A Benzyne Insertion Approach to Hetisine-Type Diterpenoid Alkaloids: Synthesis of Cossonidine (Davisine)

The hetisine-type natural products
exhibit one of the most complex
carbon skeletons within the diterpenoid alkaloid family. The use of
network analysis has enabled a synthesis strategy to access alkaloids
in this class with hydroxylation on the A-ring. Key transformations
include a benzyne acyl-alkylation to construct a key fused 6-7-6 tricycle,
a chemoselective nitrile reduction, and sequential C–N bond
formations using a reductive cyclization and a photochemical hydroamination
to construct an embedded azabicycle. Our strategy should enable access
to myriad natural and unnatural products within the hetisine-type.