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TfO
-
OH
O
OSO
3
TCE
+
O
S
TBSO
BnO
O
TBSO
BnO
N
Cl
3
C
O
OPMB
O
OPMB
N
3
O
N
3
O
O
O
STol
BnO
STol
BnO
W, 80 °C, 94%
OBz
μ
OBz
108
109
OR
1
O
HO
HO
OR
2
110
R
1
=SO
3
-
,R
2
=H,R
3
=SO
3
-
111
R
1
=SO
3
-
,R
2
=H,R
3
=Ac
112
R
1
=H,R
2
=SO
3
-
,R
3
=SO
3
-
113
R
1
=H,R
2
=SO
3
-
,R
3
=Ac
-
OOC
R
3
NH
O
O
HO
HO
O
HO
OH
-
OOC
R
3
NH
O
O
O
NH
2
HO
OH
Scheme 26
OAc
O
HO
STol
BnO
OTBDPS
OBz
O
2-NAPO
p
115
exclusively
HS/heparin
analogues
-B rBnO
OC(NH)CCl
3
α
-disaccharides
N
3
or
O
HO
114
BnO
OB z
O
116
Scheme 27
a-stereoselectivity was achieved by carefully selecting a set of orthogonal
protecting groups on
D
-glucosaminyl donor 114, see Scheme 27.
68
A ra-
tional design led to a protecting group combination that provided ex-
cellent stereoselectivity, which was found to be independent of leaving
groups and activators. The orthogonal protecting groups were manipu-
lated to carry out the total syntheses of heparosan tri- and penta-
saccharides and heparin di-, tetra-, hexa-, and octasaccharide analogues.
The synthesis of a series of amine-functionalized heparin tetra-
saccharide (117) and hexasaccharides (118, 119) was performed (Fig. 5)
using a n
þ
2 modular approach.
69
The conditions of the glycosylation
reactions were carefully optimized to produce eciently the desired
synthetic intermediates with an N-benzyloxycarbonyl-protected ami-
noethyl spacer at the reducing end. The use of microwave heating greatly
facilitates O- and N-sulphation steps.
70
Heparanase is an endo-glucuronidase that recognizes a few specific
sequences of HS as GlcA-GlcN(NS,6S) and GlcA-GlcN(NS,3S), however
the susceptibility to cleavage is influenced by other residues in longer
sequences, and the substrate specificity is not completely unravelled.
71
Regiospecifically
sulphated HS tetrasaccharide b-
D
-GlcA-(1
-
4)-a-
D
-
GlcN(NS,6S)-(1
4)-a-
D
-GlcN(NS,6S) was first synthesized
as an octyl glycoside as a key substrate for heparanase.
72
On N-sulphation
of the non-protected tetrasaccharide 120 with SO
3
.pyridine in aq. NaOH,
-
4)-b-
D
-GlcA-(1
-
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