Kiliani-Fischer

An older version of this sequence is called the Kiliani-Fischer synthesis It too proceeds through a cyanohydrin but it uses a less efficient method for converting the cyano group to the required aldehyde... 

The Kiliani-Fischer synthesis pro ceeds by nucleophilic addition of HCN to an aldose followed by con version of the cyano group to an al dehyde A mixture of stereoisomers results the two aldoses are epi meric at C 2 Section 25 20 de scribes the modern version of the Kiliani-Fischer synthesis The example at the right illus trates the classical version... 

Addition of hydrogen cyanide to an aldose to form a cyanohydrin is the first step in the Kiliani-Fischer method for increasing the carbon chain of aldoses by one unit. Cyanohydrins react with Grignard reagents (see Grignard reaction) to give a-hydroxy ketones. 

Kiliani-Fischer synthesis (Section 25.20) A synthetic method for carbohydrate chain extension. The new carbon-carbon bond is formed by converting an aldose to its cyanohydrin. Reduction of the cyano group to an aldehyde function completes the synthesis. 

Fischer s original method for conversion of the nitrile into an aldehyde involved hydrolysis to a carboxylic acid, ring closure to a cyclic ester (lactone), and subsequent reduction. A modern improvement is to reduce the nitrile over a palladium catalyst, yielding an imine intermediate that is hydrolyzed to an aldehyde. Note that the cyanohydrin is formed as a mixture of stereoisomers at the new chirality center, so two new aldoses, differing only in their stereochemistry at C2, Tesult from Kiliani-Fischer synthesis. Chain extension of D-arabinose, for example, yields a mixture of D-glucose and o-mannose. 

Problem 25.21 1 What product(s) would you expect from Kiliani-Fischer reaction of n-ribose ... 

Problem 25.22 What aldopentose would give a mixture of L-gulose and L-idose on Kiliani-Fischer chain extension ... 

Just as the Kiliani-Fischer synthesis lengthens an aldose chain by one carbon, the Wohl degradation shortens an aldose chain by one carbon. The Wohl degradation is almost the exact opposite of the Kiliani-Fischer sequence. That is, the aldose aldehyde carbonyl group is first converted into a nitrile, and the resulting cyanohydrin loses HCN under basic conditions—the reverse of a nucleophilic addition reaction. 

Much of the chemistry of monosaccharides is the familiar chemistry of alcohols and aldehydes/ketones. Thus, the hydroxyl groups of carbohydrates form esters and ethers. The carbonyl group of a monosaccharide can be reduced with NaBH4 to form an alditol, oxidized with aqueous Br2 to form an aldonic acid, oxidized with HNO3 to form an aldaric acid, oxidized enzymatically to form a uronic acid, or treated with an alcohol in the presence of acid to form a glycoside. Monosaccharides can also be chain-lengthened by the multistep Kiliani-Fischer synthesis and can be chain-shortened by the Wohl degradation. 

Kiliani-Fischer synthesis (Section 25.6) A method for lengthening the chain of an aldose sugar. 

Arabinose, configuration of. 982 Kiliani-Fischer synthesis on. 995 Arachidic acid, structure of, 1062 Arachidonic acid, eicosanoids from, 1069-1070... 

Keto-enol tautomerism, 264, 842-844 Kiliani, Heinrich, 994 Kiliani-Fischer synthesis, 994-995 Kimbail, George, 216 Kinetic control, 491 Kinetics, 362... 

Frequently, it is the bisulfite addition product that is treated with CN. This method is especially useful for aromatic aldehydes, since it avoids competition from the benzoin condensation. If desired, it is possible to hydrolyze the cyanohydrin in situ to the corresponding a-hydroxy acid. This reaction is important in the Kiliani-Fischer method of extending the carbon chain of a sugar. 

Scheme 8.32 Kiliani-Fischer synthesis of higher sugars.

A sequence known as the Kiliani-Fischer synthesis was developed primarily for extending an aldose chain by one carbon, and was one way in which configurational relationships between different sugars could be established. A major application of this sequence nowadays is to employ it for the synthesis of " C-labelled sugars, which in turn may be used to explore the role of sugars in metabolic reactions. 

Aminosugars such as glucosamine may be synthesized by a modified Kiliani-Fischer process (see Box 12.1). The starting aldose, here o-arabinose, is treated with ammonia, producing an imine, and then with HCN to yield epimeric 2-aminonitriles. The... 

Kiliani-Fischer synthesis is a means of lengthening the carbon backbone of a carbohydrate. The process begins with the reaction of hydrogen cyanide (HCN) with an aldehyde to produce a cyanohydrin. Treatment of the cyanohydrin with barium hydroxide followed by acidification yields an aldose with an additional carbon atom, as shown in Figure 16-16. The formation of the cyanohydrin creates a new chiral center as a racemic mixture. 

Figure 16-17 shows a specific example of Kiliani-Fischer synthesis. 

The free nitriles of iV-methyl-L-glucosaminic acid and iV-methyl-L-mannosaminic acid have been prepared by Wolfrom, Thompson and Hooper by the Kiliani-Fischer cyanohydrin synthesis. 

Fucosidase inhibiting l,4,5-trideoxy-l,4-imino-L-lyxitol (78) was prepared [124] from D-ribose via protected 5-amino-5-deoxy-L-lyxose (79) by a chemical route. This compound, as well as the 1-aminomethyl homologue (80), obtained by Kiliani-Fischer chain extension of (79), inhibited a-L-fucosidase with K around 2 pmol/1. l,4-Dideoxy-l,4-imino-D-iditol (81) [71] was found to be a moderate inhibitor of the enzyme. 

Kiliani-Fischer Step-up Method (Addition of One Carbon)... 

Problem 22.9 Why does the Kiliani-Fischer method give unequal amounts of diastereomeric products ... 

Problem 22.10 Outline the steps in the Wohl degradation, which employs a dehydration of an aldose oxime and is thus a reversal of the Kiliani-Fischer step-up method. 

Problem 22.17 ( + )-Glucose. ( + )-mannose and (+ )-galactose are among the hexoses isolated after three Kiliani-Fischer step-ups. beginning with d-(+ )-glyceraldehyde. Do these hexoses belong in the d or l families ... 

Problem 22.18 Write shorthand formulas for the tetroses prepared from (a) L-glycerose, (b) o-glycerose, by the Kiliani-Fischer synthesis. -4... 

Among the classic methods for the extension of the aldose chain by one carbon atom from the reducing end [9J, the Kiliani-Fischer cyanohydrin synthesis [10] is a milestone in carbohydrate chemistry. However after 110 years from discovery and numerous applications [11], including the preparation of carbon and hydrogen isotopically labeled compounds for mechanistic and structural studies [12], there are still several drawbacks that make the method impractical. These are the low and variable degree of selectivity and the harsh reaction conditions that are required to reveal the aldose from either the aldonic acid or directly from the cyanohydrin. Synthetic applications that have appeared in recent times confirmed these limitations. For instance, a quite low selectivity was registered [13] in the addition of the cyanide ion to the D-ga/acfo-hexodialdo-l,5-pyranose derivative 1... 

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