Total Synthesis of Marine Alkaloid Hyellazole and its Derivatives

Abstract

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.