Recent advances in the field of chiral crystallization

Abstract

Crystallization is one of the largest and most economical bulk purification techniques used in industry today. There has been an increase in demand for enantiomerically pure compound production for research, organic synthesis, pharmaceutical drug production, and other applications. Even after asymmetric synthesis, chiral purification will always be necessary. The focus of this review is on recent advances in chiral crystallization for the purification of enantiomers. A comprehensive discussion of three techniques and their mechanisms is provided, namely: attrition‐enhanced deracemization, cocrystallization, and inorganic ionic cocrystallization. Several examples of attrition‐enhanced deracemization are discussed. The key advantage of this technique is that it eliminates enantiomeric waste and can be used to produce enantiomeric excesses of greater than 99% from racemic mixtures. Chiral cocrystallization is examined, with over 60 cocrystallizing compounds, as an excellent means for enantiomeric enrichment. Selective chiral inclusion complexation was shown to be a novel approach for the formation of cocrystals. Chiral inorganic ionic cocrystallization is a new technique involving the formation of cocrystals between chiral ligands and certain metal salts in order to produce conglomerate crystal behavior in otherwise racemic compounds.

Case of Chiral Resolution through Converting Two Racemic Compounds into a Conglomerate

“…Although the former has made excellent progress in the past few decades, the synthesis is a complex and uneconomical process; moreover, the selectivity of reactions is not high enough. Among the general methods of chiral resolution, crystallization-based enantioseparation, including classical resolution, preferential crystallization, and so on, is the most flexible and productive way that is easy to be applied on an industrial scale . In classical resolution, a racemic compound (∼90% racemates) is usually resolved by a chiral enantiomerical resolving agent to form diastereomeric salts. , However, only conglomerates (5–10% racemates) and some of the low-component eutectic point racemic compounds (to avoid excessive consumption of pure enantiomers) can be separated into enantiopure components by directly adding the seeds of preferential crystallization …”

Teicoplanin aglycone media and carboxypeptidase Y: Tools for finding low‐abundance D‐amino acids and epimeric peptides

“…[14][15][16] Traditional methods of isolating and characterizing D-AAs and DAACPs have analytical impediments including partial racemization during acid hydrolysis, and they are isobaric to dominant L-amino acids (L-AAs) and all L-AA peptides. [14][15][16][17][18][19][20][21][22][23] A selective solid-phase extraction (SPE) type of format would be ideal if it could facilitate the extraction of D-AAs and D-AA-containing peptides from complex biological samples.…”

“…With the resurgence in interest involving biological roles and impacts of free D‐AAs as well as those incorporated in peptides/proteins, there is an increasing demand for sequence‐dependent stereospecific methodologies to aid in the search for these low‐abundance analytes in complex biological matrices 14–16 . Traditional methods of isolating and characterizing D‐AAs and DAACPs have analytical impediments including partial racemization during acid hydrolysis, and they are isobaric to dominant L‐amino acids (L‐AAs) and all L‐AA peptides 14–23 . A selective solid‐phase extraction (SPE) type of format would be ideal if it could facilitate the extraction of D‐AAs and D‐AA‐containing peptides from complex biological samples.…”

Organocatalytic‐racemization reaction elucidation of aspartic acid by density functional theory

“…Viedma ripening can be employed to obtain either L-or D-type enantiopure crystals. [7][8][9][10][11][12] Viedma provided the first evidence for the deracemization phenomenon of chiral crystals using sodium chlorate. 7 His group also showed that pure enantiomeric crystals (conglomerates) of aspartic acid (Asp) can be obtained by growing the crystal during stirring and under racemization conditions.…”

“…This organocatalytic reaction is an efficient and inexpensive method for amino acid racemization, 6 and has been exploited upon incorporation into a solid‐phase amino acid deracemization method termed Viedma ripening, despite the existence of a wide variety of other amino acid racemization methods such as under strong acids. Viedma ripening can be employed to obtain either l ‐ or d ‐type enantiopure crystals 7–12 . Viedma provided the first evidence for the deracemization phenomenon of chiral crystals using sodium chlorate 7 .…”