Studies on Asymmetric Synthesis of Alkaloids from Poison-Dart Frogs

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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.