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获得正确的光学活性产物的ee值和绝对构型。Mosher的方法曾被用于这一目的，但有时它缺乏准确性和/或反应性，因此人们一直在寻求改进的方法。在这种情况下，我们开发了一种新型的手性衍生化试剂CFTA(α-氰基-α-氟对甲苯基乙酸)，它的手性中心直接带有氟原子。CFTA方法是利用CFTA进行手性衍生化的方法，在手性识别能力和反应活性方面都表现出了很高的性能。为了提高CFTA的使用价值，对CFTA的可及性和适用性进行了研究，开发了酶法制备光学纯CFTA和非对映异构体制备光学纯CFTA的三条新途径。将得到的CFTA与各种手性化合物，如仲醇、α-氚基苯甲醇、伯胺和氨基酸酯缩合，得到相应的CFTA酯或酰胺。从各个非对映异构体的~1H和~(19)F核磁共振谱中得到了Δδ值，即各非对映异构体原子间δ的差值。在核磁共振氢谱中，Δδ值信号与绝对构型之间存在稳定的相关性。Δδ的绝对值一般超过改良的Mosher法的值。Δδ_F的相关性因化合物基团的不同而不同。从头算结果表明，CFTA酯的最稳定构型为F-C-C=O共面构象，与X射线晶体结构分析结果一致。另一方面，计算得到CFTA酰胺中含有F-C-C=O，O=C-N-H反平面构象的最稳定构型，这一结果得到了X射线分析的支持。这些构型很好地解释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.