Synthesis of the Bicyclic Core of Pumiliotoxins

The bicyclic core of the pumiliotoxins was synthesized in nine to eleven steps starting from L-(−)-proline. This chiral pool starting material was initially converted into an optically active 2-vinylpyrrolidine by standard operations. The first key step allowed the generation of a nine-membered ring lactam by means of a zwitterionic aza-Claisen rearrangement. The 1,4 chirality transfer was found to be low, but the double bond of the azoninone was generated with an exclusive trans configuration in a planar-S arrangement. The mixture of diastereomers thus obtained was immediately epoxidized; the planar chiral information could be completely used to build up new stereogenic centers. Subsequent ring closure under hydrogenolytic conditions resulted in the formation of the bicyclic core with a bridgehead of defined configuration. The hydroxyl group of that material could be protected as a TBS ether, or alternatively a sequence of a Swern oxidation and subsequent methyl Grignard addition gave the complete bicyclic framework with low C8 diastereoselectivity. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)