SHIBATA Norio TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY Faculty of Pharmaceutical Sciences, Lecturer, 薬学部, 講師 (40293302)
TAKAHASHI Tamiko TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (10115181)
KABUTO Kuninobu Tohoku University, Graduate School of Science, Department of Chemistry, Professor, 大学院・理学研究科, 教授 (40005799)
|Budget Amount *help
¥5,800,000 (Direct Cost : ¥5,800,000)
Fiscal Year 2000 : ¥1,300,000 (Direct Cost : ¥1,300,000)
Fiscal Year 1999 : ¥2,000,000 (Direct Cost : ¥2,000,000)
Fiscal Year 1998 : ¥2,500,000 (Direct Cost : ¥2,500,000)
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.