S -2-arylpropionic acid

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... 

Enzymatic reduction, oxidation, ligase, or lyase reactions, especially, provide us with numerous examples in which prochiral precursor molecules are stereo-selectively functionalized. Ajinomoto s S-tyrosinase-catalyzed L-dopa process [112], the formation of L-camitine from butyro- or crotonobetaine invented by Lonza [113], and the IBIS naproxen route oxidizing an isopropylnaphthalene to an (S)-2-arylpropionic acid are representative, classic examples for many successful applications of enzymatic asymmetric synthesis on an industrial scale. A selection of recent industrial contributions in this field are summarized below. 

A lipase immobilized in this way retained 80% of its activity after 336 h. The catalyst could be reused three times before its activity dropped to 50% of the original value and it was still yielding more than 90% enantiomeric excess of S(+)-2-arylpropionic acids. An enzyme from Candida... 

Figure 10 Synthesis of (S)-2-arylpropionic acids by an (S)-specific nitrilase from Rhodococcus rhodochrous ATCC 21197.

Chemoenzymatic Preparation of Enantiomerically Pure S(+)-2-Arylpropionic Acids with Anti-Inflammatory Activity... 

We previously mentioned the importance of determining the appropriate solvent for acyl transfer reactions (esterification and transesterification). Nevertheless, it is difficult to select a universal solvent for the esterification of (R,S) 2-arylpropionic acids. In fact, hydrophobic solvents such as cyclohexane [98,102], isooctane [97], or the mixtures isooctane/ChC or isooctane/toluene [100] are recommended for the highly hydrophobic substrates naproxen and ibuprofen (see Tables 6 and 7). On the contrary, moderately hydrophilic acids such as ketoprofen (Table 5 [92]) or flurbiprofen (Table 8 [111]) are better esterified in sUghtly hydrophilic solvents such as cffisopropyl ether, methylwobutyl ketone, or 1,4-dioxane. Iherefore, we can conclude that depending on the hydrophobicity of the substrate we must select the organic solvent in order to obtain the best catalytic performance. 

Considerable effort has been directed towards the catalytic addition of HCN to vinylarenes since this represents a route to 2-arylpropionic acids, well-known anti-inflammatory agents.75 High levels of asymmetric induction are required (R)-naproxen has undesirable properties associated with it and only the ([Pg.277]

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. 

Styrene 20 mmols in benzene. [Rh] = O.OlOmmol. L = 0.040 mmol. The e.e. s were determined by GLC analysis of the corresponding 2-arylpropionic acids derived by Jones oxidation of the products... 

Alcaro, S. et al., Enantioselective semi-preparative HPLC of two 2-arylpropionic acids on glycopeptides containing chiral stationary phases, Tetrahedron Asymmetry, 13, 69, 2002. 

The 2-arylpropionic acid derivatives (profens) are important classes of NSAIDs that have been in clinical use for over 20 years. The profens have been used clinically as racemic agents with the exception of (S)-(+)-naproxen, which has been developed and used only as a single enantiomeric drug. 

The hydroformylation reaction of vinyl aromatics (Table 4)60 lends itself to the synthesis of a number of 2-arylpropionic acids in high enantiomeric excess that are nonsteroidal antiinflammatory agents.61 Previous asymmetric syntheses of these acids required the use of stoichiometric amounts of chiral auxiliaries, which in most cases are not easily recovered. The branched aldehyde was oxidized to (S)-(+)-na-proxen,62 in 84% yield. 

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... 

Okamoto, Y., Aburatani, R., Kaida, Y., Hatada, K., Inotsume, N., and Nakano, M. (1989) Direct chromatographic separation of 2-arylpropionic acid enantiomers using tris(3,5-dimethylphenylcarbamate)s of cellulose and amylose as chiral stationary phases, Chirality 1, 239-242. 

J. Caldwell, A. J. Hutt, and S. Foumel-Gigleux, The metabolic chiral inversion and dispositional enantioselecHvity of the 2-arylpropionic acids and their biological consequences," Biochem. Pharmacol., 37 105-114 (1988). 

The 2-arylpropionic acid ( profen ) non-steroidal anti-inflammatory drugs, each of which contains a single chiral center, are formulated as racemic (50 50) mixtures of the S(+)- and R(-)-enantiomers, with the exception of naproxen, which is formulated as the S(- -)-enantiomer. Based on inhibition of cyclooxygenase activity, the S(- -)-enantiomer is the eutomer (more potent enantiomer). These drugs differ markedly in both pharmacodynamic activity and pharmacokinetic behavior and, in addition, enantiomer pharmacokinetics of each drug varies among animal species. After intravenous administration of racemic keto-profen to horses, sheep, and 20-week-old calves and measurement of individual enantiomers in plasma, significant differences between the enantiomers were found in systemic clearance in horses and in both systemic clearance and volume of distribution in sheep... 

It is usual in humans for the S(+)-enantiomer of 2-arylpropionic acids to predominate in plasma and for the S(- -)- to R(-)-enantiomeric ratio of plasma concentrations to increase with time after administration of the racemate, which is often attributed to metabolic inversion of the chiral center of the R( )-enantiomers to their S(- -)-antipodes. ° In humans, the S(- -)-enantiomer is generally eliminated more slowly than is the R( )-enantiomer. The extent of chiral inversion of fenoprofen, which has been attributed to the differential rate of formation of the CoA-thioester by hepatic microsomes, varies widely among species. It has been estimated to be 90% in dogs, 80% in sheep, 73% in rabbits, 60% in humans, 42% in rats,f and 38% in horses. ... 

The 2-arylpropionic acid NSAIDs (the profens ) possess a chiral centre at the carbon atom a to the carboxyl function, and it is known that the activity of these drugs resides in the S(+) [szrasferj-enantiomers while the R(-) [rectus]-enantiomers either have low activity or are inactive (Shen, 1981). The NSAIDs of this subclass are formulated as racemic mixtures containing equal quantities of the two enantiomers, with the exception of naproxen which is commercially... 

Garcia, M.L., Tost, D., Vilageliu, J., Lopez, S., Carganico, G. Mauleon, D. (1998) Bioavailability of S(+)-ketoprofen after oral administration of different mixtures of ketoprofen enantiomers to dogs. Journal of Clinical Pharmacology, 38, 22S-26S. Hayball, P.J. Meffin, P.J. (1987) Enantioselective disposition of 2-arylpropionic acid nonsteroidal anti-inflammatory drugs. III. Fenoprofen disposition. Journal of Pharmacology and Experimental Therapeutics, 240, 631-636. 

The 2-arylpropionic acid class (2-APA) of nonsteroidal anti-inflammatory drugs (NSAlDs) (Table 1) is characterized by each member having an asymmetric carbon a to the carboxylic acid moiety. The R-enantiomer of this chiral center of some 2-APAs may undergo an in vivo inversion to the S-enantiomer. This inversion process varies substantially between the different members of this class and also varies between species of animal studied. The members of this class that are currently in clinical use include ibuprofen, ketoprofen, tiaprofenic acid, fenoprofen, and flurbiprofen. The majority are marketed as racemates. Naproxen and its sodium salt are internationally marketed as the pure S(-l-)-enantiomer, while ibuprofen and ketoprofen are now marketed in several European countries as the stereochemically pure S(-l-)-enantiomer. 

Hall, S.D. Xiaotao, Q. The role of coenz5me A in the biotransformation of 2-arylpropionic acids. Chem. Biol. Interact. 1994, 90, 235-251. 

Chen, C.S. Chen, T. Shieh, W.R. Metabolic stereoisomeric inversion of 2-arylpropionic acids. On the mechanism of ibuprofen epimerization in rats. Biochemica Biophysica Acta 1990, 1033, 1-6. 

Hall, S.D. Hassanzadeh-Khayyat, M. Knadler, M.P. Mayer, P.R. Pulmonary inversion of 2-arylpropionic acids influence of protein binding. Chirality 1992, 4, 349-352. 

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