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.
Eichberg
M J
MJ
Center for New Directions in Organic Synthesis, Department of Chemistry, University of California at Berkeley, 94720-1460, USA.
Dorta
R L
RL
Grotjahn
D B
DB
Lamottke
K
K
Schmidt
M
M
Vollhardt
K P
KP
D002625:Chemistry, Organic / Q000379:methods; D003035:Cobalt / Q000737:chemistry*; D018684:Glycine Agents / Q000138:chemical synthesis; D009682:Magnetic Resonance Spectroscopy; D009532:Nickel / Q000737:chemistry; D010084:Oxidation-Reduction; D010165:Palladium / Q000737:chemistry; D011042:Poisons / Q000138:chemical synthesis; D013237:Stereoisomerism; D013331:Strychnine / Q000138:chemical synthesis*
D018684:Glycine Agents; D011042:Poisons; D003035:Cobalt; D010165:Palladium; D009532:Nickel; D013331:Strychnine