684
3
Chemical Glycosylation Reactions
The mechanism involves the rearrangement of the intermediate into the 1-S-(S-thio-p-nitrobenzoyl)dithiocarbonyl glycopyranose followed by a subsequent rearrangement with loss of
carbon oxide sulphide to give the product (compare > Scheme 40).
3 Synthesis of Thiooligosaccharides
As mentioned in the introduction, thiooligosaccharides (i. e., oligosaccharides in which at least
one interglycosidic oxygen atom is substituted by a sulfur atom) are of great value as glycosylhydrolase stable analogues of O-glycosides and an increasing number of syntheses of complex
thiooligosaccharides is continuously being reported [15,16,17,18,168].
The two general approaches to thiooligosaccharides are identical to the ones discussed above
in the synthesis of thiomonosaccharides. Either a “normal” glycosylation is performed, but
with a saccharide thiol acceptor, or the anomeric thio function is introduced first to yield an
anomeric thiol or thiolate which then is reacted with a saccharide electrophile to form the
inter-S-glycosidic linkage through a S N 2 displacement reaction. Both approaches are commonly used, but perhaps the second approach, where the anomeric conformation is more easily
controlled, since it is constructed during the formation of the anomeric thiol function and not
during the coupling reaction, has been the most abundant.
General problems, as compared to the formation of O-glycosides, are the incompatibility
between catalytic hydrogenolysis and sulfur functions, which complicates the use of benzyl
ethers as protecting groups, although Birch reduction might be an alternative, and the easy
formation of disulfides from thiols, irrespective of if they are used as donors or acceptors.
An interesting new possibility is to use enzymes in the synthesis of thiooligosaccharides,
a methodology that has been made possible by the development of “thioglycoligases” by point
mutation of glycosidases (See > Sect. 3.3).
3.1 Glycosylations with Thiol Acceptors
Under this heading methods according to > Scheme 1 will be discussed, i. e., with thiol saccharide acceptors. As compared to the synthesis of monosaccharides along this pathway, the
formation of thiooligosaccharides is complicated by the fact that now the acceptor moiety is
often the most laborious to construct and thus cannot, if necessary, be used in large excess to
effect the glycosidic bond formation. Only glycosylation methods using promoters that are not
thiophilic can obviously be used, and this disqualifies many O-glycosylation methods. More
or less only the trichloroacetimidate method has been generally applied together with a few
examples utilizing anhydro sugars and glycals as donors. Also thioglycosylation reactions
under basic conditions have been employed quite frequently.
3.1.1 Anhydro Sugars as Donors
Benzylated 1,6-anhydroglucose has been used as donor in the construction of maltose and
maltotriose structures with high α-selectivity ( > Scheme 52) [112]. Interestingly, 1,6-anhydrodisaccharides were found to be unreactive as donors with 4-thiosaccharide acceptors, and
could consequently be used as alternative acceptors.
3
Chemical Glycosylation Reactions
The mechanism involves the rearrangement of the intermediate into the 1-S-(S-thio-p-nitrobenzoyl)dithiocarbonyl glycopyranose followed by a subsequent rearrangement with loss of
carbon oxide sulphide to give the product (compare > Scheme 40).
3 Synthesis of Thiooligosaccharides
As mentioned in the introduction, thiooligosaccharides (i. e., oligosaccharides in which at least
one interglycosidic oxygen atom is substituted by a sulfur atom) are of great value as glycosylhydrolase stable analogues of O-glycosides and an increasing number of syntheses of complex
thiooligosaccharides is continuously being reported [15,16,17,18,168].
The two general approaches to thiooligosaccharides are identical to the ones discussed above
in the synthesis of thiomonosaccharides. Either a “normal” glycosylation is performed, but
with a saccharide thiol acceptor, or the anomeric thio function is introduced first to yield an
anomeric thiol or thiolate which then is reacted with a saccharide electrophile to form the
inter-S-glycosidic linkage through a S N 2 displacement reaction. Both approaches are commonly used, but perhaps the second approach, where the anomeric conformation is more easily
controlled, since it is constructed during the formation of the anomeric thiol function and not
during the coupling reaction, has been the most abundant.
General problems, as compared to the formation of O-glycosides, are the incompatibility
between catalytic hydrogenolysis and sulfur functions, which complicates the use of benzyl
ethers as protecting groups, although Birch reduction might be an alternative, and the easy
formation of disulfides from thiols, irrespective of if they are used as donors or acceptors.
An interesting new possibility is to use enzymes in the synthesis of thiooligosaccharides,
a methodology that has been made possible by the development of “thioglycoligases” by point
mutation of glycosidases (See > Sect. 3.3).
3.1 Glycosylations with Thiol Acceptors
Under this heading methods according to > Scheme 1 will be discussed, i. e., with thiol saccharide acceptors. As compared to the synthesis of monosaccharides along this pathway, the
formation of thiooligosaccharides is complicated by the fact that now the acceptor moiety is
often the most laborious to construct and thus cannot, if necessary, be used in large excess to
effect the glycosidic bond formation. Only glycosylation methods using promoters that are not
thiophilic can obviously be used, and this disqualifies many O-glycosylation methods. More
or less only the trichloroacetimidate method has been generally applied together with a few
examples utilizing anhydro sugars and glycals as donors. Also thioglycosylation reactions
under basic conditions have been employed quite frequently.
3.1.1 Anhydro Sugars as Donors
Benzylated 1,6-anhydroglucose has been used as donor in the construction of maltose and
maltotriose structures with high α-selectivity ( > Scheme 52) [112]. Interestingly, 1,6-anhydrodisaccharides were found to be unreactive as donors with 4-thiosaccharide acceptors, and
could consequently be used as alternative acceptors.