Multigram syntheses of the disaccharide repeating units of chondroitin 4- and 6-sulfates

Article abstract of DOI:10.1016/S0008-6215(98)00298-5

The multigram syntheses of β-D-glucopyranosyluronic acid-(1→3)-2-acetamido-2-deoxy-4- and 6-O-sulfo-D-galactopyranose disodium salt, the disaccharide repeating units of chondroitin 4- and 6-sulfates, are described. The disaccharide benzyl methyl 2,3,4-tri

Full text of DOI:10.1016/S0008-6215(98)00298-5

Carbohydrate Research 314 (1998) 283–288
Note
Multigram syntheses of the disaccharide repeating units
of chondroitin 4- and 6-sulfates
Jean-Claude Jacquinet a,*, Laurence Rochepeau-Jobron a, Jean-Philippe Combal b
a Institut de Chimie Organique et Analytique, UPRES-A CNRS 6005, U.F.R. Faculte´ des Sciences,
Uni6ersite´ d’Orle´ans, B.P. 6759, F-45067 Orle´ans, France
b Institut de Recherche Pierre Fabre, Centre de De´6eloppement, rue Jean Rostand, B.P. 687,
F-31319 Labe`ge, France
Received 17 October 1998; accepted 2 December 1998
Abstract
The multigram syntheses of b-
topyranose disodium salt, the disaccharide repeating units of chondroitin 4- and 6-sulfates, are described. The
disaccharide benzyl methyl 2,3,4-tri-O-benzoyl-b- -glucopyranosyluronate-(1“3)-2-acetamido-2-deoxy-a- -galac-
D
-glucopyranosyluronic acid-(1“3)-2-acetamido-2-deoxy-4- and 6-O-sulfo-
D-galac-
D
D
topyranoside was used as a common intermediate. Selective benzoylation at O-6 followed by O-sulfonation at C-4
of the aminosugar moiety, saponification and catalytic hydrogenation afforded the 4-O-sulfo derivative, whereas
selective O-sulfonation at C-6 followed by similar deprotection steps provided the 6-O-sulfo derivative in high yield.
© 1998 Elsevier Science Ltd. All rights reserved.
Keywords: Oligosaccharide synthesis; Chondroitin sulfates; Glycosaminoglycans
Chondroitin sulfate proteoglycans (ChS) are
found in various body fluids, at the cell sur-
face or in the extracellular matrix, or intracel-
lularly in secretory granules [1]. Structural
studies showed chondroitins to be essentially
linear copolymers built from dimeric units
positions are also known. These sulfation pat-
terns give rise to biologically important func-
tions deeply related to the position and the
number of sulfate groups. For example, ChS
play a role in cellular recognition [2], inhibi-
tion of human C1q factor [3], blood-coagula-
tion system [4], and in many other, still poorly
understood, biological processes. The use of
ChS for the treatment of human osteoarthritis
has also been reported [5]. Determination of
the precise structure of sequences having bio-
logical effects is, however, complicated by the
microheterogeneity of the polymers. Con-
trolled chemical degradation affords complex
mixtures of products in low yield, and
enzymatic hydrolysis provides unsaturated
derivatives for which the geometry of the
composed of
2-acetamido-2-deoxy-
namely [4)-b- -GlcpA-(1“3)-b-
D
-glucuronic acid (GlcA) and
-galactose (GalNAc),
-GalNAc-
D
D
D
(1“]n. In the major variants, the 4-O- and
6-O-positions of the GalNAc residue are
found sulfonated, but several types of ChS
having one or more sulfate groups at various
* Corresponding author. Tel.: +33-238-417072; fax: +33-
238-417281.
E-mail address: jean-claude.jacquinet@univ-orleans.fr (J.-
C. Jacquinet)
0008-6215/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(98)00298-5

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J.-C. Jacquinet et al. / Carbohydrate Research 314 (1998) 283–288
It is to be noted that addition of a base
(sym-collidine) in the reaction mixture caused
extensive formation of the corresponding or-
tho-disaccharide derivative which could not be
transformed easily into 5. Treatment of 5 with
aqueous acetic acid at 100 °C gave the crys-
talline diol 6, the common intermediate, in
87% yield.
Preparation of the target molecule 1 was
achieved as follows. Treatment of diol 6 with
benzoyl cyanide [12] in pyridine at rt afforded
the crystalline 6-O-benzoyl derivative 7 in
93% yield. The free hydroxyl group in 7 was
then O-sulfonated by treatment with the sulfur
trioxide–trimethylamine complex in N,N-
dimethylformamide at 50 °C, followed by ion-
exchange chromatography (Na+ resin) to give
the crystalline sodium salt 8 in 90% yield.
non-reducing GlcA unit is modified. The basic
disaccharides of the 4- and 6-sulfate series are
commercially available and are obtained by
degradation of natural polymers. However, as
homogeneous pure 4- or 6-sulfated polymers
are not found in nature, the chemical purity of
these products cannot exceed 90%, and the
exact role of each isomer cannot be deter-
mined with precision. Thus, there is a need for
chemically pure samples to further study in
detail the different biological functions of
these molecules.
Several syntheses of derivatives of the basic
disaccharides of the 4- and 6-sulfate series
have been reported, such as methyl glycosides
[6,7] or 4-methoxyphenyl glycosides [8], but
the preparation of the corresponding reducing
disaccharides has never been described. We
now report on expeditious and stereocon-
trolled multigram syntheses of both 4-O-sulfo
(1) and 6-O-sulfo (2) species using the disac-
charide diol 6 as a common intermediate.
1
Comparison of the H NMR spectra of 8 and
For the construction of the disaccharide
7 (Table 1) showed the expected [7] downfield
shift (0.88 ppm) of the signal for H-4 in 8.
Saponification of the ester groups was
achieved by treatment of 8 with lithium hy-
droperoxide [13] in aqueous tetrahydrofuran
followed by methanolic sodium hydroxide to
give the crystalline disodium salt 10 in 83%
yield. Hydrogenolysis (Pd–C) of 10 in
aqueous methanol afforded the target
skeleton, bromide 3, easily prepared [9] from
commercial
D-glucurono-6,3-lactone was se-
lected as the donor, and known galac-
tosaminide 4 [10], prepared in 4 steps [11]
from easily available benzyl 2-acetamido-2-de-
oxy-a- -glucopyranoside was used as the
D
acceptor.
1
molecule 1 in 97% yield. The H (Table 1) and
13C NMR spectra for 1 are in full agreement
with the expected structure, and in accord
with those reported for synthetic disaccharide
derivatives [7] and for polymeric chondroitin
4-sulfate [14].
Preparation of the second target molecule 2
was then achieved as follows. Regioselective
O-sulfonation at C-6 in diol 6 was examined.
Treatment of 6 with the sulfur trioxide–
Condensation of 3 (1.4 equiv) with 4 in
dichloromethane at room temperature (rt)
promoted by silver triflate afforded the crys-
talline disaccharide derivative 5 in 70% yield.

J.-C. Jacquinet et al. / Carbohydrate Research 314 (1998) 283–288
285
trimethylamine complex (3 equiv) in N,N-
dimethylformamide at 50 °C, followed by ion-
exchange chromatography, gave the crystalline
sodium salt 9 in 90% yield. A very small amount
(B2%) of the corresponding 4,6-disulfated
derivative was also obtained, but easily sepa-
rated from 9 by simple chromatography. At-
tempted tin-mediated regioselective sulfation
[15–17] proceeded in much lower yield due to
the difficulty in removing completely the tin
Saponification of 9, as described for the prepa-
ration of 10, gave crystalline 11 in 82% yield,
and final catalytic hydrogenation (Pd–C) af-
forded the second target molecule 2 in 96%
yield. The H (Table 1) and C NMR spectra
of 2 are in full agreement with the expected
structure, and also accord with those reported
for synthetic [7] and natural [14] products.
1
13
1
salts. Comparison of the H NMR spectra of
9 and 6 (Table 1) also showed the expected
downfield shifts (0.31 and 0.42 ppm) of the
signals for H-6a and H-6b, respectively, in 9,
and no change of the signal for H-4, demon-
strating that monosulfation occurred at C-6.
Table 1
1H NMR data for disaccharide derivatives 5–11 and 1–2a
Chemical shifts (l, ppm)
Compounds
5
6
7
8b
9b
10c
11c
1c
2c
H-1I
5.18
4.64
4.25
4.37
3.68
4.21
3.98
5.81
1.65
5.02
4.60
3.90
4.28
3.89
3.98
3.82
5.43
1.50
5.00
4.60
3.90
4.30
4.20
4.60
4.60
5.39
1.43
4.81
4.42
4.01
5.18
4.29
4.77
4.69
4.82
4.37
3.92
4.33
4.24
4.29
4.24
4.99
4.39
4.23
4.89
4.19
3.82
3.73
5.00
4.36
4.07
4.33
4.15
4.27
4.21
5.23, 4.74
4.38, 4.30
4.24, 4.23
4.87, 4.81
4.08
5.24, 4.73
4.38, 4.34
4.05, 3.88
4.31, 4.30
4.15
H-2I
H-3I
H-4I
H-5I
H-6Ia
H-6Ib
NH
3.78
3.78
4.28
4.28
CH3CO
1.42
1.32
2.01
2.01
2.06, 2.05
2.05, 2.04
H-1II
5.28
5.54
5.90
5.70
4.38
3.62
5.07
5.49
5.90
5.69
4.41
3.67
5.09
5.50
5.89
5.71
4.40
3.63
5.03
5.58
5.93
5.68
4.47
3.65
5.11
5.50
5.93
5.55
4.47
3.68
4.52
3.38
3.45
3.55
3.67
4.57
3.36
3.54
3.54
3.74
4.54, 4.49
3.38
3.49
3.57
3.68
4.58, 4.53
3.37
3.52
3.52
3.71
H-2II
H-3II
H-4II
H-5II
COOCH3
Coupling constants (J, in Hz)
J1 ,2
3.5
11.0
3.5
3.5
11.0
3.5
3.5
11.0
3.5
3.5
11.0
3.0
3.5
11.0
3.5
3.5
11.0
3.5
3.5
11.0
3.5
4.0, 8.0
10.5
3.0
4.0, 8.0
10.5
3.0
I
I
I
I
I
J2 ,3
I
J3 ,4
I
J4 ,5
0.8
0.6
0.8
0.6
0.8
0.5
0.5
0.5
0.5
I
J5 ,6 a
1.5
5.0
4.5
9.0
4.0
8.0
I
I
J5 ,6 b
2.0
4.0
8.0
8.0
9.0
I
I
J6 a,6 b
J2, NH
12.5
8.0
11.0
9.0
12.0
9.0
12.5
12.0
12.0
I
I
J1
J2
J3
J4
7.5
9.0
9.0
9.0
7.0
9.0
9.0
9.0
7.0
9.0
9.0
9.0
7.5
9.5
9.5
9.5
7.5
9.5
9.5
9.5
7.5
9.0
9.0
9.0
7.5
9.5
9.5
9.5
7.5, 7.5
9.5
9.5
7.5, 7.5
9.5
9.5
II II
,2
II II
,3
II II
,4
9.5
9.5
II II
,5
a For solutions in CDCl3, unless otherwise stated.
b CD3OD.
c D2O, equilibrium.

286
J.-C. Jacquinet et al. / Carbohydrate Research 314 (1998) 283–288
heptane and crystallized from EtOAc–heptane
In conclusion, expeditious, stereocontrolled,
to give 5 (9.47 g, 70%); mp 123–125 °C; [h]D
1
+93° (c 1, CHCl3); H NMR (CDCl3): see
and high-yielding preparations of chondroitin
4- and 6-sulfate disaccharides are reported. All
intermediates were obtained in crystalline form,
thus ensuring the purity of each compound.
These molecules, readily obtained in gram
amounts, are currently being evaluated in bio-
logical studies.
Table 1; MS: m/z 902, [M+H]+. Anal. Calcd
for C50H47NO15: C, 66.58; H, 5.25; N, 1.55.
Found: C, 66.46; H, 5.26; N, 1.50.
Benzyl methyl 2,3,4-tri-O-benzoyl-i-
copyranosyluronate - (1“3) - 2 - acetamido - 2-
deoxy-h- -galactopyranoside (6).—A mixture
D-glu-
D
of 5 (10 g) and AcOH (65 mL) was stirred at
100 °C. Water (35 mL) was added dropwise,
and the mixture was stirred for 30 min at
100 °C, then cooled, concentrated, evaporated
with water (3×30 mL), and dried. The solid
residue was recrystallized from hot MeOH to
give 6 (7.83 g, 87%); mp 200–202 °C; [h]D
1. Experimental
General methods.—Melting points were de-
termined in capillary tubes with a Bu¨chi ap-
paratus and are uncorrected. Optical rotations
were measured at 20–25 °C with a Perkin–
Elmer 241 polarimeter. 1H and 13C spectra were
recorded at 25 °C with Bruker DPX-250 or
AM-300 spectrometers at 250 or 300 MHz, and
63 or 75.4 MHz, respectively, with Me4Si as
internal standard, unless otherwise stated. As-
signments were based on homonuclear decou-
pling experiments, and homo- and hetero-
nuclear correlations. Chemical-ionization (am-
monia) mass spectra (CIMS) were recorded
with a Nermag R 10-10 spectrometer. The
purity of the products was determined by TLC
on Silica Gel F254 (E. Merck), with detection by
charring with methanolic H2SO4. Flash-column
chromatography was performed on Silica Gel
(E. Merck, 40–63 mm). Elemental analyses were
performed by the Service Central de Micro-
analyses du CNRS (Vernaison, France).
1
+78° (c 1, CHCl3); H NMR (CDCl3): see
Table 1; MS: m/z 814, [M+H]+. Anal. Calcd
for C43H43NO15: C, 63.46; H, 5.32; N, 1.72.
Found: C,63.39; H, 5.22; N, 1.61.
Benzyl methyl 2,3,4-tri-O-benzoyl-i-
copyranosyluronate - (1“3) - 2 - acetamido-6-
O-benzoyl-2-deoxy-h- -galactopyranoside (7).
D-glu-
D
—A solution of 6 (8.14 g, 10 mmol) and benzoyl
cyanide (2.62 g, 20 mmol) in dry pyridine (100
mL) was stirred for 16 h at rt under dry Ar.
Methanol (10 mL) was added, and the mixture
was concentrated, then evaporated with toluene
(3×30 mL). The residue was crystallized from
MeOH–CH2Cl2 to give 7 (8.58 g, 93%); mp
266–268 °C; [h]D +64° (c 1, CHCl3); 1H NMR
(CDCl3): see Table 1; MS: m/z 918, [M+H]+.
Anal. Calcd for C50H47NO16: C, 65.42; H, 4.51;
N, 1.52. Found: C, 65.45; H, 4.47; N, 1.43.
Benzyl methyl 2,3,4-tri-O-benzoyl-i-
copyranosyluronate - (1“3) - 2 - acetamido-
4,6-O - benzylidene - 2 - deoxy-h- -galactopyra-
noside (5).—A mixture of benzyl 2-acetamido-
4,6-O-benzylidene-2-deoxy-a- -galactopyra-
noside 4 [10] (6.0 g, 15 mmol), methyl 2,3,-
4-tri-O-benzoyl-1-bromo-1-deoxy-a- -gluco-
D-glu-
Benzyl methyl 2,3,4-tri-O-benzoyl-i-
copyranosyluronate - (1“3) - 2 -acetamido-6-
O-benzoyl-2-deoxy-4-O-sulfo-h- -galactopyr-
D-glu-
D
D
anoside, sodium salt (8).—A mixture of 7 (4.59
g, 5 mmol) and sulfur trioxide–trimethylamine
complex (5.57 g, 50 mmol) in dry DMF (70 mL)
was stirred for 48 h at 50 °C under dry Ar, then
cooled. MeOH (10 mL) was added, and the
mixture was concentrated. The residue was
eluted from a column (200 g) of silica gel with
11:1 CH2Cl2–MeOH, then from a column
(1.5×20 cm) of Sephadex SP C25 (Na+)
with 5:9:1 CH2Cl2–MeOH–water, and cry-
stallized from aq EtOH to give 8 (4.59 g, 90%);
mp 187–190 °C (dec); [h]D +70° (c 1, MeOH);
1H NMR (CD3OD): see Table 1; Anal. Calcd
for C50H46NNaO19S: C, 58.88; H, 4.55; N, 1.37.
Found: C, 58.62; H, 4.65; N, 1.31.
D
D
pyranuronate 3 [9] (12.26 g, 21 mmol), and 4
˚
A powdered molecular sieves (8 g) in dry
CH2Cl2 (200 mL) was stirred for 1 h at rt under
dry Ar. Silver triflate (9.8 g, 38 mmol) was
added, and the mixture was stirred for 4 h at
rt. Dry pyridine (4 mL) was added, and the
mixture was diluted with CH2Cl2 (100 mL),
filtered, washed with 5% aq Na2S2O3, satd aq
NaHCO3, and water, dried (MgSO4), and con-
centrated. The residue was eluted from a
column (300 g) of silica gel with 2:1 EtOAc–

J.-C. Jacquinet et al. / Carbohydrate Research 314 (1998) 283–288
287
C, 41.25; H, 4.46; N, 2.29. Found: C, 41.11;
H, 4.59; N, 2.10.
Benzyl methyl 2,3,4-tri-O-benzoyl-i-
copyranosyluronate - (1“3) - 2 - acetamido - 2-
deoxy-6-O-sulfo-h- -galactopyranoside, sod-
D
-glu-
i-D
-glucopyranosyluronic acid-(1“3)-2-ac-
-galactopyranose,
D
etamido-2-deoxy-4-O-sulfo-
D
ium salt (9).—A mixture of 6 (4.07 g, 5 mmol)
and sulfur trioxide–trimethylamine complex
(2.09 g, 15 mmol) in dry DMF (80 mL) was
stirred for 4 h at 50 °C, then cooled. Methanol
(20 mL) was added, and the mixture was
concentrated. The residue was eluted from a
column (150 g) of silica gel with 8:1 CH2Cl2–
MeOH, then from a column (1.5×20 cm) of
Sephadex SP C25 (Na+) and crystallized as
described for the preparation of 8 to give 9
(4.12 g, 90%); mp 178–181 °C (dec); [h]D +66°
disodium salt (1).—A solution of 10 (3.06 g, 5
mmol) in 5:1 water–MeOH (60 mL) was hy-
drogenated in the presence of 10% Pd–C (1 g)
for 24 h at rt, then filtered, and concentrated.
The residue was eluted from a column (2×25
cm) of 1:1 charcoal–Celite with water and
freeze-dried to give 1 as an amorphous pow-
der (2.53 g, 97%); [h]D +2° (c 1, equil.,
1
water); H NMR (D2O, internal H2O): see
13
Table 1; C (D2O, internal MeOH, lC 49.40):
1
l 178.34, 178.10, 174.60 (CꢀO), 103.40, 103.12
(C-1II), 93.04 (C-1Ib), 89.12 (C-1Ia), 79.20,
79.05 (C-3I), 76.80, 76.54, 76.25 (C-4I,5II),
73.25, 73.04, 72.80, 72.34 (C-5I,3II,4II), 71.30,
71.05 (C-2II), 65.48, 65.12 (C-6I), 52.04, 51.60
(C-2I), and 22.65, 22.18 (CH3CO). Anal.
Calcd for C14H21NNa2O15S: C, 32.25; H, 4.06;
N, 2.68. Found: C, 32.08; H, 4.12; N, 2.51.
(c 1, MeOH); H NMR (CD3OD): see Table
1. Anal. Calcd for C43H42NNaO18S: C, 56.39;
H, 4.62; N, 1.53. Found: C, 56.21; H, 4.68; N,
1.42.
Benzyl i-
3) - 2 - acetamido - 2 - deoxy - 4 - O - sulfo - h -
-galactopyranoside, disodium salt (10).—A
D-glucopyranosyluronic acid-(1“
D
solution of 8 (5.1 g, 5 mmol) in 7:3 THF–wa-
ter (50 mL) was treated at −5 °C with 30%
H2O2 (12.5 mL) and lithium hydroxide (1 M,
25 mL), and the mixture was stirred for 2 h at
this temperature and 15 h at rt, then cooled to
0 °C. Methanol (40 mL) and NaOH (4 M, 30
mL) were then added, and the mixture was
stirred for 6 h at rt, then treated with Amber-
lite IR-120 (H+) resin to pH 2 (pH meter
control), filtered, and concentrated. The
residue was stirred for 1 h at 0 °C with abs
EtOH (50 mL), and the solids were filtered
off, washed with cold abs EtOH (20 mL), and
dissolved in water (100 mL). The pH of the
solution was brought to 6.5 with M NaOH,
and the mixture was concentrated. The residue
was crystallized from 5:1 MeOH–water to
give 10 (2.57 g, 83%); mp 254–258 °C (dec);
i-
D
-glucopyranosyluronic acid-(1“3)-2-ac-
-galactopyranose,
etamido-2-deoxy-6-O-sulfo-
D
disodium salt (2).—Compound 11 (3.06 g, 5
mmol) was treated as described for the prepa-
ration of 1 to give 2 (2.5 g, 96%); [h]D +4° (c
1
1, equil., water); H NMR (D2O, internal
13
H2O): see Table 1; C (D2O, internal MeOH):
l 178.60, 177.82, 173.80 (CꢀO), 103.60, 103.10
(C-1II), 93.25 (C-1Ib), 89.42 (C-1Ia), 81.10,
80.60 (C-3I), 76.50 (C-5II), 74.20, 73.80, 73.12,
72.80 (C-5I,3II,4II), 71.24, 70.90, 70.52 (C-
4I,2II), 69.04, 68.72 (C-6I), 52.25, 51.95 (C-2I),
and 23.40, 22.85 (CH3CO). Anal. Calcd for
C21H27NNa2O15S: C, 32.25; H, 4.06; N, 2.68.
Found: C, 32.11; H, 4.11; N, 2.51.
1
[h]D +71° (c 1, water); H NMR (D2O, inter-
Acknowledgements
nal H2O, lH 4.754): see Table 1. Anal. Calcd
for C21H27NNa2O15S: C, 41.25; H, 4.45; N,
2.29. Found: C, 41.08; H, 4.60; N, 2.10.
Financial support was from Institut de
Recherche Pierre Fabre (Labe`ge, France).
Benzyl i-
3) - 2 - acetamido - 2 - deoxy - 6 - O - sulfo - h-
-galactopyranoside, disodium salt (11).—
D-glucopyranosyluronic acid-(1“
D
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(2.51 g, 82%); mp 275–278 °C (dec); [h]D +73°
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