Kiliani method

This simple reaction has introduced an extra carbon atom into the original molecule. Furthermore, this extra carbon is contained within a functional group that may be subsequently developed, for instance, by hydrolysis to reveal a carboxylic acid functionality, or by reduction to an amine. This synthetic route is the basis of the Kiliani method for extending the carbon chain of a sugar. 

Kiliani method Used in carbohydrate chemistry to extend the length of the carbon chain by one carbon atom. Following the formation of a cyanohydrin of the corresponding ketone, the nitrile group is then hydrolysed to give the a-hydroxycarboxylic acid. 

During the synthesis of n-apiose, 3-0-benzyl-n-fructose was treated in the same way (Kiliani method), and a crystalline 3-0-benzyl lactone was formed (m.p. 150-152°). Reduction by means of sodium borohydride gave the branched-chain heptitol (75), showing that this method provides an interesting tool for the synthesis of branched-chain sugars. - ... 

A simpler and more efficient version of the traditional Kiliani method has been used to prepare [6- C]-labelled hexoses. K CN was added to 1,2-Q-isopropylidene-a-D-xylo-pentodialdo-l,4-furanose. Hydrogenation of the adducts and in situ borohydride reduction followed by deprotection gave D-[6- C]glucose and L-[6- C]idose, which were separable on a DOWEX 50 x 8 (Ca " ) column-Molybdate epimerisation of these products afforded D-[6-... 

A rapid, high yield synthesis of C-enriched intermediates of the pentose-phosphate pathway has been developed based on a combination of chemical and enzymic reactions. [l- C]Ribose and [l- C]arbinose 5-phospha,tes, available by the classical Kiliani method, were converted to a variety of specifically labelled 5-, 6-, 7-, and 8-carbon sugar phosphates (e.g.. D-erythro-pentulosc 5-phosphate, sedoheptulose mono- and di-phosphates) with the help of aldolase, transaldolase, and transketolase. ... 

Digoxin is a crystalline glycoside obtained from Digitalis lanata and no assay is required in the standard of the B.P, For the injection and tablets, however, application is made of the Keller-Kiliani reaction. The U.S,P, assays Digoxin by an application of the w-nitrobenzene reaction and a similar method, based on the work of Honk et al. has been adopted by the A.O.A.C, For the assay of digoxin injection and tablets the IJ.S.P. also uses the Keller-Kiliani method. Suitable examples of the m-dinitrobenzene and Keller-Kiliani methods are given below ... 

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... 

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. 

Discovery of the chain-lengthening sequence was initiated by the observation of Heinrich Kiliani in 1886 that aldoses react with HCN to form cyanohydrins (Section 19.6). Emil Fischer immediately realized the importance of Kiliani s discovery and devised a method for converting the cyanohydrin nitrile group into an aldehyde. 

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. 

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. 

The carbon-chain structure of the sugar obtained from hamameli-tannin was established by the classical method of Kiliani,26 which is based on the reduction, with hydrogen iodide, of polyhydroxy acids to fatty acids. Treatment of the calcium salt of hamamelonic acid under these conditions led to inconclusive results. The reduction of the corresponding, crystalline ammonium salt, however, furnished 3.5 to 5% of 2-methylvaleric acid, which was identified by the properties of its crystalline p-iodophenacyl ester. Thus, it was proved that the sugar must have structure XIV. 

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. 

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. 

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. 

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 ... 

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