Solvent-Induced Chirality Switching in the Enantioseparation of Hydroxycarboxylic Acids with a Quaternary Stereogenic Center

Abstract

The enantiomer separation of three isomeric hydroxycarboxylic acids with a quaternary stereogenic center via diastereomeric salt formation with (1R,2S)-2-amino-1,2-diphenylethanol was demonstrated. Racemic acid 1, with a quaternary chiral center at the β-position, was separated with nearly ideal efficiency. The stereochemistry of acids 2 and 3 incorporated in the less-soluble salts was reversed depending on the recrystallization solvents, and both enantiomers were accessible. The mechanism of this chirality switching was discussed based on the crystal structures of the less-soluble diastereomeric salts; the solvation of the salt with an alcohol molecule changed the hydrogen-bonding network and its stability.

Scheme 1. Structures of the Resolving Agent, (1R,2S)-ADPE, and Target Hydroxycarboxylic Acids with a Quaternary Chiral Center (1–3)

Figure 1

Crystal structure of (S)-1·(−)-ADPE salt viewed from the a axis. Oxygen and nitrogen atoms are represented with red and blue balls, respectively. The dotted lines and arrows show hydrogen bonds and CH/π interactions, respectively.

Figure 2

Crystal structure of (S)-1·(−)-ADPE·H₂O salt viewed from the a axis. Oxygen and nitrogen atoms are represented with red and blue balls, respectively. The dotted lines and arrows show hydrogen bonds and CH/π interactions, respectively.

Figure 3

Crystal structure of 3·(−)-ADPE·0.5H₂O salt viewed from the b axis. Oxygen and nitrogen atoms are represented with red and blue balls, respectively. The dotted lines and arrows show hydrogen bonds and CH/π interactions, respectively.

Figure 4

Crystal structures of (R)-3·(−)-ADPE·n-PrOH·H₂O salt viewed from the a axis. Oxygen and nitrogen atoms are represented with red and blue balls, respectively. The dotted lines and arrows show hydrogen bonds and CH/π interactions, respectively.