Hydroxynitrile lyases keton

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... 

The hydroxynitrile lyase (HNL)-catalysed cyanohydrin reaction is a useful method to synthesize enantiopure a-hydroxy nitriles and the corresponding a-hydroxy acids. However, small ketones, such as 2-butanone, are converted with low selectivities, due to the poor discrimination between methyl and ethyl. ... 

Selective Cyanohydrin Formation from Aromatic Ketones Using Hydroxynitrile Lyases... 

The production of optically active cyanohydrins, with nitrile and alcohol functional groups that can each be readily derivatized, is an increasingly significant organic synthesis method. Hydroxynitrile lyase (HNL) enzymes have been shown to be very effective biocatalysts for the formation of these compounds from a variety of aldehyde and aliphatic ketone starting materials.Recent work has also expanded the application of HNLs to the asymmetric production of cyanohydrins from aromatic ketones. In particular, commercially available preparations of these enzymes have been utilized for high ee (5)-cyanohydrin synthesis from phenylacetones with a variety of different aromatic substitutions (Figure 8.1). 

Roberge, C., Fleitz, F., Pollard, D. and Devine, P., Synthesis of optically active cyanohydrins from aromatic ketones evidence of an increased substrate range and inverted stereoselectivity for the hydroxynitrile lyase from Linum usitatissimum. Tetrahedron Asymm., 2007,18, 208. 

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. ... 

Chiral hydroxynitriles are useful synthetic intermediates. They can be prepared using errzymatic synthesis in reactions between aldehydes or ketones and hydrogen cyanide (Griengl et al., 1997) (Figme 9.10). There are different kinds of ertzymes (hydroxynitrile lyases) catalysing the formation of the (R)- and the (S)-enantiomers, respectively. It is a problem that the reactants can react spontaneously as well. 

The hydroxynitrile lyase (HNL) class of enzymes, also referred to as oxynitrilases, consists of enzymes that catalyze the formation of chiral cyanohydrins by the stereospecific addition of hydrogen cyanide (HCN) to aldehydes and ketones (Scheme 19.36).275 279 These chiral cyanohydrins are versatile synthons, which can be further modified to prepare chiral a-hydroxy acids, a-hydroxy aldehydes and ketones, acyloins, vicinal diols, ethanolamines, and a- and P-amino acids, to name a few.280 Both (R)- and (.S )-selective HNLs have been isolated, usually from plant sources, where their natural substrates play a role in defense mechanisms of the plant through the release of HCN. In addition to there being HNLs with different stereo-preferences, two different classifications have been defined, based on whether the HNL contains a flavin adenine dinucleotide (FAD) co-factor. 

Dihydroxyacetone phosphate (DHAP) is the donor ketone that is utilized by the DHAP-dependent aldolases. These aldolases come under the class of lyases, just like the hydroxynitrile lyases (see Section 5.2.1.1). As for the HNLs, no cofactor... 

Oxynitrilases or hydroxynitrile lyases (HNL) constitute a group of enzymes that catalyze the reversible addition of HCN to ketones and aldehydes. The natural role of these enzymes is a defence mechanism of higher plants against herbivores, whereby HCN is liberated from cyanoglucosides such as prunasin (almond, cherry, apple) by the action of a glycosidase and a hydroxynitrile lyase. 

The reason why these enzymes have received considerable attention over the years is that they display a high degree of enantiotopic selectivity on the prochiral aldehyde and ketone substrates. The selectivity of these enzymes is in many instances masked by the rate of spontaneous racemization of the cyanohydrins, which are prone to racemization under non-acidic conditions. This balance of selectivity of the enzymes versus the competition with the spontaneous racemization reaction as a function of the pH was described as early as 1921 using the hydroxynitrile lyase enzyme from peach leaves [22], These early experiments describe one of the challenges of applying hydroxynitrile lyases on an industrial scale. 

Hydroxynitrile lyase enzymes catalyze the asymmetric addition of hydrogen cyanide onto a carbonyl group of an aldehyde or a ketone thus forming a chiral cyanohydrin [1520-1524], a reaction which was used for the first time as long ago as 1908 [1525]. Cyanohydrins are rarely used as products per se, but they represent versatile starting materials for the synthesis of several types of compounds [1526] ... 

The stereoselectivity of the hydroxynitrile lyase (HNL) catalysed cyanohydrin formation of monosubstituted cyclic ketones is of general interest for the synthesis of biologically active compounds. In the course of a systematic investigation of the stereoselectivity of HNL-catalysed addition of HCN to a variety of monosubstituted cyclopentanones, Kobler and Effenberger observed a DKR for the addition of HCN to alkyl 2-oxocyclopentanecarboxylates... 

Figure 11.12 Possible pathways for the synthesis of higher value chemicals from ketones and aldehydes using hydroxynitrile lyase in a cascade reaction. R, and Rj = H, alkyl, aryl.

Like the benzoxazinones, cyanogenic glucosides belong to the preformed defense of the plant and are stored in the vacuole. Upon disruption of the plant tissue, they are degraded by P"glucosidases to the corresponding a-hydrox-ynitriles, which are hydrolyzed by a-hydroxynitrile lyases to aldehydes or ketones and toxic hydrogen cyanide (HCN) (Fig. 13). Since the a-hydroxynitriles are unstable, they can also... 

Cyanohydrin formation Aldehyde or ketone 2-Hydroxy nitrile Synthesis of 2-hydroxy nitriles Oxynitrilase (Hydroxynitrile lyase)... 

Enzymes of the hydroxynitrilase dass catalyze the addition of HCN to aldehydes, produdng cyanohydrins. Recendy, the reaction has been extended to a few ketones with modified hydroxynitrilase enzymes. In many cases, these are formed with good optical purities and such reactions are the simplest type of enzyme catalyzed carbon-carbon bond formation. By pairing hydroxynitrile lyases with nitrilases or nitrile hydratases, one-pot, multistep conversions become possible, and this also shifts the equilibrium to favor the addition products. Such concerns are particularly important when applying these catalysts to ketones where the equilibrium generally favors the starting carbonyl compound (Figure 1.17). 

Most of the aforementioned hydroxynitrile lyases are able to catalyze the addition of HCN to ketones to furnish (R)- or (S)-ketone cyanohydrins (Table 10.3). Using PflHnL as catalyst, alkyl methyl ketones gave moderate yields and high optical purities, whereas with alkyl ethyl ketones the)fields and optical purities were lower [39,42]. The substrate scope has been extended to methyl phenyl ketones, cyclic, bicyclic, heterocyclic, as well as silicon-containing compounds [16]. Concerning (S)-ketone cyanohydrins, excellent results were achieved with aliphatic and aromatic ketones, for example, acetophenone cyanohydrin, using (S)-HbHnL (40% conversion, 99% ee.. Table 10.3) or (S)-MeHnL (87% conversion, 98% ee... 

Historically, enzyme catalysis has played a highly prominent role, with the first enzyme-catalyzed asymmetric addition of HCN to aldehydes dating back to 1908 [167]. A wide range of both aromatic and aliphatic ketones are suitable substrates and produce cyanohydrins of high optical purity. The most readily available and hence most commonly employed enzyme for asymmetric cyanohydrin formation is (R)-hydroxynitrile lyase isolated from almonds. Recent cloning and over-expression techniques have also made a number of (S)-hydroxynitrile lyases available for organic synthesis [164, 165]. This was utilized in Griengl s synthesis of coriolic acid (255), a natural product that displays calcium ionophoric activity and acts as a prostacyclin mimic (Scheme 2.32) [168]. Thus, an (S)-hydroxynitrile lyase was cloned from rubber trees (Hevea brasiliensis), overexpressed in Pichia pastoris, and used to provide cyanohydrin 254 in 99 % ee. 

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