American Chemical Society
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Efficient Crystallization-Induced Dynamic Resolution of α-Substituted Carboxylic Acids

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journal contribution
posted on 2004-06-11, 00:00 authored by Susanne Kiau, Robert P. Discordia, Gary Madding, Francis J. Okuniewicz, Victor Rosso, John J. Venit
Herein we present a novel route to enantiomerically enriched chiral α-substituted carboxylic acids by crystallization-induced dynamic resolution (CIDR) of their diastereomeric salts with chiral amines. Thus, the racemic α-bromo acid 3 is converted reliably with (1R,2S)-2-amino-1,2-diphenylethanol in the presence of a catalytic amount of tetrabutylammonium bromide into its R-enantiomer 4 in 90% yield with 88% ee. Similarly, the racemic α-thiobenzoyl acid 5 could be resolved to 90% ee in 74% yield. Further enrichment to enantiomeric homogeneity could be achieved in both cases by crystallization. In a telescoped, two-step process, S-α-thiobenzoyl acid 6 (≥99.6% ee) was prepared from the racemic bromide 3 in 63% yield. State-of-the-art parallel experimentation enabled rapid screening for suitable dynamic resolution conditions. Kinetic studies defined the influence of temperature, tetrabutylammonium bromide concentration, molarity, and solvent polarity on the resolution rate, product yield, and enantiomeric excess.