Development of mild oxidation reaction and its application to total synthesis of highly oxygenated natural products

• Project/Area Number: 25460003
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: Kobe University (2015); Tohoku University (2013-2014)
• Principal Investigator: Okano Kentaro 神戸大学, 工学(系)研究科(研究院), 准教授 (30451529)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: MPC1001 / アコニチン / ジケトピペラジン / 全合成 / マクロラクトン / C-H酸化 / アラノチン / タラチサミン

Outline of Final Research Achievements

In this study we accomplished a total synthesis of MPC1001B, antiproliferative activity against DU145 human prostate cancer cell line, based on inversion of the two stereogenic centers that were generated in the key TBAF-mediated formation of the macrolactone. Preliminary experiments on introduction of the hydroxyl group on the dihydrooxepine skeleton for the late-stage oxidation were performed using a model substrate with selenium dioxide to establish mild oxidation conditions.
We also investigated construction of the partial skeleton of aconitine through formation of enone from in five steps including Birch reduction. Conversion to the corresponding silyl enol ether followed by Diels-Alder reaction provided the desired tetracyclic compound, which was converted to the secondary alcohol. The mesylate was treated with silica gel to provide the allylic alcohol as a single isomer via Wagner-Meerwein rearrangement. Synthetic studies on acochlearine was also performed.

Research Products

• [Journal Article] Total Synthesis of (+)-MPC1001B (2016)
  • Author(s): T. Kurogi, S. Okaya, H. Fujiwara, K. Okano, H. Tokuyama
  • Journal Title: Angewandte Chemie International Edition Volume: 55 Issue: 1 Pages: 283-287
  • DOI: 10.1002/anie.201507830
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Synthetic Studies on Acochlearine: Construction of A/B/C/E/F Ring System (2016)
  • Author(s): K. Fujioka, N. Miyamoto, H. Toya, K. Okano, H. Tokuyama
  • Journal Title: Synlett Volume: 27 Issue: 04 Pages: 621-625
  • DOI: 10.1055/s-0035-1560384
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Total Synthesis of Acetylaranotin and Structural Determination of Its Congener (2014)
  • Author(s): Hideto Fujiwara, Taichi Kurogi, Shun Okaya, Kaori Yamada, Malipan Sappan, Masahiko Isaka, Kentaro Okano, Hidetoshi Tokuyama
  • Organizer: The 4th Junior International Conference on Cutting-Edge Organic Chemistry in Asia (JICCEOCA-4) 2014
  • Place of Presentation: タイ国バンコク市
  • Year and Date: 2014-11-18 – 2014-11-20
• [Presentation] (-)-Acetylaranotinの全合成 (2014)
  • Author(s): ○黒木太一，藤原栄人，岡谷駿，中村崇則，岡野健太郎，徳山英利
  • Organizer: 第24回万有福岡シンポジウム
  • Place of Presentation: 福岡市
  • Year and Date: 2014-06-07
• [Presentation] Synthetic Studies on Rostratin B (2013)
  • Author(s): Shun Okaya, Taichi Kurogi, Hideto Fujiwara, Kentaro Okano, Hidetoshi Tokuyama
  • Organizer: International Symposium for the 70th Anniversary of the Tohoku Branch of the Chemical Society of Japan
  • Place of Presentation: Sendai, Japan