Cyanohydrins enantioselective synthesis

Baeza, A., Casa, J., Najera, C., Sansano, J.M. and Saa, J.M., Enantioselective synthesis of O-methoxycarbonyl cyanohydrins chiral building blocks generated by bifunctional catalysis with BINOLAM-AICI. Eur. J. Org. Chem., 2006, 1949. 

F. Effenberger, and K. Pfizenmaier, Enantioselective synthesis of aliphatic (S)-cyanohydrins in organic solvents using hydroxynitrile lyase from Manihot esculenta, Ann. N. Y. Acad. Sci. 1996, 799, 771-776. 

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-... 

Scheme 2.2 Novozym 435 catalyzes the enantioselective synthesis of aliphatic cyanohydrins via a DKR.

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). 

When Upases are immobiUzed on Celite they can readily be used in dry organic solvents. Pseudomonas cepacia (also named B. cepacia) Upase was immobiUzed in the presence of sucrose on Hyflo super-cel CeUte [36, 40, 41] and used in the first enantioselective synthesis of cyanohydrin acetates via a DKR. Similarly, other successful syntheses of cyanohydrin acetates via DKR were catalyzed by Upases immobiUzed on CeUte [42]. This is in contrast to Novozym 435, which had successfully been used for the DKR of aUphatic cyanohydrin acetates (see Section 2.2.1 and Scheme 2.2) [29]. When Novozym 435 was used for the enantioselective synthesis of mandelonitrile acetate (la) via DKR, the reaction did not proceed [43]. It was... 

Cyanohydrins are versatile and important building blocks in organic synthesis [20]. Consequently, their enantioselective synthesis has attracted considerable attention... 

The enantioselective synthesis of 2-phenylisoserine derivatives is an attractive goal and several attempts, such as the application of acylase (36), lipase [37], and, more recently, bakers yeast reductase enzymes [38], were made to prepare the taxol side chain (see Section 15.1). No nitrile-converting enzymes have been investigated so far. The chemical instability of 2-hydroxy-3-amino-3-phenylpropionitrile (a cyanohydrin) in aqueous solution afforded the preparation of the cyclic protection products tron.s-( )-8a and ds-( )-9a (Figure 15.2). 

Recently, the group of Herrera, Bernardi, and Ricci realized the enantioselective synthesis of protected a-amino nitriles from the corresponding a-amino sulfones 137, which act as effective precursors for the in situ generation of imines, by the use of acetone cyanohydrin (138) as a cyanide source using quinine-derived PTC 136 [64]. The aminonitriles 139 were produced with broad generality in 50-88% ee (Scheme 8.53). However, a similar protocol using KCN and TMSCN resulted in a lower ee value. 

The toolbox of catalyst systems for enantiopure cyanohydrin synthesis comprises racemate resolutions (yielding 50% of the desired product), dynamic kinetic race-mate resolutions (enantioselective derivatization and racemization of the non-deri-vatized starting material, yielding 100% of the desired product) and enantioselective synthesis (yielding 100% of the desired product). Fig. 5 gives an overview of the different catalysts. Advantages and disadvantages of the four methods outlined in Fig. 5 are summarized in Tab. 1. 

Scheme 6.20 The use of polymer-supported Lewis acid catalyst 76 for the enantioselective synthesis of the cyanohydrin 77, using EOF as the pumping mechanism.

A more recent example of enzyme-catalyzed synthesis performed in micro reactors was reported by Rutjes and co-workers [81], who demonstrated the use of crude enzyme lysates, containing hydroxynitrile lyase, for the enantioselective synthesis of cyanohydrins. Employing a wet-etched borosilicate glass micro reaction channel, containing pillars to promote biphasic laminar flow, the authors evaluated the... 

In the case of the enzymatic synthesis of cyanohydrins, enantioselectivity is the most important criterion. Investigation of the kinetics of the whole system (enzymatic and non-enzymatic reaction) offers the possibility to optimize reaction conditions to... 

In the last decade, optically pure cyanohydrins (a-hydroxynitriles) have become a versatile source for the synthesis of a variety of chiral building blocks. Diverse methods for the enantioselective synthesis of cyanohydrins have been published and reviewed111. Besides enzyme catalyzed methods, hydrocyanation or silylcyanation of aldehydes or ketones controlled by chiral metal complexes or cyclic dipeptides, as well as diastereoselective hydrocyanation of chiral carbonyl compounds, have been applied with moderate success. 

When the preceding conditions for the enantioselective synthesis of cyanohydrin acetates via DKR were applied to aliphatic substrates, only a kinetic resolution was observed. However, Hanefeld s group has shown that, by... 

Trost BM, Martinez-Sanchez S (2005) Enantioselective synthesis of cyanohydrins by a novel aluminum catalyst. Synlett 627-630... 

F.L. Cabirol, U. Hanefeld, Immobilized Hydroxynitrile Lyases for Enantioselective Synthesis of Cyanohydrins Sol-Gels and Cross-Linked Enzyme Aggregates, Adv. Synth. Catal. (2006)... 

Hydroxynitrile lyases (also known as oxynitrilases) are used for the synthesis of chiral cyanohydrins. Because the hydroxynitrile moiety can be easily converted into a wide range of functional groups (Scheme 28.1), the cyanohydrins represent a versatile building block in total synthesis of natural products. Moreover, both R- and S-selective enzymes are available. They are also straightforward to handle and therefore represent catalysts of choice for syntheses on an industrial scale. Already as early as 1908, they had been used in enantioselective synthesis indeed, the first enantio-selective reaction was performed with an HNL. Consequently, many applications for these enzymes have been developed in natural products synthesis. 

Cabirol FL, Hanefeld U, Sheldon RA. Immobilized hydroxy-nitrile lyases for enantioselective synthesis of cyanohydrins sol-gels and cross-linked enzyme aggregates. Adv. Synth. Catal. 2006 348 1645-1654. 

Veum L, Kanerva LT, Hailing PJ, Maschmeyer T, Hanefeld U. Optimisation of the enantioselective synthesis of cyanohydrin esters. Adv. Synth. Catal. 2005 347 1015-1021. 

I. ENANTIOSELECTIVE SYNTHESIS OF R- AND S-CYANOHYDRINS USING HYDROXYNITRILE LYASE... 

Today, the most promising synthesis of optically active cyanohydrins, especially with respect to the enantioselectivity of the reaction, is the enzyme-catalyzed addition of hydrogen cyanide to aldehydes and ketones, respectively. 

Recently, the enantioselective addition of hydrocyanic acid to aldehydes, analogous to the synthesis of (/ )-cyanohydrins, yielding (.S)-cyanohydrins in very high optical purity, with (S )-oxynitrilase as catalyst, was reported20,21. 

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. 

Vorlop et al. described a novel cross-linked and subsequently poly(vinyl alcohol-entrapped PaHNL for synthesis of (//(-cyanohydrins. These immobilized lens-shaped biocatalysts have a well-defined macroscopic size in the millimeter range, show no catalyst leaching, and can be recycled efficiently. Furthermore, this immobilization method is cheap and the entrapped (/ )-oxynitrilases gave similar good results compared with those of free enzymes. The (//(-cyanohydrin was obtained in good yields and with high enantioselectivity of up to >99% ee [55],... 

Cyanohydrination (addition of a cyano group to an aldehyde or ketone) is another classic reaction in organic synthesis. Enantioselective addition of TMSCN to aldehyde, catalyzed by chiral metal complexes, has also been an active area of research for more than a decade. The first successful synthesis using an (5,)-binaphthol based complex came from Reetz s group142 in 1986. Their best result, involving Ti complex, gave 82% ee. Better results were reported shortly thereafter by Narasaka and co-workers.143 They showed that by... 

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. ... 

A new hydroxynitrile lyase (HNL) was isolated from the seed of Japanese apricot Prunus mume). It accepts benzaldehyde and a large number of unnatural substrates for the addition of HCN to produce the corresponding (7 )-cyanohydrins in excellent optical and chemical yields. A new high-performance liquid chromatography (HPLC)-based enantioselective assay technique was developed for the enzyme, which promotes the addition of KCN to benzaldehyde in a buffered solution (pH 4.0). Asymmetric synthesis of (7 )-cyanohydrins by a new HNL is described (Figure 8.4). ... 

In the last decades, cyanohydrins have become versatile chiral building blocks, not only for laboratory synthesis, but also for a range of pharmaceuticals and agrochemicals. Several methods for the enantioselective preparation of these compounds have been published [1, 2]. The most important synthetic approaches are catalysis by oxynitrilases, also termed hydroxynitrile lyases (HNLs), wording used in this chapter, [3] and by transition metal complexes [4], whereas the relevance of cyclic dipeptides as catalysts is decreasing [2]. 

J. D. Elliott, V. M. F. Choi, and W. S. Johnson, Asymmetric synthesis via acetal templates. 5. Reactions with cyanotrimethylsilane. Enantioselective preparation of cyanohydrins and derivatives, J. Org. Chem. 78 2294 (1983). 

Initial preparative work with oxynitrilases in neutral aqueous solution [517, 518] was hampered by the fact that under these reaction conditions the enzymatic addition has to compete with a spontaneous chemical reaction which limits enantioselectivity. Major improvements in optical purity of cyanohydrins were achieved by conducting the addition under acidic conditions to suppress the uncatalyzed side reaction [519], or by switching to a water immiscible organic solvent as the reaction medium [520], preferably diisopropyl ether. For the latter case, the enzymes are readily immobilized by physical adsorption onto cellulose. A continuous process has been developed for chiral cyanohydrin synthesis using an enzyme membrane reactor [61]. Acetone cyanhydrin can replace the highly toxic hydrocyanic acid as the cyanide source [521], Inexpensive defatted almond meal has been found to be a convenient substitute for the purified (R)-oxynitrilase without sacrificing enantioselectivity [522-524], Similarly, lyophilized and powered Sorghum bicolor shoots have been successfully tested as an alternative source for the purified (S)-oxynitrilase [525],... 

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