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.

已经开发了一种多功能的一般方法，用于制备pumiotoxin obaloids，采用PD催化的均匀有促有链有力的有链有促有孔和乙烯基碘化物之间的PD催化的交叉耦合反应，从而导致粉状毒素A和225F。使用HFCLI D24E D2介导的Allenylsilane添加到（S）-2-乙酰吡咯烷酮和随后的分子内乳酸化中，通过PD催化的殖民化羰基化作为关键步骤，使用HFCLI D2介导的甲烯基添加到（S）-2-乙酰吡咯烷酮和随后的分子内乳酸化中，用高度的立体控制合成。在这项研究的过程中，首次实现了（ - ） - Pumiliotoxin 225F的合成。因此获得的同甲碘通过与T-Buli进行转换，然后用ZnCli D22E D2转换为同层锌衍生物，该锌衍生物与均使用PD（Philion D23E D2 D2 Catalysention in Collesention in fore in foremallical-d2配置。随后提供的（+） - dibromoolefin的总收率为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)

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: "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。

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)。