UC Berkeley

Diterpenoid alkaloid natural products, isolated from plants in the Aconitum, Delphinium, Consolida, and Spiraea genera, possess complex, caged, highly oxygenated skeletons and display potent biological activities through interactions with voltage-gated ion channels. Several of these alkaloids are currently used clinically for the treatment of arrhythmia, while others act as incredibly potent neurotoxins. Until recently, there were very few successful total syntheses of any diterpenoid alkaloid natural products, a testament to the structural complexity of these molecules. We explored synthetic strategies targeting two major types of these natural products: the aconitine-type C19-diterpenoid alkaloids and the hetisine-type C20-diterpenoid alkaloids.

Initial work explored Diels–Alder cycloadditions with maleic anhydride-derived dienophiles toward the eventual construction of aconitine-type diterpenoid alkaloids. We examined the selective ring-opening of these adducts with a variety of nucleophiles and utilized an ester-stabilized benzylic nucleophile to achieve C–C bond formation with complete positional selectivity. This product was rapidly elaborated to a vinyl lactone intermediate, which following amine addition and oxidation underwent a high-yielding, diastereoselective methylation reaction to install the challenging C18 carbon atom.

Synthesis of the hetisine-type diterpenoid alkaloid cossonidine built off of previous work performed in the Sarpong lab. Reexamining the previously-developed route, we optimized several steps and implemented new reactions to increase the yield and reproducibility of the chemistry and reduce the overall step count. Subsequent functional group transformations involving deprotection and inversion of the C1 hydroxyl group and installation of the allylic alcohol moiety completed the first total synthesis of cossonidine.

Recognizing the connections between the various diterpenoid alkaloid types, we explored ways to convert the vinyl lactone intermediate developed in our studies toward aconitine-type natural products into the hetisine-type skeleton of cossonidine. Following the introduction of an iodine atom on the aromatic ring, magnesium-halogen exchange leads to an intramolecular cyclization reaction to forge the central 6-7-6 tricycle with carbonyl groups at all three nitrogen-bearing carbon atoms following oxidation. Efforts to install the C18 methyl group and accomplish a triple reductive amination cascade to complete this second-generation total synthesis are ongoing.