Hydrolysis of cyanohydrins

The hydrolysis of nitriles to carboxylic acids is one of the best methods for the preparation of these compounds. Nearly all nitriles give the reaction, with either acidic or basic catalysts. Hydrolysis of cyanohydrins, RCH(OH)CN, is usually carried out under acidic conditions, because basic solutions cause competing reversion of the cyanohydrin to the aldehyde and CN . However, cyanohydrins have been hydrolyzed under basic conditions with borax or alkaline borates. ... 

Reisinger, C., Osprian, I., Glieder, A. et al. (2004) Enzymatic hydrolysis of cyanohydrins with recombinant nitrile hydratase and amidase from Rhodococcus erythropolis. Biotechnology Letters, 26, 1675-1680. 

Osprian, 1., Fechter, M.H. and Griengl, H., Biocatal3ftic hydrolysis of cyanohydrins an efficient approach to enantiopure a-hydroxy carboxylic acids. J. Mol. Catal. B Enzymatic, 2003,24-25, 89-98. 

Hydrolysis of cyanohydrins 6-16 Reaction between aldehydes, ammonia. and carboxylic acids or esters 6-50 Addition of cyanide and ammonium ions to aldehydes or ketones, followed by hydrolysis (Strecker)... 

A more generally satisfactory method is the hydrolysis of cyanohydrins. Here a mixture of the carbonyl compound and aqueous sodium cyanide is gradually acidified at room temperature resulting in the sequential formation of the cyanohydrin and its subsequent hydrolysis to the acid (the cyano group is of course a latent carboxyl group). 

Figure 7.8 a) Enzymatic (oxynitrilase-catalyzed) formation of cyanohydrins from aldehydes, b) Chemical hydrolysis of cyanohydrins to hydroxy acids. 

Lipases have been used to effect the enantioselective esterification of cyanohydrins or the enantioselective hydrolysis of cyanohydrin esters. This works for aldehyde cyanohydrins. Selective (S)-cyanohydrin esterification is effected by the enzyme from Pseudomonas sp. [11], There is also an example of selective (R)-cyanohydrin esterification by Candida cylindracea lipase [12]. Effenberger has shown the feasibility of this approach in principle to produce a number of enantiopure cyanohydrins derived from aldehydes. In situ derivatization with racemization as shown in Fig. 7 is possible, resulting in theoretically 100% yield of the desired enantiomer [13]. Ketone cyanohydrins, which are tertiary alcohols, do not easily undergo this reaction. 

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... 

By hydrolysis of cyanohydrins and other nitriles. We saw, in Section 16.9, that aldehydes and ketones can be converted to cyanohydrins and that these can be hydrolyzed to ct-hydroxy acids. In the hydrolysis the —CN group is converted to a — CO2H group. The mechanism of nitrile hydrolysis is discussed in Section 17.8H ... 

The preparation of cyanohydrins is an important reaction in organic synthesis because it is used to lengthen the hydrocarbon chain by one C-atom the molecule of 1-cyanopropanol in the scheme above has one carbon atom more than the starting propanal. Some cyanohydrins are natural products, especially the derivatives of benzaldehyde, which are poisonous and used by particular insects for their defense. The toxic activity of these compounds is based on the hydrolysis of cyanohydrins into benzaldehyde and highly toxic HCN. 

Scheme 2.70 Hydrolysis of cyanohydrin esters using microbial lipases...

In 2003, Griengl s group reported the hydrolysis of cyanohydrins by treatment with bacterial cells of Rhodococcus erythropolis NCIMB 11540, which have a highly active nitrile hydratase/amidase enzyme system. In this manner, (R)-2-chloromandelic acid and (R)-2-hydroxy-4-phenylbutyric acid, two important pharmaceutical intermediates, could be prepared in high optical and chemical yield after short reaction times (3 and 1.5 h, respectively) (Scheme 3.43). 

Hydrolysis of cyanohydrins, which are obtained by the addition of HCN to an aldehyde or a ketone (Section 16.5D), provides a valuable way to create a-hydroxy-carboxylic acids, as illustrated by the synthesis of mandelic acid. 

Lipase-Catalyzed Hydrolysis of Cyanohydrin Acetates. Hydrolytic enzymes, especially lipases, are widely used for enantioselective transformations, and have been used to prepare optically active cyanohydrins. For example, the lipase-catalyzed kinetic resolution of racemic w-phenoxybenzaldehyde cyanohydrin acetate was an essential step in the synthesis of (li ,ci5,aiS)-cypermethrine 19). Another recent report described the lipase-catalyzed kinetic resolution of pentafluorobenzaldehyde cyanohydrin acetate 20). To examine this approach, 2- and 6-fluoro-3,4-dibenzyloxybenzaldehyde cyanohydrin acetates (12b,d) were prepared from the aldehydes 10b,d. Preliminary attempts to carry out lipase-catalyzed kinetic resolutions of Aese cyanohydrin acetates were unsuccessfiil (unpublished results). 

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