Kiliani-Fischer method

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. 

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. 

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

Abb. 7.15. Kiliani-Fischer method for the homologation of aldoses to give the dia-stereomeric mixture of the next higher aldose. Three-step syntheses of this kind (here D-arabinose —> D-glucose + D-mannose) played a central role when about a hundred years ago Emil Fischer managed to determine the configuration of aldoses by chemical ( ) methods. 

A modification of the Kiliani-Fischer method for amino functionality introduction involves the condensation of free sugars with arylamines to give imines, which are treated directly with hydrogen cyanide to produce aminonitriles. Hydrogenolysis and hydrolysis of the resulting aminonitriles gives 2-amino-2-deoxyaldoses with one carbon extended [103],... 

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... 

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. 

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

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

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. 

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... 

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 ... 

A method for elongating an aldose at the aldehyde end. The aldose is converted into two epimeric aldoses with an additional carbon atom. For example, Kiliani-Fischer synthesis converts D-arabinose to a mixture of D-glucose and D-mannose. (p. 1125)... 

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). 

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