Glycosyl Trichloroacetimidates
3.2
455
oxide structure from a pyranose or a furanose and then anomeric O-alkylation leading directly and irreversibly to glycosides should be also available [ > Fig. 1, (C)]. Surprisingly, no
studies employing this simple ‘anomeric O-alkylation method’ as termed by us [1,2,3,4], for
the synthesis of complex glycosides and glycoconjugates had been reported before our work.
Only a few scattered examples with simple alkylating agents, for instance, excess methyl
iodide or dimethyl sulfate, have been found in the literature [1]. However, in our hands, direct
anomeric O-alkylation of variously protected and totally unprotected sugars in the presence of
a base and triflates or Michael acceptors, respectively, as alkylating agents has become a very
convenient method for glycoside bond formation [8,9,10,11]. Base-promoted decomposition
reactions, particularly of the acyclic form, were practically not observed. Often even high
anomeric diastereocontrol was available. The high diastereocontrol in pyranoses is based on
the enhanced nucleophilicity of equatorial oxygen atoms (due to steric effects and the stereoelectronic kinetic anomeric effect) [1,2,3,4] and on the higher stability of axial oxygen atomderived products (due to the thermodynamic anomeric effect). Chelation effects can be also
employed to design anomeric stereocontrol. The availability and to some extent the stability of
the carbohydrate-derived alkylating agents precluded the general applicability of this simple
method to the synthesis of complex oligosaccharides and glycoconjugates.
4 Glycosyl Donor Generation
Through Retention of the Anomeric Oxygen
The requirements for an efficient glycosylation method are the following:
• high chemical and stereochemical yield,
• applicability to large-scale preparations, and
• avoidance of large amounts of waste materials, i. e. activation of the donor by catalytic
amounts of reagent.
These demands were not met by any of the above-described methods for the synthesis of
complex oligosaccharides and glycoconjugates. However, the general strategy for glycoside
bond formation seems to be correct:
• The first step (activation step) should consist of an activation of the anomeric center under
formation of a stable glycosyl donor—best by a catalyzed attachment of a leaving group to
the anomeric hydroxy group.
• The second step (glycosylation step) should consist of a sterically uniform high-yielding
glycosyl transfer to the glycosyl acceptor based on glycosyl donor activation with catalytic
amounts of promoter, i. e. a catalyst. Obviously, this catalytic procedure has to be orthogonal to the glycosyl donor preparation procedure. Diastereocontrol in the glycosylation step
may be derived from the anomeric configuration of the glycosyl donor (by inversion or
retention), by anchimeric assistance, by the solvent influence, by thermodynamic and/or
stereoelectronic effects, or by any other effects.
The experience with the direct anomeric O-alkylation exhibited that these demands can be
fulfilled by a simple base-catalyzed anomeric O-transformation into a leaving group and
3.2
455
oxide structure from a pyranose or a furanose and then anomeric O-alkylation leading directly and irreversibly to glycosides should be also available [ > Fig. 1, (C)]. Surprisingly, no
studies employing this simple ‘anomeric O-alkylation method’ as termed by us [1,2,3,4], for
the synthesis of complex glycosides and glycoconjugates had been reported before our work.
Only a few scattered examples with simple alkylating agents, for instance, excess methyl
iodide or dimethyl sulfate, have been found in the literature [1]. However, in our hands, direct
anomeric O-alkylation of variously protected and totally unprotected sugars in the presence of
a base and triflates or Michael acceptors, respectively, as alkylating agents has become a very
convenient method for glycoside bond formation [8,9,10,11]. Base-promoted decomposition
reactions, particularly of the acyclic form, were practically not observed. Often even high
anomeric diastereocontrol was available. The high diastereocontrol in pyranoses is based on
the enhanced nucleophilicity of equatorial oxygen atoms (due to steric effects and the stereoelectronic kinetic anomeric effect) [1,2,3,4] and on the higher stability of axial oxygen atomderived products (due to the thermodynamic anomeric effect). Chelation effects can be also
employed to design anomeric stereocontrol. The availability and to some extent the stability of
the carbohydrate-derived alkylating agents precluded the general applicability of this simple
method to the synthesis of complex oligosaccharides and glycoconjugates.
4 Glycosyl Donor Generation
Through Retention of the Anomeric Oxygen
The requirements for an efficient glycosylation method are the following:
• high chemical and stereochemical yield,
• applicability to large-scale preparations, and
• avoidance of large amounts of waste materials, i. e. activation of the donor by catalytic
amounts of reagent.
These demands were not met by any of the above-described methods for the synthesis of
complex oligosaccharides and glycoconjugates. However, the general strategy for glycoside
bond formation seems to be correct:
• The first step (activation step) should consist of an activation of the anomeric center under
formation of a stable glycosyl donor—best by a catalyzed attachment of a leaving group to
the anomeric hydroxy group.
• The second step (glycosylation step) should consist of a sterically uniform high-yielding
glycosyl transfer to the glycosyl acceptor based on glycosyl donor activation with catalytic
amounts of promoter, i. e. a catalyst. Obviously, this catalytic procedure has to be orthogonal to the glycosyl donor preparation procedure. Diastereocontrol in the glycosylation step
may be derived from the anomeric configuration of the glycosyl donor (by inversion or
retention), by anchimeric assistance, by the solvent influence, by thermodynamic and/or
stereoelectronic effects, or by any other effects.
The experience with the direct anomeric O-alkylation exhibited that these demands can be
fulfilled by a simple base-catalyzed anomeric O-transformation into a leaving group and