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OH
OH
HO
HO
NaSO
3
HN
O
O
HO
HO
NaSO
3
HN
COONa
COONa
O
O
O
O
NO
2
HO
O
O
HO
OH
OH
O
124
125
O
Fig. 6
their original strategy adapted a [3
þ
2
þ
3] glycosylation approach, by
coupling the trisaccharide 127 with disaccharide 128 and the b-
D
-Gal-
(1
4)-b-
D
-Xyl-Ser derivative 129, see Fig. 7.
The modular synthesis of HS fragments was greatly facilitated by
employing an anomeric aminopentyl linker protected by a benzyloxy-
carbonyl group modified by a perfluorodecyl tag, which made it possible
to purify highly polar intermediates by fluorous solid phase extraction.
77
The first example of a gram-scale synthesis of a structurally defined,
heparin-related dodecasaccharide was reported.
78
An iterative 14-step
process using an iduronate donor disaccharide delivers W1g quantities
of the dodecasaccharide sequence [a-
D
-GlcNS-(1
-
4)-b-
D
-Gal-(1
-
4)-a-
L
-IdoA2S]
6
-OMe in
15% overall yield from the reducing terminal disaccharide, a two orders
of magnitude increase in scale for access to synthetic heparanoid dode-
casaccharide mimetics. The synthesis also delivers multigram amounts
of the protected oligosaccharides from tetra- through to dodecasacchar-
ide. The same Gardiner's group used a tetrasaccharide-iteration-based
approach for the synthesis of a tritium labelled heparin-related dodeca-
saccharide, by incorporation of a latent aldehyde tag, fore monitoring
in vivo tissue distribution and in vivo stability of a biologically active,
structurally defined heparin related dodecasaccharide.
79
-
2.3.2 Chondroitin sulphate. CS-E repeating octasaccharide was ef-
fectively synthesized in a stereocontrolled manner by adopting an acet-
amide-type disaccharide unit.
80
In the tetrasaccharide synthesis the
authors isolated a characteristic glycosyl imidate as a reactive inter-
mediate. An acetamide auxiliary is involved in the glycosylation mech-
anism. A review by Gemma et al.
81
surveys the known methods for the
preparation of GAG (CS, HS) oligosaccharides and conditions for the
selective functionalisation of both the reducing and non-reducing ends.
Jacquinet's group developed the divergent synthesis of CS oligosacchar-
ides (from di- to octasaccharides) and biotinylated conjugates. The ori-
ginal strategy involved the synthesis of the key building blocks by
selective modification of the disaccharides obtained by hydrolysis of the
polymer, see Scheme 29. Acid hydrolysis of the native polymer afford the
basic disaccharide unit, a process that also results in complete desulfa-
tion and N-deacetylation. The basic disaccharide was obtained in good
yield in a simple procedure: IR-120 [H
þ
]resin,H
2
O; then 0.5M H
2
SO
4
,
100 1C, 6 h; then 0.02M HCl in MeOH, 0 1C, 4 days. It was then easily
transformed into the crystalline methyl ester 130 on a 50-100 g scale.
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