Biomedical Engineering Reference
In-Depth Information
12.5.2. Synthesis of N-Glycolylneuraminic Acid and KDN-
Containing Oligosaccharides
N
-Glycoyl
-sialoside-based oligosaccharides are of interest because of their potential
as markers for human tumors [115]. With this in mind, Crich and Wu prepared a 5-
N
-
glycoyl-5-
N
,4-
O-
oxazolinone-protected sialyl donor (Scheme 12.38), again carrying
the highly activated
S
-adamantanyl thioglycoside, and showed that it could be activated
in the presence of an aryl thioglycoside in the galactopyranosyl series, provided that it
was protected with benzoyl groups at the 2- and 6-positions [116]. This observation
enabled them, for the first time, to couple stereoselectively a sialyl thioglycoside to a
hydroxyl thioglycoside, thereby paving the way for the direct introduction of a second
glycosidic bond. Because of the relatively low reactivity of most sialyl thioglycosides,
such sequences in the sialic acid field previously had to rely on the use orthogonal pairs
of donors, such as those of thioglycosides with glycosyl fluorides [117]. Unfortunately,
the increased reactivity of the glycolyl unit meant that selective hydrolysis of the
oxazolidinonewas no longer possible and a complete saponification had to be effected,
followed by reinstallation of the glycolyl amide [116].
The beneficial effect of the oxazolidinone ring in the stereocontrolled synthesis
of
N
-acetyl neuraminosides led to the application of an analogous cyclic carbonate
protecting group in another class of the sialic acid family [118], the KDN glyco-
sides [119]. These members of the sialic acid family of carbohydrates are commonly
found at the nonreducing terminus of cell surface glycans [1a], in the lipooligosacchar-
ides of variousGram-negative bacteria [115a], and,more recently, inhumans [118,120].
Given the poor availability of KDN itself and the microheterogeneity of isolated
natural samples, the donor was best accessed from neuraminic acid by adaptation of
the Zbiral oxidative cleavage of the 5-amino group. Making use of the highly reactive
adamantanyl thioglycoside (Scheme 12.39), this type of protecting group enabled the
a
OH
HO
OBz
OH
O
O
BnO
BnO
OMe
SAr
OAc
OAc
SAda
OBz
OBn
OAc
OAc
CO
2
Me
OBn
AcO
O
OBz
CO
2
Me
NIS TfOH
NIS TfOH
OH
Bn
BnO
AcO
N
OMe
O
AcO
O
O
O
N
CH
2
Cl
2
/CH
3
CN (2:1), -78°C
Acid-washed MS
(Ar = 4-Cl-Ph)
55%
O
O
AcO
O
O
O
O
OBz
O
1. LiOH
2. Acetoxyacetyl chloride
3. LiOH
82%
OH
OBn
CO
2
H
OH
HO
OH
BnO
OH
OMe
BnO
H
N
O
O
O
O
O
HO
HO
OH
O
SCHEME 12.38
Direct synthesis of a
N
-glycoyl
a
-sialoside.
OAc
OAc
CO
2
Me
OAc
OAc
BnO
NIS/TfOH, -78°C
CH
2
Cl
2
/MeCN (2/1)
CO
2
Me
SAda
OBn
OBn
AcO
O
O
O
O
AcO
OMe
O
+
OMe
HO
O
OBn
O
O
81%
OBn
O
BnO
O
O
α
only
SCHEME 12.39
Carbonate controlled synthesis of a
-KDN glycoside.
a
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