A-arylpropionic acids

Electrochemistry offers new routes to the production of several commercially relevant a-arylpropionic acids, used as non-steroidal anti-inflammatory agents (NSAI) [178,182]. A preparative method based on sacrificial Al-electrodes has been set up for the electrocarboxylation of ketones [117,183-187] and successfully applied to the electrocarboxylation of aldehydes, which failed with conventional systems. The electrocarboxylation of 6-methoxy-acetonaphthone to 2-hydroxy-2-(6-methoxynaphthyl)propionic acid, followed by chemical hydrogenation to 2-(6-methoxynaphthyl)-2-propionic acid - one of the most active NSAI acids - has been developed up to the pilot stage [184,186],... 

Non-steroidal anti-inflammatory a-arylpropionic acids were also prepared from the corresponding benzylic chlorides and CO2 using as catalyst Ni-dppe or Ni-dppp in the presence of COD (Table 16) [103]. The use of the catalyst in this reaction is not absolutely required but its use limits the homocoupling reaction which would be the main process at high concentration of the benzylic halide and low pressure of CO2 [104]. 

Biocatalytk decarboxylation is a imique reaction, in the sense that it can be considered to be a protonation reaction to a carbanion equivalent intermediate in aqueous medimn. Thus, if optically active compoimds can be prepared via this type of reaction, it would be a very characteristic biotransformation, as compared to ordinary organic reactions. An enzyme isolated from a specific strain of Alcaligenes bronchisepticus catalyzes the asymmetric decarboxylation of a-aryl-a-methyhnalonic acid to give optically active a-arylpropionic acids. The effect of additives revealed that this enzyme requires no biotin, no co-enzyme A, and no ATP, as ordinary decarboxylases and transcarboxylases do. Studies on inhibitors of this enzyme and spectroscopic analysis made it clear that the Cys residue plays an essential role in the present reaction. The imique reaction mechanism based on these results and kinetic data in its support are presented. 

Keywoids Asymmetric decarboxylation. Enzyme, Reaction mechanism, a-Arylpropionic acid. 

At the start of this project, we chose a-arylpropionic acids as the target molecules, because their S-isomers are well established anti-inflammatory agents. When one plans to prepare this class of compounds via an asymmetric decarboxylation reaction, taking advantage of the hydrophobic reaction site of an enzyme, the starting material should be a disubstituted malonic acid having an aryl group on its a-position. 

The hydrocarboxylation of styrene (Scheme 5.12) and styrene derivatives results in the formation of arylpropionic acids. Members of the a-arylpropionic acid family are potent non-steroidal anti-inflammatory dmgs (Ibuprofen, Naproxen etc.), therefore a direct and simple route to such compounds is of considerable industrial interest. In fact, there are several patents describing the production of a-arylpropionic acids by hydroxycarbonylation [51,53] (several more listed in [52]). The carbonylation of styrene itself serves as a useful test reaction in order to learn the properties of new catalytic systems, such as activity, selectivity to acids, regioselectivity (1/b ratio) and enantioselectivity (e.e.) in the branched product. In aqueous or in aqueous/organic biphasic systems complexes of palladium were studied exclusively, and the results are summarized in Table 5.2. 

Aryl fluorides, 149 Arylpenta-2,4-dienoates, 161 a-Arylpropionic acids, 314 Arylsulfonylalkynes, 7 Arylthallium bistrifluoroacetates, 462 a-Atlantone, 514 Atiolactic acid methyl ether, 290 Aucubin, 73... 

Evans s oxazolidinones 1.116 and 1.117 are a class of chiral auxiliaries that has been widely applied [160, 167, 261, 411]. Deprotonation of 7/-acyl-l,3-oxa-zolidin-2-ones 5 30 and 5.31 smoothly gives chelated Z-enolates, which then suffer alkylation between -78 and -30°C on their least hindered face [167, 1036]. After hydrolysis, the corresponding enantiomeric acids are obtained according to the auxiliary that was used (Figure 5.21). Due to the low reactivity of lithium enolates, sodium analogs are preferred in some cases [411, 862, 1036], This methodology has been applied to the synthesis of chiral a-arylpropionic acid anti-inflammatory drugs [1037, 1038], natural products [1039, 1040], and a-substituted optically active 3-lactams en route to nonracemic a,a-disubstituted aminoacids [136,1041]. 

The hydrocarboxylation of styrene (Scheme 5.12) and styrene derivatives results in the formation of arylpropionic acids. Members of the a-arylpropionic acid family are potent non-steroidal anti-inflammatory drags (Ibuprofen, Naproxen etc.), therefore a direct and simple route to such compounds is of considerable industrial interest. In fact, there are several patents describing the production of a-arylpropionic acids by... 

Since this method allows us easily to construct structures branched at benzylic positions, it was applied to the synthesis of a-arylpropionic acids, including anti-inflammatory agents. An example is the facile synthesis of ibuprofen by such an allyl-aryl coupling and subsequent oxidation (Scheme 10-8) [29]. The cross-coupling was more effective when the substrate had an electron-withdrawing group. 

Many kinetic resolutions of rac-nitriles were performed in search of a method to produce (S)-configurated a-arylpropionic acids, such as ketoprofen, ibuprofen, or naproxen, which are widely used as nonsteroidal antiinflammatory agents. Overall, enantioselectivities depended on the strain used, and whether a nitrilase- or nitrile hydratase-amidase pathway was dominant, which determines the nature of (enantiomeric) products consisting of a mixture of nitrile/carboxylic acid or amide/ carboxylic acid, respectively [687, 693-696]. 

R)-4-Methyl-5-phenyl-oxazolidin-2-one, a chiral auxiliary for an electrochemical approach to the preparation of a-arylpropionic acids, has been obtained in one step by fusing above the melting point (R)-2-phenylglycinol with urea [570]. The urea first decomposes to free cyanic acid, which then reacts with the amino group to form a j5-hydroxyethylurea derivative. This subsequently cyclizes with loss of ammonia to afford the product [571]. 

Scheme 2.1 Enantioselective hydrolysis of a-arylpropionic acid esters using whole cells or isolated enzymes.

Roy O, Riahi A, Henin F, Muzart J. Catalysed asymmetric protonation of simple linear keto-enolic species. A route to chiral a-arylpropionic acids. Eur. J. Org. Chem. 2002 3986-3994. 

Kumar A, Salunkhe RV, Rane RA, Dike SY. Novel catalytic enantioselective protonation (proton transfer) in Michael addition of benzenethiol to a-acrylacrylates synthesis of (5)-naproxen and a-arylpropionic acids or esters. J. Chem. Soc. Chem. Commun 1991 485-486. 

Sonawane et al. investigated the photorearrangement of several para-substituted propiophenones as a convenient entry for substituted a-arylpropionic acids, as shown in Eq. (69.9) ... 

Reduction of a-arylvinylphosphonates in the HCOONH -Pd/C system led to a-arylethylphosphonates, which represent phosphorus-substituted analogs of a-arylpropionic acids (including Naproxen and Ibuprofen). These derivatives are in demand in pharmaceutical applications due to their biological activity [69]. 

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