posted on 2004-06-11, 00:00authored bySusanne 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.