Biomimetic synthetic studies on the hicksoane alkaloids

Abstract

The hicksoane alkaloids contain an unusual propane-2,2-diamine unit embedded within a 1,3,6-triazocane, the only natural product known to possess this eight-membered heterocycle. Herein, we report the results examining a biosynthesis proposal that this heterocycle emerges from a late-stage reaction of a dipeptide with acetone. Ile-Trp-CONH₂ and Trp-Ile-CONH₂ dipeptides were trialled as substrates; in both cases, the intermediate iminium ion did not engage with the primary amide to form the triazocane, reacting instead to generate an imidazolidinone and a β-carboline, respectively. The results from this study infer the triazocane present in these alkaloids is unlikely to be biosynthesised by the late-stage reaction of a dipeptide with biogenic acetone.