Arylacetic acids, asymmetric

Among the different synthetic procedures available for the preparation of hydratropic acids (e.g., indirect methylation of arylacetic acids. asymmetric hydroformylation of styrenes,5 rearrangements of a-bromoalkyl aryl ketals, etc.), direct methylation of arylacetic acid derivatives seems the most attractive from both economical and synthetic aspects the reagents are easily accessible and a one-pot reaction is involved. Nevertheless, this procedure is seldom used since the yields of the monomethyl derivatives are severely limited by the low selectivity of the reaction. Sizeable amounts of dimethylated by-products form.2 Even under phase-transfer catalysis conditions, high selectivity in monomethylation is elusive. ... 

In an industrial asymmetric synthesis en route to the antiinflammatory agent naproxen, the dimethyl L-tartrate acetals of ethyl aryl ketones are brominated in high yield and selectivity to give the corresponding a-bromo derivatives. Subsequent stereospecific Ag -promoted 1,2-aryl migration provides the 2-alkyl-2-arylacetic acid after hydrolysis of the tartrate auxiliary, which is recovered (e.g. eq 4). 

As an alternative to the use of auxiliaries for the asymmetric alkylation of carboxylic acid derivatives, in 2011, Zakarian and Stivala reported on the direct stereoselective alkylation of arylacetic acids with chiral lithium amide bases.This method offers an alternative to traditional auxiliary-based methods and operates through the formation of enediolates also, it builds on earlier work by Shioiri and Ando and by Koga and Matsuo . Zakarian and Stivala examined several C2-symmetric tetramines for their enan-tiodirecting power. After significant experimentation, conditions were established that used 4 equivalents of -BuLi and a slight excess of the tetramine that provided clean formation of the desired product. The enantioselectivity was found to be dependent on the quality of the -butyllithium. The reaction scope was examined with a variety of... 

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