| Abstract | Hippadine, a lycorine-type alkaloid isolated from several plants of the family Amaryllidaceae, contains an interesting pentacyclic skeleton, specifically the aromatic pyrrolophenanthridinone core. This molecule has shown myriad biological activity including reversible inhibition of spermatogenesis in rats and the ability to alter several cardiac functions. Previous syntheses of Hippadine have focused on a late-stage formation of the C-ring, often catalyzed by palladium. However, our synthesis begins with a molecule that already contains the A, B, and C rings intact. Alkylation of nitrogen in the starting material affords a functionalized tether on nitrogen that can be used to induce formation of the E ring via an unusual intramolecular de Mayo reaction. A simple aldol addition then closes the ring system. Our current work includes high-yielding constructions of several of the intermediates in this new synthetic pathway toward Hippadine and some potentially useful improvements and modifications designed to replace reactions that require costly organometallic materials. |
