Esters, enantioselective hydrolysis

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. 

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

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). 

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. 

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

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. 

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. 

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. 

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

Camell, A.J., Barkely, J. and Singh, A., Desymmetrisation of prochiral ketones by catal3ftic enantioselective hydrolysis of their enol esters using enzymes. Tetrahedron Lett., 1997, 38, 7781-7784 Allan, G.R., Carnell, A.J. and Kroutil, W., One-pot deracemisation of an enol acetate derived from a prochiral cyclohexanone. Tetrahedron Lett., 2001, 42, 5959-5962. 

Camell, A.J., Barkley, J. and Singh, A., Desymmetrisation of prochiral ketones by catalytic enantioselective hydrolysis of their enol esters using enzymes. Tetrahedron Lett., 1997,38,7781. 

The results actually showed a deracemization of the racemic hydroxyester 10 as opposed to enantioselective hydrolysis with formation of optically pure (R)-hydroxyester 10 and only 20 % loss in mass balance. Small quantities of ethyl 3-oxobutanoate 9 (<5%) were also detected throughout the reaction, leading the authors to suggest a multiple oxidation-reduction system with one dehydrogenase enzyme (DH-2) catalysing the irreversible reduction to the (R)-hydroxy-ester (Scheme 5). 

A semi-synthetic metalloenzyme that catalyses the enantioselective hydrolysis of simple amino acid esters has been reported. Iodoacetamido-l,10-phenanthroline (238) was interacted with a cysteine residue in adipocyte lipid binding protein (ALBP) to produce the conjugate ALBP-Phen (239), which was converted into its Cu(II) complex. The ALBP-Phen-Cu(II) was found to catalyse the enantioselective... 

Enzymes such as pig liver esterase have been successfully applied in enantioselective hydrolysis of allenyl esters on a scale of 2 mmoles131. This provides the enantiomerically enriched allene-carboxylic acid as well as the ester of opposite configuration, by what is in fact a catalytic kinetic resolution (6-90% oy). Conversely, partial enantioselective esterification of /1-hydroxy-allenes (3-72% oy) employing lipases has been reported132,133. 

Proteases have also been successfully used in ionic liquids. Papain mediated the enantioselective hydrolysis of a number of amino acid esters in an 80 20 mixture of [BMIm][BF4] and water [68]. The reaction rate was approx. 50% of that in aqueous buffer and equal to that in aqueous mixtures containing 70- 80% of solvents such as acetonitrile or tert-butyl alcohol. 

Lipase-mediated enantioselective hydrolysis of an N-unprotected aminoacid ester has been demonstrated with methyl phenylglycinate (Figure 10.9). In the presence of CaLB the E ratio was a rather modest 12, which improved when acetonitrile (ACN) or tert-butyl alcohol was added to the medium and further improved to 34 with 20% [BMIm][BF4] [68, 120]. The addition of more strongly hydrogen-... 

The enzymatic enantioselective hydrolysis of esters of naproxen and ibuprofen has attracted considerable attention because the (S)-enantiomers of these nonsteroidal anti-inflammatory drugs (NSAIDs) are the pharmacologically active isomers. These reactions have been successfully performed in a range of ionic liquids (Figure 10.10) [60, 65, 121]. 

Figure 10.10 Enantioselective hydrolysis of naproxen and ibuprofen esters. ...

Subtilisin is an endoprotease that has been used in the enantioselective hydrolysis of N-acylamino acid esters (Figure 10.16) into the corresponding (S)-amino acid derivatives. An organic solvent, such as acetonitrile, is often added to improve the solubility of the amino acid derivative, and this function can also be performed by an ionic liquid mixture [133, 134, 135]. 

The first enantioselective hydrosilylation of a-keto esters was carried out in 1977 by using DIOP-Rh catalysts, giving a-hydroxy esters after hydrolysis [401- i-Propyl pyruvate 44 was reduced to i-propyl (R)-lactate with 85.4% ee by using l-NpPhSiH2 (3) and a (-)-DIOP-Rh catalyst. 

The kinetic results for the lipase-catalysed enantioselective hydrolysis of the esters (236)-(240) can be interpreted in terms of frontier orbital localization.213 The porcine pancreatic lipase (PPL)-mediated optical resolution of 18 racemic esters can be explained by a mechanistic model involving a W-shaped active conformation of the substrate lying in a diastereo-discriminating plane.214... 

In order to reduce the time needed to perform a complete kinetic resolution Lindner et al53 reported the use of the allylic alcohol 30 in enantiomerically enriched form rather than a racemic mixture in kinetic resolution. Thus, the kinetic resolution of 30 was performed starting from the enantiomerically enriched alcohol (R) or (S)-30 (45%) ee obtained by the ruthenium-catalyzed asymmetric reduction of 32 with the aim to reach 100 % ee in a consecutive approach. Several lipases were screened in resolving the enantiomerically enriched 30 either in the enantioselective transesterification of (<5)-30 (45% ee) using isopropenyl acetate as an acyl donor in toluene in non-aqueous medium or in the enantioselective hydrolysis of the corresponding acetate (R)-31, (45% ee) using a phosphate buffer (pH = 6) in aqueous medium. An E value of 300 was observed and the reaction was terminated after 3 h yielding (<5)-30 > 99% ee and the ester (R)-31 was recovered with 86% ee determined by capillary GC after 50 % conversion. 

The rapid screening of different hydrolases for the enantioselective hydrolysis of esters of the difficult to resolve substrates such as pentalactone 47, 1-methoxy-2-propanol 48, 3-butyn-2-ol 49 and 3-hydroxy-tetrahydrofuam 50 was studied by Baumann et al. The screening was performed in a pH-indicator-based format in microtiter plates.72... 

Inure et al94 reported the enzymatic resolution of trans-10-Azido-9-acetoxy-9,10-dihydrophenanthrene 111 in gram-scale using Candida cyclindracea lipase-catalyzed enantioselective hydrolysis in phosphate buffer. The substrate 111 (the ester) was obtained in 89 % yield and 83 % ee while the product 112 (the alcohol) was obtained in 90 % yield and 98 % ee. 

The use of extracellular lipases of microbial origin to catalyze the stereoselective hydrolysis of esters of 3-acylthio-2-methylpropionic acid in an aqueous system has been demonstrated to produce optically active 3-acylthio-2-methyl-propionic acid [41-43], The synthesis of the chiral side chain of captopril by the lipase-catalyzed enantioselective hydrolysis of the thioester bond of racemic 3-acetylthio-2-methylpropionic acid (15) to yield 5 -(-)-(15) has been demonstrated [44], Among various lipases evaluated, lipase from Rhizopus oryzae ATCC 24563 (heat-dried cells), BMS lipase (extracellular lipase derived from the fermentation of Pseudomonas sp. SC 13856), and lipase PS-30 from Pseudomonas cepacia in an organic solvent system (l,l,2-trichloro-l,2,2-tri-fluoroethane or toluene) catalyzed the hydrolysis of thioester bond of undesired enantiomer of racemic (15) to yield desired S-(-) (15), R-(+)-3-mercapto-2-methylpropionic acid (16) and acetic acid (17) (Fig. 8A). The reaction yield of... 

Enantioselective Hydrolysis of a-Amino Esters Catalyzed by Humicola Amino Esterase... 

Initial scale up of the enzymatic resolution for production of kilogram quantities of (R)-2-amino-2-ethylhexanoic acid was performed in a batch process. The oil of ethyl 2-amino-2-ethyl-hexanoate was suspended in an equal volume of water containing the enzyme. The enantioselective hydrolysis of the ester proceeded at room temperature with titration of the produced acid by NaOH through a pH stat (Figure 6.4). 

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