Efficient preparation of a highly versatile chiral derivatizing agent, CFTA, for determination of absolute configurations.

不对称合成中的一个问题是如何方便地得到正确的ee值和光活性产物的绝对构型。Mosher的方法已被用于此目的，然而，有时它缺乏准确性和/或反应性，因此一直渴望改进的方法。在这种情况下，我们开发了一种新的手性衍生剂，CFTA （α-氰基-α-氟-对己乙酸），它的氟原子直接位于手性中心。CFTA方法是一种利用CFTA进行手性衍生化的方法，在手性识别能力和反应性方面都表现出了很高的性能。为了提高利用价值，对CFTA的可达性和适用性进行了研究。通过酶法和非对映体法，开发了三种光纯CFTA的新途径。得到的CFTA与仲醇、α-氘化苄基醇、伯胺、氨基酸酯等手性化合物缩合生成相应的CFTA酯或酰胺。从各非对映体的^1H和^<19>F核磁共振谱中得到各非对映体原子间δ值的差异Δδ值。在^1H NMR中，Δδ值的信号与绝对构型之间存在稳定的相关性。Δδ的绝对值普遍超过修正Mosher方法的值。对于^<19>F的NMR观测，不同基团的化合物之间Δδ_F的相关性不同。从头计算表明，CFTA酯最稳定的构型为F-C-C=O共面构象，与x射线晶体结构分析一致。另一方面，计算出CFTA酰胺在最稳定的构型中含有F-C-C=O， O=C-N-H反周平面构象，x射线分析支持了这一结论。这些结构很好地合理化了核磁共振实验的结果。

One problem included in asymmetric synthesis is how to reach the correct ee values and absolute configurations of optically active products in convenience way. Mosher's method has been used for such purpose, however, sometimes it lacks accuracy and/or reactivity, and so improved method has been longed. In such situations, we have developed a novel chiral derivatizing agent, CFTA (α-cyano-α-fluoro-p-tolylacetic acid), which possess fluorine atom directly on the chiral center. CFTA method, the chiral derivatizing method using CFTA, has shown its high performance for both chiral recognition ability and reactivity. In order to raise the utility value, the accessibility and applicability of CFTA have been investigated.Three new routes to optically pure CFTA have been developed, by enzymatic and diastereomer procedure. The obtained CFTA was condensed with various kinds of chiral compounds, for example, secondary alcohols, α-deuterated benzylalcohols, primary amines, and amino acid esters to afford the corresponding CFTA esters or amides. Δδ values, differences of δ values between diastereomeric atoms, were obtained from ^1H and ^<19>F NMR spectrum for each diastereomers. In ^1H NMR, stable correlation was observed between the signals of Δδ values and the absolute configurations. The absolute values of Δδ generally exceeded the values from modified Mosher's method. As for ^<19>F NMR observation, the correlation of Δδ_F, was varied from groups of compounds. Ab initio calculations indicated the most stable configuration of CFTA esters includes F-C-C=O synperiplanar conformation, that was agreed with X-ray crystal structure analysis. On the other hand, CFTA amide was calculated to contain F-C-C=O, O=C-N-H antiperiplanar conformation in the most stable configuration, which was supported with X-ray analyses. These configurations well rationalized the results of NMR experiments.