Development of Convergent Strategy for General Synthesis of the Pumiliotoxin Class of Dendrobatid Alkaloids

• Project/Area Number: 12672066
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: CHIHIRO Kibayashi Tokyo University of Pharmacy and Life Science,School of Pharmacy , Professor, 薬学部, 教授 (80057330)
• Project Period (FY): 2000 – 2001
• Project Status: Completed (Fiscal Year 2001)
• Budget Amount: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2001: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2000: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: Total Synthesis / Asymmetric Synthesis / Dendrobatid Alkaloids / Pumiliotoxins / Indolizidine / Homoallylzinc Compound / Cross-Coupling Reaction / プミリオトキシンA / クロスカップリング / 不斉全合成 / プミリオトキシンB

Research Abstract

The pumiliotoxin class of dendrobatid alkaloids are characterized structurally by a (Z)-6-alkylidene-8-hydroxy-8-methylindolizidine ring system differing in only the alkylidene side chain. Our synthetic plan for pumiliotoxins A and B thus called for connecting two fragments, the (Z)-alkylidene indolizidine and the alkenyl side chain, by cross-coupling reaction. The (Z)-iodoalkylidene indolizidine fragment, which served as a common key intermediate, was synthesized through highly stereoselective addition of the chiral silylallene to (S)-acetylpyrrolidine followed by a palladium-catalyzed intramolecular carbonylation-cyclization sequence. This synthetic process allowed the first total synthesis of (+)-pumiliotoxin 225F. The intermediate (Z)-iodoalkylidene indolizidine obtained was converted to a homoallylzinc chloride derivative and subjected to homoallyl-vinyl cross-coupling with the (E)-vinyl iodide to give the cross-coupled product. Subsequent deprotection provided (+)-pumiliotoxin A. On the other hand, the (Z)-iodoalkylidene indolizidine was transformed into the homoallyl-terf butyl zinc derivative, which underwent the palladium-catalyzed cross-coupling with the (E)-vinyl iodide and subsequent deprotection to afford (+)-pumiliotoxin B.

Research Products

• [Publications] Sakae Aoyagi, Shintaro Hirashima, Kosuke Saito, Chihiro Kibayashi: "A Convergent Approach to Pumiliotoxin Alkaloids. Asymmetric Total Synthesis of (+)-Pumiliotoxins A, B, and 225F"I. Org. Chem. (in press).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Chihiro Kibayashi, Sakae Aoyagi: "A Convergent Total Synthesis of Pumiliotoxins A and B via Palladium-Catalyzed Cross-Coupling Reaction of Homoallylic Organozine Compounds with Vinyl Iodides"J. Organomet. Chem.. (in press).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Sakae Aoyagi, Shintaro Hirashima, Kosuke Saito, and Chihiro Kibayashi: "A Convergent Approach to Pumiliotoxin Alkaloids. Asymmetric Total Synthesis of (+)-Pumiliotoxins A, B, and 225F"J.Org.Chem. (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Chihiro Kibayashi and Sakae Aoyagi: "A Convergent Total Synthesis of Pumiliotoxins A and B via Palladium-Catalyzed Cross-Coupling Reaction of Homoallylic Organozinc Compounds with Vinyl Iodides"J.Organomet.Chem.. (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 樹林千尋他2名: "Total Synthesis of Pumiliotoxin B"J. am. Chem. Soc.. 121巻. 9873-9874 (1999)
• [Publications] 樹林千尋 他: "Total Synthesis of Pumiliotoxin B"J.Am.Chem,Soc,. (発表予定).