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

为了了解非对映异构体盐结晶时的手性分辨机理，开发新的分辨试剂，研究了扁桃酸对1-芳基烷基胺的分辨。结果发现，取代基在胺的芳香基团上的位置与分辨效率有相当大的相关性。取代基拉长了胺的分子长度，降低了分辨效率。较难溶非对映异构体盐的晶体结构表明，通常形成由氢键柱组成的具有平面边界面的特征性氢键层；从氢键和范德华相互作用的角度认为这些晶体是稳定的。这样一个稳定的氢键层是有效分解所必需的，为了实现这样一个稳定的氢键层，外消旋体的分子长度应该与分解试剂的分子长度相似或略短。相比之下，对于相应的易溶盐和非对映异构体盐，由于无法通过结晶分离，因此并非所有情况下都能实现这种稳定的晶体结构。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1-芳基烷基胺的新分解试剂；发现这些溶解试剂对1-芳基烷基胺的溶解能力比扁桃酸高。

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.