Kinetic resolution of enantiomers

Quantitative Analysis of Selectivity. One of the principal synthetic values of enzymes stems from their unique enantioselectivity, ie, abihty to discriminate between enantiomers of a racemic pair. Detailed quantitative analysis of kinetic resolutions of enantiomers relating the extent of conversion of racemic substrate (c), enantiomeric excess (ee), and the enantiomeric ratio (E) has been described in an excellent series of articles (7,15,16). 

The variety of enzyme-catalyzed kinetic resolutions of enantiomers reported ia recent years is enormous. Similar to asymmetric synthesis, enantioselective resolutions are carried out ia either hydrolytic or esterification—transesterification modes. Both modes have advantages and disadvantages. Hydrolytic resolutions that are carried out ia a predominantiy aqueous medium are usually faster and, as a consequence, require smaller quantities of enzymes. On the other hand, esterifications ia organic solvents are experimentally simpler procedures, aHowiag easy product isolation and reuse of the enzyme without immobilization. 

As was the case for kinetic resolution of enantiomers, enzymes typically exhibit a high degree of selectivity toward enantiotopic reaction sites. Selective reactions of enaiitiotopic groups provide enantiomerically enriched products. Thus, the treatment of an achiral material containing two enantiotopic functional groups is a means of obtaining enantiomerically enriched material. Most successful examples reported to date have involved hydrolysis. Several examples are outlined in Scheme 2.11. 

The great selectivity of Ru-BINAP species is also evident when they are used in kinetic resolution of enantiomers. When a racemic allylic alcohol reacts with H2 in the presence of Ru-(A)-BINAP, the (R)-alcohol reacts preferentially, thus leaving the (S)-enantiomer unreacted (Equation (7)).71... 

The C = C bond in the hydroxy allylic system of a fluoroalkanol can be selectively epoxidized without affecting the hydroxy group. Enantioselective epoxidation of racemic unsaturated fluoro alcohols by using the chiral Sharpless reagent can be exploited for the kinetic resolution of enantiomers. The recovered stereoisomer (e.g., 1) has 14-98% enantiomeric excess.165... 

Chen C-S, Lujimoto Y et al (1982) Quantitative analyses of biochemical kinetic resolutions of enantiomers. J Am Chem Soc 104 7294—7299... 

Chen, C.-S. Wu, S.-H. Girdaukas, G. Sih, C. J. Quantitative analyses of biochemical Kinetic resolution of Enantiomers. 2. Enzyme-catalyzed esterification in water-organic solvent biphasic systems, J. Am. Chem. Soc. 1987, 109, 2812-2817. 

Chirally modified ruthenium clusters have also been used for a kinetic resolution of enantiomers in the catalytic hydrogenation of non-functiona-lized terpene olefins (Scheme 5) The hydrogenation of a-pinene (IR,5R 27 S,5S 28) leads in principle to the cis- and /rans-pinanes (11 ,25,5/ 29 15,21 , 55 30 IR,2R,5R 31 IS",25,55 32). When a racemic mixture of both a-pinene enantiomers (27 and 28) is hydrogenated in the presence of the (15,25,35,5.R)-isopinocampheyl cluster HRu3(CO)9[//3, //2-NEt-... 

Consider, for example, a hypothetical kinetic resolution of enantiomers (R) and (S)-239 by esterification of one of them. Compare this to the esterification and desymmetrisation of diol 241. In many ways, a desymmetrisation is a kinetic resolution but with the two enantiomers joined together in the same molecule. The features that make a reagent work well in a desymmetrisation, may well make it work in a kinetic resolution. Indeed, in Double Methods in Chapter 28 we see that this is the case. 

This method relies on the chemical transformation of a racemate in which one of the enantiomers forms a product more rapidly than the other. The very first kinetic resolution of enantiomers was described by Pasteur [65]. This was the resolution of tartaric acid by fermenting yeast. Later, it was found that not only enzymes but also other chiral inductors such as chiral reagents, chiral catalysts, solvents or polarized light beam may effect kinetic resolution. It is important to note that the interaction time must be carefully controlled in kinetic resolution. The reaction has to be stopped at some point short of 100% conversion. Otherwise, both enantiomers of the starting material will be converted into the product, and no resolution is obtained. The slower interacting enantiomer can be obtained in an enantiomeri-cally enriched or even pure form. The product of a kinetic resolution may be either chiral or achiral. 

Other limitations of enzyme-catalyzed kinetic resolutions of enantiomers are that the enzymes are easily denatured, they often require stoichiometric amounts of co-factors, and they are expensive and substrate-specific. 

Continuous-flow biphasic IL-SCCO2 has also been applied in biocatalysis. Thus enzymatic reactions including transesteriflcation [41], acylation [42], and kinetic resolution of enantiomers [43] have been reported. 

Faber K, Honig H, Kleewein A (1995) Recent developments determination of the selectivity of biocatalytic kinetic resolution of enantiomers - the enantiomeric ratio . In Roberts SM (ed) Preparative Biotransformations. Wiley, New York... 

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