Reactions at Oxygen Atoms
2.1
121
2.2 Acetalation Reactions: Acetal-Type Protecting Groups
Emil Fischer described as early as 1895 the formation of acetals of glycoses [121]. Since then,
this type of protecting group has been extensively used in carbohydrate chemistry. Acetal
protecting groups are readily available, easily introduced and removed, and stable to a good
range of reactions. Standard conditions for the formation of acetals include treatment of a diol
with a carbonyl reagent together with some acid catalyst.
Cyclic acetals such as benzylidene, isopropylidene, or 1,2-diacetals have been effectively used
in the regioselective protection of diol systems. The ease of formation and the structures of
products are a function of the regio- and stereochemistry of the hydroxyl groups and the properties of the employed carbonyl reagent. Acetals have been applied as protecting groups in
many sugars including aminosugars and oligosaccharides. Exhaustive lists of catalyst and conditions can be found in reviews devoted to carbohydrates [122].
2.2.1 Cyclic Acetals
Isopropylidene (acetonides) and benzylidene derivatives are the most commonly used acetals
for the simultaneous protection of 1,2- and 1,3-diols in carbohydrate and nucleoside chemistry [123]. Cyclohexylidene acetals are occasionally used, most often as an alternative to benzylidene acetals. Protection using cyclohexane-1,2-diacetals or the related butane-2,3-diacetals
represents a new approach which has proved its value in complex oligosaccharide synthesis [124].
Besides being useful for selective protection of monosaccharides, cyclic acetals can display
a number of interesting reactions, such as reductive or oxidative ring opening, that amplify the
synthetic interest of these protecting groups [125].
Isopropylidene, Benzylidene, and Related Acetals Isopropylidene or benzylidene acetals are
formed either by direct condensation of the diol with the appropriate carbonyl compound (acetone or benzaldehyde, respectively) or by transacetalation with the corresponding dimethoxy
acetal. Both processes are carried out in acidic conditions [123].
One advantage of these acetals is their regioselective introduction. Benzylidene derivatives are
formed preferentially with 1,3-diols of which anomeric or primary hydroxyl groups are a part.
Therefore, they are generally used for 4,6-O-protection of pyranoses forming either cis- or
trans-fused 1,3-dioxane rings. In these six-membered rings only the thermodynamically more
stable [126] equatorial phenyl-substituted derivatives are observed. Formation of benzylidene
acetals has also been achieved under basic conditions using α,α-dihalotoluenes in refluxing
pyridine [127].
In contrast, isopropylidene acetals are more stable as five-membered 1,3-dioxane rings formed
on cis-1,2-diols. Practically all examples in the literature show that, the use of acetone for the
acetonation of sugars, leads to 1,3-dioxane rings, which are thermodynamically favored [128].
If 2-alkoxypropene is used as reagent, a reversal on the regioselectivity is observed, and the
kinetic products (4,6-O-isopropylidene acetals) are preferentially formed [129]. An intermediate behavior is observed for the transacetalation process involving 2,2-dimethoxypropane
which gives results either similar to those obtained with acetone or similar to those obtained
with enol ethers ( > Scheme 18) [130].
2.1
121
2.2 Acetalation Reactions: Acetal-Type Protecting Groups
Emil Fischer described as early as 1895 the formation of acetals of glycoses [121]. Since then,
this type of protecting group has been extensively used in carbohydrate chemistry. Acetal
protecting groups are readily available, easily introduced and removed, and stable to a good
range of reactions. Standard conditions for the formation of acetals include treatment of a diol
with a carbonyl reagent together with some acid catalyst.
Cyclic acetals such as benzylidene, isopropylidene, or 1,2-diacetals have been effectively used
in the regioselective protection of diol systems. The ease of formation and the structures of
products are a function of the regio- and stereochemistry of the hydroxyl groups and the properties of the employed carbonyl reagent. Acetals have been applied as protecting groups in
many sugars including aminosugars and oligosaccharides. Exhaustive lists of catalyst and conditions can be found in reviews devoted to carbohydrates [122].
2.2.1 Cyclic Acetals
Isopropylidene (acetonides) and benzylidene derivatives are the most commonly used acetals
for the simultaneous protection of 1,2- and 1,3-diols in carbohydrate and nucleoside chemistry [123]. Cyclohexylidene acetals are occasionally used, most often as an alternative to benzylidene acetals. Protection using cyclohexane-1,2-diacetals or the related butane-2,3-diacetals
represents a new approach which has proved its value in complex oligosaccharide synthesis [124].
Besides being useful for selective protection of monosaccharides, cyclic acetals can display
a number of interesting reactions, such as reductive or oxidative ring opening, that amplify the
synthetic interest of these protecting groups [125].
Isopropylidene, Benzylidene, and Related Acetals Isopropylidene or benzylidene acetals are
formed either by direct condensation of the diol with the appropriate carbonyl compound (acetone or benzaldehyde, respectively) or by transacetalation with the corresponding dimethoxy
acetal. Both processes are carried out in acidic conditions [123].
One advantage of these acetals is their regioselective introduction. Benzylidene derivatives are
formed preferentially with 1,3-diols of which anomeric or primary hydroxyl groups are a part.
Therefore, they are generally used for 4,6-O-protection of pyranoses forming either cis- or
trans-fused 1,3-dioxane rings. In these six-membered rings only the thermodynamically more
stable [126] equatorial phenyl-substituted derivatives are observed. Formation of benzylidene
acetals has also been achieved under basic conditions using α,α-dihalotoluenes in refluxing
pyridine [127].
In contrast, isopropylidene acetals are more stable as five-membered 1,3-dioxane rings formed
on cis-1,2-diols. Practically all examples in the literature show that, the use of acetone for the
acetonation of sugars, leads to 1,3-dioxane rings, which are thermodynamically favored [128].
If 2-alkoxypropene is used as reagent, a reversal on the regioselectivity is observed, and the
kinetic products (4,6-O-isopropylidene acetals) are preferentially formed [129]. An intermediate behavior is observed for the transacetalation process involving 2,2-dimethoxypropane
which gives results either similar to those obtained with acetone or similar to those obtained
with enol ethers ( > Scheme 18) [130].