Palladium-Catalyzed Enantioselective Desymmetrizing Aza-Wacker Reaction: Development and Application to the Total Synthesis of (-)-Mesembrane and (+)-Crinane

Reported is an unprecedented catalytic enantioselective desymmetrizing aza-Wacker reaction. In the presence of a catalytic amount of a newly developed Pd(CPA)(2)(MeCN)(2) catalyst (CPA = chiral phosphoric acid), a pyrox ligand, and molecular oxygen, cyclization of properly functionalized prochiral 3,3-disubstituted cyclohexa-1,4-dienes afforded enantioenriched cis-3a-substituted tetrahydroindoles in good yields with excellent enantioselectivities. A cooperative effect between the phosphoric acid and the pyrox ligand ensured efficient transformation. This reaction was tailor-made for Amaryllidaceae and Sceletium alkaloids as illustrated by its application in the development of the concise and divergent total synthesis of (-)-mesembrane and (+)-crinane.