Oxidative Coupling Approach to Sarpagine Alkaloids: Total Synthesis of (-)-Trinervine, (+)-Vellosimine, (+)-Normacusine B, and (-)-Alstomutinine C.

Sarpagine alkaloids are bioactive indole natural products that contain a highly rigid indole-fused 1-azabicyclo[2.2.2]octane, for which more than 100 members have been identified. Herein, a detailed examination of the intramolecular oxidative coupling between a ketone and a Weinreb amide for assembling the complex 1-azabicyclo[2.2.2]octane core structure of sarpagine family alkaloids is described. Precise late-stage manipulations of ketone and Weinreb amide enables the divergent syntheses of (-)-trinervine, (+)-vellosimine, (+)-normacusine B, and (-)-alstomutinine C. Other notable transformations of the synthesis featured an aza-Achmatowicz/indole cyclization cascade to generate the azabicyclo[3.3.1]nonane structure,  a regioselective elimination reaction to form the ethylidene motif embedded in the (+)-vellosimine and (+)-normacusine B, and a diastereoselective indole oxidative rearrangement to form the spiro oxindole structure in (-)-alstomutinine C.