Studies on Asymmetric Synthesis of Alkaloids from Poison-Dart Frogs

已经从新热带毒箭蛙的皮肤提取物中分离出200多种生物碱。由于缺乏天然材料和已研究化合物的迷人生物活性，这些生物碱成为全合成的理想目标。结合旋毛虫生物碱的全合成研究，作者选择了（-）-吲哚嗪（1989年）和（-）-短小毒素C（1990年）作为目标生物碱。该合成方案基于不对称的分子内杂Diels-Alder环加成。因此，由（R）-香茅醇制备的异羟肟酸进行杂Diels-Alder反应，得到手性恶嗪内酰胺。随后的转化，包括立体选择性地将烷基侧链引入到所得的恶嗪内酰胺中，导致（-）-吲嗪205 A、207 A、209 B和235 B的首次手性合成。随后包括烷基侧链的立体选择性引入的几个序列导致十氢喹啉衍生物的立体选择性构建。该产物可通过涉及脱氧的一个步骤转化为目标短小毒素C。

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.