An Asymmetric Approach toward the <i>Aristotelia</i> Alkaloid (−)-Penduncularine

We report a catalytic enantioselective total synthesis of an endocyclic alkene regioisomer of (-)-peduncularine, termed (-)-pseudo-peduncularine, and also a synthesis of its C7 epimer. Highlights of the syntheses include a new strategy for the construction of the peduncularine framework by palladium-catalyzed ynamide cycloisomerization/enamide reduction, which could be performed on a multigram scale. By introducing the indole side chain as a substituent on the ynamide, this approach contrasts with previous strategies that have relied on late-stage Fischer indole synthesis. Inversion of the C7 stereocenter installed in the cycloisomerization process could be readily achieved by temporary azabicycle ring opening, using an enamide hydrolysis/ketone reduction/Mitsunobu cyclization sequence. A catalytic asymmetric sulfonamidation of a racemic allylic benzoate enabled an enantioselective synthesis of (-)-pseudo-peduncularine.