From molecular recognition to racemic resolution by fractional crystallization of diastereomeric salts

Synthesis and isolation of enantiopure compounds remains an important challenge in medicinal, pharmaceutical, alimentary as well as material chemistry. Amongst many methods leading to enantiopure compounds, formation and fractional crystallization of diastereomeric salts of an enantiopure resolving agent is the most popular one. Since its discovery many years went by, and yet it has been performed by the trial and error method. Selection of the suitable resolving agent is crucial for racemic resolution efficiency. Hence, this review is concerned with common features of crystal structures of salts, in which resolving agents, frequently used for separation of racemic acids, are involved. Among them, there are crystal structures of salts of primary, secondary and tertiary chiral amines (1-arylethylamines, ephedrine, pseudoephedrine, deoxyephedrine, chinine, chinidine, cinchonine, cinchonidine, strychnine and brucine). In most of them, cations and anions are involved in characteristic systems of hydrogen bonds leading to formation of cationic-anionic self-assemblies. In this respect, brucine and strychnine appear as unique, because presence of anions usually does not affect formation of common cationic self-assemblies stabilized by weak hydrophobic interactions. Comparison of the common structural motifs indicates different factors being crucial in molecular recognition and in diastereomeric diversification. Formation of common hydrogen bonded cationic-anionic self-assemblies plays a dominant role in molecular recognition of a given acid by most of the studied amines. In turn, formation of common cationic self-assemblies stabilized by hydrophobic interaction plays a crucial role in molecular recognition of a given acid by brucine or strychnine. Diastereomeric diversification can be realized in various ways. In extreme cases, when molecular recognition in crystals of particular diastereomeric salts is similar, diastereomeric diversification is governed by different factors, depending on factors governing molecular recognition. Hydrophobic interactions play an important role in diastereomeric diversification when molecular recognition is governed by hydrogen bonds. In turn, when molecular recognition is governed by hydrophobic interactions, different hydrogen bond systems in crystals of particular salts are responsible for their diastereomeric deversification