Approaches to the Synthesis of (±)-Strychnine via the Cobalt-Mediated [2 + 2 + 2] Cycloaddition: Rapid Assembly of a Classic Framework

Five synthetic approaches to racemic strychnine (1), with the cobalt-mediated [2 + 2 + 2]
cycloaddition of alkynes to indoles as the key step, are described. These include the generation and attempted
cyclization of macrocycle 8 and the synthesis of dihydrocarbazoles 15, 22, and 26 and their elaboration to
pentacyclic structures via a conjugate addition, dipolar cycloaddition, and propellane-to-spirofused skeletal
rearrangement, respectively. Finally, the successful total synthesis of 1 is discussed. The development of a
short, highly convergent route (14 steps in the longest linear sequence) is highlighted by the cyclization of
enynoylindole 40 with acetylene and the formal intramolecular 1,8-conjugate addition of amine 49 to form
pentacycle 50. Numerous attempts toward the formation of the piperidine ring of 1 from vinyl iodide 56 were
made and its successful formation via palladium-, nickel-, and radical-mediated processes is described.