Synthetic Study of Hasubanan-type Alkaloids based on Oxidative Phenolic Coupling Reaction

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K05488
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 33020:Synthetic organic chemistry-related
• Research Institution: Tokyo University of Agriculture and Technology
• Principal Investigator: Odagi Minami 東京農工大学, 工学(系)研究科(研究院), 助教 (30772157)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 全合成 / アルカロイド / 脱芳香族化 / アザーマイケル反応 / ハスバナンアルカロイド

Outline of Final Research Achievements

In this study, we have developed the synthetic methodology of fused polycyclic alkaloids through the dearomative oxidative cyclization of phenols followed by regioselective intramolecular aza-Michael reactions of dienones. This method efficiently produces a series of hasubanan alkaloids. We have synthesized three hasubanan alkaloids: (-)-Metaphanine, (+)-Stephadiamine, and cepharatines. The synthesis of (-)-Metaphanine was achieved through an efficient construction of the hasubanan skeleton by utilizing the regioselective aza-Michael reaction at C14. (+)-Stephadiamine was synthesized using an aza-benzylic acid-type rearrangement reaction to contract the C ring. Additionally, cepharatines were successfully synthesized through the reorganization of the D ring, involving a cascade of reactions featuring a retro aza-Michael reaction and subsequent aminal formation.

Free Research Field

天然物合成化学

Academic Significance and Societal Importance of the Research Achievements

本研究では、酸化的フェノールカップリング反応および位置選択的な分子内アザ－マイケル反応を基盤としたハスバナンアルカロイド類の網羅的全合成法の確立に成功した。ハスバナンアルカロイド類は、オピオイド受容体に対して結合能を有する類縁体が存在することから、本研究成果は、抗うつ剤の創薬シード化合物の創出に寄与するものである。