Cyanohydrins resolution

Other possibilities to prepare chiral cyanohydrins are the enzyme catalysed kinetic resolution of racemic cyanohydrins or cyanohydrin esters [107 and references therein], the stereospecific enzymatic esterification with vinyl acetate [108-111] (Scheme 2) and transesterification reactions with long chain alcohols [107,112]. Many reports describe the use of fipases in this area. Although the action of whole microorganisms in cyanohydrin resolution has been described [110-116],better results can be obtained by the use of isolated enzymes. Lipases from Pseudomonas sp. [107,117-119], Bacillus coagulans [110, 111], Candida cylindracea [112,119,120] as well as lipase AY [120], Lipase PS [120] and the mammalian porcine pancreatic lipase [112, 120] are known to catalyse such resolution reactions. 

Figure 6.30 Nitrilase-catalyzed dynamic kinetic resolution of cyanohydrins.

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. 

Scheme 6.7 Lipase-catalyzed resolution of cyanohydrin library DCL-D, yielding ester (35) as the major product.

In conjunction with the establishment of the cyanohydrin DCL, the DCR process was subsequently addressed. Thus, selected lipases and a suitable acyl donor [isopropenyl acetate (34)] were applied to the system (Scheme 6.7). This selective enzymatic resolution of the DCL provided cyanoacetate product (35) as the major product at the reaction conditions used, thus demonstrating the efficiency of the concept. 

Inagaki, M. Hiratake, J. Nishioka, T Oda, J. One-pot synthesis of optically active cyanohydrin acetates from aldehydes via lipase-catalyzed kinetic resolution coupled with in situ formation and racemization of cyanohydrins. J. Org. Chem. 1992, 57, 5643-5649. 

The presence of the aldehyde as cyanide acceptor is essential to achieve the resolution of ketone cyanohydrins with good enantioselectivities. The unreacted (S)-ketone cyanohydrin and the (R)-co-bromoaldehyde cyanohydrin formed could be isolated in moderate to good enantiopurity (50 to 95% and 75 to 92% respectively) [53]. 

In the optical resolution of cyanohydrins, it was first found that brucine (4) is a suitable host for the cyanohydrins which substituted with one aromatic group and one bulky alkyl group. In this case, not only a simple enantiomer separation of rac-cyanohydrin but also its transformation to one enantiomer occurred and one pure enantiomer was obtained in a yield of more than 100%. For example, when a solution of rac-l-cyano-2,2-dimethyl-l-phenylpropanol (61a) (1.0 g, 5.3 mmol) and 4 (2.1 g, 5.3 mmol) in MeOH (2 ml) was kept in a capped flask for 12 h, a 1 1 brucine complex of (+)-61a (2.08 g, 134%, mp 112-114 °C) separated out as colorless prisms. Decomposition of the complex with dil HC1 gave (+)-61a of 97% ee (0.67 g, 134%). From the filtrate, rac-61a (0.33 g, 33%) was obtained.273 The... 

The chiral hosts 8a and 9a were found to be useful for the resolution of cyanohydrins which cannot be resolved with 4. For examples, 61g and 61m were resolved by complexation with 9a and 8a, respectively, to give (-)-61g of 72.5% ee (70%) and (+)-61m of 100% ee (47.6%), respectively, in the yield indicated. The most simple chiral cyanohydrin derived from acetaldehyde (62g) was resolved by complexation with 8a and optically pure (+)-62g was obtained in 52.6% yield.23... 

Toda, F., Matsuda, S., and Tanaka, K. (1991) Efficient Resolution of Secondary Alcohols, Cyanohydrins, and Glycerol Acetates by Complexation with the Host Derived from Tartaric Acid, Tetrahedron Asymm., 2, 983-986. 

Conversion of Racemic Cyanohydrin into One Optically Acrtive Iosmer in the Presence of Brucine, Chem. Lett., 661-664. b) Tanaka, K. and Toda, F. (1987) Chiral Recognition and Optical Resolution of Cyanohydrin by Complexation with Brucine, Nippon Kagaku Kaishi, 456-459. 

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]. 

A drawback of this reaction has recently been addressed. Only very few S-selective nitrilases were known this problem has been solved a systematic screening program yielded a number of S-selective nitrilases that have successfully been employed in this dynamic kinetic resolution (Scheme 5.17) [38]. In an alternative approach, combining the enantioselectivity of an HNL with the hydrolytic power of a not very selective nitrilase that did accept cyanohydrins as substrates, the synthesis of optically enriched a-hydroxy acids starting from alde-... 

The dynamic cyanohydrin system was next challenged with lipase-catalyzed transesterification resolution using different operational conditions. Thus, different lipases, organic solvents, additives, and acyl donors were evaluated. Isopropenyl acetate 26 was chosen and used as acyl donor because its reaction produces acetone as by-product, which does not interfere in the reaction and the NMR spectra. Molecular sieve 4 A was also added in the dynamic resolution process to control the water activity. The lipase preparation PS-C I was chosen in the resolution process since it expressed the highest lipase activities for both the substrate structure and the enantiomeric selectivities. Different organic solvents were also... 

To improve the enzyme activities, decreasing the reaction temperature has been reported to enhance the enantiomeric discrimination [46—48]. Lower reaction temperatures were also applied to the lipase-catalyzed resolution of the dynamic cyanohydrin system. At 0 °C, the resolution process required a longer time, but the dynamic system was stable and showed similar intermediate ratios until the reaction was completed. The results (Fig. 6b) indicated that the non-substituted ester products 27B and 27D were preferentially amplified from the dynamic system, especially when the reaction temperature was decreased. Compared to the ratio of the corresponding alcohol intermediates 25A and 25C in the dynamic system, the ratios of the orf/io-substituted esters 27A and 27C were less favored by decreasing the amount of lipase and the reaction temperature. The ratio of the para-substituted ester product 27E did not show any significant enhancement compared to the ratio of its corresponding intermediate 25E. 

Inagaki M, Hiratake J, Nishioka T, Oda J (1989) Kinetic resolution of racemic benzaldehyde cyanohydrin via stereoselective acetylation catalyzed by lipase in organic solvent. Bull Inst Chem Res, Kyoto Univ 67 132-135... 

Xu Q, Geng X, Chen P (2008) Kinetic resolution of cyanohydrins via enantioselective acylation catalyzed by lipase PS-30. Tetrahedron Lett 49 6440-6441... 

This eoncept has been known for a long time in pure enzymatic synthesis, e.g. amino acid synthesis via hydantoins [1] or oxazolidinones [2]. Cyanohydrins [3] and lactols [4] are prone to in situ racemization as well and may serve as substrates in kinetic resolutions. 

Optically active a-hydroxy carboxylic acids are useful intermediates in medicinal chemistry and asymmetric synthesis (Coppola and Schuster 1997). Enantioselective biotransformations of a-hydroxy nitriles (cyanohydrins) are important because they can lead to a dynamic kinetic resolution from readily available starting material. 

FIGURE 17.8 Dynamic kinetic resolution of cyanohydrins catalyzed by nitrilases. 

Resolution The reagent 1 reacts with racemic alcohols, thiols, amines, and cyanohydrins to give diastcreomeric derivatives that can be separated by column chromatography or crystallization. Subsequent hydrolysis gives the enantiomers and 1 is recovered. With racemic alcohols, preferential acetalization of the (R)-cnantiomers is observed. 

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