Cyanohydrin enantioselective formation

Activation of Me3SiCN by coordination of the Si to lithium BINOL-ate as catalyst has been shown to result in the enantioselective formation of cyanohydrins 73 from aromatic and heteroaromatic aldehydes with 82-98% ee (Scheme 7.15) [71]. (For experimental details see Chapter 14.5.4). Several other groups have used dual activation with a chiral Lewis acid and a non-chiral Lewis base [72]. Asymmetric cyanosilylation of PhCOMe and its congeners has also been reported to occur in the presence of sodium phenyl glycinate as catalyst, with up to 94% ee [73],... 

Scheme 2.6 HbHNL encapsulated in an aqua gel catalyzes the enantioselective formation of S-cyanohydrins.

When certain cyclodipeptides are used as catalysts for the enantioselective formation of cyanohydrins, an autocatalytic improvement of selectivity is observed in the presence of chiral hydrocyanation products [80]. A commercial process for the manufacture of a pyrethroid insecticide involving asymmetric addition of HCN to an aromatic aldehyde in the presence of a cyclic dipeptide has been described [80]. Besides HCN itself, acetone cyanohydrin is also used (usually in the literature referred to as the Nazarov method), which can be activated cata-lytically by certain lanthanide complexes [81]. Acetylcyanation of aldehydes is described with samarium-based catalysts in the presence of isopropenyl acetate cyclohexanone oxime acetate is hydrocyanated with acetone cyanohydrin as the HCN source in the presence of these catalytic systems [82]. 

Brusse J, vrm der Gen A (2000) Biocatalysis in the enantioselective formation of chiral cyanohydrins, vrduable building blocks in organic synthesis. In Patel RN (ed) Stereoselective biocatalysis. Marcel Dekker, New York/Basel, pp 289-320... 

Emil Fischer s result involving cyanide additions to carbohydrates had demonstrated the power of diastereoselective synthesis early as the 1890s (Equation 1) [4, 34,162]. The corresponding enantioselective formation of cyanohydrins has been the subject of immense efforts. It has long been appreciated that optically active cyanohydrins are synthetically useful intermediates that can be elaborated into a number of chiral building blocks, such as hydroxy acids. In general, there are three main classes of catalysts for the preparation of chiral cyanohydrins enzymes, cyclic dipeptides, and transition metal complexes [163-166]. 

Biocatalysis in the Enantioselective Formation of Chiral Cyanohydrins, Valuable Building Blocks in Organic Synthesis... 

Diels-Alder reaction of 2-bromoacrolein and 5-[(ben2yloxy)meth5i]cyclopentadiene in the presence of 5 mol % of the catalyst (35) afforded the adduct (36) in 83—85% yield, 95 5 exo/endo ratio, and greater than 96 4 enantioselectivity. Treatment of the aldehyde (36) with aqueous hydroxylamine, led to oxime formation and bromide solvolysis. Tosylation and elimination to the cyanohydrin followed by basic hydrolysis gave (24). 

Figure 19 Enantioselective cyanohydrin formation using hydroxynitrile lyase in...

Until 1987, the (R)-PaHNL from almonds was the only HNL used as catalyst in the enantioselective preparation of cyanohydrins. Therefore, it was of great interest to get access to HNLs which catalyze the formation of (5 )-cyanohydrins. (5 )-SbHNL [EC 4.1.2.11], isolated from Sorghum bicolor, was the first HNL used for the preparation of (5 )-cyanohydrins. Since the substrate range of SbHNL is limited to aromatic and heteroaromatic aldehydes as substrates, other enzymes with (5 )-cyanoglycosides have been investigated as catalysts for the synthesis of (5 )-cyanohydrins. The (5 )-HNLs from cassava (Manihot esculenta, MeHNL) and from Hevea brasiliensis (HbHNL) proved to be highly promising candidates for the preparation of (5 )-cyanohydrins. Both MeHNL and HbHNL have been overexpressed successfully in Escherichia coli, Saccharomyces cerevisiae and Pichia pastoris. 

Recent work [64] by Kiljunen and Kanerva has been directed towards the search for novel sources of (R)-oxynitrilases which may transform bulky aryl aldehydes. For this purpose whole cell preparations (called meal) from apple seeds and cherry, apricot and plum pips were tested for their (R)-cyanohydrin activity. In this study a comparison of almond and apple meal showed that they possess similar properties for the formation of the (R)-stereogenic centre. However, in certain cases higher enantioselectivity was observed using the apple meal preparation. Additionally, apple meal (R)-Hnl has also been applied to transform ketones into their corresponding cyanohydrins [65] thus creating a wider repertoire of substrates for this latest of (R)-Hnls. Thus it has only recently been shown that apple meal (R)-oxynitrilase is now an additional member of the (R)-Hnl family. 

Scheme 5. Selective (S)-cyanohydrin formation by enantioselective decomposition of a racemic mixture...

When complexation was carried out in MeOH, a 1 1 1 complex of the host, (—)-37 and MeOH was formed. Distillation in vacuo gave (—)-37 in 42% ee and 44% yield. In the case of complexes formed by the host 28, the large hydrophobic void space can competitively include a disordered toluene molecule or (—)-cyanohydrin [48], (S,S)-(—)-6, which in the solid state forms much smaller hydrophobic cavities, could not resolve rac-36 in either solvent. Under the same conditions, however, it successfully resolved rac 3-acetylcyclohex-2-enol, 38, forming 1 2 complexes in both solvents. From these (+)-38 was obtained in 40 % ee and 86 % yield, and 66 % ee and 79 % yield, respectively, from toluene and MeOH solutions. The above cases suggest that each of the hosts (28, 34 and 35) contains two recognition sites-one enantioselective, located around sterically hindered OH groups, and the other nonspecific, and located in the hydrophobic cavity. If molecules of one enantiomer and a solvent compete for the enantioselective recognition site (with H-bond formation), the enantioselectivity of the host... 

Cyanohydrins are versatile building blocks that are used in both the pharmaceutical and agrochemical industries [2-9]. Consequently their enantioselective synthesis has attracted considerable attention (Scheme 5.1). Their preparation by the addition of HCN to an aldehyde or a ketone is 100% atom efficient. It is, however, an equilibrium reaction. The racemic addition of HCN is base-catalyzed, thus the enantioselective, enzymatic cyanide addition should be performed under mildly acidic conditions to suppress the undesired background reaction. While the formation of cyanohydrins from aldehydes proceeds readily, the equilibrium for ketones lies on the side of the starting materials. The latter reaction can therefore only be performed successfully by either bio- or chemo-cat-... 

A completely different enzyme-catalyzed synthesis of cyanohydrins is the lipase-catalyzed dynamic kinetic resolution (see also Chapter 6). The normally undesired, racemic base-catalyzed cyanohydrin formation is used to establish a dynamic equilibrium. This is combined with an irreversible enantioselective kinetic resolution via acylation. For the acylation, lipases are the catalysts of choice. The overall combination of a dynamic carbon-carbon bond forming equilibrium and a kinetic resolution in one pot gives the desired cyanohydrins protected as esters with 100% yield [19-22]. 

The bifunctional nature and the presence of a stereocenter make a-hydroxyketones (acyloins) amenable to further synthetic transformations. There are two classical chemical syntheses for these a-hydroxyketones the acyloin condensation and the benzoin condensation. In the acyloin condensation a new carbon-carbon bond is formed by a reduction, for instance with sodium. In the benzoin condensation the new carbon-carbon bond is formed with the help of an umpolung, induced by the formation of a cyanohydrin. A number of enzymes catalyze this type of reaction, and as might be expected, the reaction conditions are considerably milder [2-4, 26, 27]. In addition the enzymes such as benzaldehyde lyase (BAL) catalyze the formation of a new carbon-carbon bond enantioselectively. Transketolases (TK)... 

The same CALB preparation was appUed in many dynamic kinetic resolutions combining two types of catalysts with each other. In the presence of homogeneous transition metal catalysts that catalyze the racemization and heterogeneous acids or bases or immobilized transition metals Novozym 435 was not deactivated [1, 26-28]. This is all the more remarkable since the reactions catalyzed by these catalysts include redox reactions at elevated temperatures (>60°C). When Novozym 435 was applied for the enantioselective synthesis of cyanohydrin acetates (10) from aliphatic aldehydes (7), good results were achieved (Scheme 2.2) for this dynamic kinetic resolution (DKR) [29]. Here NaCN is used as the base for the dynamic racemic formation and degradation of the cyanohydrins (6 and 8). 

Enantioselective Cyanohydrin Formation. Magnesium complexes formed with the anionic semicorrin-type ligand (5) catalyze the addition of Cyanotrimethylsilane to aldehydes, leading to optically active trimethylsilyl-protected cyanohydrins. In the presence of 20 mol % of the chloromagnesium complex (9), prepared from equimolar amounts of (5) and BuMgCl, cyclohexanecarbaldehyde is smoothly converted to the corresponding cyanohydrin derivative with 65% ee. Addition of 12 mol % of the bisoxazoline (10) results in a dramatic increase of enantioselectivity to 94% ee (eq 8). Replacement of (10) by its enantiomer reduces the selectivity to 38% ee. This remarkable... 

The Lewis acid-Lewis base bifunctional catalyst 178a, prepared from Ti(Oi-Pr)4 and diol 174 (1 1), realizes highly enantioselective cyanosilylation of a variety of ketones to (R)-cyanohydrin TMS ethers (Scheme 10.241) [645]. The proposed mechanism involves Ti monocyanide complex 178b as the active catalyst this induces reaction of aldehydes with TMSCN by dual activation. Interestingly, the catalyst prepared from Gd(Oi-Pr)3 and 174 (1 2) serves for exclusive formation of (S)-cyanohy-drin TMS ethers [651]. The catalytic activity of the Gd complex is much higher than that of 178a. The results of NMR and ESI-MS analyses indicate that Gd cyanide complex 179 is the active catalyst. It has been proposed that the two Gd cyanide moieties of 179 play different roles - one activates an aldehyde as a Lewis acid and the other reacts with the aldehyde as a cyanide nucleophile. 

Generally, the use of other heterocycles besides quinoline would be considered modifications of the original Reissert protocol. This reaction has been extended to convert an acyl chloride into an aldehyde through a one-pot process by adding the acyl chloride to a solution of quinoline and hydrocyanic acid, and subsequent steam distillation of the entire mixture with sulfuric acid. In addition, the formation of the Reissert compound has been modified to occur enantioselectively using TMSCN as the nucleophilic species in the presence of a Lewis acid-Lewis base bifunctional catalyst. Moreover, tri-n-butyltin cyanide and acetone cyanohydrin are also used for the preparation of the Reissert compounds. 

Feng developed a highly enantioselective cyanosilylation of ketones catalysed by L-phenylglycine sodium salt 54 to give the corresponding cyanohydrins (Scheme 2.34). H, and Si NMR analyses suggested the possible formation of hypervalent silicate species from the carboxylate ion of 54 and trimethylsilylcyanide. Introduction of i-PrOH greatly enhanced the reactivity without a loss of enantioselectivity. 

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