Cyanohydrins synthesis

Optically pure cyanohydrins serve as highly versatile synthetic building blocks [24], Much effort has, therefore, been devoted to the development of efficient catalytic systems for the enantioselective cyanation of aldehydes and ketones using HCN or trimethylsilyl cyanide (TMSCN) as a cyanide source [24], More recently, cyanoformic esters (ROC(O)CN), acetyl cyanide (CH3C(0)CN), and diethyl cyanophosphonate have also been successfully employed as cyanide sources to afford the corresponding functionalized cyanohydrins. It should be noted here that, as mentioned in Chapter 1, the cinchona alkaloid catalyzed asymmetric hydrocyanation of aldehydes discovered 

In 1991, Mukaiyama et al. reported that high enantioselectivity can be achieved using the chiral tin (II) complex 6 derived from cinchonine (Cn) as a Lewis acid catalyst in the reactions of aldehydes and TMSCN [28]. However, the utilization of this protocol is limited to aliphatic aldehydes, where up to 96% ee was obtained (Table 4.4). However, when this protocol was applied to an aromatic aldehyde (benzaldehyde), no reaction was observed with TMSCN under the same conditions. 

Moberg and coworkers also achieved the highly enantioselective cyanation of aldehydes by using the dual activation concept (Table 4.5) [30]. It is known that the Lewis acidic dimeric salen-Ti complex 8 catalyzes the cyanation of benzaldehyde with 

Carbon-carbon bond forming reactions can be catalyzed by enzymes such as aldolases for aldol reactions, hydroxynitrile lyase for cyanohydrin synthesis and decarboxylases for carboxylations. Some examples are shown in this section.  

Aldol reactions have been catalyzed by aldolases as well as by catalytic antibodies. For example, L-threonine aldolase was applied to C—C bond formation of an aldehyde with glycine. The resulting adduct could be further converted to a precursor of N-acetyl-4-deoxy-D-mannosamine, a potent inhibitor of N-acetylneuraminic acid synthetase (Fig. 10.39(a)).  

Aldol reaction using monoclonal aldolase antibodies, generated against a ketosulfone hapten by reactive immunization, was used to catalyze rapid and highly enantioselective retro-aldol reaction of a thiazole aldol, providing optically pure aldol by kinetic resolution. The product was used for the synthesis of epothilone E (Fig. 10.39(b) and (c)).  

With the use of bio catalysts, the preparation of chiral cyanohydrins is possible. (R)- as well as (S)-cyanohydrins are now easily available as a result of the excellent accessibility, the relatively high level of stability and the easy handling of hydroxynitrile lyases (HNLs). An example of the synthesis of (S)-cyanohydrins is shown in Fig. 10.40. The optimization of reaction conditions (solvent, temperature and site-directed mutagenesis) has enabled HNL-catalyzed preparation of optically active cyanohydrins on an industrial scale. 

Carboxylation of organic molecules using CO2 has received attention as an environmentally benign synthetic method. A decarboxylase, an enzyme from Bacillus megaterium that catalyzes the elimination of CO2 from organic molecules, has been found to also catalyze the reverse CO2 fixation reactions. The substrate scope of this enzyme, however, is limited to pyrrole, which is carboxylated to form pyrrole-2-carboxylate (Fig. 10.41(a)). For the carboxylations of phenol and catechol, decarboxylases from Clostridium hydroxybenzoicum have been isolated and employed (Fig. 41(b) and(c)).  

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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 present method is adapted from Fischer employing recently developed modifications of the cyanohydrin synthesis. - ... 

Catalytic Asymmetric Cyanohydrin Synthesis," North. M. Synlett, 1993, 807... 

Deoxy-3-fluoro-D-glucose (25%) and -mannose (40%) were prepared from 2-deoxy-2-fluoro-D-arabinose by a chain-extension reaction (cyanohydrin synthesis). Likewise, 4-deoxy-4-fluoro-D-glucose ° (27%) and -mannose (45%) were prepared from 3-deoxy-3-fluoro-D-arabinose. ... 

HCN is the most preferred cyanide source in cyanohydrin synthesis. Besides HCN, several different cyanide sources, like potassium cyanide, are being used in biotransformation. Alternative methods for the safe handling of cyanides on a laboratory scale are, for instance, to use cyanide salts in solution. These solutions can be acidified and used as the aqueous layer in two-phase systems or the HCN can be extracted into the organic layer with the desired solvent for reactions in an organic phase. After the reaction, excess cyanide can readily be destroyed with iron(II) sulfate, or iron(III) chloride or bleach. Cyanide can also be presented in the form of organic cyano, such as acetone cyanohydrin [46] or cyanoformates. However, as claimed by Effenberger, some results could not be reproduced [47]. 

Effenberger, F., Ziegler, T. and Forster, S. (1987) Enzyme-catalyzed cyanohydrin, synthesis in organic solvents. Angewandte Chemie (International Edition in English), 26, 458-460. 

C. S. Hudson, The Fischer Cyanohydrin Synthesis and the Configurations of Higher-carbon Sugars and... 

The work discussed above by Snapper, Hoveyda, and co-workers (27) illustrates the power of a parallel approach to catalyst development. The authors took a basic ligand type that had been reported by Inoue and co-workers (25) for the catalysis of cyanohydrin synthesis and optimized the system for two other reactions and a number of substrates. 

As early as 1917, it was known that C2 and C3 in this trimethyl sugar each carried a methoxyl group, since (a) it failed to yield an osazone, and (b) the trimethyl-D-glucoheptonic acid derived from it by a cyanohydrin synthesis gave a lactone only with the concomitant loss of one of the methyl radicals.135 The production of a dimethyl- and not a trimethyl-... 

The cyanohydrin synthesis of higher sugars, which involves intermediate aldonolactones, allows the introduction of a 14C label in the sugar chain. Thus, for example, L-[5-l4C]arabinose was synthesized (12) from D-xylose, which was first converted, by addition of K14CN and hydrolysis, into D-[ 1-... 

Lemieux and Spohr (Alberta) here trace our understanding of enzyme specificity in broad perspective as they assess Emil Fischer s lock and key concept advanced a century ago in relation to current ideas of molecular recognition. It may be noted that the very first article in Volume 1 of Advances, by Claude S. Hudson, was devoted to the Fischer cyanohydrin synthesis and the consequences of asymmetric induction. 

The condensation product is then converted, with elimination of potassium cyanide, into benzoin. The catalytic participation of the potassium cyanide is obvious. The distinction between this reaction and the cyanohydrin synthesis should be thoroughly grasped. 

The cyanohydrin synthesis has been applied in the study of the sugars by H. Kiliani, who used it in the synthesis of higher members of the class. The carboxylic adds which result from the hydrolysis of the nitriles can be reduced, in the form of their lactones, to the corre-... 

It is of some historical interest that Kiliani s cyanohydrin synthesis (24) enabled Emil Fischer (25) to carry out the first asymmetric synthesis. Lapworth (26) used this base-catalyzed nucleophilic 1,2-addition reaction in one of the first studies of a reaction mechanism. Bredig (27,28) appears to have been the first to use quinine (29) in this reaction as the chiral basic catalyst. More recently, others (20) have used basic polymers to catalyze the addition of cyanide to aldehydes. The structure of quinine has been known since 1908 (30). Yet it is of critical importance that Prelog s seminal work on the mechanism of this asymmetric transformation (eq. [4]) could not have begun (16) until the configuration of quinine was established in 1944 (31,32). 

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). 

Figure 8.1 Enzymatic (S)-seiective substituted phenyiacetone cyanohydrin synthesis...

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. 

Serianni, A.S., Nunez, H.A. and Barker, R., Cyanohydrin synthesis studies with carbon-13-labeled cyanide. 7. Org. Chem., 1980, 45, 3329. 

The characteristics of a support material are of great importance to the measured enzyme activity [79, 101]. Hydrophobic carriers have a low ability to attract water, thus leaving more available for the enzyme, hence Wehtje et al. [102, 103] have shown that celite is a suitable carrier for the PaHnl to yield an immobilized form of the enzyme. In contrast, controlled pore glass (CPG) and Sephadex G25 were found to be less well suited to enzyme support as, using these systems, cyanohydrin synthesis was significantly reduced (over 30%). Sephadex also promoted the spontaneous addition of HCN to benzaldehyde [102]. A series of batch experiments showed that if the solvent (diisopropyl ether) surrounding the immobilised PaHnl contained insufficient water (i. e. less than 2 %), it would be extracted from the enzyme preparation and consequently enzyme activity was lost [102]. These results were the basis for the production... 

Hatano, M. Ikeno, T Miyamoto, T Ishihara, K. Chiral lithium binaphtho-late aqua complex as a highly effective asymmetric catalyst for cyanohydrin synthesis. J. Am. Chem. Soc. 2005,127, 10116-10111. 

The free nitriles of iV-methyl-L-glucosaminic acid and iV-methyl-L-mannosaminic acid have been prepared by Wolfrom, Thompson and Hooper by the Kiliani-Fischer cyanohydrin synthesis. 

L-Mannitol has been prepared by the reduction of L-mannosaccharo-dilactone or L-mannose. By far the most convenient procedure is that used by Baer and Fischer for their preparation of L-glyceraldehyde by the oxidative cleavage of l,2 5,6-diisopropylidene-L-mannitol with lead tetraacetate. L-Arabinose was converted to L-mannonolactone by the cyanohydrin synthesis and this was hydrogenated over platinum oxide to the desired L-mannitol. High hydrogen pressures, rather than low as usually employed with this catalyst, were used. 

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