Biomedical Engineering Reference
In-Depth Information
because the coupling procedure is usually quantitative, requiring neither
protection nor activation steps and secondly because the synthesis of different
building blocks is generally easier. Such strategies result from the condensation
of fully deprotected polyfunctional building blocks bearing mutually highly
reactive functions. Despite the presence of other reactive chemical functions, the
coupling reaction occurs generally in aqueous conditions to provide the full
molecular construction without additional chemical manipulation. Moreover, the
resulting conjugate contains unnatural linkages which can be advantageous to
improve immunogenicity as well as stability against enzymatic degradation.
3.2.1.
Convergent assembly by oxime ligation
Among other chemoselective methods, oxime ligation has found increasing
applications over the last decade, particularly for the glycoconjugate preparation
[39]. It requires the prior introduction in both partners of either an aldehyde or a
keto group and an aminooxy function. In the context of synthetic vaccine
preparation, this strategy ensures a controlled molecular assembly as shown by
Bertozzi with the synthesis of oxime-linked mucin mimics [40]. In this study,
two tumor related Tn
8
and STn
9
antigens bearing aminooxy function at the
anomer position were first prepared (Figure 7). The key step of this procedure is
the glycosylation with
N
-hydroxysuccinimide from glycosyl chloride
10
using
a phase transfer catalysis protocol [41], which leads to the
ŋ
-glycoside
intermediate
11
in moderate yield (57%). The subsequent azide reduction and
hydrazinolysis afford aminooxy carbohydrate
8
with a defined anomer
configuration which can be readily engaged in oxime coupling. A similar
procedure was followed for the aminooxy STn
9
synthesis.
OH
CO
2
H
HO
OH
OH
HO
O
O
AcHN
O
HO
HO
HO
AcHN
ONH
2
O
8
HO
AcHN
9
ONH
2
O
OAc
OH
OAc
N
O
AcO
AcO
1. H
2,
Pd/C, Ac
2
O
2. hydrazine
O
O
8
AcO
AcO
TBAHS
CH
2
Cl
2
Na
2
CO
3
N
3
O
N
3
Cl
O
N
10
11
Fig. 7. Synthesis of aminooxy carbohydrate epitopes using phase transfer catalysis.
O
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