Kiliani-Fischer synthesis

The Kiliani-Fischer synthesis is a method for synthesizing monosaccharides. It proceeds via synthesis and hydrolysis of a cyanohydrin, thus elongating the carbon chain of an aldose by one carbon atom while preserving stereochemistry on all the old chiral carbons. The new chiral carbon is produced with both stereochemistries, so the product of a Kiliani-Fischer synthesis is a mixture of two diastereomeric sugars, called epimers. For example, D-arabinose is converted to a mixture of D-glucose and D-mannose.

Classical Kiliani-Fischer synthesis

The original version of the Kiliani-Fischer synthesis proceeds through cyanohydrin and aldonic acid lactone intermediates. The first step is to react the starting sugar with aqueous cyanide (typically NaCN); the cyanide undergoes nucleophilic addition to the carbonyl group of the sugar (while sugars tend to exist mainly as cyclic hemiacetal, they are always in chemical equilibrium with their open-chain aldehyde or ketone forms, and in the case of these aldoses it is that aldehyde form that reacts in this synthesis). The cyanohydrin resulting from this addition is heated in water, which hydrolyzes the cyanide into a carboxylic acid group that quickly reacts with itself to form a more stable lactone. Now there are two diastereomeric lactones in the reaction mixture. They are separated (by chromatography, partition into different solvents, or any of the numerous other separation methods) and then the desired lactone is reduced with a sodium amalgam. As illustrated below, D-arabinose is converted to a mixture of D-glucononitrile and D-mannononitrile, which is then converted to D-gluconolactone and D-mannonolactone, separated, and reduced to D-glucose or D-mannose. The chemical yield by this method tends to be around 30%.

Improved version

More recently, an improved reduction method has been developed that produces somewhat higher yields of the larger sugars. Instead of conversion of the cyanohydrin to a lactone, the cyanohydrin is reduced with hydrogen with a palladium on barium sulfate catalyst, in water as the solvent. The cyanohydrin is then reduced to an imine that quickly hydrolyzes under the conditions to an aldehyde--thus the final sugars are produced in just two steps rather than three. Then the final sugars are separated instead of the lactones. The special catalyst is needed to avoid further reduction of the aldehyde group to a hydroxyl group, which would yield an alditol. These catalysts that limit hydrogenation to one step are called poisoned catalysts; Lindlar palladium is another example. The reactions below illustrate this improved method for the conversion of L-erythrose to L-xylose and L-lyxose.

Uses and Problems

The Kiliani-Fischer synthesis is usually used for production of sugars that are difficult or impossible to obtain from natural sources; it is an invaluable tool for this purpose. However it is limited by its low yield, its use of toxic reagents, and the fact that it only works for aldoses; sometimes the starting sugars can also be hard to find. Some unusual ketoses may be accessible from similar aldoses via an enediol intermediate; for example, on standing in aqueous base, glucose, fructose, and mannose will slowly interconvert since they share an enediol form. (See mutarotation). Some unusual sugars are also accessible via aldol addition.

ee also

*Homologation reactions

References

-Carey, Francis A. (2006). Organic Chemistry, Sixth Edition, New York, NY: McGraw-Hill. ISBN 0-07-111562-5.