Desymmetrization enzyme catalyzed

For desymmetrization of diesters 3 via their hydrolysis in water, pig Hver esterase [12], o -chymotrypsin [12, 13a], and Candida antarctica Hpase (CAL-B) [14] were successfully used. However, further studies showed that respective anhydrides 5 can be used as substrates for enzyme-catalyzed desymmetrization in organic solvents [15]. The desired monoesters 4 were obtained in high yield in this way, using immobilized enzymes Novozym 435 or Chirazyme L-2 (Scheme 5.3). After the reaction, enzymes were filtered off, organic solvents were evaporated, and the crude products were crystalHzed. This was a much simpler experimental procedure in which control of the reaction progress was not necessary, and aU problems associated with extraction of products from aqueous phase and their further purification were omitted [15]. 

Enzyme-catalyzed reactions can provide a rich source of chiral starting materials for organic synthesis.2 Enzymes are capable of differentiating the enantiotopic groups of prochiral and mew-compounds. The theoretical conversion for enzymatic desymmetrization of mew-compounds is 100% therefore enzymatic desymmetrization of mew-compounds has gained much attention and constitutes an effective entry to the synthesis of enantiomerically pure compounds. 

Grogan, G., Graf, J., Jones, A., Parsons, S., Turner, N. J. and Flitsch, S. L An asymmetric enzyme-catalyzed retro-Claisen reaction for the desymmetrization of cyclic diketones. Angew. Chem. 2001,113 1145-1148 [Angew. Chem. Int. Ed. 40 1111-1114]. 

The proper stereochemistry was achieved by enzyme catalyzed desymmetrization of the prochiral 1,3-diol 30. Candida antarctica lipase (CAL)-catalyzed transesterification yielded the monoacetate 31, which gave rise to the methyl with the proper stereochemistry 32. The generation of the desired chiral epoxide 35 was achieved by asymmetric dihydroxylation employing AD-mix-a,42 followed by epoxide formation. Base-catalyzed etherification yielded the mixture of the enantiopure (+)-heliannuol A and (-)-heliannuol D. Unfortunately these compounds correspond to the opposite d/l series and correspond to the enantiomers of the natural products (-)-heliannuol A and (+)-heliannuol D (Fig. 5.6.A). 

Fig. 2.11 Enzyme-catalyzed desymmetrization of meso-epoxides using epoxide hydrolases of microbial origin that were screened for maximum activity. Note that the relative rate (measured as the turnover frequency, TOE) offormingthe (R,R)-stereoisomer is about 250 times higher than for the (S,S) one.

The enzyme-catalyzed kinetic asymmetric transformation (KAT) of a diastereomeric 1 1 syn anti mixture is limited to a maximum theoretical yield of 25% of one enantiomer. This important drawback has been overcome by the combination of the actions of a ruthenium complex and a lipase in a dynamic kinetic asymmetric transformation (DYKAT), the desymmetrization of racemic or diastereomeric mixtures involving interconverting diastereomeric intermediates, implying different equilibration rates of the stereoisomers. Thus, this strategy allows the preparation of optically active diols, widely employed in organic and medicinal chemistry, as they are an important source of chiral auxiliaries and ligands and they can be easily employed as precursors of much other functionality. 

However, whatever the mechanism of action is, the effect of solvents on enzyme selectivity is sometimes really dramatic. For example, Hrrose et al. [42] reported that in the Pseudomonas species lipase-catalyzed desymmetrization of prochiral... 

CHMO is known to catalyze a number of enantioselective BV reactions, including the kinetic resolution of certain racemic ketones and desymmetrization of prochiral substrates [84—87]. An example is the desymmetrization of 4-methylcyclohexanone, which affords the (S)-configurated seven-membered lactone with 98% ee [84,87]. Of course, many ketones fail to react with acceptable levels of enantioselectivity, or are not even accepted by the enzyme. 

Nitrilases catalyze the synthetically important hydrolysis of nitriles with formation of the corresponding carboxylic acids 7-11). Enantioselectivity is relevant in the kinetic resolution of racemic nitriles or desymmetrization of prochiral dinitriles. Both versions have been applied successfully to a number of different substrates using one of the known currently available nitrilases. Recently, scientists at Diversa expanded the collection of nitrilases by metagenome panning 150). Nevertheless, in numerous cases the usual limitations of enzyme catalysis become visible, including poor or only moderate enantioselectivity and limited activity. 

Biocatalysis plays a central role in the manufacturing of statin side chains (Figure 6.2). A first set of approaches exploits enzymatic desymmetrization reactions, for example, of the methoxyacetyl ester of glutaric acid diethyl ester with commercially available a-chymotrypsin as explored by Ciba SC with a yield of 94% and enantiomeric excess of up to 98% [1]. In the optimized procedure, the substrate was available in a concentration of 1 M at an enzyme/substrate ratio of 7% (wt/wt), and the reaction took approximately a day. The subsequent steps to the final acetonide also involved a pig-liver esterase (PLE) catalyzed selective hydrolysis of the methoxyacetyl group (Figure 6.2a). 

One of the reactions catalyzed by esterases and lipases is the reversible hydrolysis of esters (Figure 19.1, Reaction 2). These enzymes also catalyze transesterilications and the desymmetrization of mew-substrates (vide infra). Many esterases and lipases are commercially available, making them easy to use for screening desired biotransformations without the need for culture collections and/or fermentation capabilities.160 In addition, they have enhanced stability in organic solvents, require no co-factors, and have a broad substrate specificity, which make them some of the most ideal industrial biocatalysts. Alteration of reaction conditions with additives has enabled enhancement and control of enantioselectivity and reactivity with a wide variety of substrate structures.159161164... 

Although the use of asymmetric Baeyer-Villiger reactions for desymmetrization of several types of prochiral ketone using enzymes or metal-catalyzed systems is well established [81], few studies have been conducted on organocatalytic variants. An interesting organocatalytic Baeyer-Villiger reaction has been reported in which the planar-chiral bisflavin 32 (Fig. 12.12) promotes desymmetrization... 

Lewis CA, Chiu A, Kubryk M, Balsells J, Pollard D, Esser CK, Murry J, Reamer RA, Hansen KB, Miller SJ (2006) Remote desymmetrization at near-nanometer group separation catalyzed by a miniaturized enzyme mimic. J Am Chem Soc 128 16454—16455... 

A procedure in Organic Syntheses used acetylcholine esterase from electric eel as the enantioselective catalyst [29], but the much less expensive and more common enzyme, C. antarctica lipase B can also be used for this reaction [30]. Desymmetrization of 15 g of diacetate vnthin 10 h requires 2 g of Novozym 435 ( US 40) or 18 mg of acetylcholine esterase from electric eel ( US 500). The procedure given below uses Novozym 435, which is C. antarctica lipase B immobilized on acrylic resin. Note that this immobilization is by ionic absorption, which is effective in organic solvents, but not in water, which this procedure uses. The lipase washes off the resin in water and cannot be recovered. Lipase from P. cepacia (Amano PS-30) also catalyzes this desymmetrization [31], but the yield was only -60% because the hydrolysis stopped for unknown reasons. 

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