Biomimetic Total Synthesis of (±)-Haloxine

2026/07/09 by Linh K. Tong, Juha H. Siitonen · 1 voice
Agricultural and Biological Sciences · Chemistry · #Advanced Synthetic Organic Chemistry #Botanical Research and Chemistry #Chemical synthesis and alkaloids

paper · doi:10.26434/chemrxiv.15005913/v1

openalex publication_date 2026/07/09 · openalex created_date 2026/07/11 · openalex updated_date 2026/07/14

Abstract

Haloxine, a naturally racemic β-ketoamide alkaloid, has eluded chemists for nearly 60 years. It has a unique tricyclic core which links it to quinolizidine alkaloid family. Herein we report a plausible biosynthesis and based on that the first total synthesis of this elusive alkaloid. The synthesis relies on a bioinspired Mannich–Mannich–Enamine domino reaction between tetrahydroanabasine and β-ketoesters to generate an enamine-ester core followed by a hydrolysis–acylation domino reaction to rearrange it into the β-ketoamide core of haloxine. The synthesis allowed the first comprehensive NMR characterization of the alkaloid.

Discussions

• Haloxine gets synthesized after nearly 60 years since its isolation! Spearheaded by PhD student Linh, a biomimetic route featuring two domino reactions builds the alkaloid in three steps. This project [bsky, 9 points, 1 comments]

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