Despite the large number of elaborate enantioselective syntheses for the preparation of a single enantiomer to achieve industrial and scientific goals, the separation and purification of enantiomers (components of racemic compounds) is also necessary. Hence, we present the most often used thought-provoking modern methods based on momentous recognitions (e.g. spontaneous resolution, induced crystallization, resolution by formation of diastereomers, resolution by formation of non-covalent diastereomers, resolution by diastereomeric salt formation, resolution by diastereomeric complex formation, "half equivalent" methods of resolution, separation by crystallization, separation by distillation, separation by supercritical fluid extraction, resolution with mixtures of resolving agents, resolution with a derivative of the target compound, enantioselective chromatography, resolution by formation of covalent diastereomers, resolution by substrate selective reaction, kinetic resolution without enzymes, kinetic resolution by enzyme catalysis, hydrolytic and redox enzymes, kinetic and thermodynamic control, resolutions combined with 2nd order asymmetric transformations, enrichment of partially resolved mixtures, role of the solvent and methods of optimization in the separation of diastereoisomers, non-linear effects and selected examples of resolution on an industrial scale).
Non-racemic enantiomeric mixtures form homochiral and heterochiral aggregates in melt or suspension, during adsorption or recrystallization, and these diastereomeric associations determine the distribution of the enantiomers between the solid and other (liquid or vapour) phases. That distribution depends on the stability order of the homo- and heterochiral aggregates (conglomerate or racemate formation). Therefore, there is a correlation between the binary melting point phase diagrams and the experimental ee(I)vs. ee(0) curves (ee(I) refers to the crystallized enantiomeric mixtures, ee(0) is the composition of the starting ones). Accordingly, distribution of the enantiomeric mixtures between two phases is characteristic and usually significant enrichment can be achieved. There are two exceptions: no enrichment could be observed under thermodynamically controlled conditions when the starting enantiomer composition corresponded to the eutectic composition, or when the method used was unsuitable for separation. In several cases, when kinetic control governed the crystallization, the character of the ee(0)-ee(I) curve did not correlate with the melting point binary phase diagram.
Despite unprecedented advances in enantioselective synthesis and separation techniques, large scale production of enantiopure substances, such as required by the pharmaceutical and pesticide industries, is still heavily dependent upon the separation of diastereomers obtained from the enantiomers and an optically active resolving agent. Economy of the process can be much enhanced when only a half-equivalent of the resolving agent is used. Substitution of the other half-equivalent by some achiral compound, as well as separation of the unreacted portion of the substrate from the diastereomer by various physical methods, is discussed. Methods for selecting optimal conditions of resolution and for the purification of partially resolved mixtures are also discussed.
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