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

Abstract

AbstractAaptamine, 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.