Replacement of carbohydrate sulfates by sugar C-sulfonic acid derivatives

Article abstract of DOI:10.1081/CAR-120037571

3′-Substituted p-methoxyphenyl β-lactosides and one of their 3′-epimer were synthesized. The common feature of these compounds is the presence of a strong negative charge at position C-3′ in the form of sulfonic acid moieties. The 3′,4′-diol derivative of

Full text of DOI:10.1081/CAR-120037571

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Replacement of Carbohydrate Sulfates by Sugar
C‐Sulfonic Acid Derivatives
Anikó Borbás a , Magdolna Csávás a , László Szilágyi b , Gábor Májer a & András Lipták a c
a Research Group for Carbohydrates of the Hungarian Academy of Sciences, P.O. Box 55,
Debrecen, H‐4010, Hungary
b Department of Organic Chemistry, Faculty of Science, University of Debrecen,
Debrecen, Hungary
c Department of Biochemistry, Faculty of Science, University of Debrecen, Debrecen,
Hungary
Version of record first published: 18 Aug 2006.
To cite this article: Anikó Borbás , Magdolna Csávás , László Szilágyi , Gábor Májer & András Lipták (2004): Replacement
of Carbohydrate Sulfates by Sugar C‐Sulfonic Acid Derivatives, Journal of Carbohydrate Chemistry, 23:2-3, 133-146
To link to this article: http://dx.doi.org/10.1081/CAR-120037571
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 23, Nos. 2 & 3, pp. 133–146, 2004
Replacement of Carbohydrate Sulfates by Sugar
C-Sulfonic Acid Derivatives#
1
Aniko Borbas, Magdolna Csavas, Laszlo Szilagyi, Gabor Majer,
1
2
1
´
´
´ ´
´
´
1,3,
and Andras Liptak
´
´
´
*
´
´
1Research Group for Carbohydrates of the Hungarian Academy of Sciences,
Debrecen, Hungary
2Department of Organic Chemistry and 3Department of Biochemistry, Faculty of
Science, University of Debrecen,
Debrecen, Hungary
ABSTRACT
30-Substituted p-methoxyphenyl b-lactosides and one of their 30-epimer were syn-
thesized. The common feature of these compounds is the presence of a strong negative
charge at position C-30 in the form of sulfonic acid moieties. The 30,40-diol derivative of
p-methoxyphenyl lactoside was also glycosylated with the thioglycoside of the sulfoulo-
sonic acid. The two-regioisomeric trisaccharides were isolated but their deprotection
failed. The aim of the present study was to find carbohydrate ligand(s), which can inhibit
the adhesion between Helicobacter pylori and the gastrointestinal epithelial cells.
Key Words: Carbohydrate sulfates; p-Methoxyphenyl lactoside; Sulfonic acid;
Epithelial cells; Proteins.
#
´
This paper is dedicated to Professor Gerard Descotes on the occasion of his 70th birthday.
*
´ ´
Correspondence: Andras Liptak, Research Group for Carbohydrates of the Hungarian Academy of
Sciences, P.O. Box 55, Debrecen, H-4010, Hungary; Fax: þ36-52-512-913; E-mail: liptaka@tigris.
klte.hu.
133
DOI: 10.1081/CAR-120037571
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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134
INTRODUCTION
The isolation of Helicobacter pylori[1] in 1982 opened a new epoch in gastroentero-
logy, and completely changed the diagnosis and therapy of gastritis and peptic ulcer.
This bacterium is a human specific gram-negative, urease-positive organism, which is a
causative agent in chronic active gastritis, gastric and duodenal ulcers, and presumably
gastric malignancies.[2]
It is estimated that 70–90% and 25–50% of the population carry H. pylori in
developing countries and in the industrialized world, respectively. Independently, of the
geographical area, clinical disease occurs in 10–20% of the colonized individuals. The
carriage of the bacterium is strongly associated with the development of atrophic gastritis,
a precursor lesion to gastric cancer. The latter is the second leading cause of cancer deaths
worldwide.[3] Recent investigations suggested that H. pylori might be transmitted via the
oral route, since the organism has been detected at different sites of the oral cavity.[4]
Presently, therapy is based a combination of antibiotics and a proton pump inhibitor,
which results in very low recurrence. Nevertheless, owing to antibiotic resistance,[3]
extension of such treatment is not recommended. Efforts focusing on vaccine development
are yet unsuccessful,[5] and carbohydrate-based antiadhesion-therapy maybe an alternative.
It is well known that many pathogens use highly specific carbohydrate–protein interactions
to attack cells and initiate diseases. The first line of defense against the resulting infectious
diseases are the oligosaccharide-type ligands in the mucous layer exposed epithelial cells and
in saliva, tears and sweat, which act as “mimics” leading to pathogen elimination. These
oligosaccharide ligands bind to the carbohydrate-binding proteins of the microorganism,
and the pathogens are eliminated by different physiological mechanisms.[6]
Pathogen proteins bind weakly to their oligosaccharide ligands. Such association can
be competitively inhibited with low concentrations either of the protein or of the oligosac-
charides. The most attractive strategy maybe to use soluble forms of oligosaccharide
ligand(s) which are small and non-immunogenic.
Some bacteria carry genes that encode more than one adhesin, each capable of binding
a different carbohydrate receptor. In this regard, the carbohydrate-binding specificity of
H. pylori is unusually high.[7] More than 10 different kinds of carbohydrate-binding
specificity have been described, including recognition of sialylated oligosaccharides as
well as that of sulfated mono-, oligo-, or polysaccharides. In all cases, multivalency
resulted in an increased inhibitor potency.[8–12]
These examples showed that inhibitors of bacterial adhesion maybe successfully used
as therapeutic agents for preventing infections caused by H. pylori. These findings
prompted us to seek not only for sulfated sugars, but also to replace the sulfate esters
by C-sulfonic acids. Till now, only one sugar-sulfonic acid, namely 6-sulfoquinovose
was found in nature. It is stable in the presence of sulfatases,[13] and belongs to the
strongest acids. In our laboratory, a method was developed to synthesize C-sulfonic
acid-containing glycosyl donors,[14,15] which were used for the synthesis of sulfoulosonic
acid-containing oligosaccharides to mimic sialyl Lewis X derivatives.
It is also worth to mention that the sulfated sugars have very different biological
activities, such as antiproliferative,[16] anticoagulant,[17,18] anticancer,[19] and antiviral[20]
properties.

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135
In this paper, we wish to report on the synthesis of some C-sulfonic acid carrying
lactose analogs having the following structures:
RESULTS AND DISCUSSION
It is known that treatment of lactosides with 2,2-dimethoxypropane results selectively
in the 30,40-O-isopropylidene derivatives. This selectivity was indeed observed for
p-methoxyphenyl b-lactoside 3[21] and p-methoxyphenyl 3,4-O-isopropylidene-b-D-
galactopyranosyl-(1 ! 4)-b-D-glucopyranoside (4) was obtained in a yield of 67%. All
free hydroxyl groups of 4 were benzylated using Brimacombe’s conditions[22] to give
compound 5 in a quantitative yield. Conventional hydrolysis of the isopropylidene acetal
with methanolic HCl resulted in diol 6 (91%). Regioselective alkylation of the vicinal
cis-diol was achieved by means of the tin-mediated procedure.[23] The reactive stannylene
derivative was prepared using an equimolar amount of Bu2SnO in methanol, without removal
of water.[24] This technique is useful, provided that the stannylene is stable in methanol.
Problems may arise with vicinal trans-diequatorial diols. The stannylene derivative was
allylated with allyl bromide in DMF to give 30-O-allyl ether 7 (88%). Alternatively, it
was treated with 2-bromomethylnaphthalene to furnish the 30-O-(2-naphthyl)methyl ether
8 (30-ONAP) in 87% yield.
In compound 7, the allyl ether offers a great potential for the generation of various func-
tions. In the present case, we describe the sulfite addition, leading to the 30-O-[3-(sodium
sulfonate)propyl]-lactoside derivative 9 (Sch. 1).
The addition of bisulfite to unsaturated compounds is a very common procedure.[25]
Kharasch et al.[26] established that this reaction can be interpreted on the basis of a free-
radical mechanism, and the addition goes anti-Markovnikov resulting in 1-alkane-sulfonates.
More recent studies[27] led to propose a three-step mechanism involving (1) the production of
a sulfite radical ion, for example by nitrate-ion oxidation of sulfite ion, (2) a bisulfite ion in
the chain-transfer reaction, and (3) termination by sulfite radical-ion oxidation and radical
coupling. Analogously to the procedure described for cyclodextrins,[28] compound 7 was
treated with NaHSO3 and a catalytic amount of tert-butyl perbenzoate in a 70% ethanolic
solution.[29] Compound 9 was obtained quantitatively and subsequently hydrogenolyzed to
give the target 1 (96%).
Compounds 7 and 8 were benzylated to obtain the fully protected lactoside derivatives
(10 and 11). The allyl group of compound 10 was removed by use of the Pd/C–TsOH
system[30] to give the 30-OH compound 12 (87%). The same compound was isolated
from the fully protected 11 through the removal of the 2-naphthylmethyl (NAP) group
by using DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone). NAP ethers have been
described previously,[31–33] and their preparative usefulness was rediscovered[34,35]
only very recently. It was demonstrated that NAP ethers can be hydrogenolyzed in the
presence of benzyl ethers or esters, and that they are less sensitive to acids than the

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Borbas et al.
136
Scheme 1. (a) NaH, BnBr, DMF, quant.; (b) 1M HCl, MeOH, 508C, 91%; (c) Bu2SnO, MeOH,
reflux, 2 hr; AllBr (2.5 equiv.), DMF, 88%; (d) Bu2SnO, MeOH, reflux, 2 hr; NAPBr (2.5 equiv.),
DMF, 87%; (e) NaHSO3, tert-butyl perbenzoate, 70% EtOH, reflux, quant.; (f) Pd–C, H2, 48 hr,
EtOH–EtOAc–DCM (4 : 1 : 1), 96%.
p-methoxybenzyl ethers. The most important observation, however, is that NAP ethers can
easily be removed either by DDQ or by ammonium cerium(IV) nitrate (CAN) under con-
ditions when other usual protecting groups such as acetyl, pivaloyl, phthalimido, benzyl,
and benzylidene survive.[34,35] These ethers were successfully applied for the synthesis of
complex oligosaccharides[35–37] (Sch. 2).
The hydroxyl group of compound 12 was converted into a keto functionality using the
Dess–Martin periodinane reagent.[38] The structure of the resulting crystalline 13 was
confirmed from its 13C-NMR spectrum (dC¼0 ¼ 203 ppm).
The keton 13 was reacted with the ethyl methanesulfonate anion generated with
n-butyllithium.[14,15] Upon nucleophilic addition of the sulfonate ester carbanion to
the carbonyl, p-methoxyphenyl 2,4,6-tri-O-benzyl-3-C-(ethoxysulfonylmethyl)-b-D-
gulopyranosyl-(1 ! 4)-2,3,6-tri-O-benzyl-b-D-glucopyranoside (14) and its C-30 epimer
(15) were obtained in a 4 : 1 ratio. The b-D-gulopyranosyl configuration of the ultimate
monosaccharide unit of the main product was determined by NMR on the basis of
3
the CH2–H-20 and CH2–H-40 JC,H coupling constants, that depend on the dihedral
3
angle in a manner similar to JH,H
[15]
.
The small values of both coupling constants
ascertained the equatorial arrangement of the –CH2–SO3Et group. The minor product
15 proved to be the appropriate 30-epimer by its mass-spectrometric analysis (MALDI-
Ms for C64H70SO15 (M, 1110.44): m/z 1133.60 [M þ Na]þ). The ester group of 14 was
transformed into the corresponding tetrabutyl ammonium salt, and hydrogenolysis of
the latter on Pd/C catalyst resulted in the desired compound 2.
We also attempted the preparation of a trisaccharide-type sulfonic acid derivative of
lactoside 17. Glycosylation of compound 6 with ethyl 3,4,5,7-tetra-O-benzyl-1-deoxy-1-
ethoxysulfonyl-2-thio-a-D-gluco-hept-2-ulopyranoside (16)[14] using NIS-TfOH activation
afforded a separable 4 : 1 mixture of the trisaccharides 17 and presumably 18. During the
reaction, a considerable amount of exo-glycal 19[14] was formed. Determination of the

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137
Scheme 2. (a) DDQ (1.2 equiv.), DCM : MeOH (4 : 1), 1 drop of water, 2 hr, 89%; (b) 10% Pd–C,
TsOH (0.1 g/1 mmol), EtOH : EtOAc (5 : 1), 808C, 2 hr, 87%; (c) Dess–Martin periodinane
(1.2 equiv.), abs. DCM, 30 min, quant.; (d) n-BuLi, CH3SO3Et, 2708C, 71% for 14, 18% for 15;
(e) Bu4NBr, CH3CN, 508C; Pd–C, H2, EtOH, 93%.
anomeric configuration of the newly formed interglycosidic bond of 17 could be achieved by
the measurement of the 3JC1–H3 coupling constant and its small value (,1.8 Hz) verified the
exclusive formation of the a-anomer (Sch. 3).
Removal of the protecting groups from 17 was attempted via nucleophilic attack of
bromide ion and subsequent catalytic hydrogenation.[15] However, decomposition of the
trisaccharide was occurred during deprotection. The failure of the deprotection step is
under investigation in our laboratory.
In conclusion, oligosaccharide derivatives having C-sulfonic acid substituent at position
3 of the nonreducing end of a lactoside, or a p-methoxyphenyl b-D-gulopyranosyl-(1 ! 4)-
b-D-glucopyranoside analog were synthesized. The potential of the synthetic targets to
inhibit adhesion between H. pylori and the epithelial cells of the gastric antrum are under-
way in two independent laboratories.
EXPERIMENTAL
General Methods
Optical rotations were measured at rt with a Perkin–Elmer 241 automatic polari-
meter. Melting points were determined on a Kofler hot-stage apparatus and are uncor-

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Borbas et al.
138
˚
Scheme 3. (a) NIS-TfOH, DCM, 4A MS, 2408C, 47% for 17, 11% for 18, 32% for 19.
rected. TLC was performed on Kieselgel 60 F254 (Merck) with detection by charring with
50% aq. sulfuric acid. Column chromatography was performed on Silica Gel 60 (E. Merck
0.062–0.200 nm). The organic solutions were dried over MgSO4 and concentrated in vac-
uum. The 1H (200, 360, and 500 MHz) and 13C NMR (50.3, 90.54, 125.76 MHz) spectra
were recorded with Bruker WP-200SY, Bruker AM-360 and Bruker DRX-500 spec-
1
trometers for solutions in CDCl3. Internal references: TMS (0.00 ppm for H), CDCl3
(77.00 ppm for 13C). COSY and HSQC spectra were used to assign carbon
signals of compound 14.
4-Methoxyphenyl 3,4-O-isopropylidene-b-D-galactopyranosyl-(1 ! 4)-b-D-gluco-
pyranoside (4). To a solution of 4-methoxyphenyl b-D-galactopyranosyl-(1 ! 4)-b-D-
glucopyranoside (15 g, 33.4 mmol) in DMF (80 mL) 2,2-dimethoxypropane (10 mL)
and p-toluenesulfonic acid (200 mg) were added and the mixture was stirred for 4 hr at
808C, then neutralized with Serdolit Blue (HO2) ion exchange resin. The resin was filtered
off and the filtrate was concentrated. The residue was crystallized from ethanol to give 4
1
(11 g, 66%) as white needles, mp: 222–2248C; [a]D þ 7.1 (c 0.41, DMSO); H-NMR
(200MHz, DMSO-d6) d (ppm): 7.07, 6.84 (2m, each 2H, Ph), 5.50 (m, 2H), 4.92
(broad t, 1H), 4.84 (d, 1H, J1,2 ¼ 8.0Hz, H-1), 4.72 (m, 2H), 4.34 (d, 1H,
J1 ,2 ¼ 8.0Hz, H-10), 4.19–3.22 (m, OCH3, and 13H), 1.44, 1.29 (2s, each 3H,
0
0
C(CH3)2); 13C-NMR (50 MHz, DMSO-d6) d (ppm): 154.4, 151.4, 117.7, 114.5 (Ph),

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139
108.8 (C(CH3)2), 102.7, 101.1 (C-1, C-10) 80.2, 79.3, 74.9 (2C), 73.4, 73.1 (2C), 72.5
(8 skeleton C), 60.5, 60.1 (C-6, C-60), 55.4 (OCH3), 28.2, 26.4 (C(CH3)2). Anal. calcd
for C22H32O12: C, 54.08; H, 6.61. Found: C, 54.06; H, 6.63.
4-Methoxyphenyl 2,6-di-O-benzyl-3,4-O-isopropylidene-b-D-galactopyranosyl-
(1 ! 4)-2,3,6-tri-O-benzyl-b-D-glucopyranoside (5). To a solution of 4 (8.0 g,
16.3 mmol) in dry DMF 80% NaH (3 g, 0.10 mol) was added in small portions at 08C.
The reaction mixture was stirred for 30 min and benzyl bromide (12 mL, 0.10 mol) was
added. After 2 hr, t.l.c. showed complete conversion (DCM : acetone, 98 : 2), then
MeOH was added in order to decompose the excess of hydride. The solvent was evapor-
ated, the residue was dissolved in DCM (1200 mL), washed with distilled water
(3 ꢀ 400 mL), dried, filtered, and evaporated. The sirupy crude product (15 g) was used
for the next step without purification.
4-Methoxyphenyl
2,6-di-O-benzyl-b-D-galactopyranosyl-(1 ! 4)-2,3,6-tri-O-
benzyl-b-D-glucopyranoside (6). A stirred mixture of 5 (15 g, ꢀ16 mmol) in methanol
(500 mL) and 1 M HCl was heated for 508C. After 2 hr, t.l.c. showed complete conversion,
the solution was evaporated and the solid residue was crystallized from methanol to give 6
(13 g, 89% for two steps), mp: 120–1248C; [a]D þ 1.9 (c 0.58, CHCl3); 1H-NMR
(200 MHz, CDCl3) d (ppm): 7.42–6.77 (m, 29H, Ph), 5.01 (dd, 2H), 4.90–4.76 (m, H-1
and 3H), 4.67, 4.56 (2d, each 1H, Jgem ¼ 12 Hz, CH2Ph), 4.49–4.33 (m, 3H, and H-10),
4.10–3.35 (m, 12H, and OCH3), 2.33 (broad s, 2H, OH); 13C-NMR (50 MHz, CDCl3) d
(ppm): 154.4–114.4 (Ph), 102.4, 102.3 (C-1, C-10), 82.8, 81.5, 80.1, 76.4, 75.2, 73.5,
73.0, 68.8 (skeleton C), 75.2, 75.1, 75.0, 73.5, 73.2 (5 CH2Ph), 68.7, 68.3 (C-6, C-60),
55.7 (OCH3). MALDI-MS for C54H58O12 (M, 898.38): m/z 922.28 [M þ Na]þ.
4-Methoxyphenyl 3-O-allyl-2,6-di-O-benzyl-b-D-galactopyranosyl-(1 ! 4)-2,3,6-
tri-O-benzyl-b-D-glucopyranoside (7). To a suspension of 6 (9 g, 10 mmol) in MeOH
(150 mL) was added dibutyltin oxide (3.1 g, 12.5 mmol). The mixture was stirred for
2 hr at reflux temperature, MeOH was evaporated, and the residue was dried under high
vacuum for 1 hr. To a suspension of the crude mixture in DMF (30 mL) was added allyl
bromide (2.6 mL, 30 mmol). After being stirred for 48 hr at rt, the mixture was concen-
trated in vacuum and purified by column chromatography (DCM : acetone, 97 : 3) to
give 7 (8.2 g, 88%) as white needles mp: 102–1048C (from ethyl acetate–n-hexane;
1
[a]D 0 (c 0.34, CHCl3); H-NMR (200 MHz, CDCl3) d (ppm): 7.50–6.80 (m, 29H, Ph),
5.99 (m, 1H, CH255CH) 5.42–5.21 (m, 2H), 5.07 (2d, 2H, Jgem ¼ 12 Hz, CH2Ph),
4.96–4.79 (m, 5H), 4.60–4.40 (m, 5H), 4.31–4.00 (m, 4H), 3.89–3.32 (m, OCH3, and
10H), 2.36 (broad s, 1H, OH); 13C-NMR (50 MHz, CDCl3) d (ppm): 154.4–114.4 (Ph),
134.4 (CH255CH), 117.0 (CH255CH), 103.0, 102.8 (C-1, C-10) 82.9, 81.8, 81.1, 79.5,
76.8, 75.5, 73.0, 66.4 (skeleton C), 75.6, 75.3, 75.1, 73.6, 73.2 (5 CH2Ph), 71.2
(CH255CH–CH2O), 68.7, 68.3 (C-6, C-60), 55.7 (OCH3). Anal. calcd for C57H62O12: C,
72.90; H, 6.66. Found: C, 73.04; H, 6.56.
4-Methoxyphenyl 2,6-di-O-benzyl-3-O-(2-naphthyl)methyl-b-D-galactopyranosyl-
(1 ! 4)-2,3,6-tri-O-benzyl-b-D-glucopyranoside (8). To a suspension of 6 (4.5 g,
5 mmol) in MeOH (80 mL) was added dibutyltin oxide (1.5 g, 6 mmol). The mixture
was stirred for 2 hr at reflux temperature, MeOH was evaporated, and the residue was
dried under high vacuum for 1 hr. To a suspension of the crude mixture in DMF
(20 mL) was added 2-bromomethyl-naphthalene (2.87 g, 13 mmol). After being stirred
for 48 hr at rt, the mixture was concentrated in vacuum and purified by column chromato-
graphy (DCM : acetone, 98 : 2) to give 8 (4.4 g, 85%) as white needles mp: 131–1338C

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Borbas et al.
140
(from ethyl acetate–n-hexane); [a]D þ 8.9 (c 0.10, CHCl3); 1H-NMR (200 MHz, CDCl3)
d (ppm): 7.90–6.78 (m, 36H, Ph), 5.09–4.77 (m, 8H and H-1), 4.58–4.35 (m, 4H and
H-10), 4.14–3.96 (m, 2H), 3.88–3.34 (m, 10H), 3.79 (s, 3H, OCH3), 2.00 (s, 1H, OH).
13C-NMR (200 MHz, CDCl3) d (ppm): 102.8 (C-10), 102.7 (C-1), 83.0 (2C), 81.6, 81.0,
79.6, 75.5, 72.8, 66.3 (8 skeleton C), 75.4, 75.4, 75.1, 73.6, 73.1, 72.0 (CH2-Np and
CH2-Ph), 68.5 (C-6), 68.3 (C-60), 55.7 (OCH3). Anal. calcd for C65H66O12: C, 75.11; H,
6.41. Found: C, 74.96; H, 6.43.
4-Methoxyphenyl 2,6-di-O-benzyl-3-O-[3-(sodium sulfonate)propyl]-b-D-galacto-
pyranosyl-(1 ! 4)-2,3,6-tri-O-benzyl-b-D-glucopyranoside (9). To a solution of 7
(750 mg, 0.8 mmol) in 70% aq EtOH (75 mL) were added NaHSO3 (500 mg, 4.8 mmol)
and tert-butyl perbenzoate (45 mL, 0.24 mmol). The mixture was stirred for 4 hr at reflux
temperature, then concentrated in vacuum. The solid residue was dissolved in 1 mL of
DCM and purified by column chromatography (DCM : methanol, 8 : 2) to give 9
(758 mg, 91%); [a]D þ 10.8 (c 0.17, CHCl3); 13C-NMR (50 MHz, CDCl3) d (ppm):
155.2–114.4 (Ph), 102.8, 102.6 (C-1, C-10) 82.6, 81.9, 81.4, 79.2, 76.9, 75.2, 73.1, 66.6
(8 skeleton C), 75.0 (2C), 75.0, 73.4, 73.2, 73.0 (5 CH2Ph and –CH2O), 68.7, 68.3 (C-
6, C-60), 55.7 (OCH3), 49.1 (CH2SO3), 24.5 (–CH2–CH2–CH2O). MALDI-MS for
C57H63SO15Na (M, 1042.38): m/z 1065.54 [M þ Na]þ.
4-Methoxyphenyl 3-O-[3-(sodium sulfonate)propyl]-b-D-galactopyranosyl-(1 ! 4)-
b-D-glucopyranoside (1). Compound 9 (500 mg, 0.47 mmol) was dissolved in a EtOH/
EtOAc/DCM mixture (4 : 1 : 1, 60 mL) and hydrogenated in the presence of 10% Pd–C
(100 mg). After 48 hr the mixture was filtered through a pad of celite, washed with
water, and the filtrate was concentrated in vacuum. The residue was purified by column
chromatography (DCM : methanol : water, 7 : 3 : 0.5) to give 1 (267 mg, 96%) as an amor-
phous solid [a]D 2 6.5 (c 0.19, H2O); 1H-NMR (200 MHz, D2O) d (ppm): 7.11 and 6.97
(2d, each 2H, Ph), 5.04 (d, 1H, J1,2 ¼ 7.5 Hz, H-1), 4.49 (d, 1H, J1 ,2 ¼ 7.5 Hz, H-10), 4.17
(d, 1H, J ¼ 2Hz), 4.04–3.41 (m, OCH3 and 13H), 3.02 (m, 2H, CH2), 2.04 (m, 2H, CH2);
13C-NMR (50 MHz, D2O) d (ppm): 155.2–114.4 (Ph), 103.3, 101.6 (C-1, C-10) 80.7, 78.3,
75.6, 75.1, 74.2, 72.9, 70.1, 65.2 (8 skeleton C), 67.6 (–CH2O), 61.3, 61.1 (C-6, C-60), 56.9
(OCH3), 48.9 (CH2SO3), 24.9 (–CH2–CH2O). MALDI-MS for C22H33SO15Na
(M, 592.14): m/z 615.21 [M þ Na]þ.
0
0
4-Methoxyphenyl
3-O-allyl-2,4,6-tri-O-benzyl-b-D-galactopyranosyl-(1 ! 4)-
2,3,6-tri-O-benzyl-b-D-glucopyranoside (10). To a solution of 7 (2.8 g, 3.0 mmol) in
dry DMF 80% NaH (140 mg, 4.5 mmol) was added at 08C and stirred for 30 min. Then
benzyl bromide (0.45 mL, 3.6 mmol) was added to the mixture. After 1 hr, t.l.c. showed
complete conversion (hexane : EtOAc, 7 : 3), then MeOH was added in order to decom-
pose the excess of hydride. The residue was dissolved in DCM (600 mL), washed with
distilled water (3 ꢀ 70 mL), dried and evaporated. The crude product was crystallized
from EtOAc–n-hexane to give 10 (2.8 g, 91%) as white crystals: mp 80–828C;
1
[a]D – 12.9 (c 0.28, CHCl3); H-NMR (200 MHz, CDCl3) d (ppm): 7.40–6.75 (m, 34H,
Ph), 5.99 (m, 1H, CH255CH) 5.33 (dd, 1H, J ¼ 17.5 Hz, 1.5 Hz, CH255CH), 5.17 (dd, 1H,
J ¼ 10.5 Hz, 1.5 Hz, CH255CH), 5.10–4.69 (m, 8H), 4.60–4.10 (m, 8H), 4.01–3.30
(m, OCH3 and 12H). 13C-NMR (50 MHz, CDCl3) d (ppm): 154.4–114.4 (Ph), 134.6
(CH255CH), 116.3 (CH255CH), 102.9, 102.8 (C-1, C-10), 82.9, 82.3, 81.5, 79.8, 76.8,
75.5, 73.5, 73.1, (8 skeleton C), 75.6, 75.4, 75.2, 74.6, 73.4, 72.9 (6 CH2Ph), 71.5
(CH255CH–CH2O), 68.4, 68.2 (C-6, C-60), 55.9 (OCH3). Anal. calcd for C64H68O12: C,
74.67; H, 6.66. Found: C, 74.60, H, 6.63.

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141
4-Methoxyphenyl 2,4,6-tri-O-benzyl-3-O-(2-naphthyl)methyl-b-D-galactopyra-
noside-(1 ! 4)-2,3,6-tri-O-benzyl-b-D-glucopyranoside (11). To a solution of 8
(2.8 g, 2.7 mmol) in dry DMF, 80% NaH (120 mg, 4 mmol) was added at 08C. The mixture
was stirred for 30 min, then benzyl bromide (0.4 mL, 3.3 mmol) was added. After 1 hr,
t.l.c. showed complete conversion, the mixture was worked up as described for the syn-
thesis of 10. The solid crude product was crystallized from EtOAc–hexane to afford 11
1
(2.7 g, 89%) as white crystals: mp. 115–1188C; [a]D þ 2.3 (c 0.43, CHCl3); H-NMR
(200 MHz, CDCl3) d (ppm): 7.82–6.84 (m, 41H, Ph), 5.16–4.28 (m, 19H), 4.86 (d, 1H,
J1,2 ¼ 6.5 Hz, H-1), 4.08–3.40 (m, 9H, and OCH3). 13C-NMR (50 MHz, CDCl3) d
(ppm): 102.8, 102.7 (C-1, C-10), 83.0, 82.4, 81.6, 79.9, 76.9, 75.4, 73.6, 73.0, (8 skeleton
C), 75.4, 75.3, 75.1, 74.7, 73.4, 73.1, 72.6 (CH2-Np, 5 CH2-Ph), 68.39 (C-6), 68.04
(C-60), 55.76 (OCH3). Anal. calcd for C72H72O12: C, 76.56; H, 6.43. Found: C 76.80;
H, 6.49.
4-Methoxyphenyl 2,4,6-tri-O-benzyl-b-D-galactopyranosyl-(1 ! 4)-2,3,6-tri-O-
benzyl-b-D-glucopyranoside (12). (a) A solution of 10 (1.0 g, 1 mmol) in EtOAc
(14 mL) and 96% EtOH (70 mL) was treated with p-toluenesulfonic acid (95 mg,
0.5 mmol) in the presence of 10% Pd-C (200 mg) at 808C for 2 hr, then filtered through
a layer of Celite, treated with Et3N, and concentrated. The crude product was crystallized
from EtOH to afford 12 (850 mg, 87%).
(b) A solution of 11 (1.2g, 1 mmol) in a DCM : MeOH mixture (4 : 1, 5 mL) was treated
with DDQ (290mg, 1.2 mmol) at rt for 1 hr, then concentrated and purified by column
chromatography (DCM : acetone, 98: 2) to afford 12 (880mg, 89%) as white crystals.
1
Compound 12 has mp. 102–1048C (from EtOH), [a]D 2 7.6 (c 0.36, CHCl3); H-NMR
(200MHz, CDCl3) d (ppm): 7.46–6.58 (m, 34H, Ph), 5.16–4.28 (m, 14H), 4.11–3.42
(m, 12H and OCH3), 2.08 (s, 1H, OH). 13C-NMR (50 MHz, CDCl3) d (ppm): 102.8 (2C,
C-10 and C-1), 82.9, 81.6, 80.7, 76.8, 75.9, 75.2, 74.2, 73.3 (8 skeleton C), 75.4, 75.1
(2C), 75.0, 73.4, 73.1 (6 CH2-Ph), 68.38 (C-6), 68.02 (C-60), 55.80 (OCH3). Anal. calcd
for C61H64O12 (988.43): C, 74.06; H, 6.53. Found: C, 73.87; H, 6.48.
4-Methoxyphenyl 2,4,6-tri-O-benzyl-b-D-xylo-hex-3-ulopyranosyl-(1 ! 4)-2,3,6-
tri-O-benzyl-b-D-glucopyranoside (13). A solution of 12 (1.0 g, 1 mmol) in DCM
(10 mL) was treated with Dess–Martin’s periodinane (1.2 mmol) at rt and stirred for
30 min. Then, 20 mL of diethyl ether and 20 mL of 1.3 M NaOH were added, and the
mixture was stirred for further 10 min. The mixture was diluted with DCM (30 mL),
washed with water, dried and concentrated in vacuum. The residue was crystallized from
EtOAc–n-hexane to give 13 (930 mg, 95%), mp. 122–1248C, [a]D 2 37.4 (c 0.33,
CHCl3); 1H-NMR (200 MHz, CDCl3) d (ppm): 7.34–6.86 (m, 34H, Ph), 5.08–4.23
(m, 14H), 4.09–3.38 (m, 11H and OCH3). 13C-NMR (50 MHz, CDCl3) d (ppm): 203.1
(CO), 103.6 (C-10), 102.6 (C-1), 83.4, 83.2, 82.2, 81.3, 78.1, 75.54, 73.8 (7 skeleton C),
75.4, 75.1, 73.6, 73.3, 73.1, 72.5 (CH2Ph), 68.8 (C-6), 68.4 (C-60), 55.9 (OCH3). Anal.
calcd for C61H64O12: C, 74.06; H, 6.53. Found: C, 73.87; H, 6.48.
4-Methoxyphenyl 2,4,6-tri-O-benzyl-3-C-ethoxysulfonylmethyl- b-D-gulopyranosyl-
(1 ! 4)-2,3,6-tri-O-benzyl-b-D-glucopyranoside (14). To a solution of 2.5 M n-BuLi
(2 equiv., 0.72 mmol, 300 mL solution in hexane) in dry THF under argon atmosphere
at 2608C ethyl methanesulfonate was added (1.5 equiv., 0.54 mmol, 60 mL). The mixture
was kept at 2608C for 15 min, then it was cooled to 2788C and the ulose compound 13
(1 equiv., 0.36 mmol, 360 mg,) was added. The mixture was kept at 2788C for 30 min.
Then, it was allowed to warm to rt, stirred for further 30 min, and concentrated.

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Borbas et al.
142
Then, the residue was diluted with 50 mL of DCM and extracted with water (3 ꢀ 10 mL).
The organic layer was dried (MgSO4) and evaporated. The products were separated by col-
umn chromatography (DCM : acetone, 98 : 2) to give 14 (280 mg, 71%) and 15 (70 mg,
18%)
1
Compound 14: [a]D 2 5.6 (c 0.55, CHCl3); H-NMR (500 MHz, CDCl3) d (ppm):
7.04–6.56 (m, 34H, aromatic), 4.96 (d, 1H, J1 ,2 ¼ 7.7 Hz, H-10), 4.90 (d, 1H,
J1,2 ¼ 7.2 Hz, H-1), 4.27 (m, 1H, H-50), 4.15 (m, 1H, H-5), 4.14 (m, 2H, CH3CH2SO3Et),
3.89 (dd, 1H, J5,6a ¼ 5.2 Hz, Jgem ¼ 10.6 Hz, H-6a,), 3.83 (dd, 1H, J5,6b ¼ 2 Hz,
Jgem ¼ 10.6 Hz, H-6b,), 3.83 (s, 3H, OCH3), 3.76 (dd, 1H, H-2, J2,3 ¼ 8.7 Hz), 3.73
(dd, 1H, H-3, J3,4 ¼ 8.7 Hz), 3.62 (dd, 1H, H-60a), 3.58 (dd, 1H, H-60b), 3.57 (m, 1H,
H-40), 3.32 (dd, 1H, H-20). 13C-NMR (125 MHz, CDCl3) d (ppm): 102.6 (C-1), 100.2
(C-10), 82.5 (C-3), 81.2 (C-2), 77.5 (C-20), 76.3 (C-4), 76.2 (C-5), 76.0 (C-40), 71.4 (C-
50), 70.9 (C-30), 75.3 (4C), 74.9, 73.3 (6 CH2Ph), 68.2 (C-6), 67.7 (C-60), 55.6 (OCH3),
0
0
3
3
0
0
51.8 (CH2SO3Et, JCH ,H-4 ffi JCH ,H-2 , 2.8 Hz), 15.0 (SO3CH2CH3). MALDI-MS for
2
2
C64H70SO15 (M, 1110.44): m/z 1133.60 [M þ Na]þ.
Compound 15: [a]D 2 36.2 (c 0.21, CHCl3); MALDI-MS for C64H70SO15
(M, 1110.44): m/z 1133.60 [M þ Na]þ.
4-Methoxyphenyl 3-C-(tetrabutylammonium sulfonato)methyl-b-D-gulopyranosyl-
(1 ! 4)-b-D-glucopyranoside (2). Compound 14 was treated with Bu4NBr in aceto-
nitrile at reflux temperature for 1 hr, when t.l.c showed complete conversion. The solution
was evaporated, the residue was dissolved in ethanol, and hydrogenated in the presence of
10% Pd–C (100 mg). After 48 hr the mixture was filtered through celite, washed with
water, and the filtrate was concentrated in vacuum. The residue was purified by column
chromatography (acetone : water, 9 : 1) to give 2 (267 mg, 96%) [a]D 2 6.5 (c 0.19,
H2O); 1H-NMR (200 MHz, D2O) d (ppm): 7.1 (m, 2H, Ph), 6.9 (m, 2H, Ph), 5.04
(d, 1H, J1,2 ¼ 7.9 Hz, H-1), 4.63 (d, 1H, J1 ,2 ¼ 8.5 Hz, H-10), 4.43 (s, 1H), 4.02–3.54
(m, 10H and OCH3), 3.40 (s, 2H), 3.19, 1.64, 1.38 (3m, each 8H, 12 CH2), 0.95 (t, 12H,
4 CH3). 13C-NMR (50 MHz, CDCl3) d (ppm): 155.3, 151.5 (Ph), 118.8 (2C), 115.6 (2C)
(Ph), 101.6 (2C, C-1, C-10), 78.7, 75.5, 75.0 (2C), 74.9, 73.4, 73.2, 68.9 (8 skeleton C),
62.3, 60.5 (C-6, C-60), 58.7 (SO3CH2–), 56.4 (OCH3), 51.6 (CH2SO3–), 23.7, 19.8
(CH2CH2 butyl), 13.5 (CH3 butyl). MALDI-MS for C22H33SO15Na (M, 592.54): m/z
618 [M þ Na]þ.
0
0
4-Methoxyphenyl 3,4,5,7-tetra-O-benzyl-1-deoxy-1-ethoxysulfonyl-a-D-gluco-hept-
2-ulopyranosyl-(2 ! 3)-2,6-di-O-benzyl-b-D-galactopyranosyl-(1 ! 4)-2,3,6-tri-O-benzyl-
b-D-glucopyranoside (17), 4-methoxyphenyl 3,4,5,7-tetra-O-benzyl-1-deoxy-1-ethoxy-
sulfonyl-a-D-gluco-hept-2-ulopyranosyl-(2 ! 4)-2,6-di-O-benzyl-b-D-galactopyranosyl-
(1 ! 4)-2,3,6-tri-O-benzyl-b-D-glucopyranoside (18), and 2,6-anhydro-3,4,5,7-tetra-
O-benzyl-1-ethoxysulfonyl-D-gluco-hept-1-enitol (19). A mixture of 6 (450 mg, 0.5 mmol),
˚
16 (530 mg, 1.5 equiv.) and molecular sieves (4 A) in dry DCM was stirred for 3 hr
under Ar. It was then cooled to 2508C and a solution of 1.5 equiv. of NIS and 0.35
equiv. of TfOH in abs THF was added. The mixture was kept at 2408C untill t.l.c.
(hexane : EtOAc, 65 : 35) showed the disappearance of 16 (ꢀ30 min). The mixture was
allowed to warm up to rt, neutralized with Et3N, filtered, diluted with DCM, washed
with water, dried, and concentrated. Column chromatography (hexane : EtOAc, 65 : 35)
of the residue afforded 19 (32%, Rf: 0.66), 17 (47%, Rf: 0.57), and 18 (11%, Rf: 0.31).
1
Compound 17 has [a]D þ 35.11 (c 0.410, CHCl3). H-NMR (200 MHz, CDCl3) d
(ppm): 7.58–6.83 (m, 49H, Ph), 5.15–4.38 (m, 22H), 4.30–4.13 (m, 5H), 4.02–3.56

ORDER
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Replacement of Carbohydrate Sulfates
143
(m, 11H and OCH3), 2.82 (broad s, 1H, OH), 1.25 (3H, t, J ¼ 7 Hz, SO3CH2CH3),
13C-NMR (50 MHz, CDCl3) d (ppm): 155.2–114.4 (Ph), 102.7 (C-10), 102.2 (C-1), 99.5
(C-200), 83.2, 82.7, 81.4 (2C), 79.9, 78.5, 77.6, 76.8, 76.5, 74.5, 73.0, 72.5 (12 skeleton
C) 75.6, 75.3, 75.1, 74.8, 74.7 (2C), 73.5 (2C), 73.3 (9 CH2Ph), 68.3, (2C), 68.1 (C-6,
C-60, C-700), 67.8 (SO3CH2CH3), 55.5 (OCH3), 53.0 (C-100, JC-1 ,H-3 , 1.8 Hz), 15.2
00
00
(SO3CH2CH3). MALDI-MS for C91H98SO20 (M, 1542.64): m/z 1566.26 [M þ Na]þ.
1
Compound 18 has [a]D þ 14.30 (c 0.36, CHCl3); H-NMR (200 MHz, CDCl3) d
(ppm): 7.46–6.77 (m, 49H, Ph), 5.18, 5.00 (2d, each 1H, Jgem ¼ 11 Hz, CH2PH),
4.98–4.70 (m, 8H), 4.56–4.33 (m, 8H), 4.25–3.92 (m, 10H), 3.82–3.41 (m, 15H and
OCH3), 1.25 (3H, t, J ¼ 7 Hz, SO3CH2CH3), 13C-NMR (50 MHz, CDCl3) d (ppm):
155.2–114.4 (Ph), 103.5 (C-10), 102.7 (C-1), 99.3 (C-200), 83.0, 82.5, 81.5, 81.8, 80.0,
78.3, 77.9, 75.6, 74.0, 72.9, 72.8, 72.2 (12 skeleton C) 75.5 (2C), 75.2, 75.1 (2C), 74.9,
73.5, 72.9 (9 CH2Ph), 68.9, 68.1, 67.7, 67.3 (C-6, C-60, C-700, SO3CH2CH3), 55.6
(OCH3), 52.4 (C-100, JC-1 ,H-3 , 3 Hz), 15.0 (SO3CH2CH3). MALDI-MS for C91H98SO20
00
00
(M, 1542.64): m/z 1566.24 [M þ Na]þ.
Compound 19 has [a]D þ 67.2 (c 0.56, CHCl3); lit.[15] [a]D þ 64.1 (c 0.23, CHCl3);
1H-NMR (200MHz, CDCl3) d (ppm): 7.49–7.26 (m, 20H, Ph), 5.77 (s, 1H, H-1), 4.82–
4.61 (8d, 8H, 4 CH2Ph), 4.41 (m, 1H, H-6), 4.24 (q, 2H, Jgem ¼ 14Hz, SO3CH2CH3),
3.96–3.91 (m, 4H, H-3, H-4, H-5, H-7a), 3.88 (dd, 1H, J6,7a ¼ 3 Hz, Jgem ¼ 11.5Hz,
H-7b), 1.30 (t, 3H, J ¼ 7 Hz, SO3CH2CH3), 13C-NMR (50MHz, CDCl3) d (ppm): 161.7
(C-2), 137.8–127.4 (Ph), 103.8 (C-1), 81.9 (C-4), 78.6 (C-6), 76.6, 76.5 (C-3, C-5), 73.4,
73.2, 72.9, 72.1 (4 CH2Ph), 67.6 (C-7), 66.6 (SO3CH2CH3), 14.6 (SO3CH2CH3).
MALDI-MS for C37H40SO8 (M, 644.24): m/z 667.31 [M þ Na]þ.
ACKNOWLEDGMENTS
This research was supported by the Hungarian Scientific Research Fund (OTKA
´
´ ´
Sciences. M. Csavas ackowledges the OTKA postdoctoral fellowship (D 45934).
T38066). A. Borbas acknowledges the Bolyai fellowship of the Hungarian Academy of
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Received July 29, 2003
Revised December 15, 2003
Accepted February 9, 2004

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