Tartaric acid, an efficient chiral auxiliary: new asymmetric synthesis of 2-alkyl-2-arylacetic acids

Abstract

A highly enantioselective synthesis of 2-alkyl-2-arylacetic acids, an important class of antiinflammatory agents, based on a new diastereoselective -bromination of homochiral acetals 1 and on the stereospecific silver-promoted rearrangement of the corresponding homochiral -bromo acetals 2 and 3, is reported. The new methodology represents a meaningful example of the use of tartaric acid as efficient and economic chiral auxiliary. The asymmetric bromination of 1 is of general character and occurs with very high diastereoselectivity, even at room temperature; a mechanism for the new reaction is proposed. The overall process has been successfully applied to the preparation of enantiomerically pure 2-alkyl-2-arylacetic acids, among them (2S)-(+)-2-(6-methoxy-2naphthyl)propanoic acid (Naproxen).

A Rearrangement Route to Fenvaleric Acid

“…Although our rearrangement employed the 3:1 mixture of threo and erythro diastereomeric amino alcohols and given that the migratory aptitude of the 4-chlorophenyl group ranges from 0.66 to 0.9 (phenyl=1) [18], our results were in accordance with the trends reported by Collins whereby a phenyl/ hydrogen migration ratio in dilute acids ranges from 0.43 -1.44 [19]. Interestingly, a simi-lar 4-chlorophenyl migration was employed in preparing optically active fenvaleric acid by treatment of a brominated chiral ketal derivative with silver ion [20]. Treatment of aldehyde 8 with Jones reagent (CrO 3 /H 2 SO 4 /H 2 O) followed by extractive workup and preparative TLC afforded the title carboxylic acid 2 (75%) as oil which slowly crystallized on standing.…”

α-Haloketal (1′R,4S,5S)-dimethyl 2-(1′-bromoethyl)-2-(3,4-dimethoxyphenyl)-1,3-dioxolane-4,5-dicarboxylate

“…Single crystals of (Ib) were obtained by a synthetic route (Castaldi et al, 1987) using 3,4-dimethoxypropylphenone as starting material which requires, in an intermediate step, an acid-promoted bromination of the enol ether by a substratecontrolled diastereoselective synthesis of the bromoketal with an observed stereochemistry, as also con®rmed by present X-ray studies of the title diastereomer. The crystal structure determination was undertaken to establish the absolute stereochemistry of the newly formed chiral centre at C10 in the reaction product, (Ib), according to the scheme below.…”

“…The absolute con®gurations of the other asymmetric centres at C12 and C13 were already known. These ®ndings are important in understanding the mechanism of diastereofacial selectivity induced by a chiral auxiliary in the halogenation of aryl enol ethers (Castaldi et al, 1986(Castaldi et al, , 1987Giordano et al, 1990), which is the key step in the industrial asymmetric synthesis ofarylpropionic acid derivatives (Giordano et al, 1989;Elks & Gamellin, 1990), the non-steroidal anti-in¯ammatory drugs widely prescribed as analgesics and in the treatment of rheumatoid arthritis (Reuben & Wittcoff, 1989), and also in the enantiomeric synthesis of the sulfur analogue of an 8,4 Hoxyneolignan derivative showing selective antagonistic activity in Platelet Activating Factor-induced platelet aggregation (Lariucci et al, 1995).…”

“…To prepare the title compound, a stirred solution of a mixture of (4S,5S)-dimethyl 2-(3 H ,4 H -dimethoxyphenyl)-2-ethyl-1,3-dioxolane-4,5-dicarboxylate (1.20 g, 33.9 mmol), easily obtained from the available 3,4-dimethoxypropylphenone in the presence of (À)-(4S,5S)-dimethyl tartrate, methyl orthoformate and methanesulfonic acid (Castaldi et al, 1987), was treated in carbon tetrachloride with 2methoxynaphthalene (8 mg, 0.05 mmol) followed by bromine (0.55 g, 34.4 mmol) at 263 K for 2 h. After pH neutralization, the solution was extracted with dichloromethane and the extract washed with water, dried over magnesium sulfate and evaporated to dryness to give a diastereomeric mixture of (Ia)/(Ib) with 1.38 g, 88% chemical yield and a diastereomeric ratio of 7:93.…”

Enantioselective hydrolysis of racemic naproxen nitrile and naproxen amide to S-naproxen by new bacterial isolates

“…Up to now the chiral synthesis of S-naproxen was achieved by chemical methods (Tsuchihashi et al, 1982;Franck and Riichardt, 1984;Giordano et al, 1984;Castaldi et al, 1987;Parrinello and Stille, 1987;Wolber and Riichardt, 1991;Sonawane et al, 1992;Brown, 1992) and by enantioselective hydrolysis of racemic esters of 0168-1656//94/$07.00 © 1994 Elsevier Science B.V. All rights reserved SSDI 0168-1656(93)E0099-J naproxen using microbial esterases (Gu et al, 1986;Battistel et al, 1991). In the present study the ability of two bacterial strains to produce pure S-naproxen (e.e.> 99%) from racemic naproxen nitrile or naproxen amide is described.…”