Enantioselective Formation of Cyanohydrins

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]. 

The use of metal catalysts for the synthesis of chiral cyanohydrins has also witnessed impressive developments (163, 164). In 1991, Oguni reported that the combination of Schiff base 261 with Ti(Oi-Pr)4 promotes the addition of TMSCN to aldehydes to give optically active adducts (20-96% ee. Equation 20) [172]. Incorporation of substituted salicylaldehydes as the corresponding Schiff bases in chiral ligand design has generally proven fruitful in a wide range of transformations. 

Chiral thioureas for cyano-silylation of ketones reported by Jacobsen [14] 

Shibasaki also developed tridentate ligand 277, which can either be conveniently derived from o-glucose or can be synthesized in both enantiomeric 

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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],... 

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]. 

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. 

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-... 

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). 

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

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... 

Addition to Carbonyls, Imines (Strecker-type Reactions), and Heteroaromatic Rings (Reissert-type Reactions). Cyanohydrin trimethylsilyl ethers are of significant synthetic interest as they can be transformed into a variety of multifunctional intermediates. Aldehydes and ketones can be enantioselectively converted to cyanohydrin trimethylsilyl ethers when treated with cyanotrimethylsilane in the presence of a Lewis acid and a chiral ligand. Enantioselective and/or diastereoselective formation of cyanohydrins and their derivatives has been reported and most of these reactions involve chiral ligands and metal catalysts containing Ti (eq 24), Sm (eq 25), and A1 (eq 26). ... 

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). 

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...

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 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. 

The kinetic resolution of cyanohydrins via enantioselective acylation may be converted into a dynamic process by making use of the chemical instability of cyanohydrins (Scheme 3.15) [235], Thus, racemic cyanohydrins were generated from an aldehyde and acetone cyanohydrin (as a relatively safe source of hydrogen cyanide) under catalysis by an anion exchange resin. The latter also served as catalytic base for the in-situ racemization. Enantioselective acylation using PSL and tsopropenyl acetate led to the exclusive formation of the corresponding (S)-cyanohydrin acetates in 47-91% optical purity. 

Keiji Maruoka of Kyoto University devised J. Am. Chem. Soc. 2008,130, 3728) a chiral amine that mediated the enantioselective iodination of aldehydes such as 12. Direct cyanohydrin formation dehvered 13 in high de and ee. The epoxide 14 is readily prepared in high ee from crotyl alcohol. Barry M. Trost of Stanford University loveoA Organic Lett. 2008,10, 1893) that 14 could be opened with 15, to give 16 with high regio- and diastereocontrol. 

The N,N -dioxide 98 has been reported to catalyze the formation of TMS-cyanohydrins ent-96 apparently without the need for dual activation (Scheme 15.21). However, the reaction requires a rather long time (80h) to reach completion at acceptable enantioselectivity (<73% ee) [90]. 

An enantioselective total synthesis including an HNL-catalyzed step of the pheromone vittatalactone, a novel P-lactone originally isolated from feeding male striped cucumber beetles, Acalymma vittatum was recently published. PaHNL catalyzes with high enantioselectivity (>96% ee) the formation of the (R)-cyanohydrin from crotonaldehyde 9 a key step in the synthesis of one of the two main building blocks 11 (Scheme 28.5). ... 

More recently, a number of exciting advances in catalytic enantioselective versions of the Strecker reaction have been described [19, 28]. Lipton reported in 1996 that the cyclic guanidine dipeptide 141 promotes the asymmetric addition of HCN to imines with high yields and optical purities (Equation 19) [103]. The importance of the basic guanidine moiety was borne out by comparison of 141 with the histidine analogue 143, known to be effective for enantioselective cyanohydrin formation (see Chapter 2, Section 2.9) [104]. However, 143 failed to lead to high enantioinduction in the corresponding Strecker reactions [103]. 

Shibasaki has described the use of bifunctional catalysis in asymmetric Strecker reactions, using BlNOL-derived Lewis acid-Lewis base catalyst 160 (Equation 24) [114]. The aluminum complex had previously been shown to catalyze enantioselective cyanohydrin formation (Chapter 2, Section 2.9) [115]. In the proposed catalytic cycle, the imine is activated by the Lewis acidic aluminum while TMSCN undergoes activation by association of the silyl group with the Lewis basic phosphine oxide. Interestingly, the addition of phenol as a putative proton source was beneficial in facilitating catalyst turnover. The nature of the amine employed for the formation of the N-substituted aldimine proved to be vital for enantioselectivity, with optimal results obtained for N-fluorenyl imines such as 159, derived from aliphatic, unsaturated, and aromatic aldehydes (70-96% ee) [114],... 

Like all enzymes, HNL catalyzes the formation of a chemical equilibrium, in this case between a-hydroxynitriles (cyanohydrins) and their corresponding aldehydes and HCN. Conversely, in the presence of an excess of HCN, HNL efficiently catalyzes the enantioselective addition of HCN to aldehydes to form optically active cyanohydrins. 

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