Synthesis of Enantiopure Cyanohydrins

Chiral cyanohydrins have been synthesized by a number of routes, which differ mainly in the form in which HCN enters the molecules and in the source of chirality. 

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Poechlauer, P., Skranc, W. and Wubbolts, M. (2004) The large-scale biocatalytic synthesis of enantiopure cyanohydrins, in Asymmetric Catalysis on Industrial Scale (eds H.-U. Blaser and E. Schmidt), Wiley-VCH Verlag GmbH, pp. 151-164. 

Chiral cyanohydrins are versatile intermediates in the synthesis of a-hydroxy acids, /3-amino alcohols, amino nitriles, a-hydroxy ketones and aziridines. For the synthesis of enantiopure cyanohydrins, the use of hydroxynitrile lyases is currently the most effective approach.Application of an organic-solvent-free system allows thermodynamically hindered substrates to be converted with moderate to excellent yields. With the use of the highly selective hydroxynitrile lyase from Manihot esculenta, the syntheses of several acetophenone cyanohydrins with excellent enantioselectivities were developed (Figure 8.2). (5)-Acetophenone cyanohydrin was synthesized on a preparative scale. ... 

OECD Report, The Application of Biotechnology to Industrial Sustainability, 2001, http //www. Loecd.org/publications/e-book/9301061e.pdf Panke, S., Held, M., and Wubbolts, M. Curr. Op. Biotech. 2004, 35, 272-279 Plomp, P., de Boer, L., van Rooijen, R., and Meima, R. 2004, Patent WO 04/030468 Pochlauer, P., Skranc, W., and Wubbolts, M. The large-scale biocatalytic synthesis of enantiopure cyanohydrins in Asymmetric Catalysis on Industrial Scale, H. U. Blaser, and E. Schmidt (Eds.), Wiley-VCH, Weinheim, 2004,151-164 Schmid, A., Dordick, J. S., Hauer, B., Kiener, A., Wubbolts, M., and Wifholt, B. Nature,... 

The large-scale biocatalytic synthesis of enantiopure cyanohydrins,... 

The Large-Scale Biocatalytic Synthesis of Enantiopure Cyanohydrins... 

The enzymatic synthesis of enantiopure cyanohydrins has been brought to a high stage of development. Both (R)- and (S)-cyanohydrins are accessible for a broad variety of substrates in as a rule excellent yield and enantiopurity. Following recent progress in overexpression, HNLs are also available in quantities needed for industrial production. The procedures for safe handling of cyanides are well established so that they do not restrict the exploitation of HNLs. 

Hydroxynitrile-lyase-catalysed Synthesis of Enantiopure (5)-Acetophenone Cyanohydrins... 

Interest in the synthesis of enantiopure 2-hydroxycarboxylic acids via asymmetric enzymatic transformations is still increasing and two pathways have risen into prominence recently. The first is based on enantioselective hydrocyanation of the appropriate aldehyde in the presence of an oxynitrilase (hydroxynitrile lyase, EC 4.1.2.10), which gives rise to the corresponding enantiomerically pure cyanohydrin, followed by chemical hydrolysis in the presence of strong acid (Figure 16.1, route a). This latter step generates copious quantities of salt and is not compatible with sensitive functional groups, which is a serious limitation. 

Hydroxynitrile lyases (HNLs or oxynitrilases) catalyze C—C bond-forming reactions between an aldehyde or ketone and cyanide to form enantiopure cyanohydrins (Figure 1.15), which are versatile building blocks for the chiral synthesis of amino acids, hydroxy ketones, hydroxy acids, amines and so on [68], Screening of natural sources has led to the discovery of both... 

Enantiopure Cyanohydrins as Intermediates for the Synthesis of Bioactive Compounds... 

Oxynitrilases are enzymes that catalyze the formation and cleavage of cyanohydrins through the stereoselective addition of hydrogen cyanide to aldehydes or methyl ketones giving enantiopure a-hydroxynitriles. The use of (R)-oxynitrilases for the preparation of chiral cyanohydrins has dramatically grown in the last decade because of their possibihties as precursors for the synthesis of many compounds with physiological properties [50]. 

In these synthesis, the optically active (R)-cyanohydrin is transformed into the corresponding a-hydroxy carboxylic ester and the hydroxyl funchon is achvated by sulfonylahon. The treatment of the corresponding intermediate with tetra-hydrothieno[3,2-c]pyridine stereoselectively yields the (S)-configured clopidogrel (Scheme 10.23). In the second case, a mutant of the recombinant almond (Pmnus amigdalus) (R)-oxynitrilase isoenzyme 5 catalyzes the formation of enantiopure (R)-2-hydroxy-4-phenylbutyronitrile [54]. Reaction of the sulfonylated hydroxyester derivative with the corresponding dipeptide leads to the formation of enalapril or lisinopril (Scheme 10.24). 

Alternatively, enantiopure 2-hydroxycarboxylic acids can be obtained via a dynamic kinetic resolution of the (chemically synthesized) cyanohydrin in the presence of an enantioselective nitrilase (EC 3.5.5.1) (see Figure 16.1, route b). Racemization of the cyanohydrin, via reversible dehydrocyanation, takes place readily at pH 7 or above. The methodology [1] is attractive on account of the mild reaction conditions and is industrially applied in the multiton-scale synthesis of (R)-mandehc acid [2]. 

The toolbox of catalyst systems for enantiopure cyanohydrin synthesis comprises racemate resolutions (yielding 50% of the desired product), dynamic kinetic race-mate resolutions (enantioselective derivatization and racemization of the non-deri-vatized starting material, yielding 100% of the desired product) and enantioselective synthesis (yielding 100% of the desired product). Fig. 5 gives an overview of the different catalysts. Advantages and disadvantages of the four methods outlined in Fig. 5 are summarized in Tab. 1. 

One of the major issues that need to be controlled is the nonspecific chemical addition of HCN to the substrate, which negatively impacts the enantiopurity of the product, as enantiopurity is the result of the ratio of enzymatic to nonenzymatic cyanohydrin formation. This nonenz3unatic background reaction is pH and temperature dependent performing the conversions at low pH values (<4-5) and low temperature (5-8 °C) allows the suppression of the xmdesired racemic product formation, thereby enabling the synthesis of cyanohydrins with higher enantiopurity. However, as an aqueous... 

Bencze, LC, Paizs, C, Tosa, MI, Vass, E, Irimie, FD. Synthesis of enantiomerically enriched (R)- and (S)-benzofuranyl-and benzo[b]thiophenyl-l,2-ethanediols via enantiopure cyanohydrins as intermediates. Tetrahedron Asymm. 2010 21 443 50. 

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