An alternative, more efficient synthesis of the picrotoxane core by palladium-catalyzed cycloisomerization of an enyne requires the design of a new catalyst system based upon 1,3-bis(dibenzophospholyl)-propane and 2-(diphenylphosphino)benzoic acid as ligands. Thus, unlike thermal processes which leave little opportunity to address failed reactions, the transition-metal-catalyzed reaction provides opportunities for catalyst modification to overcome limitations. In this way; a seven-step synthesis of the picrotoxane core from carvone emerges. The formation of the bislactone depends critically on the ring substitution pattern. A myriad of selective transannular cyclizations occur as a function of this substitution pattern. The bislactone serves as a pivotal intermediate to picrotoxinin, picrotin, and corianin. During the course of the manipulation of the oxidation pattern to create the correct bislactone, an intermediate generated also provides access to methyl picrotoxate. An improved sequence from the bislactone to corianin compared to the first generation evolves-in part derived from enhanced control of stereoselectivity in the functionalization of the double bond in the cyclohexenyl portion of the picrotoxane skeleton. Later in the sequence, a hydroxyl-directed chemoselective lactone reduction is employed using lithium triacetoxyborohydride. In the course of these studies, two reactions that involve substitution with retention of configuration occur in high yield as a result of the remarkable reactivity of this densely functionalized ring system.