Stereoselective SN2 Reactions of the (R)-Pantolactone Ester of Racemic .alpha.-Halo Carboxylic Acids with Aryl Oxides. A Synthesis of (S)-2-Aryloxy and (S)-2-Hydroxy Acids

Abstract

Optically active -hydroxy acids and esters are important and versatile building blocks in organic synthesis.1 Various methods have been developed for their preparation. These methods include the reduction of a-oxo esters2•3 and asymmetric oxygenation of chiral imide enolates.4 Very recently Corey and Link demonstrated that reduction of -trichloromethyl ketones by catecholborane in the presence of chiral oxazaborolidine catalyst yielded optically active trichloromethyl carbinols which on treatment with 4-methoxyphenoxide afforded optically active -aryloxy acids. Treatment of the methyl esters of the -aryloxy acids with ceric ammonium nitrate (CAN) furnished the desired -hydroxy esters.5The methodology reported in this paper for the preparation of optically active -hydroxy acids and a-aryloxy acids make use of the recently discovered reaction of (R)pantolactone esters of racemic -halo carboxylic acids with amines which furnished predominantly one of the two possible diastereomeric -amino esters with diastereoselectivity ranging from 88:12 to >95: <5 and in yields up to 80%.6 The greater than 50% yield of one diastereomer is due to epimerization of the slower reacting (2S)--halo ester into the faster reacting (2ñ)-isomer by the halide generated in the displacement reaction or added to the reaction mixture.

One-step synthesis of homochiral O-aryl and O-heteroaryl mandelic acids and their use as efficient 1H NMR chiral solvating agents

“…In a one-pot process, aryl and heteroaryl halides can be coupled to homochiral mandelic acid in yields ranging from 9% to 41% and in excellent enantiomeric purity, making this a superior method to those described previously. 15,[21][22][23][24][25][26] The method reported herein proceeds smoothly using a diverse array of aryl and heteroaryl halides; it seems to be applicable to both electrondeficient and electron-rich substrates, and to sterically hindered substrates as well. Some of the thus-obtained mandelic acid derivatives 4a,d,f,h were tested as CSAs for direct 1 H NMR ee determinations of amines.…”

“…However, partial racemization occurred (3a enantiomeric purity 41%) and the chemical yield was low (17%). 24 Recently, Durst's four-step procedure 25 was applied to the preparation of highly enriched forms of (S)-3a, 15 and (R)-and (S)-3b. 26 Looking for a more straightforward entry to O-aryl and O-heteroaryl mandelic acids 4a-h, we considered Job and Buchwald's one-step copper-promoted coupling of alcohols 27 and aminoalcohols 28 with iodoarenes.…”

Asymmetric Synthesis of Arylpropionic Acids and Aryloxy Acids by Using Lactamides as Chiral Auxiliaries

“…In an effort to improve the stereoselectivity previously obtained with other lactamidic auxiliaries, [5] we have investigated the nucleophilic substitution reaction of 2-bromobutanoyl esters 5a-d, derived by coupling of racemic 2-bromobutanoyl chloride and lactamides (S)-1a-d in equimolar ratios. Much like in a typical DKR, [9] treatment of 5a-d with sodium 4-chlorophenoxide was performed in THF at 0°C or 60°C, in the presence of NEt 3 and n-hexylammonium iodide as additives, gaining the diastereomeric mixtures of aryloxy esters (R,S)-6a-d and (S,S)-6a-d with good yields (Scheme 2). Thus, we have investigated the effects of chiral auxiliary and temperature on stereochemical outcome of substitution reaction, gaining diastereomeric ratios from 88:12 to 99:1 (Table 3); the diastereoselectivities are excellent and almost identical at 0°C (Entries 1,3,5,7), while a mild decrease was observed at 60°C (Entries 2,4,6,8); no substantial differences were found varying the lactamide.…”

H-NMR determination of the enantiomeric excess of the antiarrhytmic drug Mexiletine by using mandelic acid analogues as chiral solvating agents

“…Commercially available 2-bromo-2-phenylacetic acid (3a, X = H) was condensed with (R)-or (S)-pantolactone by a 1,3-dicyclohexylcarbodiimide (DCC) coupling in the presence of catalytic amounts of dimethylaminopyridine (DMAP) and the esters so obtained reacted, under Durst conditions, 61 with the suitable aryloxides to give compounds 4a-c with high diastereoselectivity. After purification by column chromatography and crystallization, the esters were hydrolyzed in mild basic conditions using 35% H 2 O 2 and LiOH to afford the desired acids 2a-c with high ee (>95%) after recrystallization.…”