Study on chiral discrimination mechanism upon crystallization and its application to development of novel general optical resolution method.

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In order to clarify the mechanism of optical resolution upon crystallization and to rationally design a tailor-made resolving agent, the optical resolution of systematically selected racemates with series of resolving agents have been studied. As a result of comparison of the crystal structures between the less- and more-soluble diastereomeric salts, it has been found that the lesssoluble salts were effectively stabilized by hydrogen-bonding, CH…π, and van der Waals interactions. On the basis of this result, we desinged 2-naphthylglycolic acid, cis-1-amino-2-indanol, etc., in which a hydrogen-bonding group and other interacting group (s) were suitably placed to stabilize the less-soluble salts. In fact, these resolving agents had excellent resolution ability for 1-arylethylamines and 2-arylalkantoic acids, respectively. Thus, we have succeeded in designing novel resolving agents on the basis of the concept of crystal engineering.On the other hand, we focused on the fact that there is a similarity in crystal structure between a conglomerate salt of a chiral amine with an achiral carboxylic acid and a less-soluble diastereomeric salt which crystallizes exclusively during optical resolution. Then, we checked the crystal structures of the salts of racemic amine with racemic carboxylic acid, in which one of the enantiopure components is a good resolving agent for the other component. As a result, it was found that conglomerate tends to be formed in extremely high probability in such a system.