Kiliani cyanohydrin synthesis

On applying the Kiliani cyanohydrin synthesis to 2 deoxy-i>-erythro-pentose, Wood and Fletcher127 obtained crystalline 3-deoxy-D-ribo-hexose and 3-deoxy-D-arabino-hexose (as the dithioacetal). Interesting comments concerning the course of the Kiliani synthesis were made by these authors. Condensation127 of 2-deoxy-D-erj/(Aro-pentose with nitromethane gave epimeric 1,3-didcoxy-l-nitrohexitols which, after hydrolysis under Nef... 

Other carbonyl compounds carrying a second functional group undergo this reaction, e.g., acrolein, chloroacetone, -hydroxybenzaldehyde, acetoacetic ester, and -dimethylaminobenzaldehyde. The method is important in the synthesis of sugars (Kiliani cyanohydrin synthesis). ... 

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... 

Methods for lengthening the carbon chains of sugars may involve the formation of aldonic acids as intermediates. The Kiliani cyanohydrin synthesis (see p. 106) creates two new aldonic acids with one more carbon atom than in the original aldose. The configuration of the new asymmetric atom can be assigned by use of the lactone rule discussed below. 

Synthesis From Lower Aldoses. The Kiliani cyanohydrin synthesis has been discussed elsewhere (see p. 106). In this method a new asymmetric center is created, and two epimeric acids are formed in varying amounts 10a). 

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. 

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. 

The cyanohydrin synthesis has been applied in the study of the sugars by H. Kiliani, who used it in the synthesis of higher members of the class. The carboxylic adds which result from the hydrolysis of the nitriles can be reduced, in the form of their lactones, to the corre-... 

It is of some historical interest that Kiliani s cyanohydrin synthesis (24) enabled Emil Fischer (25) to carry out the first asymmetric synthesis. Lapworth (26) used this base-catalyzed nucleophilic 1,2-addition reaction in one of the first studies of a reaction mechanism. Bredig (27,28) appears to have been the first to use quinine (29) in this reaction as the chiral basic catalyst. More recently, others (20) have used basic polymers to catalyze the addition of cyanide to aldehydes. The structure of quinine has been known since 1908 (30). Yet it is of critical importance that Prelog s seminal work on the mechanism of this asymmetric transformation (eq. [4]) could not have begun (16) until the configuration of quinine was established in 1944 (31,32). 

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. 

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. 

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 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 synthesis of D-psicose as a colorless sirup ([< ]% + 3.1° in water) by Steiger and Reichstein13 may be regarded as the first authentic preparation of this ketohexose. The Kiliani-Fischer cyanohydrin synthesis furnished D-allonic lactone (VII) from D-ribose. This lactone, on reduction with sodium amalgam, gave D-allose (VIII) which was transformed into D-psicose (I) by refluxing with pyridine. Pyridine had been introduced into the Lobry de Bruyn-Van Ekenstein reaction by Fischer, Danilov and their coworkers.13 ... 

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. 

The Kiliani-Fischer synthesis, shown here beginning with D-arabinose, consists of three steps. Squiggly lines are meant to indicate that two different stereoisomers are formed at the new stereogenic center. As with the Wohl degradation, the key intermediate is a cyanohydrin. 

---