Chiral compounds enzymatic resolution

Enzymatic KRs, as all resolutions, are limited to a maximum theoretical yield of 50%. Strategies to increase the yield are therefore of great importance. The opposite of a resolution, that is, the racemization of a chiral compound, can sometimes be highly desirable and applicable in enantioselective synthesis. By combining a... 

Unless asymmetric induction is complete, it is necessary to remove the undesired enantiomer from the product mixture. Whereas in conventional diastereoselective asymmetric syntheses this removal can typically be readily accomplished by crystallization or chromatography, the separation of enantiomeric products can be problematic. Often, though, with enantio-enriched samples it is possible to recrystallize either the racemate from the pure enantiomer or, preferably, one enantiomer from the other [I2a,16,17], Another very effective method to produce enan-tiopure compounds is by enzymatic resolution of the enantio-enriched product from chiral PTC [16,18]. These methods are illustrated by examples in the alkylation section of this chapter (Chart 10.6). 

Enantioselective enzymatic transesterifications have been used as a complementary method to enantioselective enzymatic ester hydrolyses. The first example of this particular type of biotransformation is the synthesis of the optically active 2-acetoxy-l-silacyclohexane (5 )-78 (Scheme 19). This compound was obtained by an enantioselective transesterification of the racemic l-silacyclohexan-2-ol rac-43 with triacetin (acetate source) in isooctane, catalyzed by a crude lipase preparation from Candida cylindracea (CCL, E.C. 3.1.1.3)62. After terminating the reaction at 52% conversion (relative to total amount of substrate rac-43), the product (S)-78 was separated from the nonreacted substrate by column chromatography on silica gel and isolated in 92% yield (relative to total amount of converted rac-43) with an enantiomeric purity of 95% ee. The remaining l-silacyclohexan-2-ol (/ )-43 was obtained in 76% yield (relative to total amount of nonconverted rac-43) with an enantiomeric purity of 96% ee. Repeated recrystallization of (R)-43 led to an improvement of enantiomeric purity by up to >98% ee. Compound (R)-43 has already earlier been prepared by an enantioselective microbial reduction of the l-silacyclohexan-2-one 42 (see Scheme 8)53. The l-silacyclohexan-2-ol (R)-43 is the antipode of compound (.S j-43 which was obtained by a kinetic enzymatic resolution of the racemic 2-acetoxy-l-silacyclohexane rac-78 (see Scheme 15)62. For further enantioselective enzymatic transesterifications of racemic organosilicon substrates, with a carbon atom as the center of chirality, see References 64 and 70-72. 

In conclusion, the combination of an enzymatic optical resolution and subsequent chemical transformations of epimerization or racemization of the asymmetric center of the unwanted antipodes have led to the successful development of processes for preparation of the two optically active pyrethroid insecticides. This work will provide a novel feature in the application of enzymes, especially lipases for the industrial production of chiral compounds. 

The number of enzymes for industrial synthetic applications is growing fast. Enzymatic synthesis can be performed under mild reaction conditions so that many problems of chemical synthesis like isomerization orracemization can be prevented. Furthermore, enzymes are highly specific and selective, especially for enantio- or regio-selective introduction of functional groups. For the preparation of chiral enantiopure compounds, the resolution of racemic mixtures by hydrolases is a well-established route, which has the advantage to be able to use enzymes free of coenzymes. Otherwise, only a maximum yield of 50% can be reached by the primary reaction and further steps of reracemization must follow to avoid loss of the undesired enantiomer. 

The resolution of racemic compounds mediated by enzymes has become a valuable tool for the synthesis of chiral intermediates. In most cases, however, only one enantiomer of the intermediate is required for the next step in the synthesis thus, the unwanted isomer must be either discarded or racemized for reuse in the enzymatic resolution process. Dynamic kinetic resolution is one way of avoiding this problem the unwanted enantiomer is racemized during the selective enzymatic process and serves as fresh starting material in the resolution. 

Gutman, A. L. Meyer, E. Kalerin, E. Polyak, F. Sterling, J., Enzymatic resolution of racemic amines in a continuous reactor in organic solvents. / Biotech. Bioeng. 1992,40,760 Gutman, A. L., Novel Methods in the Synthesis of Chiral Compounds. Spec. Chem. 1996, 16(7), 242. 

CCCs may obtain chiral compounds by classical resolution, kinetic resolution using chemical or enzymatic metlrods, biocatalysis (enzyme systems, whole cells, or cell isolates), fermentation (from growing whole microorganisms), and stereoselective chemistry (e.g., asymmetric reduction, low-temperature reactions, use of chiral auxiliaries). CCCs may also be CCEs by capitalizing on a key raw material position and going downstream. Along with companies manufacturing chiral molecules primarily for other purposes, such as amino acid producers, these will be the key sources for the asymmetric center. 

A related though simpler compound from Bristol-Meyers Squibb 216 is their anti-psychotic agent BMS 181100. It has two p-fluorophenyl groups joined through a C4-piperazine linker containing a chiral secondary alcohol. The compound is easily made58 by alkylation of an amine with the primary chloride 217. There are two opportunities from enzymatic resolution. 

Both chiral compounds have been prepared by enantioselective reduction of ethyl-5-oxohexanoate 71 and 5-oxohexanenitrile 72 by Pichia methanolica SC 16116. Reaction yields of 80%-90% and more than 95% EEs were obtained for each chiral compound. In an alternate approach, the enzymatic resolution of racemic 5-hydroxy-hexane nitrile 73 by enzymatic succinylation was demonstrated using immobilized lipase PS-30 to obtain (S)-5-hydroxyhexanenitrile 69 in 35% yield (maximum yield is 50%). (S)-5-Acetoxy-hexanenitrile 74 was prepared by enantioselective enzymatic hydrolysis of racemic 5-acetoxyhexanenitrile 75 by Candida antarctica lipase. A reaction yield of 42% and an EE of more than 99% were obtained [96]. 

Similarly, allylic C-H oxidation can streamline the eonstruetion of oxygenated compounds by reducing functional group manipulations necessary for working with bisoxygenated intermediates. For example, a chiral allylic C-H oxidation/enzymatic resolution sequence furnished bisoxygenated compound 14 in 97% ee and in 42% overall yield in just 3 steps from a commercially available... 

The hydrolysis of carboxylic acid derivatives using a DKR-based approach is not hmited to cyclic carhonyl compounds as exemplified in Scheme 5.6. For example, when an acyclic racemic thioester (possessing an electron-withdrawing arylsulfanyl group at the a-position) is subjected to enzymatic resolution, hydrolysis occurs smoothly to give the chiral carboxylic acid in high enantiomeric excess... 

In Chapter 7, we briefly mentioned that there were a number of biological methods for resolution of racemic mixtures of chiral compounds. Because enzymes, biological catalysts, are composed of chiral amino acids, they will generally accept only the natural enantiomer of a compound as their substrate. Some enzymes are very specific as to their substrate, but others can be used with whole classes of substrate, even where these are not very close in overall structure to their natural substrates. The simplest form of resolution involves a racemate, where one enantiomer is transformed by the enzyme and the other is not. This is called kinetic resolution, since it depends on the relative rates of enzymatic catalysis of the reactions of one enantiomer over the other. Our first example is shown in Figure 15.22. When the epoxide is opened by the Grignard reagent, only the tra s-product is formed, but this is a racemic mixture. The alcohol is converted to an ester, which is then hydrolyzed enzymatically using a lipase enzyme from Pseudomonas fluorescens. Notice the very mild conditions for... 

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