Cyanohydrins esters

Very few optically active cyanohydrins, derived from ketones, are described in the literature. High diastcrcosclectivity is observed for the substrate-controlled addition of hydrocyanic acid to 17-oxosteroids27 and for the addition of trimethyl(2-propenyl)silane to optically active acyl cyanides28. The enantioselective hydrolysis of racemic ketone cyanohydrin esters with yeast cells of Pichia miso occurs with only moderate chemical yields20. 

Leroy, E Bensel, N. and Reymond, J.L (2003) Fluorogenic cyanohydrin esters as chiral probes for esterase and lipase activity. Advanced Synthesis Catalysis,... 

Oxidation of a cyanohydrin derived from a conjugated aldehyde (as the 0-TMS derivative) using py-ridinium dichromate (PE)C) in DMF gave an a,3-unsaturated lactone (5 -butenolide) as the major product (equation 12). Simple nonconjugated cyanohydrins are not satisfactory substrates for the synthesis of acyl cyanides using PDC, because they seem to add to the initially formed acyl cyanides, leading ultimately to cyanohydrin esters. Oxidation of cyanohydrin to acyl cyanides can be carried out either by means of manganese dioxide, ruthenium-catdyzed oxidation with t-butyl hydroperoxide or NBS. ... 

Acid-catalyzed addition of aliphatic, aromatic or heteroaromatic cyanohydrins to ethyl vinyl ether, n-butyl vinyl ether or dihydro-4//-pyran provides base stable, protected cyanohydrin derivatives. Phase transfer catalyzed alkylation of aliphatic cyanohydrins with allylic bromides gave a-substituted a-allyl-oxyacetonitrile. Carbonyl compounds react wiA cyanide under phase transfer catalysis to give cyanohydrin anions, which are trapped by an acyl chloride or ethyl chloroformate to give acyl- or alkoxycarbonyl-protected cyanohydrins respectively. The reduction of the carbonyl group of an acyl cyanide by NaBH4 under phase transfer conditions followed by esterification serves as an alternative route to aldehyde-derived cyanohydrin esters. ... 

Other possibilities to prepare chiral cyanohydrins are the enzyme catalysed kinetic resolution of racemic cyanohydrins or cyanohydrin esters [107 and references therein], the stereospecific enzymatic esterification with vinyl acetate [108-111] (Scheme 2) and transesterification reactions with long chain alcohols [107,112]. Many reports describe the use of fipases in this area. Although the action of whole microorganisms in cyanohydrin resolution has been described [110-116],better results can be obtained by the use of isolated enzymes. Lipases from Pseudomonas sp. [107,117-119], Bacillus coagulans [110, 111], Candida cylindracea [112,119,120] as well as lipase AY [120], Lipase PS [120] and the mammalian porcine pancreatic lipase [112, 120] are known to catalyse such resolution reactions. 

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. 

Esterase or lipase as catalyst. Application of hydrolytic enzymes is realized in three different systems enzymatic hydrolysis or transesterification of racemic cyanohydrin esters (see Figure 14.7-4.) as well as enzymatic acylation of racemic cyanohy-... 

Cyanohydrin esters. Reaction of acyl cyanides with aldehydes in the presence of... 

K2CO3 in aqueous acetonitrile leads to a-cyanohydrin esters. 

But what do we do if we want the product of a ketene [4 + 2] cycloaddition We must use a compound that is not a ketene but that can be transformed into a ketone afterwards—a masked ketene or a ketene equivalent. The two most important types are nitroalkenes and compounds such as the cyanohydrin ester in the second example. 

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

A similar methodology was applied by the same group to the preparation of novel phenylfuran-based cyanohydrin esters by using Pseudomonas cepacia lipase and vinyl butanoate as the acylating agent. The results are summarised in Scheme 3.25. 

In the context of these studies, the same group has demonstrated that the synthesis of cyanohydrin esters via DKR was highly dependent on the carrier of the enzyme. The carrier influenced the amount of water available in the reaction mixture, suppressing or enhancing the undesired hydrolysis of the acyl donor and the final product. Indeed, the DKR proved to be prone to residual water. However, when the hpase was immobilised on cehte as a carrier, the celite absorbed the water and suppressed the water-induced side reactions. Thereby, the enantioselectivity and the reaction times (3 10 days without cehte) for this DKR were improved, enabling a nearly enantiospecific and high-yielding synthesis of mandelonitrile acetate (Scheme 3.28). 

Figure 11 - Synthesis of cyanohydrin esters and amino nitriles...

In an acetonitrile suspension, the intermediate a-cyanoalkoxide can be trapped by acyl chlorides to give cyanohydrin esters. In a preparation of synthetic pyrethroids, the comparison between the sonicated reaction and its PTC equivalent gave an advantage to the latter in terms of reaction time and yield. i A modest change in stereoselectivity is observed in some cases. The same reaction in the presence of ammonium chloride leads to a-amino nitriles, the first step of the Strecker amino acid synthesis.4 72 xhe procedure is more efficient in the presence of alumina. The formation of by-products, cyanohydrins or benzoins, is avoided. From an experimental viewpoint, the work-up is considerably easier than with conventional procedures, and consists mostly of a simple filtration. With ketones, and in the presence of ammonium carbonate, a hydantoin is formed (Eq. 21)7 ... 

Sonosynthesis of cyanohydrin esters from aldehydes, acylating agent, and solid potassium cyanide in acetonitrile is a useful method as a substitute for liquid-liquid phase transfer catalyzed reactions. This method is applicable for the preparation of pyrethroid insecticides such as Cyphenothrin or Fenvalerate . 

During the generation of the cyanohydrine esters e.g. 373 and 375 under the conditions outlined above, different amounts of diastereomeric pairs of esters 373 are produced [816] in a kinetically and thermodynamically controlled manner, depending on the applied racemic acid chloride, thus deviating from the statistically expected 1 1 ratio in case of fenvalerate (Reaction scheme 257 a). 

Only racemate II contains the insecticidally active S-S -isomer. Theoretically it is possible, that a peculiar stereoselectivity predominates, leading to the preferential formation of the uninteresting racemate I. In case of the epimerizable cyanohydrine esters 373 and others the kinetically controlled primary isomeric ratio can be changed afterwards by thermodynamic equilibration. 

Single Optically Active Cyanohydrine Ester-Isomers... 

Cyanohydrin esters are prepared by the reduction of acyl cyanides with sodium borohydide in the presence of an acylating agent. " If no acylating agent is present, unreacted acyl cyanide serves this purpose. 

General Synthesis and Reactions.—Linear primary alcohols with at least seven carbon atoms are transformed into esters in high yield using copper oxide at temperatures above 170 C in the liquid phase. RusfCO) catalyses the conversion of an aldehyde, or an alcohol with the same number of carbon atoms, into an ester in the presence of diphenylacetylene. " The carbonylation of organic halides in the presence of cyclic ethers is catalysed by PhPdI(PPh3)2 , it provides a synthesis of halohydrin esters in reasonable yield. Cyanohydrin esters have been synthesized by the sodium borohydride reduction of acyl cyanides in the presence of tetra-n-butylammonium bromide. ... 

Acyl cyanides are the starting materials for a new synthesis of cyanohydrin esters via a two-phase reduction with sodium borohydride in the presence of tetra-n-butylammonium bromide. 

The formation of aldehyde cyanohydrin esters has been achieved under phase transfer catalytic conditions in which the two liquid phases are aqueous sodium or potassium cyanide and a methylene chloride solution of an aromatic aldehyde and an acid chloride. Both quaternary ammonium salts and 18-crown-6 are effective catalysts in this reaction. The formation of aldehyde cyanohydrin esters according to equation 7.7 probably occurs by a mechanism similar to that proposed for the formation of benzoyl cyanide dimers (see Eq. 7.5) [3, 22]. Accordingly, cyanide anion adds to the aldehyde carbonyl group to yield an alkoxide anion which in turn is acylated by the acid chloride. 

The racemization of the unreacted substrate can be accomplished either by spontaneous equilibration between the two enantiomers or by using a chemical or biological catalyst. The basic requirements for a successful DKR are that (i) the KR conditions must be compatible with the racemization process, (ii) the KR process must be very stereoselective, (iii) the catalyst for the racemization must not react with the product, and (iv) the racemization must be faster than the reaction of the slow reacting enantiomer k c 2> ksiow [la,b]. The concept of DKR has been applied to a variety of compounds such as a-amino acids, hemithioacetal esters, a-(hetero) arylcarboxylic acids, a-substituted nitriles, beta-keto esters, cyanohydrin esters, a-substituted thioesters, 4-substituted oxazolin-5-ones and thiazolin-5-ones [la]. 

Veum L, Kanerva LT, Hailing PJ, Maschmeyer T, Hanefeld U. Optimisation of the enantioselective synthesis of cyanohydrin esters. Adv. Synth. Catal. 2005 347 1015-1021. 

Paizs C, Tahtinen P, Lundell K, Poppe L, Irimie F-D, Kanerva LT. Preparation of novel phenylfuran-based cyanohydrin esters hpase-catalysed kinetic and dynamic resolution. Tetrahedron Asymm. 2003 14 1895-1904. 

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