Glycosyl Trichloroacetimidates
3.2
457
ation of the influence of the substituents R and R 1 on these two competing reactions an attack
of R 2 –OH leads to the following expectations:
• Acylation [reaction (3A)] is supported by R being a small electron-withdrawing group, R 1
destabilizing carbenium ion formation.
• Alkylation [reaction (3B)] is supported by R being a sterically demanding electron-withdrawing group, R 1 supporting carbenium ion formation.
From these considerations it can be deduced that the bulky and strongly electron-withdrawing
trichloromethyl group as R and the glycosyl group as R 1 , which through the α-oxygen atom
supports oxocarbenium ion formation at the anomeric center, should provide excellent alkylating agents; hence, O-glycosyl trichloroacetimidates should on acid activation exhibit excellent
glycosyl donor properties.
As expected, on base-catalyzed addition of the anomeric hydroxy group to trichloroacetonitrile
the O-glycosyl trichloroacetimidate is formed for which, due to the reversibility of the addition, the different nucleophilicities of the anomeric oxides, and the different thermodynamic
stabilities of the O-glycosyl trichloroacetimidates, anomeric stereocontrol is possible. Thus,
the weak base potassium carbonate could be employed for preferential or exclusive formation
of the β-anomer and the strong base sodium hydride could be employed for the thermodynamically more stable α-anomer ( > Fig. 3). This stereocontrol could be successfully extended to
S N 2-type glycosidation reactions in solvents of low donicity and under low temperature conditions and particularly to glycosylations of O=X–OH nucleophiles with X being RC or R 2 P
(see below). However, for many cases anomeric stereocontrol is based on other effects such
as for instance neighboring group participation and/or steric effects, stereoelectronic effects,
solvent participation effects, etc.
The experience with the trichloroacetimidate method exhibited that the demands on a new
glycosylation methodology are fulfilled:
(i) The O-glycosyl trichloroacetimidates are readily formed and generally stable under room
temperature conditions. However, on acid catalysis they exhibit extraordinary high glycosyl donor properties.
(ii) The release of nonbasic trichloroacetamide fulfills the criteria for acid catalysis: The
acid is not consumed by the leaving group, therefore generally only catalytic amounts
of (Lewis) acid are required (∼0.001 to 0.1 equivalents).
(iii) The released trichloroacetamide is also not acidic, therefore the acidity provided by the
catalyst amount is maintained throughout the reaction course. Hence, negative effects
of increasing acidity in the reaction mixture (found for instance for phosphate, sulfate,
sulfonate leaving groups, > Fig. 1, D) are avoided.
(iv) Glycosidation is basically a condensation reaction. In this procedure, water is bound to
trichloroacetonitrile under trichloroacetamide formation. Hence, drying agents are not
required. Often molecular sieves are used in glycosidation reactions. Because they may
affect the acidity of the reaction in an unpredictable fashion, their use is not even recommended in this method.
(v) Trichloroacetamide can be removed from the reaction mixture and transformed back
to trichloroacetonitrile, thus exhibiting the cost-effectiveness and ecofriendliness of this
method in large-scale preparations.
3.2
457
ation of the influence of the substituents R and R 1 on these two competing reactions an attack
of R 2 –OH leads to the following expectations:
• Acylation [reaction (3A)] is supported by R being a small electron-withdrawing group, R 1
destabilizing carbenium ion formation.
• Alkylation [reaction (3B)] is supported by R being a sterically demanding electron-withdrawing group, R 1 supporting carbenium ion formation.
From these considerations it can be deduced that the bulky and strongly electron-withdrawing
trichloromethyl group as R and the glycosyl group as R 1 , which through the α-oxygen atom
supports oxocarbenium ion formation at the anomeric center, should provide excellent alkylating agents; hence, O-glycosyl trichloroacetimidates should on acid activation exhibit excellent
glycosyl donor properties.
As expected, on base-catalyzed addition of the anomeric hydroxy group to trichloroacetonitrile
the O-glycosyl trichloroacetimidate is formed for which, due to the reversibility of the addition, the different nucleophilicities of the anomeric oxides, and the different thermodynamic
stabilities of the O-glycosyl trichloroacetimidates, anomeric stereocontrol is possible. Thus,
the weak base potassium carbonate could be employed for preferential or exclusive formation
of the β-anomer and the strong base sodium hydride could be employed for the thermodynamically more stable α-anomer ( > Fig. 3). This stereocontrol could be successfully extended to
S N 2-type glycosidation reactions in solvents of low donicity and under low temperature conditions and particularly to glycosylations of O=X–OH nucleophiles with X being RC or R 2 P
(see below). However, for many cases anomeric stereocontrol is based on other effects such
as for instance neighboring group participation and/or steric effects, stereoelectronic effects,
solvent participation effects, etc.
The experience with the trichloroacetimidate method exhibited that the demands on a new
glycosylation methodology are fulfilled:
(i) The O-glycosyl trichloroacetimidates are readily formed and generally stable under room
temperature conditions. However, on acid catalysis they exhibit extraordinary high glycosyl donor properties.
(ii) The release of nonbasic trichloroacetamide fulfills the criteria for acid catalysis: The
acid is not consumed by the leaving group, therefore generally only catalytic amounts
of (Lewis) acid are required (∼0.001 to 0.1 equivalents).
(iii) The released trichloroacetamide is also not acidic, therefore the acidity provided by the
catalyst amount is maintained throughout the reaction course. Hence, negative effects
of increasing acidity in the reaction mixture (found for instance for phosphate, sulfate,
sulfonate leaving groups, > Fig. 1, D) are avoided.
(iv) Glycosidation is basically a condensation reaction. In this procedure, water is bound to
trichloroacetonitrile under trichloroacetamide formation. Hence, drying agents are not
required. Often molecular sieves are used in glycosidation reactions. Because they may
affect the acidity of the reaction in an unpredictable fashion, their use is not even recommended in this method.
(v) Trichloroacetamide can be removed from the reaction mixture and transformed back
to trichloroacetonitrile, thus exhibiting the cost-effectiveness and ecofriendliness of this
method in large-scale preparations.