202
2
General Synthetic Methods
sponding L-iduronic acid 63 by bromination and subsequent debromination ( > Scheme 18)
[153]. It is important that the reaction is carried out with the α-anomer. If the corresponding β-anomer 58 is subjected to the same debromination conditions, the starting D-glucuronic
acid 57 is obtained as the major product [151].
3 Reductions
Numerous reduction procedures are available in organic synthesis [154] and many of these can
be applied for the reduction of carbohydrates.
3.1 Reduction at the Anomeric Center
Unprotected aldoses and ketoses can be reduced to afford alditols while aldonolactones can
be reduced to give either aldoses or alditols. The reagent of choice for reduction to alditols
is sodium borohydride since it is both cheap and convenient to use. The reduction is carried
out under mild conditions at room temperature in an aqueous solution. Sodium borohydride is
stable in water at pH 14 while it reacts with the solvent at neutral or slightly acidic pH, but at
a slower rate than the rate of carbonyl reduction. In some cases, the product will form esters
with the generated boric acid. These borate complexes can be decomposed by treatment with
hydrochloric acid or a strongly acidic ion-exchange resin and the boric acid can be removed
in the work-up as the low boiling trimethyl borate by repeated co-evaporation with methanol
at acidic pH [155].
The reduction of aldoses/ketoses occurs readily with sodium borohydride and during the reaction the pH increases to about 9 ( > Scheme 19) [155]. For the reduction of aldonolactones in
water the first step of the reduction has to be carried out at a pH around 5 in order to avoid
ring-opening of the lactone to the corresponding sodium salt which will not react with sodium
borohydride. The pH control can be achieved by performing the reduction in the presence of
an acidic ion-exchange resin, e. g., Amberlite IR-120 [156]. In this way, it is possible to stop
the reduction at the aldose step. Alternatively, more sodium borohydride can be added and
thereby increasing the pH to 9 by which the alditol is obtained ( > Scheme 19). The reduction
of aldonolactones to alditols can also be performed in anhydrous methanol or ethanol where
hydrolysis of the lactone is not a side reaction [156].
Sodium borohydride only reduces aldonolactones when there is an electronegative substituent
at C2. As a result, 2-deoxylactones are not reduced with this reagent, but can instead be reduced
with disiamylborane in THF to the corresponding 2-deoxyaldose [157] or with calcium borohydride in ethanol to the alditol [158]. Disiamylborane is easily generated in situ by reacting
borane-dimethylsulfide complex with 2-methyl-2-butene prior to addition of the lactone [157].
Sodium borohydride is not a useful reagent for large-scale industrial applications. In this case,
catalytic hydrogenation in an aqueous solution over a heterogeneous catalyst is the preferred
method for reducing aldoses and ketoses. The favored catalyst is Raney nickel [159] or a promoted Raney nickel [160]. The hydrogenations are typically carried out at high pressure and
at temperatures around 120 °C. Lately, Ru/C and modifications thereof are gaining more attention due to a higher activity and fewer problems with metal leaching [161]. A particularly
challenging example is the hydrogenation of D-fructose to afford D-mannitol where the best
catalysts give D-mannitol:D-glucitol in a ratio of about 3:2 [162].
2
General Synthetic Methods
sponding L-iduronic acid 63 by bromination and subsequent debromination ( > Scheme 18)
[153]. It is important that the reaction is carried out with the α-anomer. If the corresponding β-anomer 58 is subjected to the same debromination conditions, the starting D-glucuronic
acid 57 is obtained as the major product [151].
3 Reductions
Numerous reduction procedures are available in organic synthesis [154] and many of these can
be applied for the reduction of carbohydrates.
3.1 Reduction at the Anomeric Center
Unprotected aldoses and ketoses can be reduced to afford alditols while aldonolactones can
be reduced to give either aldoses or alditols. The reagent of choice for reduction to alditols
is sodium borohydride since it is both cheap and convenient to use. The reduction is carried
out under mild conditions at room temperature in an aqueous solution. Sodium borohydride is
stable in water at pH 14 while it reacts with the solvent at neutral or slightly acidic pH, but at
a slower rate than the rate of carbonyl reduction. In some cases, the product will form esters
with the generated boric acid. These borate complexes can be decomposed by treatment with
hydrochloric acid or a strongly acidic ion-exchange resin and the boric acid can be removed
in the work-up as the low boiling trimethyl borate by repeated co-evaporation with methanol
at acidic pH [155].
The reduction of aldoses/ketoses occurs readily with sodium borohydride and during the reaction the pH increases to about 9 ( > Scheme 19) [155]. For the reduction of aldonolactones in
water the first step of the reduction has to be carried out at a pH around 5 in order to avoid
ring-opening of the lactone to the corresponding sodium salt which will not react with sodium
borohydride. The pH control can be achieved by performing the reduction in the presence of
an acidic ion-exchange resin, e. g., Amberlite IR-120 [156]. In this way, it is possible to stop
the reduction at the aldose step. Alternatively, more sodium borohydride can be added and
thereby increasing the pH to 9 by which the alditol is obtained ( > Scheme 19). The reduction
of aldonolactones to alditols can also be performed in anhydrous methanol or ethanol where
hydrolysis of the lactone is not a side reaction [156].
Sodium borohydride only reduces aldonolactones when there is an electronegative substituent
at C2. As a result, 2-deoxylactones are not reduced with this reagent, but can instead be reduced
with disiamylborane in THF to the corresponding 2-deoxyaldose [157] or with calcium borohydride in ethanol to the alditol [158]. Disiamylborane is easily generated in situ by reacting
borane-dimethylsulfide complex with 2-methyl-2-butene prior to addition of the lactone [157].
Sodium borohydride is not a useful reagent for large-scale industrial applications. In this case,
catalytic hydrogenation in an aqueous solution over a heterogeneous catalyst is the preferred
method for reducing aldoses and ketoses. The favored catalyst is Raney nickel [159] or a promoted Raney nickel [160]. The hydrogenations are typically carried out at high pressure and
at temperatures around 120 °C. Lately, Ru/C and modifications thereof are gaining more attention due to a higher activity and fewer problems with metal leaching [161]. A particularly
challenging example is the hydrogenation of D-fructose to afford D-mannitol where the best
catalysts give D-mannitol:D-glucitol in a ratio of about 3:2 [162].