Development and application of versatile asymmetric Nazarov cyclization with novel biphenol-boric acid catalyst system

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K06937
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: University of Toyama
• Principal Investigator: SUGIMOTO Kenji 富山大学, 学術研究部薬学・和漢系, 准教授 (60400264)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: ナザロフ環化 / 不斉触媒反応 / 光学活性ビフェノール / ホウ酸 / 2-aza-Cope転位 / Fischerインドール合成

Outline of Final Research Achievements

To improve a thermal stability, derivatization of optically active biphenols has been examined. Since the chiral inductivity of the chiral biphenol on the Nazarov reaction showed some relationship with the dihedral angle of biphenyl unit, we prepared several conformationally locked biphenols avoiding racemization owing to a rotation of the chiral axis. Finally, we obtained a potent congener which enables the Nazarov cyclization in good chemical yield (79%) under good enantioselectivity (70% ee). During the efforts on the derivatization, we also found that the introduction of bromo group on the biphenol unit strongly enhances the reaction rate probably due to an increase of the acidity. Based on these findings, further improvement of our catalyst system is now going.
Apart from the use of biphenol/B(OH)3 catalyst system in the asymmetric Nazarov cyclization, we could reveal that our catalyst system enables to accelerate 2-aza-Cope rearrangement and Fischer indole synthesis.

Free Research Field

有機合成化学

Academic Significance and Societal Importance of the Research Achievements

独自に見出した新規ビフェノール／ホウ酸触媒系を発展させ、不斉反応へと展開することに成功し、未だ改善の余地を残すものの、良好な収率と良好な立体選択性にてナザロフ環化を進行させうる学術的に新規な不斉触媒系を見出すことができた。また、本触媒系は弱酸の組み合わせであるにもかかわらず、ナザロフ環化以外においても有用な強酸触媒系として機能することを確認できた。反応後には分液操作にてビフェノールを回収するとともに、廃水中には安全なホウ酸のみを排出する環境負荷の小さな手法であり、社会的要請に応えうる方法論を確立できたといえる。