2-Arylpropionic acids, synthesis

Hodous BL, Ruble JC, Fu GC (1999) Enantioselective addition of alcohols to ketenes catalyzed by a planar-chiral azaferrocene catalytic asymmetric synthesis of arylpropionic acids. J Am Chem Soc 121 2637-2638... 

Platinum complexes with chiral phosphorus ligands have been extensively used in asymmetric hydroformylation. In most cases, styrene has been used as the substrate to evaluate the efficiency of the catalyst systems. In addition, styrere was of interest as a model intermediate in the synthesis of arylpropionic acids, a family of anti-inflammatory drugs.308,309 Until 1993 the best enantio-selectivities in asymmetric hydroformylation were provided by platinum complexes, although the activities and regioselectivities were, in many cases, far from the obtained for rhodium catalysts. A report on asymmetric carbonylation was published in 1993.310 Two reviews dedicated to asymmetric hydroformylation, which appeared in 1995, include the most important studies and results on platinum-catalogued asymmetric hydroformylation.80,81 A report appeared in 1999 about hydrocarbonylation of carbon-carbon double bonds catalyzed by Ptn complexes, including a proposal for a mechanism for this process.311... 

In the preparation described above we have an important means of making fi-arylacrylic acids, and from them, by hydrogenation, fi-arylpropionic acids. The method is used in the investigation of alkaloids and in the synthesis of coumarin from salicylaldehyde. 

The cathodic substitution of halides has been applied in the synthesis of antiinflammatory agents. Arylpropionic acids are formed by reductive dehalogenation of the corresponding benzylic halides in the presence of carbon dioxide as electrophile [22] ... 

In other cases, carbon dioxide has been used as an electrophile, such as in the synthesis of arylpropionic acids (Eq. 22.19). 

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. 

Mono-C-Methylation of Arylacetonitriles and Methyl Arylacetates by Dimethylcarbonate A General Method for the Synthesis of Pure 2-Arylpropionic Acids. 

Multiatomic [6] as well as cationic [7] rhodium catalysts also display a high preference for linear hydroformylation products. However, a catalyst system which generally yields branched hydroformylation products has not yet been found. Vinylarenes, such as styrene (16), form preferentially the (.vo-aldehyde 20 and not the n-aldehydes. The possibility to form a relatively stable Rh- -allyl complex 18 is most likely the decisive factor for this result [8]. Subsequent oxidation of 20 leads to 2-arylpropionic acids 21, of which some derivatives like 22-24 are of great importance as non-steroidal inflammatory drugs (NSID) (Scheme 3) [9]. For their synthesis by the hydroformylation of styrenes, not only a regioselective but also an enantioselective reaction process is... 

Since this method allows us easily to construct structures branched at benzylic positions, it was applied to the synthesis of -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. 

Scheme 7 displays a possibility of the synthesis of chiral 2-arylpropionic acids via the oxidative tranformation of (7 )-3-aryl-l-butenes. The requisite chiral olefins may be obtained by transition metal-catalyzed asymmetric coupling between a benzylic Grignard reagent and vinyl bromide (93 % optical yield) [28] or, more attractively, asymmetric hydrovinylation of an aromatic olefin with ethylene. The asymmetric combination of styrene and ethylene, giving the adduct 25 in 95 % ee, has been performed on a 10-kg scale with a dinuclear Ni catalyst formed from ( -allyl)NiCl2 and a unique chiral dimeric aminophosphine obtainable from (/ )-myrtenal and (5)-l-phenylethylamine [7a],... 

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. 

Tundo, P. Selva, M. Bomben, A., Mono-C-methylation of Aryacetonitriles and Methyl Arylac-etates by Dimethyl Carbonate A General Method for the Synthesis of Pure 2-Arylpropionic Acids. 2-Phenylpropionic Acid. Org. Syn. 1998,16,169. 

For other anti-inflammation drugs such as Naproxen59 and Fenoprofen,60 only the S-isomer is biologically active. Since tedious resolutions are necessary to prepare these compounds, it would be desirable to develop a general asymmetric synthesis of the S(+) arylpropionic acids by microbial oxidation of pro-chiral substrates. This concept has been successfully applied in the preparation of a chiral metabolite of 29. Oxidation of one of the enan-tiotopic methyl groups in 30 with sulfurescens furnished the chiral diol 31.61 A similar oxidation of isobutyric acid (32)62 to S-(+)-3-hydroxy-2-mdthylpropionic acid (33) has been recently employed in the synthesis of the a-tocopherol synthon (34).63... 

Reactions of chiral allylic boranes with carbonyl compounds Reactions of chiral allyl boranes with imines Asymmetric Addition of Carbon Nucleophiles to Ketones Addition of alkyl lithiums to ketones Asymmetric epoxidation with chiral sulfur ylids Asymmetric Nucleophilic Attack by Chiral Alcohols Deracemisation of arylpropionic acids Deracemisation of a-halo acids Asymmetric Conjugate Addition of Nitrogen Nucleophiles An asymmetric synthesis of thienamycin Asymmetric Protonation... 

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]. 

Dihydrocoumarins and Dihydroisocoumarins. - The potential of thalHum compounds in organic synthesis continues to be developed in a variety of reactions. One of these was the synthesis of dihydrocoumarins by oxidative cyclization of 3-arylpropionic acids, e.g. (177), by thallium(in) trifluoro-acetate-trifluoracetic acid (TTFA). The coumarin was accompanied by methyl 3-(2-hydroxyphenyl)propionate (178), which was formed by ring-... 

A GENERAL METHOD FOR THE SYNTHESIS OF PURE 2-ARYLPROPIONIC ACIDS. 2-PHENYLPROPIONIC ACID (Benzeneacetic acid, a-methyl-)... 

FLUORO-2-PHENYLPROPANE, represents another route to a number of monofluorinated compounds. The mono-C-methylation of arylacetonitriles and methyl arylacetates by dimethyl carbonate as a route to 2-arylpropionic acids is exemplified by the synthesis of 2-PHENYLPROPIONIC ACID, the simplest member of an important class of anti-inflammatory agents. 

---