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

高效制备高度通用的手性衍生剂 CFTA，用于确定绝对构型。

• 批准号: 10470465
• 负责人: TAKEUCHI Yoshio
• 金额: $ 3.71万
• 依托单位: TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10470465/
• 关键词: CFTA; chiral derivatizing agent; NMR; enantiomer excess; absolute configuration; chiral fluoro compound; multifunctional carbon; optical resolution; 絶対構造; キラル一級アミン; アミノ酸; ^1H NMR; ^<19>F NMR; ab initio 計算; X線結晶解析; キラル-2級アルコール; sp配座

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.

不对称合成中存在的一个问题是如何方便地得到正确的ee值和光学活性产物的绝对构型。Mosher的方法已经用于这种目的，然而，有时它缺乏准确性和/或反应性，因此一直期待改进的方法。在这种情况下，我们开发了一种新型的手性衍生剂CFTA（α-氰基-α-氟代-对甲苯乙酸），它的氟原子直接位于手性中心上。CFTA法是一种利用CFTA进行手性衍生化的方法，具有良好的手性识别能力和反应活性。为了提高CFTA的实用价值，本文对CFTA的可得性和适用性进行了研究，开发了三种新的制备光学纯CFTA的方法，即酶法和非对映体法。将CFTA与仲醇、α-氘代苄醇、伯胺、氨基酸酯等手性化合物缩合，得到相应的CFTA酯或酰胺。Δδ值，即非对映体原子之间δ值的差异，由<19>每种非对映体的^1H和1H NMR光谱获得。在^1H NMR中，Δδ值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的Mosher法的值。~ 1FNMR<19>观测结果表明，不同化合物的Δδ_F的相关性不同。从头算结果表明，CFTA酯的最稳定构型为F-C-C=O同面构型，这与X射线晶体结构分析结果一致。另一方面，计算CFTA酰胺以F-C-C=O，O=C-N-H反周平面构象存在于最稳定的构型中，这与X射线分析相一致。这些构型很好地合理化了NMR实验的结果。

项目成果

Takahashi, T. ; Fukushima, A. ; Tanaka, Y. ; Takeuchi, Y. ; Kabuto, K. ; Kabuto, C.: "CFTA, a new efficient agent for determination of absolute configurations of chiral secondary alcohols."Chem.Commun.. 787-788 (2000)

高桥，T.；

Y. Takeuchi et al.: "Simple Synthesis of α-Cyano-α-fluoro-p-tolylacetic Acid (CFTA), a New Efficient Chiral Derivatizing Agent"Enantiomer. 4. 339-344 (1999)

Y. Takeuchi 等人：“新型高效手性衍生剂 α-氰基-α-氟-对甲苯乙酸 (CFTA) 的简单合成”对映体 4. 339-344 (1999)

竹内義雄: "未開拓の化合物,キラル有機フッ化物,その合成と薬学への応用に挑戦."ファルマシア. 36. 113-115 (2000)

Yoshio Takeuchi：“一种未经探索的化合物，手性有机氟化物，对其合成和在制药科学中的应用提出了挑战。”Pharmacia。

Takahashi,T.,Fukushima,A.,Tanaka,Y.,Segawa,M.,Hori,H.,Takeuchi,Y.,Burchardt,A.,Haufe.G.: "New efficient chiral derivatizing agent, α-cyano-α-fluoro (2-naphthyl) acetic acid (2-CFNA). Application to the ee determination of (-)-3-acetoxy-2-fluoro-2-(hexadec

Takahashi, T.、Fukushima, A.、Tanaka, Y.、Sekawa, M.、Hori, H.、Takeuchi, Y.、Burchardt, A.、Haufe。“新型高效手性衍生剂，α-氰基。 -α-氟(2-萘基)乙酸 (2-CFNA) 在 (-)-3-乙酰氧基-2-氟-2-(十六进制) ee 测定中的应用。

Y.Takeuchi et al.: "Simple Synthesis of α-Cyano-α-fluoro-p-tolylacetic Acid(CFTA),a New Effcient Chiral Derivatizing Agent" Enantiomer. (1999)

Y.Takeuchi 等人：“α-氰基-α-氟-对甲苯乙酸（CFTA）的简单合成，一种新型有效的手性衍生剂”对映体（1999）。