Asymmetric Synthesis of (−)-Anatoxin-a via an Asymmetric Cyclization Using a New Ligand for Pd-Catalyzed Alkylations

Palladium-catalyzed asymmetric allylic alkylations have been explored in the context of medium-sized ring substrates, intramolecular vs intermolecular processes involving attack on a formally meso π-allyl intermediate in the desymmetrization, and the presence of electron-withdrawing groups on the cationic π-allylpalladium intermediate. The synthesis of anatoxin-a, also known as the “very fast death factor”, raises all of these questions. Ligands derived from trans -1,2-diaminocyclohexane and 2-diphenylphosphinobenzoic acid effect asymmetric alkylations with an allyl substrate bearing an electron-withdrawing group. On the other hand, a new type of ligand wherein the diamine is derivatized with both 2-diphenylphosphinobenzoic acid and 2-picolinic acid was required to effect asymmetric cyclization to form the 9-azabicyclo[4.2.1]non-2-ene system. A total synthesis of anatoxin-a from 5-hydroxy-1,8-nonadiene employing a metathesis reaction to form the cycloheptene and a palladium-catalyzed asymmetric cyclization to form the bicyclic ring system is achieved in 15% overall yield.