Total Synthesis of (+)-Pumiliotoxin 251D

Abstract

The convergent total synthesis of pumiliotoxins by attachment of the side chain to a suitably functionalized core indolizidinone derivative has been achieved. The use of an aldol-type addition condensation strategy, intended to provide for the stereoselective generation of the exocyclic double bond, gave no satisfactory results. The method of choice was a Horner olefination. Initially, the reactant core indolizidinone was converted into an α phosphono amide by amide enolate formation, enol phosphate generation, and a final phosphate-phosphonate migration. The amido phosponates smoothly underwent Horner-type olefinations to allow successful introduction of the side chain with high Z selectivity in the exocyclic double bond. Similarly, the introduction of the phosphonate and the subsequent olefination could be run as a one-pot process. The final reductive removal of the lactam function provided (−)-8-epi-pumiliotoxin 209 F and (+)-pumiliotoxin 251 D. The structure of the pumiliotoxin 251 D was confirmed by X-ray analysis. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)