Rapid Access to Spirocyclic Oxindole Alkaloids: Application of the Asymmetric Palladium-Catalyzed [3 + 2] Trimethylenemethane Cycloaddition

The
marcfortines are complex secondary metabolites that show potent
anthelmintic activity and are characterized by the presence of a bicyclo[2.2.2]­diazaoctane
fused to a spirooxindole. Herein, we report the synthesis of two members
of this family. The synthesis of marcfortine B utilizes a carboxylative
TMM cycloaddition to establish the spirocyclic core, followed by an
intramolecular Michael addition and oxidative radical cyclization
to access the strained bicyclic ring system. In addition, the first
asymmetric synthesis of (−)-marcfortine C is described. The
key step involves a cyano-substituted TMM cycloaddition, which proceeds
in nearly quantitative yield with high diastereo- and enantioselectivity.
The resulting chiral center was used to establish all remaining stereocenters
in the natural product.