Unusual Enantiomeric Resolution Phenomenon Observed upon Recrystallization of a Racemic Compound

Abstract

Efficient enantiomeric resolution of the antiallergenic agent (±)‐ST, which shows crystalline polymorphism, is accomplished by simple recrystallization. Both stable crystals of the racemic compound and metastable mixed crystals are formed, and the enantiomeric enrichment of the mother liquor virtually reaches 100% ee.

Chiral Symmetry Breaking Phenomenon Caused by a Phase Transition

“…In 1996 we found the first instance where such an ideal enantiomeric resolution by simple recrystallization of a series of racemic crystals is feasible [5,6]. In 1998, this new phenomenon was referred to as preferential enrichment [20], which is completely opposed to preferential crystallization; in preferential enrichment it is in the mother liquor that substantial enantiomeric enrichment occurs by recrystallization, and at the same time slight enrichment of the opposite enantiomer always occurs in the deposited crystals ( Figure 3).…”

“…However, until our discovery of "preferential enrichment", an unusually symmetry-breaking enantiomeric resolution phenomenon observed upon recrystallization of organic racemic crystals [5][6][7][8], this fascinating subject was not realized.…”

“…These results strongly support our proposed mechanism of preferential enrichment. After a thorough investigation on the mechanism, preferential enrichment has been found to be initiated by the solvent-assisted solid-to-solid transformation of a metastable polymorphic form into a thermodynamically stable one during crystallization from the supersaturated solution of certain kinds of racemic mixed crystals (i.e., solid solutions or pseudoracemates) composed of two enantiomers without the aid of any external chiral element [5][6][7][8]. Most notably, this polymorphic transition process is followed by partial crystal disintegration inside the transformed crystal lattice to release the excess enantiomer into solution until the deposited crystals are slightly enriched with the opposite enantiomer (<10% ee), with full reproducibility [5][6][7][8].…”

“…After a thorough investigation on the mechanism, preferential enrichment has been found to be initiated by the solvent-assisted solid-to-solid transformation of a metastable polymorphic form into a thermodynamically stable one during crystallization from the supersaturated solution of certain kinds of racemic mixed crystals (i.e., solid solutions or pseudoracemates) composed of two enantiomers without the aid of any external chiral element [5][6][7][8]. Most notably, this polymorphic transition process is followed by partial crystal disintegration inside the transformed crystal lattice to release the excess enantiomer into solution until the deposited crystals are slightly enriched with the opposite enantiomer (<10% ee), with full reproducibility [5][6][7][8]. Thus, the interplay of i) such a solvent-assisted solid-tosolid polymorphic transition, ii) the subsequent selective redissolution process of the excess enantiomer, which arises from the increasing solubility of the sample with increasing ee value, and iii) the resulting deposition of mixed crystals, which can retain the resulting fairly-random alignment of two enantiomers inside the crystal lattice to memorize an event of chiral symmetry-breaking, has turned out to be responsible for this unique enantiomeric resolution phenomenon [5][6][7][8].…”

“…Most notably, this polymorphic transition process is followed by partial crystal disintegration inside the transformed crystal lattice to release the excess enantiomer into solution until the deposited crystals are slightly enriched with the opposite enantiomer (<10% ee), with full reproducibility [5][6][7][8]. Thus, the interplay of i) such a solvent-assisted solid-tosolid polymorphic transition, ii) the subsequent selective redissolution process of the excess enantiomer, which arises from the increasing solubility of the sample with increasing ee value, and iii) the resulting deposition of mixed crystals, which can retain the resulting fairly-random alignment of two enantiomers inside the crystal lattice to memorize an event of chiral symmetry-breaking, has turned out to be responsible for this unique enantiomeric resolution phenomenon [5][6][7][8].…”