Rationalization of Chiral Discrimination upon Crystallization of Diastereomeric Salt and Development of Novel Practical Resolving Reagent

为了了解手性拆分对非对映异构体结晶的作用机理，开发新型拆分试剂，研究了扁桃酸拆分1-芳基烷基胺的反应。结果发现，取代基在胺的芳香基上的位置与拆分效率有很大的关系。取代基延长了胺的分子长度，降低了拆分效率。难溶的非对映异构体的晶体结构表明，通常形成了由氢键柱组成的具有平面界面的特征氢键层；从氢键和范德华相互作用的角度来看，这些晶体被认为是稳定的。这种稳定的层对于有效拆分是必要的，为了实现这种稳定的氢键层，外消旋体的分子长度应该与拆分剂的分子长度相似或略短。相反，在不能通过结晶分离的相应的更易溶的盐和非对映异构体的情况下，并不是在所有情况下都能实现如此稳定的晶体结构。在此基础上，选择(S)-对甲基扁桃酸和(R)-对甲氧基扁桃酸作为拆分1-芳基烷基胺的新试剂，发现这两种拆分剂对1-芳基烷基胺的拆分能力高于扁桃酸。

In order to understand the mechanism of chiral discrimination upon crystallization of diastereomeric salt and to develop novel resolving reagents, the resolution of 1-arylalkylamines by mandelic acid was studied. As a result, it was found that the position of a substituent on the aromatic group of the amines was correlated with the resolution efficiency to a considerable extent. A substituent, which elongated the molecular length of the amine, diminished the resolution efficiency. The crystal structures of less-soluble diastereomeric salts revealed that a characteristic hydrogen-bond layr, consisting of hydrogen-bond columns and having planar boundary surfaces, was commonly formed ; these crystals were considered to be stable from the viewpoint of both hydrogen-bonding and van der Waals interactions. Such a stable layr would be necessary for efficient resolution, and in order to realize such a stable hydrogen-bond layr, the molecular length of a racemate should be similar to or a little shorter than that of the resolving reagent. In contrast, in the cases of the corresponding more-soluble salts and diastereomeric salts, which could not be separated by crystallization, such a stable crystal structure was not realized in all cases. On the basis of these results, (S)-p-methylmandelic acid and (R)-p-methoxymandelic acid were selected as new resolving reagents for 1-arylalkylamines ; these resolving reagents were found to have a higher resolving ability for 1-arylalkylamines than mandelic acid.