A Straightforward Synthesis of 5-Methylaaptamine from Eugenol, Employing a 6π-Electrocyclization Reaction of a 1-Azatriene

Abstract

Aaptamine, isolated from tropical marine sponges of the Demospongiae class, is the most prominent member of a growing family of natural products. Many aaptaminoids have been shown to have interesting biological activity. The efficient access to 5-methylaaptamine, an unnatural analogue of aaptamine, was achieved by using economic and naturally-occurring eugenol as the starting material. The synthesis involved the preparation of a 5-aminoeugenol derivative through successive nitration, O-methylation, and nitro group reduction reactions. An Elderfield-Johnson sequence was employed to synthesize the N-tosyl-5-allyl-7,8-dimethoxydihydro-1H-quinolin-4-one ring system. A catalytic double-bond isomerization followed by a carbonyl methoximation and 6-π electrocyclization of the 1-azatriene motif afforded the 2,3-dihydro-1H-benzo[de][1,6]naphthyridine tricyclic intermediate, which underwent a reductive desulfonylation and catalytic dehydrogenation to afford the target product.