title: Indole synthesis by radical cyclization of o-alkenylphenyl isocyanides and its application to the total synthesis of natural products.
abstract: Development of indole synthesis by tin-mediated radical cyclization of o-alkenylphenyl isocyanide is described. Upon heating o-alkenylphenyl isocyanide in the presence of tri-n-butyltin hydride and AIBN, 2-stannyl-3-substituted indole was formed via 5-exo-trig cyclization of the imidoyl radical intermediate. After acidic workup, 3-substituted indoles were isolated. For substrates bearing simple alkyl groups, a substantial amount of tetrahydroquinoline derivatives were generated through 6-endo-trig cyclization. This undesired cyclization was suppressed by using an excess amount (five equivalents based on o-alkenylphenyl isocyanide) of ethanethiol instead of tri-n-butyltin hydride. The 2-stannylindole intermediates proved to be a suitable substrate for Stille coupling, giving 2,3-disubstituted indoles in a one-pot procedure. In addition, the 2-stannylindole intermediates could be converted to 2-iodoindoles by treatment with iodine or N-iodosuccinimide. The 2-iodoindoles thus obtained served as good substrates for Heck reactions, Stille couplings, Suzuki couplings, and palladium-mediated carbonylations, to afford a variety of 2,3-disubstituted indoles. The utility of this protocol was demonstrated by application to synthetic studies on gelsemine and discorhabdin A, and the total synthesis of an aspidosperma alkaloid, (-)-vindoline.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-0033, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tokuyama
authors.forename: Tohru
authors.initials: T
authors.lastname: Fukuyama
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis; D001688:Biological Products / Q000138:chemical synthesis*; D003500:Cyclization; D005609:Free Radicals / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis*; D009570:Nitriles / Q000737:chemistry; D011809:Quinones / Q000138:chemical synthesis; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000138:chemical synthesis
chemical_list: D000470:Alkaloids; D001688:Biological Products; D005609:Free Radicals; D007211:Indoles; D009570:Nitriles; D011809:Quinones; C009667:vindoline; D014747:Vinblastine; C063230:gelsemine; C019519:phenylisocyanide