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

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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.