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Total Synthesis of Marine Alkaloid Hyellazole and its Derivatives

The total synthesis of the naturally occurring marine alkaloids hyellazole and chlorohyellazole was attempted from the corresponding easily accessible 2-methyl-1-ketotetrahydrocarbazoles obtained through the Japp–Klingemann reaction, followed by Fischer indole cyclization and subsequent Grignard coupling with phenylmagnesium bromide. Grignard coupling with 2-methyl-1-ketotetrahydrocarbazole unfortunately led directly to 2-methyl-1-phenylcarbazole through dehydration followed by aromatization through aerial oxidation, but application of the same reaction conditions to 6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one, with careful treatment, led to the isolation of 6-chloro-2-methyl-1-phenyl-4,9-dihydro-3H-carbazole. However, selenium dioxide oxidation of this dihydrochloro derivative led to the formation of 6-chloro-2-methyl-1-phenyl-9H-carbazole. A different route was then adopted: a suitably substituted aromatic amine was used to establish the substitution pattern of the required carbazole derivative with a bromo group at C-1, and the required phenyl group at the 1-postion was then attached through Suzuki–Miyaura cross-coupling to furnish hyellazole.