Design and evaluation of inclusion resolutions, based on readily available host compounds.
S. Muller, M.C. Afraz, R. de Gelder, G.J.A. Ariaans, B. Kaptein, Q.B. Broxterman, A. Bruggink
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY 2005, 6, 1082-1096

Abstract:
Resolution of enantiomers through selective crystallisation of diastereomeric inclusion compounds can extend the scope of traditional racemate resolution beyond salt forming compounds. To assess the practical value of this approach the literature was carefully screened and promising results were checked. Also an extensive range of new inclusion hosts suitable for resolution processes, derived from simple hydroxy- and amino acids were prepared and tested. Several techniques, including the Dutch Resolution approach utilizing mixtures of resolving agents, were applied. Over 70 potential resolving agents were tested in combinations with 34 racemates (over 100 racemates if literature results are included). Reproducibility of literature results was found to be problematic. Also the number of successful new resolutions found was very limited: only two efficient resolutions out of 1200 combinations of racemate and resolving agent tested in over 10.000 experiments! Crystal studies of representative combinations of resolving agents and inclusion compounds revealed some of the causes for the low rate of success in inclusion resolution. Compared to diastereomeric salts, the absence of strong electrostatic interactions substantially reduces the probability of forming crystals including both components. Molecular structure features allowing formation of intricate intramolecular and intermolecular H-bond networks were found to be responsible for inclusion crystal formation, and for the quality of the ensuing resolution through selective diastereomer crystallisation, in the successful cases. Whereas diastereomeric salt resolution continues to be of scientific and industrial interest, inclusion resolution should be viewed as of very limited scope; useful in specific instances, but lacking the wide applicability of classical resolution.