Asymmetric Synthesis of Poison-Dart Alkaloids Pumiliotoxins

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A versatile general approach for preparing the pumiliotoxin alkaloids has been developed employing Pd-catalyzed cross-coupling reaction between a homoallylic organozinc and a vinyl iodide, which led to the convergent asymmetric synthesis of pumiliotoxin A and 225F.The (Z)-alkylideneindolizidine, which is a common organic part of the organozinc reagent in this approach, was synthesized with a high degree of stereocontrol using HfClィイD24ィエD2-mediated addition of the allenylsilane to (S)-2-acetylpyrrolidine and subsequent intramolecular lactonization by Pd-catalyzed carbonylation as key steps. In the course of this investigation, the synthesis of (-)-pumiliotoxin 225F was achieved for the first time. The homoallyl iodide thus obtained was converted via halogenmetal exchange with t-BuLi followed by transmetalation with ZnClィイD22ィエD2 into the homoallylic zinc derivative, which underwent homoallylalkenyl cross-coupling with the vinyl iodide using Pd(PhィイD23ィエD2)ィイD24ィエD2 catalyst to afford the 1, 5-diene product with complete retention of the configurations. Subsequent provided (+)-pumiliotoxin A in 6% overall yield from the dibromoolefin.