2- Arylpropionic esters

While the reactions ofketenes with enantiopure alcohols usually give modest selectivities [769], the use of (ethyl lactate (isopropyl lactate (/ )-2.1 (R = Me, R = i-Pr) or (R)-pantolactone 1.16 as proton donors has allowed the highly enantioselective formation of 2-arylpropionic esters. A mild hydrolysis (AcOH/HCl or LiOH) leads to the corresponding adds, which are anti-inflammatory drugs [554,923] (Figure 4.8). This method has been extended by Durst and Koh [861, 999] to the synthesis of enantioenriched a-halogenated esters, which are precursors of aminoacids (Figure 4.8). 

PdCl2(PhCN)2 associated with phosphines such as (+)-neomenthyldiphenylphosphine (NMDPP) and /)-toluenesul-fonic acid (TsOH) dissolved in [G4CiIm]BF4 catalyzes the hydroesterification of styrene derivatives to produce 2-arylpropionic esters in very good yields and regioselectivities (Scheme 18). The simple separation of the products and the use of lower CO pressures are the major advantages of the use of ILs in the hydroesterification of styrene derivatives as compared with the reactions performed under homogeneous conditions. ... 

The route (a) was explored [20] with a-halogenoesters (CICH2CO2R or C1CH (CH3)C02R) it yields -arylace tic or a-arylpropionic esters. 

More recently acids have been resolved with enzymes cloned and over-expressed in their own organisms, such as an esterase from Bacillus subtilis that resolves ibuprofen methyl ester 138 to give ibuprofen 139 of 99% ee. A range of anti-inflammatory arylpropionic esters, including 138, could also be resolved with a cell-free extract from Pseudomonas fluorescens showing that purified enzymes are not essential.34... 

Noel, S., Luo, C.H., Pinel, C. and Djakovitch, L. (2007) Efficient heterogeneously palladium-catalysed Heck arylation of acrolein diethyl acetal. Selective synthesis of cinnamaldehydes or 3-arylpropionic esters. Adv. Synth. Catal., 349, 1128-40. 

Malonic acid ester synthesis is a classic but still one of the most important C—C bond-forming reactions, because it is widely applicable to various types of compounds and the reaction can be performed under mild conditions without special care to remove the trace amount of water and oxygen contained in the solvent. This reaction is especially useful in the synthesis of carboxylic acids. One important class of carboxylic acids is arylpropionates because optically active ones are known to have anti-inflammatory activity and other interesting physiological... 

Many nonsteroidal anti-inflammatory drugs (NSAIDs) are substituted 2-arylpropionic acids. Most NSAIDs also have a chiral carbon next to the carboxylate and are administered as a racemic mixture of the two enantiomers. In general, the (S)-enantiomcr is responsible for most of the antiinflammatory activity of these agents. It was found that the (/ -enantiomer is converted to the (S)-enantiomer but the reverse does not occur (23). As with amino acid conjugation, the pathway involves reaction with ATP to form an AMP ester, which is, in turn, converted to a Co-A ester, and it is the Co-A ester that undergoes chiral inversion (Fig. 7.14). Substrates include ibuprofen, naproxen, and fenoprofen. 

The enantioselective esterification of 2-arylpropionic acids catalysed by a lipase was discussed earlier.26 Steady-state kinetics of the Pseudomonas cepacia lipase-catalysed hydrolysis of five analogous chiral and achiral esters (R)- and (.S )-(235 R1 = Me, R2 = H), (R)- and (reaction mixtures of water-insoluble substrates.212 The Km values were all die same and the apparent kcat values reflected the binding abilities of the alcoholate ions for the fast-reacting enantiomers. All the substrates are believed to be... 

Arylpropionic acids are important class of non-steroidal anti-inflammatory drugs (NSAID). Their pharmacological activity is mainly in one of both enantiomers. Thus, efforts had been made to access to the enantiomerically pure substance. The kinetic resolution of racemic 2-(2-fluoro-4-biphenyl) propanoic acid 56 and 2(4-isobutylphenyl) propanoic acid 59 (Ibuprofen) was performed via enzymatic esterification and transesterification using an alcohol and vinyl acetate, respectively in a membrane reactor. The unreacted acid is obtained in highly enantiomerically enriched form. A consecutive approach consisting of the enzymatic hydrolysis of the resulted esters is needed to achieve the alcohol in optically pure form.77... 

The lipase-catalysed hydrolysis of methyl 2-fluoro-2-arylpropionates was proposed to proceed via a mechanism whereby, after ester hydrolysis, the enzyme facilitates the elimination of fluoride ion with the formation of a carbocation stabilized by the adjacent C02 group.230 Determination of the crystal structure of human sialidase Neu2, an enzyme that catalyses the hydrolysis of sialic acids, reveals a tyrosine residue that is positioned in the active site to stabilize the carbocation proposed as an intermediate in the hydrolysis.231 ll-Fluoro-all-frans-retinol is found to undergo isomerization to its 11 -cis form in the presence of visual cycle enzymes, in contrast to a previous study where no isomerization was reported.232 The result of the prior study was taken as evidence for a carbonium ion pathway in the isomerization. Although the authors of the present study do not rule out such a mechanism, they suggest that the isomerization mechanism remains unknown. Data obtained in a study of the oxidation of... 

Diastereoselective protonation of arylmethylketenes. Merck chemists1 have described a conversion of (R,S)-2-arylpropionic acids (1) into the optically active forms. Thus 1 is converted into the corresponding arylmethylketene (2). Addition of a chiral alcohol can give optically active a-hydroxy esters 3 (and the acids). Of a... 

Two groups of chiral aromatic carboxylic acids are important commercial intermediates for the agricultural and pharmaceutical industries. The R enantiomer of a-phenoxypropionic adds confers biological activity for a number of herbiddes. The S enantiomer of a variety of arylpropionic adds is the biologically active form of the nonsteroidal antiinflammatory products labeled profens. Racemic mixtures of the alkyl esters of these propionic add derivatives have been effectiwly resolved to yield the desired optically active carboxylic acids (64-66). Figure 20 shows examples of the resolution of aromatic propionic acid esters. 

Figure 20 Lipase solution of (R,S)-arylpropionic acid and (R,S -oi-phenoxy-propionic acid esters.

Various arylpropionic acids show similar specificity. For most, if not all, the (5) enantiomer is the pharmacologically active one, whereas the R) enantiomer is usually much less active, although the ratio of iS)/ R) activity varies from drug to drug (and species to species). Only one of these drugs, however, is administered as the separated (S) enantiomer (naproxen, Naprosyn ). Normally these drugs are considered safe, and one cannot readily differentiate between the relative activities of the (S) and (R) forms because the in vivo half-life is very short, typically one or two hours. In patients with impaired renal function, where clearance is much slower, however, problems can arise. From in vivo studies of ibuprofen, it was established that the (S)-(-l-) isomer was responsible for antiinflammatory activity. In vivo, however, the (/ )-(-) isomer may become active because there is stereoselective inversion from R) to (S) (but not from 5 to R) in vivo with a half-life of about two hours. This inversion apparently proceeds by stereoselective formation of the coenzyme A (CoA) ester of the (f )-(-)-arylpropionic acid, followed by epimerization and release of the (S)-(+)-enantiomer. This epimerization is observed in vivo before the oxidative metabolism. Such inversion from (R) to (S) in vivo is also known for fenoprofen and benoxa-profen, and is expected to occur for most of the drugs of this series. ... 

Moreover, hydrocarboxylation reactions have been expanded to include functionalized olefins as substrates, leading to arylpropionic acids [16], fluorinated acids [17], silylated esters [18], and y5-amino acids [19] as products (Structures 1-6). 

It is assumed that the coenzyme A ester (CoA-ester) of the R(-)-enantiomer acts as a substrate for the fatty acid deshydrogenase, thus eliminating the chiral center. The next step may, or may not, take place, depending whether or not the CoA-ester must be transferred to an acyl-carrier protein or another site in the fatty acid synthetase system, so that a stereoselective reduction by an enoykeductase can take place. Thus the nature of X is unknown. Similar epimerization reactions were also described for some other arylpropionic acids such as benoxaprofen, carprofen, and isopropyl-indanyl-propionic acid. ° It was demonstrated that the configural inversion does not take place in the liver, and that the responsible enzyme, R-(-)-aryIpro-... 

Typical kinetic resolutions of the arylpropionic acids are those of flurbiprofen 16 and ketoprofen 18 with a cell-free extract of Pseudomonas fluorescens. Note the special ester (trifluoroethyl) selected for maximum efficiency and how successful that is perfect ee in the hydrolysed products at close to 50% conversion.8 The unreacted esters 15 and 17 can of course be racemised by enolisation and added to the next resolution. 

Steric physicochemical properties, where it was imagined that the metabolic hydrolysis rate could be quickened by extending the initial ester linkages away from the bulky aryl-group such that the sterically unhindered methyl 3-arylpropionate metabophore was finally identified... 

The arylation of esters is of importance as a synthetic method of arylacetic acids and 2-arylpropionic acids, which may exhibit antiinflammatory activity. Use of relatively bulky and strong bases such as hexamethyldisilazides has been reported to allow satisfactory results (Eqs. 18 and 19) [62-64]. The arylation of trimethylsilyl enolates of esters has also been described to occur effectively in the presence of a zinc(II) species, which proceeds via zinc enolates [65]. 

Kemal, C. Casida, J.E. Coenzyme A esters of 2-aryloxyphenoxypropio-nate herbicides and 2-arylpropionate antiinflammatory drugs are potent and... 

Ciimamaldehydes 111 are prepared by the reaction of acrolein diethyl acetal (110) with aryl halides and hydrolysis of the coupling product. Formation of saturated esters (3-arylpropionates) is competitive, and cinnamaldehydes were obtained with high selectivity in the presence of Pd(OAc)2, BU4NOAC, K2CO3, and KCl in DMF at 90 °C [66]. 

Scheme 2.1 Enantioselective hydrolysis of a-arylpropionic add esters using whole ceils or isolated enzymes.

As mentioned above, ketoprofen is widely used in clinical practice as a nonsteroidal anti-inflammatory drug, like the other 2-arylpropionic acids such as naproxen and ibuprofen. The anti-inflammatory activity of ketoprofen was previously believed to reside in its (S)-enantiomer. However, research has indicated that the (f )-enantiomer of ketoprofen was able to prevent periodontal disease and was thus of pharmacological value as a toothpaste additive. It has also been discovered that (i )-ketoprofen has several previously unappreciated advantages as an analgesic and antipyretic. Another yeast strain, Citeromyces matriemis CGMCC 0573, was therefore isolated for the enantioselective hydrolysis of (i )-ketoprofen ethyl ester. ... 

The enantioseparation of arylpropionic non-steroidal anti-inflammatory drug methyl esters was performed with a stationary phase containing methylated and silylated-(S-CD derivatives. The separation of salsolinol, levetiracetam, fluoxetine, norfluoxetine, ephedrine, methamphetamine, ephedrine type alkaloids, per-fluorodiether, iV-trifluoroacetyl-O-alkyl nipecotic ester, camphor, and 7-butyrolactone derivatives using different native CDs and CD derivatives were also reported. 

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