Approaches to the synthesis of (+/-)-strychnine via the cobalt-mediated [2 + 2 + 2] cycloaddition: rapid assembly of a classic framework |
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Authors: | Eichberg M J Dorta R L Grotjahn D B Lamottke K Schmidt M Vollhardt K P |
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Institution: | Center for New Directions in Organic Synthesis, Department of Chemistry, University of California at Berkeley, 94720-1460, USA. |
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Abstract: | 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. |
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