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

石斛毒素类生物碱通用合成的收敛策略的发展

• 批准号: 12672066
• 负责人: CHIHIRO Kibayashi
• 金额: $ 2.05万
• 依托单位: Tokyo University of Pharmacy and 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: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672066/
• 关键词: 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

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.

树枝状生物碱的pumiliotoxin类在结构上以A（Z）-6-烷基二烯-8-羟基-8-羟基-8-甲基丁氨基丁氨基氨基烷基环系统在仅在烷基二烯侧链中不同的表征。因此，我们通过交叉偶联反应将两个（Z） - 烷基二氨基苯胺和烷基侧链连接两个片段A和B的合成计划。 （Z） - 二烷基二氨氨磺苷片片段是通用的关键中间体，通过高度立体选择性添加手性甲基二甲二基烯与（s） - 乙酰吡咯烷酮进行合成，然后是钯催化的内核内碳胶质碳纤维化的序列。该合成过程允许（+） - pumiliotoxin 225f的第一个总合成。将获得的中间体（Z） - 二烷基二氨基丁烷转化为同甲基氯化物衍生物，并与（E） - 乙烯基碘化物进行均烯丙基 - 乙烯基交叉偶联以获得交叉耦合产物。随后提供的脱身（+） - pumiliotoxin A.另一方面，将（Z） - 二烷基二氨氨氨氨氨磺碱转化为同甲基-TERF丁基锌衍生物，该二氨基二氨基烷衍生物接受了钯催化的（e） - 乙基碘化物偶联的 - 随后的脱身负担得起（+） - pumiliotoxinB。

项目成果

樹林千尋他2名: "Total Synthesis of Pumiliotoxin B"J. am. Chem. Soc.. 121巻. 9873-9874 (1999)

Chihiro Kirin 等 2 人：“Pumiliotoxin B 的全合成”J. am. Soc.. Vol. 121. 9873-9874 (1999)

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).

Chihiro Kibayashi，Sakae Aoyagi：“通过钯催化高烯丙基有机嗪化合物与乙烯基碘的交叉偶联反应，收敛全合成 Pumiliotoxins A 和 B”J。

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).

Sakae Aoyagi、Shintaro Hirashima、Kosuke Saito 和 Chihiro Kibayashi：“Pumiliotoxin 生物碱的收敛方法。( )-Pumiliotoxins A、B 和 225F 的不对称全合成”J.Org.Chem。

樹林千尋 他: "Total Synthesis of Pumiliotoxin B"J.Am.Chem,Soc,. (発表予定).

Chihiro Kirin 等人：“Pumiliotoxin B 的全合成”J.Am.Chem，Soc，（待提交）。

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).

Sakae Aoyagi、Shintaro Hirashima、Kosuke Saito、Chihiro Kibayashi：“Pumiliotoxin 生物碱的收敛方法。( )-Pumiliotoxins A、B 和 225F 的不对称全合成”I。