Hydrolysis, enantioselective

A number of examples of enantioselective hydrolysis of diesters (I and 2) of malonic and glutaric acids are given in Table I. 

Table 1. Enantioselective Hydrolysis of Malonate and Glutarate Esters...

It is generally beheved that selectivity of hydrolytic enzymes strongly depends on the proximity of the chiral center to the reacting carbonyl group, and only a few examples of successful resolutions exist for compounds that have the chiral center removed by more than three bonds. A noticeable exception to this rule is the enantioselective hydrolysis by Pseudomonasfluorescens Hpase (PEL) of racemic dithioacetal (5) that has a prochiral center four bonds away from the reactive carboxylate (24). The monoester (6) is obtained in 89% yield and 98% ee. 

Optically Active Acids and Esters. Enantioselective hydrolysis of esters of simple alcohols is a common method for the production of pure enantiomers of esters or the corresponding acids. Several representative examples are summarized ia Table 4. Lipases, esterases, and proteases accept a wide variety of esters and convert them to the corresponding acids, often ia a highly enantioselective manner. For example, the hydrolysis of (R)-methyl hydratropate [34083-55-1] (40) catalyzed by Hpase P from Amano results ia the corresponding acid ia 50% yield and 95% ee (56). Various substituents on the a-carbon (41—44) are readily tolerated by both Upases and proteases without reduction ia selectivity (57—60). The enantioselectivity of many Upases is not significantly affected by changes ia the alcohol component. As a result, activated esters may be used as a means of enhancing the reaction rate. 

PPL and Hpase from Pseudomonas sp. catalyze enantioselective hydrolysis of sulfinylalkanoates. For example, methyl sulfinylacetate (46) was resolved by Pseudomonas sp. Hpase in good yield and excellent selectivity (62). This procedure was suitable for the preparation of sulfinylalkanoates where the ester and sulfoxide groups are separated by one or two methylene units. Compounds with three methylene groups were not substrates for the Hpase (65). 

A very efficient and universal method has been developed for the production of optically pue L- and D-amino adds. The prindple is based on the enantioselective hydrolysis of D,L-amino add amides. The stable D,L-amino add amides are effidently prepared under mild reaction conditions starting from simple raw materials (Figure A8.2). Thus reaction of an aldehyde with hydrogen cyanide in ammonia (Strecker reaction) gives rise to the formation of the amino nitrile. The aminonitrile is converted in a high yield to the D,L-amino add amide under alkaline conditions in the presence of a catalytic amount of acetone. The resolution step is accomplished with permeabilised whole cells of Pseudomonas putida ATCC 12633. A nearly 100% stereoselectivity in hydrolysing only the L-amino add amide is combined with a very broad substrate spedfidty. 

Numerous other examples of enantioselective hydrolysis of esters have been reported. For example chymotrypsin, immobilised in a liquid membrane of kerosene or cydohexane, can be used for resolution of D,L-amino add esters in an emulsion type... 

Very few optically active cyanohydrins, derived from ketones, are described in the literature. High diastcrcosclectivity is observed for the substrate-controlled addition of hydrocyanic acid to 17-oxosteroids27 and for the addition of trimethyl(2-propenyl)silane to optically active acyl cyanides28. The enantioselective hydrolysis of racemic ketone cyanohydrin esters with yeast cells of Pichia miso occurs with only moderate chemical yields20. 

The phosphotriesterase from Pseudomonas diminuta was shown to catalyze the enantioselective hydrolysis of several racemic phosphates (21), the Sp isomer reacting faster than the Rp compound [65,66]. Further improvements using directed evolution were achieved by first carrying out a restricted alanine-scan [67] (i.e. at predetermined amino acid positions alanine was introduced). Whenever an effect on activity/ enantioselectivity was observed, the position was defined as a hot spot. Subsequently, randomization at several hot spots was performed, which led to the identification of several highly (S)- or (R)-selective mutants [66]. A similar procedure was applied to the generation of mutant phosphotriesterases as catalysts in the kinetic resolution of racemic phosphonates [68]. 

Figure 5.28 Enantioselective hydrolysis of sulfate esters using S. acidocaldarius.

Figure 6.28 Enantioselective hydrolysis of racemic trans-2,3-epoxy-3-arylpropanenitriles.

P-Lactamases (EC 3.5.2.6) produced by bacteria cleave the P-lactam ring and are responsible for their resistance to P-lactam antibiotics. Lactamases are useful catalysts for the enantioselective hydrolysis of P-lactams and other cyclic amides. P-lactams shown in Figure 6.40 were resolved by whole-cell systems containing an amidase [106]. 

Biocatalysis has emerged as an important tool for the enantioselective synthesis of chiral pharmaceutical intermediates and several review articles have been published in recent years [133-137]. For example, quinuclidinol is a common pharmacophore of neuromodulators acting on muscarinic receptors (Figure 6.50). (JJ)-Quinudidin-3-ol was prepared via Aspergillus melleus protease-mediated enantioselective hydrolysis of the racemic butyrate [54,138]. Calcium hydroxide served as a scavenger of butyric acid to prevent enzyme inhibition and the unwanted (R) enantiomer was racemized over Raney Co under hydrogen for recycling. 

Subtilisin E was found to efficiently catalyse enantioselective hydrolysis of certain A-acyl arenesulfinamides 34 to arenesulfinamides 35. Noteworthy, among... 

Layh N, A Stolz, S Eorster, E Effenberger, H-J Knackmuss (1992) Enantioselective hydrolysis of O-acetyl-mandelonitrile to O-acetylmandelic acid by bacterial nitrilases. Arch Microbiol 158 405-411. 

Ricks, E.E., Estrada-Vades, M.C., McLean, T.L. and Iacobucci, G.A. (1992) Highly enantioselective hydrolysis of (/ ,Sl-phenylalanine isopropyl ester by subtilisin Carlsberg. Continuous synthesis of (Sl-phenylalanine in a hollow fibre/liquid membrane reactor. Biotechnology Progress, 8, 197-203. 

Table 8.5 Enantioselective hydrolysis of /3-hydroxynitriles catalyzed by nitrilase bll6402 ...

Figure 5 Time-resolved IR thermographic imaging of the enantioselective hydrolysis of epoxide (48c) catalyzed by >S,//-(50a-c) after (a) 0, (b) 2.5, (c) 4, (d) 5, (e) 7, (g) 8, (h) 15, and (i) 32 min. In (f) the same images is shown as in (e), except that the temperature window ranges over 10 K. The bar on the far right of each image is the temperature/colour key of the temperature window used (°C).SS...

The enantioselective hydrolysis of racemic esters to give optically active acids and/or alcohols (Figure 1.1) is a well established protocol using esterases or lipases. In general, esterases from microorganisms or animal sources (such as... 

Enantioselective hydrolysis reactions, especially esters, amides and nitriles. 

Medicinal chemists are interested not only in hydrolysis of amides by mammalian amidases as exemplified above, but also in bacterial amidases as useful biosynthetic tools. Of particular interest is the enantioselective hydrolysis of chiral amides by various bacterial amidases. Some of these... 

Another promising development is the enantioselective hydrolysis of various racemic xenobiotic esters in healthy and cancerous rat liver cell lines [22], This has led to the design of anticancer prodrugs selectively activated by cancerous cell lines. 

Interestingly, asymmetry originating in an axis rather than in a stereogen-ic center can also result in enantioselective hydrolysis. Thus, pig liver car-boxylesterase has been shown to discriminate between the enantiomers of racemic allenic esters [23], The preferred substrates (7.8) had the ( -configuration when R and R were relatively small or acyclic, but the ( -configuration when one substituent was cyclic. For example, a very high enantioselec-tivity was seen for R = Ph and R and R" = Me or Et. 

Diesters ofalicyclic dicarboxylic acids are also valuable as tools to study the specificity of hydrolases. Such substrates can be achiral (e.g., cis-1,2-dicar bo xy 1 ate s) or chiral (e.g., fram-l,2-dicarboxy laics), allowing product-enantioselective hydrolysis or substrate-enantioselective hydrolysis, respectively, to take place. Considering first cis-7,2- and cis-1,3-diesters (e.g., 7.36,... 

R. Dernoncour, R. Azerad, Enantioselective Hydrolysis of 2-(Chlorophenoxy)propion-ic Esters by Esterases , Tetrahedron Lett. 1987, 28, 4661 -4664. 

K. Adachi, S. Kobayashi, M. Ohno, Chiral Synthons by Enantioselective Hydrolysis of meso-Diesters with Pig Liver Esterase Substrate-Stereoselectivity Relationships , Chi-mia 1986, 40, 311-314. 

S. K. Yang, K. Liu, F. P. Guengerich, Enantioselective Hydrolysis of Oxazepam 3-Acetate by Esterases in Human and Rat Liver Microsomes and Rat Brain S9 Fraction , Chirality 1990, 2, 150-155. 

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