Synthetic studies on the norditerpenoid alkaloid aconitine

Aconitine is a potent neurotoxin isolated from the monkshood plant. The hexacyclic, monobasic structure of aconitine is characterized by a unique bridging carbon framework and a dense array of oxygen functional groups. Two strategies toward the synthesis of the norditerpenoid alkaloid are described. In the first approach, a deoxygenated model of aconitine was constructed in order to investigate the viability of an emerging method for C--C bond formation and the introduction of nitrogen-functionality into complex natural products. C--H insertion of sulfamate esters into alpha-ethereal centers affords a unique class of oxathiazinane N,O-acetal products. The intramolecular addition of electron-rich arenes to iminium ions generated from these heterocycles provides access to novel spirodienone scaffolds. In the assembly of the model system, the bicyclo[3.2.1]octane of the aconitine C and D rings was constructed through a Hg-mediated carbocyclization and the electron-rich aromatic ring was installed through an enol triflate cross-coupling reaction. C--H amination to afford the oxathiazinane N,O-acetal was highly effective and represents the most complex illustration of the reaction tested to date. Addition of the arene to an iminium ion generated from the N,O-acetal in the presence of a Lewis acid promoter furnished an intriguing rearrangement product that was unfortunately not a viable intermediate towards the synthesis of aconitine.; In the second approach, a route to the fully functionalized natural product was targeted in which the nitrogen center would be installed through a late-stage C--H amination reaction. To this end, the highly oxygenated B and D rings were assembled from a vanillyl alcohol starting material. Key transformations in the assembly of this advanced intermediate include phenol oxidation with a hypervalent iodine oxidant, ring-closing metathesis of a vinyl sulfide and selective methylation of a tetraol species. These strategies toward the synthesis of aconitine lay the foundation for the construction of alkaloid natural products using C--H amination methodology.