Enantiomeric cyanohydrin

Complexation of an amino acid derivative with a transition metal to provide a cyanation catalyst has been the subject of investigation for some years. It has been shown that the complex formed on reaction of titanium(IV) ethoxide with the imine (40) produces a catalyst which adds the elements of HCN to a variety of aldehydes to furnish the ( R)-cyanohydrins with high enantioselectivity[117]. Other imines of this general type provide the enantiomeric cyanohydrins from the same range of substrates11171. 

The enantiomerically pure amino acids also can be produced through a similar synthetic pathway catalyzed by enzymes. For example, reaction of hydrogen cyanide with benzaldehyde catalyzed by either (R)- or (S)-oxynitrilase enzyme yields the enantiomeric cyanohydrins (R)- or (S)-mandelonitrile. Alternatively, by adding carbon dioxide and hydrogen cyanide and ammonia as feedstocks, aldehydes can be converted to hydantoins (4-alkylimidazolidine-2,5-diones), which can be then hydrolyzed with either D- or L- hydan-toinases to produce D- or L-a-amino acids, respectively. 

Cyanohydrin Synthesis. Another synthetically useful enzyme that catalyzes carbon—carbon bond formation is oxynitnlase (EC 4.1.2.10). This enzyme catalyzes the addition of cyanides to various aldehydes that may come either in the form of hydrogen cyanide or acetone cyanohydrin (152—158) (Fig. 7). The reaction constitutes a convenient route for the preparation of a-hydroxy acids and P-amino alcohols. Acetone cyanohydrin [75-86-5] can also be used as the cyanide carrier, and is considered to be superior since it does not involve hazardous gaseous HCN and also virtually eliminates the spontaneous nonenzymatic reaction. (R)-oxynitrilase accepts aromatic (97a,b), straight- (97c,e), and branched-chain aUphatic aldehydes, converting them to (R)-cyanohydrins in very good yields and high enantiomeric purity (Table 10). 

The enantiomeric excesses of the cyanohydrins obtained are determined via the diastereomcric Mosher esters with (/ )-a-methoxy-a-(trifluoromethyl)phenylacetyl chloride16 by GC. 

The comparison shows that, although the reaction in ethyl acetate requires longer reaction times, the enantiomeric purity of the (R)-cyanohydrins is appreciably better than for the reaction in ethanol/ water. 

The enantiomeric excess values of the (S)-cyanohydrins are obtained from the ( + )-(R)-Mosher ester derivatives [a-methoxy-a-(trifluoromethyl)phenylacetates], whereas the corresponding benzeneacetic acids are first converted into their isopropyl carboxylates which then yield the ( + )-(ft)-Mosher ester derivatives. 

By simply hydrolyzing the easily accessible 2-hydroxy-2-methylalkanenitriles with concentrated acid, 2-hydroxy-2-methylalkanoic acids are obtained without measurable racemization (Table 3). The reaction sequence from the starting ketone to the carboxylic acid can be carried out in one pot without isolation of the cyanohydrin. The enantiomeric excesses of the (/ )-cyanohydrins and the (ft)-2-hydroxyalkanoic acids are determined from the ( + )-(/T)-Mosher ester derivatives and as methyl alkanoates by capillary GC, respectively. The most efficient catalysis by (R)-oxynitrilase is observed for the reaction of hydrocyanic acid with 2-alkanoncs. 3-Alkanoncs are also substrates for (ft)-oxynitrilase, to give the corresponding (/ )-cyanohydrins32. 

For successful DKR two reactions an in situ racemization (krac) and kinetic resolution [k(R) k(S)] must be carefully chosen. The detailed description of all parameters can be found in the literature [26], but in all cases, the racemization reaction must be much faster than the kinetic resolution. It is also important to note that both reactions must proceed under identical conditions. This methodology is highly attractive because the enantiomeric excess of the product is often higher than in the original kinetic resolution. Moreover, the work-up of the reaction is simpler since in an ideal case only the desired enantiomeric product is present in the reaction mixture. This concept is used for preparation of many important classes of organic compounds like natural and nonnatural a-amino acids, a-substituted nitriles and esters, cyanohydrins, 5-alkyl hydantoins, and thiazoUn-5-ones. 

Because of the instability of cyanohydrins, the characterization of cyanohydrins mostly should be hydroxyl protected. In 2001, Gerrits et al. [26] investigated the influence of solvent composition on the stability of unprotected cyanohydrins and then described a method to analyze unprotected cyanohydrins (with regard to enantiomeric purity and conversion) via chiral high-performance liquid chromatography (HPLC). Hernandez et al. [27] and the groups... 

Enantiomeric or specific synthesis of cyanohydrin is influenced by the reaction medium, cyanide source, water content, buffer pH, enzyme, and temperature during the HNL-catalyzed reaction. To maximize the enantiomeric excess of the cyanohydrin product, care must be taken to minimize the parallel chemical (nonenzymatic) condensation and racemi-zation of products. 

Kragl and coworkers investigated using organic-solvent-free systems to overcome the thermodynamic limitations in the synthesis of optically active ketone cyanohydrins. With organic-solvent-free systems under optimized reaction conditions, conversions up to 78% with > 99.0 enantiomeric excess (ee) (S) were obtained. Finally, 5 mL of (S)-acetophenone cyanohydrin with an ee of 98.5% was synthesized using MeHNL [52]. 

Hernandez, L., Luna, H., Solfsa, A. and Vazquez, A. (2006) Application of crude preparations of leaves from food plants for the formation of cyanohydrins with high enantiomeric excesses. Tetrahedron Asymmetry, 17, 2813-2816. 

An important contribution was recently made by Inoue and co-workers (35) (eq. [4]). Using the chiral cyclic dipeptide cyclo(L-Phe-L-His) these authors obtained a better than 90% e.e. in the reaction of benzaldehyde with cyanide ion. The preparation of the enantiomeric unnatural dipeptide obviously poses far fewer problems than the synthesis of an enantiomeric enzyme. It appears that, at least in principle, optically pure cyanohydrins of the desired configuration are accessible via catalysis by chiral amines or amides. 

Distillation under reduced pressure occurred without racemization or decomposition to afford (5)-acetophenone cyanohydrin (5 g, 10 %) in >95 % purity and 98.5 % enantiomeric excess. ... 

The conversion of acetophenone to acetophenone cyanohydrin and enantiomeric excess were determined by gas chromatographic analysis after product derivatisation as the trifluoroacetate. GC was performed using a Chiraldex capillary GC column (G-PN -y-Cyclodextrin, Propionyl) from Astec using a CP3800 (Varian) with a flame ionization detector. Carrier gas was helium at 2 mL min . Temperature gradient 80 °C for 0.5 min, raise at 10.8°C min to 130 °C and hold 130 °C for 15 min. The injector and detector temperamres were set to 250 °C. 

The use of organic-solvent-free systems can be applied to the cyanohydrin synthesis of a wide range of acetophenone derivatives (Table 8.2) electronegative substituents (e.g. fluorine) facilitate high conversions and enantiomeric excess of the product, whereas electropositive substituents (e.g. methoxy-) result in low to no conversion into the corresponding cyanohydrins. 

One of the earliest examples in this field [94] was reported by Mao and Anderson who showed that the SbHnl was specific for the dehydrocyanation of p-hydroxybenzaldehyde cyanohydrin. In a recent patent [95] the process of dehydrocyanation was successfully demonstrated using the PaHnl as the catalyst and a gas-membrane extraction method to remove the undesired aldehydes and HCN, which yielded a wide range of (S)-cyanohydrins, often with excellent enantiomeric excess. In further patent literature, Niedermeyer [96] also generated (S)-cyanohydrins via decomposition of a racemic mixture, but the problems of workup resulted in decreased yields. 

Another notable new advance is the development of hydroxynitrile lyases for the synthesis of enantiomerically active aromatic and aliphatic cyanohydrins. For instance, an S-specific hydroxynitrile lyase has been obtained from Hevea brasiliensis and the resulting fS)-cyanohydrin can be used to obtain both hydroxy acids and aminoalcohols. 

As well as almond meal, Sorghum bicolor shoots have also found application in the synthesis of aromatic cyanohydrins [55]. The enantiomeric purity obtained in transhydrocyanation experiments with acetone cyanohydrin as the cyanide source suffers from the high water content (>14% v/v) necessary for the decomposition of acetone cyanohydrin. In contrast, the application of HCN allows the use of low amounts of water (2% v/v), leading to yields and optical purities comparable with those obtained by the isolated enzymes. 

If 2-camphanyloxyacrylonitrile (15 R = C8H 02C00) is taken for cycloaddition, diastereoisomeric cycloadducts can be separated, and the basic system, 7-oxabicyclo-[2.2.1]hept-5-en-2-one 17, can be obtained in optically pure form [36]. Another way of obtaining enantiomeric ketones is based on crystallization of a brucine complex obtained from the corresponding cyanohydrines (see Sec. III). Ketone 17 can be converted [e.g., by cis-hydroxylation (—>18), protection of the diol system, and Baeyer-Villiger oxidation] to lactone 19, the opening of which leads to furanuronic acid 20. A new development in this field is based in cycloaddition between furan and 2-chloro- or 2-bromoacrolein in the presence of 5 mol% chiral oxazaborolidine 21 as catalyst [37],... 

Reactions catalyzed by solid bases were obvious candidates for testing hypotheses on the nature and the mode of action of enzymes. Bredig [40] used aminated cellulose (B2) as a model because an enzyme was thought to consist of "a specific active function and a colloidal carrier". Indeed, cyanohydrin 40 was formed with an enantiomeric excess of 22% Fig. 3 and Table 3 contain a summary of the reported results for base-catalyzed reactions. It is not clear whether the ZnO/ffuctose catalyst (Bl) described by Erlenmeyer [39] is really heterogeneous but it is the first report on using sugars as modifiers. Some reactions are probably just curiosities (39, 41), but two... 

In general, the method of enzymatic cyanohydrin synthesis promises to be of considerable value in asymmetric synthesis because of the synthetic potential offered by the rich chemistry of enantiomerically pure cyanohydrins, including their stereoselective conversion into other classes of compounds such as a-hydroxy carboxylic acids or respective esters, w c-diols, / -aminoalcohols, aziridins, a-azido(amino/fluoro)nitriles, and acyloins [501, 516]. 

The situation is further complicated by chiral autoinduction, first reported by Danda et al. for the hydrocyanation of 3-phenoxybenzaldehyde [39]. It was found that the enantiomeric excess of the product increases with reaction time, and that addition of small amounts of optically pure cyanohydrin at the beginning of the reaction led to high ee of the bulk product, irrespective of catalyst ee. It was concluded that the active catalyst is not the diketopiperazine alone but a 1 1 aggregate with the product cyanohydrin of the opposite configuration (e.g. (R,R)-1 plus S-mandelonitrile) [39]. Lipton et al. later developed a mathematical model for this effect and exploited it to improve the enantioselectivity of the hydrocyanation of... 

In summary, much information has been gathered by different methods, but there is still room for improvement of the substrate spectrum of the diketopiperazine catalyst 1 and for detailed understanding of the mechanism - and thus predictability - of this fairly complex heterogeneous catalyst system. Nevertheless, enantiomerically pure cyanohydrins - prepared with the aid of 1 - have already been used for synthesis of several natural product (and other) target molecules... 

The search for other amino acid-based catalysts for asymmetric hydrocyanation identified the imidazolidinedione (hydantoin) 3 [49] and the e-caprolactam 4 [21]. Ten different substituents on the imide nitrogen atom of 3 were examined in the preparation, from 3-phenoxybenzaldehyde, of (S)-2-hydroxy-2-(3-phenoxy-phenyl)acetonitrile, an important building block for optically active pyrethroid insecticides. The N-benzyl imide 3 finally proved best, affording the desired cyanohydrin almost quantitatively, albeit with only 37% enantiomeric excess [49]. Interestingly, the catalyst 3 is active only when dissolved homogeneously in the reaction medium (as opposed to the heterogeneous catalyst 1) [49]. With the lysine derivative 4 the cyanohydrin of cyclohexane carbaldehyde was obtained with an enantiomeric excess of 65% by use of acetone cyanohydrin as the cyanide source [21]. 

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