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

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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.