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OSO
3
-
OSO
3
-
O
-
O
2
C
O
OH
-
O
2
C
OH
HO
O
-
O
3
SHN
O
O
O
NH
2
O
HO
HO
-
O
3
SHN
O
OS O
3
-
OSO
3
-
117
OSO
3
-
118
R=H
OSO
3
-
R=SO
3
-
119
OSO
3
-
O
-
O
2
C
O
O
OH
-
O
2
C
OH
O
HO
RO
-
O
2
C
-
O
3
SHN
O
HO
O
O
-
O
3
SHN
OH
NH
2
O
O
HO
O
-
O
3
SHN
O
OSO
3
-
O
OSO
3
-
OSO
3
-
Fig. 5
the formation of an inseparable mixture of the desired 121 and the
sulphated analogue at O-3
III
122 in 75% and 25% yields, respectively, was
observed. Contrarily, when the sulphation was performed in aq. Et
3
N, the
final compound 121 was obtained in 78% yield without the formation of
117. The authors rationalized the unexpected sulphation at O-3
III
as a
result of a chelation of the sodium cation in carboxylic acid and O-3
III
,
such as 123, see Scheme 28.
A tetrasaccharide, corresponding to the HS heparanase substrate,
namely
4)-a-
D
-
GlcN(NS,6S)-OMe, was synthesized in a convergent manner coupling a
pair of disaccharide building blocks as a key step.
73
A 2-(azido-
methyl)benzoyl group was used to protect the 2-position of Glc unit
precursor of 2-sulphated GlcA. Selective oxidation of a primary hydroxyl
group was performed with the combination of a catalytic amount of
TEMPO and a slight excess of BAIB in a biphasic dichloromethane-water
solvent system. The use of a disaccharide trifluoroacetimidate donor,
TBSOTf as promoter, toluene as solvent and low temperatures (
40 1C)
led to the best yield and stereoselectivity in the key [2
รพ
2] glycosylation
reaction. A series of glucuronides and glycosyl glucuronides were
synthesised as putative heparanase substrates.
74
It was found that the N-
sulphated 4-nitrophenyl glycosyl glucuronide 124 and the N-sulphated
methylumbelliferyl glycosyl glucuronide 125 were hydrolysed by re-
combinant human heparanase, see Fig. 6.
Tanaka et al.
75
described an effective method for the elongation of a
a-
D
-GlcN-(1
b-
D
-GlcA(2S)-(1
-
4)-a-
D
-GlcN(NS,6S)-(1
-
4)-b-
D
-GlcA-(1
-
4)-
D
-
GlcA disaccharide unit and the synthesis of the N- and/or O-sulphated
a-
D
-GlcN-(1
-
4)-b-
D
-GlcA-(1
-
4) sequence using a a-
D
-GlcNTroc-(1
-
-
4)-b-
D
-GlcA-(1
-
4) oligosaccharides. N-Troc protection of
a-
D
-GlcN-(1
-
4)-
D
-GlcA units was effective for the synthesis of the a-
D
-
GlcN-(1
4) oligosaccharides in comparison with the
azido substituent. The a-
D
-GlcN-(1
-
4)-b-
D
-GlcA-(1
-
4) dodecasaccharide
was prepared by the direct b-selective glycosidation of glucuronate in
the a-
D
-GlcN-(1
-
4)-b-
D
-GlcA-(1
-
4) tet-
rasaccharide. Fluorous-assisted deprotection and sulphation was used to
facilitate the separation of the products from highly polar reagents. Yang
et al.
76
reported the synthesis of Syndecan-1 (126), a HS glycopeptide. To
prepare the octasaccharide moiety of the corresponding glycopeptide,
-
4)-b-
D
-GlcA-(1
-
4)-a-
D
-GlcN-(1
-
4)-b-
D
-GlcA-(1
-
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