Aldoses Kiliani reaction

Cyanide ions react with aldehydes and ketones to yield cyanohydrins (Kiliani) (Fig. 2-28). Hydrolysis of the cyanohydrins gives aldonic acids, which can be reduced to aldoses. Kiliani reaction thus opens the possibility for chain lengthening of aldoses. Because of the formation, of a hydroxyl group in place of the aldehyde group a new asymmetric center is generated. It is to be observed, however, that the reaction is subject to so-called asymmetric induction, which means that the diastereoisomers are formed in unequal proportions. 

Natural D-mannose is the aldehyde of natural D-mannitol, and is transformed by the action of bromine water into D-mannonic acid, which was isolated as its phenylhydrazide. The acid was regenerated from the phenyl-hydrazide and isolated as its crystalline lactone. Kiliani hod obtained the enantiomorph of this lactone on applying the cyanohydrin reaction to natural L-arabinose. A mixture of both lactones formed a racemate. Then, by taking recourse to his newly discovered reduction of the lactones to the aldoses, a reaction which Fischer designated the most significant in the... 

Extension of the carbon chain of an aldose from the carbonyl by one unit at a time can be carried out fairly readily by the Kiliani reaction. A cyanhydrin is formed by addition of cyanide ion, followed by reduction and hydrolysis (in either order) historically, the sugar was unprotected, and the cyanohydrin was hydrolysed to the sugar lactone, and then reduced with sodium amalgam (Figure 1.4). Because a new asymmetric centre is formed, two epimeric sugars result (epimers are diastereomers that differ in the configuration of only one carbon). 

In the first step of the synthesis (the Kiliani portion), the aldose is treated with sodium cyanide and HCl (Section 18.4). Addition of cyanide ion to the carbonyl group creates a new asymmetric carbon. Consequently, two cyanohydrins that differ only in configuration at C-2 are formed. The configurations of the other asymmetric carbons do not change, because no bond to any of the asymmetric carbons is broken during the course of the reaction (Section 5.12). Kiliani went on to hydrolyze the cyanohydrins to aldonic acids (Section 17.18), and Fischer had previously developed a method to convert aldonic acids to aldoses. This reaction sequence was used for many years, but the method currently employed to convert the cyanohydrins to aldoses was developed by Serianni and Barker in 1979 it is referred to as the modified Kiliani-Fischer synthesis. Serianni and Barker reduced the cyanohydrins to imines, using a partially deactivated palladium (on barium sulfate) catalyst so that the imines would not be further reduced to amines. The imines could then be hydrolyzed to aldoses (Section 18.6). 

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. 

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. 

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. 

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. 

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... 

H. Kiliani, as Fischer always emphatically acknowledged, discovered and developed the method of building up the aldose series by the cyanohydrin reaction to give nitriles from the nitrile, the next higher aldonic acid could then be prepared. In 1890, A. Wohl, working in Fischer s Berlin laboratory, elaborated the dehydration of an aldose oxime to the nitrile, from which the next lower aldose could be prepared by loss of hydrocyanic acid. Fischer exploited the possibilities of sugar extension and degradation afforded by the use of these two important methods. 

Figure 7.15 displays the classic Kiliani-Fischer synthesis, a three-step reaction sequence for the homologation of aldoses. You can see the Cj -lengthening of D-arabinose to produce D-glu-cose and D-mannose. 

The duration of the reaction time alone determines whether carbonyl compounds, sodium cyanide and ammonium chloride will generate a cyanohydrin (Figure 9.9, top) or an a-aminonitrile (Figure 9.9, bottom). We are already familiar with the first reaction pattern from the initial reaction of the three-step Kiliani-Fischer synthesis of aldoses (Figure 7.15). The second reaction pattern initiates the Strecker synthesis of a-amino acids, which is completed by a total hydrolysis of the C=N group, as in the Bucherer modification discussed elsewhere (Figure 7.11). 

The final reaction to be covered in this section is known as the Kiliani-Fischer synthesis. It is a method that converts an aldose to two diastereomeric aldoses that contain one more carbon than the original sugar. The Kiliani-Fischer synthesis is illustrated in the following reaction sequence, which shows the formation of the aldopentoses D-ribose and D-arabinose from the aldotetrose D-erythrose ... 

Two common procedures in carbohydrate chemistry result in adding or removing one carbon atom from the skeleton of an aldose. The Wohl degradation shortens an aldose chain by one carbon, whereas the Kiliani-Fischer synthesis lengthens it by one. Both reactions involve cyanohydrins as intermediates. Recall from Section 21.9 that cyanohydrins are formed from aldehydes by addition of the elements of HCN. Cyanohydrins can also be re converted to carbonyl compounds by treatment with base. 

In their speed of reaction with the halogens, in acid or in alkaline solutions, the simple sugars may be divided into two main classes, the aldoses and the ketoses. The oxidation of the former is very rapid compared with that of the latter. Kiliani showed that when D-glucose and D-fructose were each treated with an equal weight of bromine in water, the ketose required 350-500 hours for completion of the oxidation, in contrast to two to three hours for the aldose. The same difference exists in buffered solutions Honig and Ruzicka found that the rates were two hours and five minutes, respectively. In alkaline solution under controlled conditions, the aldoses can be quantitatively oxidized with sodium hypoiodite in the presence of D-fructose or L-sorbose without appreciable attack on the ketoses. Ochi reported a similar but less clear-cut difference with calcium hypochlorite as the oxidant. Chlorous acid attacks only the aldoses, leaving the ketoses unaltered. The same effect was noted with the keto acids Kiliani reported that 2-keto-L-rhamnonic acid was stable to the action of bromine water. A little preliminary work has been done with iodic acid by Williams and Woods who found that D-fructose was oxidized more rapidly than the aldoses. No confirmation of this work has appeared. 

In 1889 Fischer discovered that the lactones of the acids of the sugar group can be reduced by sodium amalgam to yield the corresponding carbonyl compound, an aldose. The addition of this reaction to the cyanohydrin procedure of Kiliani made possible the first synthesis of... 

The pr e-Woodwardhn era largely concerned itself with the collection and classification of synthetic tools chemical reactions suited to broad application to the constitutional construction of molecular skeletons (including Kiliani s chain-extension of aldoses, reactions of the aldol type, and cycloadditions of the Diels-Alder type). The pre- Woodwardian era is dominated by two synthetic chemists Emil Fischer and Robert Robinson. Emil Fischer was emphasizing the importance of synthetic chemistry in biology as early as 1907 [30]. He was probably the first to make productive use of the three-dimensional structures of organic molecules, in the interpretation of isomerism phenomena in carbohydrates with the aid of the Van t Hoff and Le Bel tetrahedron model (cf. family tree of aldoses in Scheme 1-6), and in the explanation of the action of an enzyme on a substrate, which assumes that the complementarily fitting surfaces of the mutually dependent partners are noncovalently bound for a little while to one another (shape complementarity) [31],... 

The Ruff degradation is the opposite of the Kiliani-Fischer synthesis. Thus, the Ruff degradation shortens an aldose chain by one carbon Hexoses are converted into pentoses, and pentoses are converted into tetroses. In the Ruff degradation, the calcium salt of an aldonic acid is oxidized with hydrogen peroxide. Ferric ion catalyzes the oxidation reaction, which cleaves the bond between C-1 and C-2, forming CO2 and an aldehyde. It is known that the reaction involves the formation of radicals, but the precise mechanism is not well understood. 

Triose, tetrose, and pentose phosphates enriched with C have been prepared by the Kiliani-Fischer reaction on the terminal phosphates of the next lower aldose. The mixed nitriles were separated on Dowex 1-X8 resin and reduced with hydrogen over Pd-BaS04. The synthesis of D-glucose 2-phosphate by phosphorylation of l,3,4,6-tetra-0-acetyl-j3-D-glucopyranosyl chloride, itself prepared by 2 1 acetyl migration, has been reported. Rates of phosphate hydrolysis in 0.25 M sulphuric acid and in 0.25 M sodium hydroxide were measured for D-glucose monophosphates in the former the order was 1-phosphate > 2-phosphate > 3-phosphate > 6-phosphate while in the latter it was 3-phosphate > 6-phosphate > 2-phosphate > 1-phosphate. ... 

This reaction was first reported by Kiliani in 1885, and then extended by Fischer in 1889. It is the conversion of an aidose into two one-carbon-higher epimeric homologs, which involves a nucleophilic addition of a cyanide to the terminal carbonyl group of an aldose, hydrolysis of cyanohydrin, and reduction of the resulting lactone. Therefore, it is known as the Kiliani synthesis, Kiliani-Fischer reaction, Kiliani cyanohydrin synthesis, Kiliani-Fischer synthesis, Kiliani-Fischer cyanohydrin synthesis, Fischer-Kiliani cyanohydrin synthesis, or cyanohydrin reaction. This reaction is carried out under alkaline conditions (e.g., at pH > 9.1) to maintain a high effective concentration of cyanide... 

The Wohl deffvdation, an alternative to the Ruff d radation, is nearly the reverse of the Kiliani-Fischer synthesis. The aldose carbonyl group is converted to the oxime, which is dehydrated by acetic anhydride to the nitrile (a cyanohydrin). Cyanohydrin formation is reversible, and a basic hydrolysis allows the cyanohydrin to lose HCN. Using the following sequence of reagents, give equations for the individual reactions in the Wohl degradation of D-arabiiK>se to D-erythrose. Mechanisms are not required. 

Other reactions of carbohydrates include those of alcohols, carboxylic acids, and their derivatives. Alkylation of carbohydrate hydroxyl groups leads to ethers. Acylation of their hydroxyl groups produces esters. Alkylation and acylation reactions are sometimes used to protect carbohydrate hydroxyl groups from reaction while a transformation occurs elsewhere. Hydrolysis reactions are involved in converting ester and lactone derivatives of carbohydrates back to their polyhydroxy form. Enolization of aldehydes and ketones leads to epimerization and interconversion of aldoses and ketoses. Addition reactions of aldehydes and ketones are useful, too, such as the addition of ammonia derivatives in osazone formation, and of cyanide in the Kiliani-Fischer synthesis. Hydrolysis of nitriles from the Kiliani-Fischer synthesis leads to carboxylic acids. 

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