Asymmetric Synthesis of Poison-Dart Alkaloids Pumiliotoxins

毒镖生物碱普米里奥毒素的不对称合成

• 批准号: 10671999
• 负责人: KIBAYASHI Chihiro
• 金额: $ 1.73万
• 依托单位: Tokyo University of Pharmacy & Life Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671999/
• 关键词: poison-dart alkaloids; pumiliotoxin A; pumiliotoxin 225F; asymmetric synthesis; exocyclic alkenyl group; palladium-catalyzed carbonylation; プミリオトキシン 229F

A versatile general approach for preparing the pumiliotoxin alkaloids has been developed employing Pd-catalyzed cross-coupling reaction between a homoallylic organozinc and a vinyl iodide, which led to the convergent asymmetric synthesis of pumiliotoxin A and 225F.The (Z)-alkylideneindolizidine, which is a common organic part of the organozinc reagent in this approach, was synthesized with a high degree of stereocontrol using HfClィイD24ィエD2-mediated addition of the allenylsilane to (S)-2-acetylpyrrolidine and subsequent intramolecular lactonization by Pd-catalyzed carbonylation as key steps. In the course of this investigation, the synthesis of (-)-pumiliotoxin 225F was achieved for the first time. The homoallyl iodide thus obtained was converted via halogenmetal exchange with t-BuLi followed by transmetalation with ZnClィイD22ィエD2 into the homoallylic zinc derivative, which underwent homoallylalkenyl cross-coupling with the vinyl iodide using Pd(PhィイD23ィエD2)ィイD24ィエD2 catalyst to afford the 1, 5-diene product with complete retention of the configurations. Subsequent provided (+)-pumiliotoxin A in 6% overall yield from the dibromoolefin.

采用pd催化的纯烯丙基有机锌与碘化乙烯之间的交叉偶联反应，制备了一种通用的矮毛藻毒素生物碱的制备方法，该方法导致矮毛藻毒素A和225F的聚合不对称合成。该方法以氟氯化氢（HfCl）介导的烯基硅烷加成至(S)-2-乙酰吡咯烷为关键步骤，并通过pd催化羰基化进行分子内内酯化反应，在高度立体控制下合成了(Z)-烷基基吲哚吡啶，是有机锌试剂中常见的有机部分。在本研究过程中，首次合成了(-)-pumiliotoxin 225F。通过与t-BuLi进行卤素金属交换，再与ZnCl φ φ D22 φ φ D2进行金属转化，得到均烯丙基锌衍生物，并在Pd(Ph φ φ D23 φ φ D2) φ φ D24 φ φ D2催化剂下与碘化乙烯基进行均烯丙基交联，得到构型完全保留的1,5 -二烯产物。随后从二溴烯烃中获得(+)-短毛霉毒素A，总产量为6%。

项目成果

C.Kibayashi,S.Aoyagi: "Development of New Synthetic Methods and Strategies for the Total Synthesis of Pumiliotoxin A Class Alkaloids"Jounal of Syntheic Organic Chemistry,Japan. 57巻・11号. 981-992 (1999)

C.Kibayashi、S.Aoyagi：“全合成普米利奥毒素 A 类生物碱的新合成方法和策略的开发”，《合成有机化学杂志》，第 57 卷，第 11 期。981-992 (1999)

C. kibayashi, S. Aoyagi: "Recent Advanced in the Synthesis of Dendrobatid Alkaioids"Studies in Natural Products Chemistry ; Atta-ur-Rahman, Ed. ; Elsevier : Amsterdam. 19巻. 66-81 (1997)

C. kibayashi, S. Aoyagi：“Dendrobatid Alkaoids 合成的最新进展”；Atta-ur-Rahman，Ed.；阿姆斯特丹，19. 66-81。

Chihiro Kibayashi, Sakae Aoyagi, Tzu-Chueh Wang, Kosuke Saito, John W.Daly, and Thomas F.Spande: "Determination of Absolute Stereochemistry and an Alternative Synthesis of Homopumiliotoxin 223G. Identification of Chiral GC Columns with the Natural Alkaloi

Chihiro Kibayashi、Sakae Aoyagi、Tzu-​​Cueh Wang、Kosuke Saito、John W.Daly 和 Thomas F.Spande：“绝对立体化学的测定和同源毒素 223G 的替代合成。用天然碱鉴定手性 GC 柱

C. Kibayashi, S. Aoyagi: "Development of New Synthetic Methods and Strategies for the Total Syntheses of Pumiliotoxin A Class Alkaloids"Journal of Synthetic Organic Chemistry, Japan. 57巻. 981-992 (1999)

C. Kibayashi, S. Aoyagi：“Pumiliotoxin A 类生物碱全合成的新合成方法和策略的开发”，《合成有机化学杂志》，日本，第 57 卷，981-992。

S. Hirashima, S. Aoyagi, C. kibayashi: "Total Synthesis of (+)-Pumiliotoxins A and 225F"Journal of the American Chemical Society. 121巻. 9873-9874 (1999)

S. Hirashima、S. Aoyagi、C. kibayashi：“(+)-Pumiliotoxins A 和 225F 的全合成”，美国化学会杂志，第 121 卷，9873-9874 (1999)。