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.

从新热带毒镖蛙的皮肤提取物中分离出了200多种微量的生物碱。由于天然物质的缺乏以及所研究的化合物具有令人着迷的生物活性，使这些生物碱成为全合成的理想目标。结合光学活性石斛生物碱的全合成研究，作者选择了几种(-)-吲哚嘧啶（1989年）和(-)-pumiliotoxin C（1990年）作为靶生物碱。合成方案是基于不对称分子内Diels-Alder杂环加成。以(R)-香茅醇为原料，经异Diels-Alder反应得到手性恶唑内酰胺。随后的转化，包括立体选择性地将烷基侧链引入到所得到的恶唑内酰胺中，导致了(-)-吲哚嘧啶205A， 207A， 209B和235B的首次手性合成。另外，从l -谷氨酸衍生的羟肟酸经过8步异Diels-Alder反应，随后包括烷基侧链的立体选择性引入在内的多个序列导致了十氢喹啉衍生物的立体选择性构建。通过一步脱氧，可将该产物转化为目标粗毛藻毒素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。

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)

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。