Studies on Asymmetric Synthesis of Alkaloids from Poison-Dart Frogs

毒箭蛙生物碱的不对称合成研究

• 批准号: 01571167
• 负责人: KIBAYASHI Chihiro
• 金额: $ 1.34万
• 依托单位: Tokyo College of Pharmacy
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1989
• 资助国家: 日本
• 起止时间: 1989 至 1990
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-01571167/
• 关键词: Alkaloids from Poison-Dart Frogs; (-)-Indolizidine; (-)-Pumiliotoxin C; N-Acyl Nitroso Compound; Herero Diels Alder Reaction; Intramolecular Cyclization; Asymmetric Symthesis; プミリオトキシンC; デカヒドロキノリン; (-)-インドリチジンアルカロイド; アシルニトロソ化合物; ヘテロディ-ルス-アルダ-反応

More than 200 alkaloids have been isolated in minute quantity from the skin extracts of neotropical poison-dart frogs of the dendrobatid species The lack of availability of natural material and the fascinating biological activity of the compounds which have been studied, make these alkaloids ideal targets for total synthesis. In connection with studies aimed at total synthesis of optically active dendrobatid alkaloids, the author has chosen several (-)-indolizidines (in1989) and (-)-pumiliotoxin C (in1990) as target alkaloids. The synthetic plan is based on asymmetric intramolecular hetero Diels-Alder cycloaddition. Thus, the hydroxamic acid, prepared from (R)-citronellol, was subjected to hetero Diels-Alder reaction to afford the chiral oxazinolactam. Subsequent transformations including stereoselective introduction of the alkyl side chain to the resulting oxazinolactam led to the first chiral synthesis of (-)-indolizidines 205A, 207A, 209B, and 235B.Otherwise, an alternative hetero Diels-Alder reaction of the hydroxamic acid, derived from L-glutamic acid in 8 steps, followed by several sequences including stereoselective introduction of alkyl side chain resulted in the stereoselective construction of the decahydroquinoline derivative. This product can be converted to objective pumiliotoxin C by one step involving deoxygenation.

已从树蛙属新热带毒箭蛙的皮肤提取物中分离出微量的 200 多种生物碱。天然材料的缺乏以及所研究的化合物具有令人着迷的生物活性，使这些生物碱成为理想的目标。全合成。在针对光学活性树突状生物碱的全合成研究中，作者选择了几种(-)-吲哚里西啶(1989年)和(-)-pumiliotoxin C(1990年)作为目标生物碱。该合成方案基于不对称分子内杂狄尔斯-阿尔德环加成。因此，由(R)-香茅醇制备的异羟肟酸进行杂狄尔斯-阿尔德反应，得到手性恶嗪内酰胺。随后的转化，包括将烷基侧链立体选择性地引入到所得恶嗪内酰胺中，导致了 (-)-吲哚里西啶 205A、207A、209B 和 235B 的首次手性合成。另外，异羟肟酸的另一种杂狄尔斯-阿尔德反应，衍生通过 8 个步骤从 L-谷氨酸中提取，然后进行几个序列，包括立体选择性引入烷基侧链，从而得到十氢喹啉衍生物的立体选择性构建。该产品可通过涉及脱氧的一步转化为目标普米里奥毒素C。

项目成果

Yuji Shishido and Chihiro Kibayashi: "A Total Syntesis of (-)-Indolizidines 205A and 235B" J. Chem. Soc., Chem. Commun.(1991)

Yuji Shishido 和 Chihiro Kibayashi：“(-)-Indolizidines 205A 和 235B 的全合成”J. Chem。

樹林千尋,宍戸祐二: "Total Synthesis of(-)-Indolizidine 205A,207A,209B,235B via Intramolecular Hetero Diels-Alder Reaction with Acylnitroso Compounds" Tetrahedron Letters.

Chihiro Kirin、Yuji Shishido：“通过分子内杂狄尔斯-阿尔德反应与酰基亚硝基化合物全合成 (-)-吲哚里西啶 205A、207A、209B、235B”四面体字母。

Yuji Shishido: "The Total Synthesis of (-)-Indolizidines 205A and 235B" J.Chem.Soc.,Chem.Commun.(1991)

Yuji Shishido：“(-)-Indolizidines 205A 和 235B 的全合成”J.Chem.Soc.,Chem.Commun.(1991)