Chiral cyanohydrines

TMSCN, (—)-DIPT [diisopropyl L-tartrate], Ti(/-PrO)4, CH2CI2, 0°, 6 h, rt, 12 h, 95% yield. These conditions afford chiral cyanohydrins. ... 

The hydroxynitrile lyase (HNL)-catalyzed addition of HCN to aldehydes is the most important synthesis of non-racemic cyanohydrins. Since now not only (f )-PaHNL from almonds is available in unlimited amounts, but the recombinant (S)-HNLs from cassava (MeHNL) and rubber tree (HbHNL) are also available in giga units, the large-scale productions of non-racemic cyanohydrins have become possible. The synthetic potential of chiral cyanohydrins for the stereoselective preparation of biologically active compounds has been developed during the last 15 years. 

In Table 2, the properties and characteristics of the five HNLs presently applied in the enzyme-catalyzed large-scale preparation of chiral cyanohydrins are summarized. ... 

Although considerable progress has been made in metal-catalyzed syntheses of non-racemic cyanohydrins in recent years, the HNL-catalyzed preparation of chiral cyanohydrins is by far the most important method especially for large-scale processes, due to the easy access of R)- and (5 )-HNLs and the high optical and chemical yields of the cyanohydrins obtained. ... 

OPTIMIZED REACTION CONDITIONS FOR THE HNL-CATALYZED FORMATION OF CHIRAL CYANOHYDRINS... 

For practical applications of HNLs as catalysts for the preparation of chiral cyanohydrins, three objectives have been achieved first, to get high enantioselec-tivity it is decisive to suppress the non-enzymatic addition of HCN to the substrate ... 

SYNTHETIC POTENTIAL OE CHIRAL CYANOHYDRINS IN STEREOSELECTIVE SYNTHESIS... 

Amino alcohols, which have a broad spectrum of biological activities, can be categorized as adrenahne-like with one chiral center at C-1 or as ephedrine-like with two chiral centers at C-1 and C-2 (Scheme 7). Although a variety of methods have been developed for the stereoselective preparation of 1,2-amino alcohols, " in most cases it is easier and more efficient to prepare these important compounds stereoselectively starting from chiral cyanohydrins (Scheme... 

Stereoselective substitution of the hydroxyl group in chiral cyanohydrins... 

Although considerable progress has been made in metal-catalyzed preparations of non-racemic cyanohydrins, the HNL-catalyzed reaction is still the most important method for the synthesis of chiral cyanohydrins, especially for large-scale reactions. The usefulness of HNLs as catalysts for the stereoselective addition of HCN to carbonyl compounds has increased substantially because (7 )-PaHNL... 

Ognyanov, V.I., Datcheva, V.K. and Kyler, K.S. (1991) Preparation of chiral cyanohydrins by an oxynitrilase-mediated transcyanation. Journal of the American Chemical Society, 113, 6992-6996. 

Decicco, C.P. and Grover, P. (1997) Asymmetric amino acid synthesis Mitsunobu reactions on chiral cyanohydrins. Synlett, 529-530. 

Warmerdam, E.G.J.C., van Rijn, R.D., Brussee, J. et al. (1996) Synthesis of a-hydroxy-/3-amino acids from chiral cyanohydrins. Tetrahedron Asymmetry, 7, 1723-1732. 

Rhodococcus erythropolis NCIMB 11540 has been employed as biocatalyst for the conversion of (R)- or (.S )-cyanohydrins to the corresponding (R)- or (S)-a-hydroxycarboxylic acids with an optical purity of up to >99% enatiomeric excess (ee) [27-29] the chiral cyanohydrins can separately be produced using hydroxynitrile lyase from Hevea braziliensis or from Prunus anygdalis [30]. Using the combined NHase-amidase enzyme system of the Rhodococcus erythropolis NCIMB 11 540, the chiral cyanohydrins were first hydrolyzed to the... 

Chiral cyanohydrins in fact are high-value building blocks and useful precursors for hydroxyamino acids and amino alcohols. The new sol-gel immobilization technology licensed from Johnson Matthey and named CTIS CACHy (CTIS Chiral Technologies Interface System)32 dramatically improves process economics for large-scale pharmaceutical manufacturing as it increases the turnover number of the catalyst... 

Brussee, J. and van der Gen, A., Biocatalysis in the enatioselective formation of chiral cyanohydrins, valuable building blocks in organic synthesis. In Stereoselective Biocatalysis, Patel, R.N. (ed.). Dekker New York, 2000, pp. 289-320. 

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. ... 

Johnson, D.V. and Griengl, H., Chiral cyanohydrins their formation synthetic potential and application. Chim. Oggi-Chem. Today, 1997, IS, 9-13. 

Procedure 2 Synthesis of (/ )-Mandelonitrile and Other Chiral Cyanohydrins... 

Chapter 8 describes the application of hydroxyl nitrile lyases to the synthesis of new chiral cyanohydrins and a-hydroxy acids and includes new approaches to the transformation of difficult aldehyde and ketone substrates using substrate engineering and immobilization techniques. 

To the synthetic chemist the chiral cyanohydrins are extremely useful building blocks as they possess a high degree of functionality and are chiral compounds... 

The chiral cyanohydrins also lead directly to a-hydroxy acids by hydrolysis (sequence B) [69] and to protected a-hydroxy aldehydes by first hydroxyl group protection, followed by reduction of the nitrile and hydrolysis of the intermediate imine (not shown) (sequence C) [114]... 

Therefore, the chiral cyanohydrins are valuable and versatile synthons as their single hydroxyl asymmetric centre is accompanied by at least one other chemical functionality. Thus with careful functional group protection, differential and selective chemical transformations can be performed. Such synthetic techniques lead to production of interesting bioactive compounds and natural products. These products include intermediates of j3-blockers 15 1117], j3-hydroxy-a-amino acids 16 [118],chiral crown ethers 17 [lll],coriolic acid 18 [120], sphingosines 19 [121], and bronchodilators such as salbutamol 20 [122] (Fig. 3). 

As chiral cyanohydrins are important synthetic intermediates for the preparation of chiral amino acids, carbohydrates, and so on, this process would be a useful asymmetric one—carbon homologation procedure widely employable for organic synthesis. 

Oxynitrilases are enzymes that catalyze the formation and cleavage of cyanohydrins through the stereoselective addition of hydrogen cyanide to aldehydes or methyl ketones giving enantiopure a-hydroxynitriles. The use of (R)-oxynitrilases for the preparation of chiral cyanohydrins has dramatically grown in the last decade because of their possibihties as precursors for the synthesis of many compounds with physiological properties [50]. 

The enzyme-catalyzed cyanohydrin reaction offers new and interesting perspectives for the synthesis of different kinds of chiral cyanohydrins, because over the next few years the continuous development of new genetically modified oxynitrilases will be without any doubt of great utility for the preparation of pharmaceuticals. 

H. Griengl, H. Schwab, M. Fechter, The synthesis of chiral cyanohydrins by oxynitrilases. Trends Biotechnol. 2000, 18, 252-256. 

Scheme 7.23 Synthesis of chiral cyanohydrins from 3-pyridinecarboxyaldehyde in organic solvent using commercially available CLEA particles of hydroxynitrile lyases.

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