Glycosyl Trichloroacetimidates
3.2
453
blocks to complex oligosaccharides and glycoconjugates is the most difficult task in this
endeavor.
2 Glycosyl Donor Generation
Through Anomeric-Oxygen Exchange Reactions
For a long time the methods developed for glycosylation have essentially favored approaches
which require for glycosyl donor generation an anomeric oxygen exchange reaction on the
half-acetal moiety of pyranoses and furanoses [ > Fig. 1, methods (A) and (B)] [1,2,3,4]. The
Fischer–Helferich method (A), as a direct acid-catalyzed anomeric-oxygen replacement reaction has been very successfully applied to the synthesis of simple alkyl glycosides. However,
because of its reversibility, it is of limited usefulness in the synthesis of complex oligosaccharides and glycoconjugates. For this endeavor, irreversible methods are required, which can be
attained by preactivation of the anomeric center by introducing good leaving groups which can
be released by leaving group specific promoters or—even better—by catalytic amounts of an
activator.
The best-known of these methods is the Koenigs–Knorr method (B) in which the anomeric hydroxy group is replaced by chlorine or bromine. Thus, an α-halogen-ether is generated
which in the glycosylation step can be readily activated by halophilic promoters frequently
incorrectly termed “catalyst.” Generally, from one up to four equivalents of heavy metal salts
are employed resulting in an irreversible transfer of the glycosyl donor moiety to the acceptor. On the basis of this general method many valuable techniques for the synthesis of complex oligosaccharides and glycoconjugates have been introduced which have been extensively
reviewed. However, the obvious limitations of this method were the reason for the search for
alternative methods [1,2,3,4,5,6,7].
Therefore, other anomeric oxygen exchange reactions closely related to the Koenigs–Knorr
method have been extensively investigated. Particularly, the introduction of fluorine and alkyland arylthio groups as leaving groups gained great interest because these groups also tolerate
manipulations of orthogonal protecting groups. Differences in thio leaving group tendencies
(in combination with the “armed”/“disarmed” principle) could be even employed for one-pot
consecutive glycosylations leading to more or less pure oligosaccharide products. However,
the basic drawbacks of the Koenigs–Knorr method are also associated with these promoter
systems. For instance, the large amounts of promoter required (and often additional reagents)
limit their usefulness particularly in large-scale oligosaccharide and glycoconjugate synthesis.
3 Direct Anomeric Oxygen Alkylation
For more than a century glycosylations were essentially based on methods where the anomeric carbon of the sugar residue to be coupled served as the electrophile (the glycosyl donor)
and the alcohol (the glycosyl acceptor) as the nucleophile [ > Fig. 1, (A), (B)]. Alternatively,
base-mediated deprotonation of the anomeric hydroxy group generating at first an anomeric
3.2
453
blocks to complex oligosaccharides and glycoconjugates is the most difficult task in this
endeavor.
2 Glycosyl Donor Generation
Through Anomeric-Oxygen Exchange Reactions
For a long time the methods developed for glycosylation have essentially favored approaches
which require for glycosyl donor generation an anomeric oxygen exchange reaction on the
half-acetal moiety of pyranoses and furanoses [ > Fig. 1, methods (A) and (B)] [1,2,3,4]. The
Fischer–Helferich method (A), as a direct acid-catalyzed anomeric-oxygen replacement reaction has been very successfully applied to the synthesis of simple alkyl glycosides. However,
because of its reversibility, it is of limited usefulness in the synthesis of complex oligosaccharides and glycoconjugates. For this endeavor, irreversible methods are required, which can be
attained by preactivation of the anomeric center by introducing good leaving groups which can
be released by leaving group specific promoters or—even better—by catalytic amounts of an
activator.
The best-known of these methods is the Koenigs–Knorr method (B) in which the anomeric hydroxy group is replaced by chlorine or bromine. Thus, an α-halogen-ether is generated
which in the glycosylation step can be readily activated by halophilic promoters frequently
incorrectly termed “catalyst.” Generally, from one up to four equivalents of heavy metal salts
are employed resulting in an irreversible transfer of the glycosyl donor moiety to the acceptor. On the basis of this general method many valuable techniques for the synthesis of complex oligosaccharides and glycoconjugates have been introduced which have been extensively
reviewed. However, the obvious limitations of this method were the reason for the search for
alternative methods [1,2,3,4,5,6,7].
Therefore, other anomeric oxygen exchange reactions closely related to the Koenigs–Knorr
method have been extensively investigated. Particularly, the introduction of fluorine and alkyland arylthio groups as leaving groups gained great interest because these groups also tolerate
manipulations of orthogonal protecting groups. Differences in thio leaving group tendencies
(in combination with the “armed”/“disarmed” principle) could be even employed for one-pot
consecutive glycosylations leading to more or less pure oligosaccharide products. However,
the basic drawbacks of the Koenigs–Knorr method are also associated with these promoter
systems. For instance, the large amounts of promoter required (and often additional reagents)
limit their usefulness particularly in large-scale oligosaccharide and glycoconjugate synthesis.
3 Direct Anomeric Oxygen Alkylation
For more than a century glycosylations were essentially based on methods where the anomeric carbon of the sugar residue to be coupled served as the electrophile (the glycosyl donor)
and the alcohol (the glycosyl acceptor) as the nucleophile [ > Fig. 1, (A), (B)]. Alternatively,
base-mediated deprotonation of the anomeric hydroxy group generating at first an anomeric