
J2,3 0, J3,4 3.4 Hz, H-3), 5.32 (dd, 1 H, J4,5 6.5
Hz, H-4), 4.84 (m, 1 H, H-5), 4.49 (dd, 1 H,
J1,2 1.7, J1,6eq ꢀ1 Hz, H-1), 4.30 (d, 1 H, H-2),
3.42 (dd, 1 H, J5,6ax 2.9, J6ax,6eq 13.9 Hz, H-
6ax), 2.15 (m, 1 H, H-6eq), 2.12, 2.08 (2s, 6 H,
COMe). Anal. Calcd for C16H17NO7S2: C,
48.11; H, 4.29; N, 3.51; S, 16.05. Found: C,
48.02; H, 4.45; N, 3.48; S, 15.87.
4-Cyanophenyl 2,5-anhydro-1,6-dithio-h- -
D
glucoseptanoside (63).—To a solution of a 1:9
mixture of 58 and 61 (5.48 g, 14.4 mmol)
obtained according to method (i) or (iv) in
MeOH (50 mL), 3 M methanolic NaOMe (0.5
mL) was added and the mixture was kept for
2 h at 20 °C. Thereafter it was neutralised with
solid CO2 and the precipitated crude thioglu-
coside was recrystallized from MeOH (32 mL)
to give 63 (3.2 g, 75%), mp 152–154 °C; [h]D
4-Cyanophenyl 2,5-anhydro-1,6-dithio-h- -
L
guloseptanoside (59).—To a solution of a 6:1
mixture of 58 and 61 (450 mg, 1.2 mmol),
obtained according to method (iii), in MeOH
(15 mL) 1 M methanolic NaOMe (0.1 mL)
was added and the mixture was kept for 1 h at
20 °C. After neutralization with solid CO2, the
precipitated material was filtered and washed
with Et2O to give 59 (160 mg, 46%), mp
148–150 °C; [h]D −442° (c 0,5, MeOH); Rf
1
+553° (c 0.5, MeOH); Rf 0.3 (solvent G); H
NMR: l 7.80–7.54 (m, 4 H, aromatic) 5.38,
5.35 (2s, 2 H, OH), 4.55 (d, 1 H, J1,2 1.5 Hz,
H-1), 4.40 (d, 1 H, J3,4 2.9, J4,5 0 Hz, H-4),
4.37 (dd, J2,3 6.8 Hz, H-2), 4.19 (d, 1 H, H-3),
4.12 (dd, 1 H, J5,6ax 2.7, J5,6eq 2.3 Hz, H-5),
3.17 (dd, J6ax,6eq 13.1 Hz, H-6ax), 2.38 (dd, 1
H, H-6eq); 13C NMR: l 143.4 (C-1%), 132.8,
128.5 (C-2%,3%,5%,6%), 118.9 (CN), 108.2 (C-4%),
81.7, 81.7, 80.4, 79.8 (C-2,3,4,5), 44.4 (C-1),
26.9 (C-6). Anal. Calcd for C13H13NO3S2: C,
52.86; H, 4.44; N, 4.72; S, 21.71. Found: C,
52.84; H, 4.52; N, 4.66; S, 21.62.
1
0.3 (solvent G); H NMR: l 7.58–7.43 (m, 4
H, aromatic), 5.38, 5.35 (2s, 2 H, OH), 4.76
(d, 1 H, J1,2 2 Hz, H-1), 4.38 (ddd, J4,5 6.8,
J5,6ax 3.2, J5,6eq 1.5 Hz, H-5), 4.35 (d, 1 H, J2,3
0, J3,4 2.9 Hz, H-3), 4.15 (dd, 1 H, H-4), 3.98
(d, 1 H, H-2), 3.06 (dd, 1 H, J6ax,6eq 13.2 Hz,
H-6ax), 2.30 (dd, 1 H, H-6eq). Anal. Calcd for
C13H13NO3S2: C, 52.86; H, 4.44; N, 4.72; S,
21.71. Found: C, 52.89; H, 4.48; N, 4.63; S,
21.59.

´
E. Bozo´ et al. / Carbohydrate Research 329 (2000) 25–40
39
NMR (Me2SO-d6): l 8.18 (d, 2 H, aromatic),
7.55 (d, 2 H, aromatic), 5.49 and 5.33 (2d, 2
H, OH), 4.61 (br., 1 H, J1,2 ꢀ1, J1,6eq ꢀ1 Hz,
H-1), 4.36–4.42 (m, 2 H, H-2 and H-4), 4.18
(m, 1 H, J2,3 6.8, J3,4 2.4 Hz, H-3), 4.14 (dd, 1
H J4,5 ꢀ0 Hz, H-5), 3.17 (dd, 1 H, J5,6ax 2.7,
J6ax,6eq 12.9 Hz, H-6ax), 2.40 (ddd, 1 H,
J5,6eqꢀ1 Hz, H-6eq); Anal. Calcd for
C16H17NO7S2: C, 45.70; H, 4.16; N, 4.44; S,
20.33. Found: C, 45.66; H, 4.15; N, 4.41; S,
20.29.
4-(Aminothiocarbonyl)phenyl 2,5-anhydro-
1,6-dithio-h- -glucoseptanoside (64).—A
D
stirred solution of 63 (1.3 g, 4.4 mmol) in dry
pyridine (30 mL) and Et3N (30 mL) was satu-
rated with a slow stream of dry hydrogen
sulfide for 2 h. The mixture was kept at rt
overnight and was then concentrated. Toluene
was evaporated from the residue, which was
subsequently recrystallized from MeOH to
yield 64 (1.2 g, 83%): mp 195–202 °C; [h]D
1
+251° (c 0.4, Me2SO); Rf 0.4 (solvent J); H
4-Acetamidophenyl 2,5-anhydro-1,6-dithio-
NMR (Me2SO-d6): l 9.84 and 9.48 (2 br., 2 H,
NH2), 7.87 and 7.37 (2d, 4 H, aromatic), 5.42
and 5.30 (2d, 2 H, OH), 4.45 (br., 1 H,
J1,2 ꢀ1, J1,6eq ꢀ1 Hz, H-1), 4.25–4.42 (m, 2
H, H-2,4), 4.05–4.20 (m, 2 H, H-3,5), 3.17
(dd, 1 H, J5,6ax 2.6, J6ax,6eq 13.2 Hz, H-6ax),
2.35 (ddd, 1 H, J5,6eq ꢀ1 Hz, H-6eq). Anal.
Calcd for C13H15NO3S3: C, 47.40; H, 4.59; N,
4.25; S, 29.19. Found: C, 47.38; H, 4.56; N,
4.20; S, 29.11.
h- -glucoseptanoside (67).—To a stirred solu-
D
tion of 66 (310 mg, 1 mmol) in EtOH (30 mL),
NaBH4 (150 mg, 4 mmol) and subsequently
NiCl2·6 H2O (10 mg) were added at 20 °C.
After 30 min the slurry was neutralized with 1
M HCl, filtered and the residue obtained on
concentration was treated with Ac2O (5 mL)
and pyridine (10 mL). The mixture was kept
at rt for 20 h to give, after usual processing, a
syrup, which was dissolved in MeOH (10 mL),
and 1 M methanolic NaOMe (0.1 mL) was
added. After 1 h at 20 °C the mixture was
neutralized with solid CO2 and the residue
obtained on concentration was submitted to
column chromatography (solvent J) to yield
67 (190 mg, 59%); mp 55–58 °C (Et2O); [h]D
4-[(Imino)(methylthio)methyl]phenyl
anhydro-1,6-dithio-h- -glucoseptanoside (65).
2,5-
D
—To a stirred solution of 34 (0.9 g, 2.7 mmol)
in dry acetone (130 mL), MeI (2 mL) was
added and the mixture was refluxed for 4 h.
After cooling to 5 °C, the precipitated crystals
were filtered off and washed with ether to give
65 (1.03 g, 80%) as its hydroiodide: mp 193–
196 °C; [h]D +278° (c 0.5, Me2SO); Rf 0.3
1
+229° (c 1, MeOH); Rf 0.4 (solvent J). H
NMR (Me2SO-d6): l 10.03 (s, 1 H, NHAc),
7.57, 7.38 (2d, 4 H, aromatic), 5.34, 5.25 (2d,
2 H, OH), 4.35 (m, 1 H, J3,4 2.7, J4,5ꢀ0 Hz,
H-4), 4.22 (dd, 1 H, J1,2 ꢀ1, J2,3 6.5 Hz, H-2),
4.00–4.15 (m, 3 H, H-1,3,5), 3.14 (dd, 1 H,
J5,6ax 2.2, J6ax,6eq 13.2 Hz, H-6ax), 2.30 (ddd, 1
H, J5,6eq ꢀ1.5, J1,6eq ꢀ1 Hz, H-6eq), 2.04 (s, 3
H, NAc). Anal. Calcd for C14H17NO4S2: C,
51.36; H, 5.23; N, 4.28; S, 19.58. Found: C,
51.30; H, 5.29; N, 4.21; S, 19.44.
1
(solvent A); H NMR (Me2SO-d6): l 10.5–
12.5 (br., 2 H, NH+2 ), 7.84 and 7.54 (2d, 4 H,
aromatic), 4.55 (br., 1 H, J1,2 ꢀ1, J1,6eq ꢀ1
Hz, H-1), 4.32–4.45 (m, 2 H, H-2 and H-4),
4.15 (dd, 1 H, J2,3 7.2, J3,4 3.2 Hz, H-3), 4.12
(br., 1 H, J4,5 ꢀ0 Hz, H-5), 3.16 (dd, 1 H,
J5,6ax 2.7, J6ax,6eq 12.9 Hz, H-6ax), 2.39 (ddd, 1
H, J5,6eq ꢀ1 Hz, H-6eq). Anal. Calcd for
C14H18INO3S3: C, 35.67; H, 3.85; I, 26.92; N,
2.97; S, 20.40. Found: C, 35.61; H, 3.90; I,
26.78; N, 2.92; S, 20.27.
4-Nitrophenyl 2,5-anhydro-1,6-dithio-h- -
D
Acknowledgements
glucoseptanoside (66).—To a solution of a 1:4
mixture of 60 and 62 (1.0 g, 2.5 mmol) in
MeOH (20 mL), 3 M NaOMe (0.1 mL) was
added at 20 °C. After 1 h the solution was
neutralised with solid CO2 and the residue
obtained on concentration was purified by
column chromatography (solvent J) to give 66
(0.60 g, 76%), mp 174–178 °C (Et2O); [h]D
The authors are very much indebted to Dr
Gabriella Szabo´ for the biological results.
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