UC Berkeley

A benzyne insertion ring expansion strategy toward the synthesis of hetisine-type C₂₀-diterpenoid alkaloids has been developed. The first chapter of this manuscript presents an introduction to C₂₀-diterpenoid alkaloids and previous synthetic work toward selected target core structures. The second and third chapters outline our ring expansion strategy for the synthesis of the core of the natural product cossonidine and efforts to complete its total synthesis.

An overview of the structural and biological properties of C₂₀-diterpenoid alkaloids is provided, as well as a survey of the synthetic studies that have been carried out thus far toward natural products containing the hetidine and hetisine-type framework. The two existing syntheses of a hetisine-type diterpenoid alkaloid are also described. This review outlines some of the salient structural challenges associated with the synthesis of these compounds, as well as the strategies applied to their construction.

An approach involving a ring expansion was developed to access a tricyclic motif conserved in the hetidine and hetisine frameworks. The acyl-alkylation of aryne intermediates by insertion into C-C sigma bonds was applied to several β-ketoesters and aryne precursors to investigate the efficacy of this transformation on complex systems. Three tricyclic intermediates were synthesized that contain functional handles at the appropriate positions for C-N bond formation to construct the hetisine core.

With a sequence in place to arrive as several desired tricyclic intermediates, they were then employed to investigate C-N bond formation. A range of conditions was explored, and the desired azabicycle was accessed in 3 steps from the tricyclic scaffold. The requisite [2.2.2] bicycle was then formed in 2 steps to complete the hetisine core. Finally, the synthetic sequence was modified in order to introduce a methyl group necessary for completion of the natural product target. This methylation pathway has been successful in providing the full hetisine core en route to the synthesis of the natural product cossonidine.