Total Synthesis of Complanadine A

Described herein is the development of a total synthesis of the Lycopodium alkaloids lycodine and complanadine A. The Lycopodium alkaloids, particularly the lycodine-type, have generated broad interest in the scientific community due to their acetylcholinesterase inhibitory and other biological activity. Complanadine A is a particularly interesting target due to both its demonstrated ability to induce secretion

of nerve growth factor in human glial cells, allowing observation of neurite outgrowth in rat neuronal PC-12 cells, and its structural complexity, being an unsymmetrical C1 − C2′ bipyridyl dimer of lycodine. Chapter 1 reviews the established routes for the synthesis of selected representative Lycopodium alkaloids, and Chapter 2 describes our efforts towards their total synthesis. The synthesis employs robust and underutilized methods for heterocycle construction, using a pyrrole intermediate for their unique nucleophilicity among aryl heterocycles. A pyrrole intermediate is converted in one step to a 3-chloropyridine derivative via a Ciamician-Dennstedt reaction, with the halide serving as a convenient handle for elaboration of the lycodine scaffold to complanadine A via Fagnou coupling.