Presentation Date: Feb 14, 2026
AGSA Abstract
(+)-Nootkatone, an EPA-registered sesquiterpenoid repellent superior to DEET, is currently priced at ~$2,500/kg, severely limiting its public-health potential. The primary cost driver in LSU’s patented 8-step synthesis from β-pinene is Step 4, the anionic oxy-Cope (AOC) rearrangement, which traditionally requires stoichiometric KH, 18-crown-6, and THF. This work focuses on replacing this expensive, homogeneous system with recyclable heterogeneous strong bases to enable scalable, low-cost production. A model substrate, (E)-1-phenyl-3,3-((E)-styryl)hexa-1,5-dien-3-ol (PPEH), chemically analogous to the patented Step 4 tertiary alcohol, was used to rapidly screen catalysts. Moderately basic Cs₂CO₃/MCM-41 (0.09 wt% Cs) and KF/Al₂O₃ (0.29 wt% K) were prepared by wet impregnation, while strongly basic 20 wt% DBU/CeO₂-Al₂O₃ and 2-cyanopyridine/CeO₂-Al₂O₃ were obtained via dry impregnation. Reactions were examined in THF, tert-butanol, acetonitrile, and dichloromethane at 0 °C and 23 °C. The most promising result was achieved with Cs₂CO₃/MCM-41 (50 mol% loading) in THF at 23 °C for 16 h, delivering the rearranged ketone in 49% isolated yield at 0.035 M concentration. Although lower than the KH/18-crown-6 benchmark (>85%), this constitutes the first reported heterogeneous catalysis of an AOC rearrangement and eliminates the need for pyrophoric KH and expensive crown ether. Parallel studies on the native nootkatone precursor are ongoing to close the remaining yield gap. Complementary optimisations include ozonolysis (Step 1) at –29 °C in methanol (93% yield) without dichloromethane and direct telescoping of crude nopinone into Step 2, further reducing solvent consumption and cost. Successful translation of the heterogeneous AOC system is projected to decrease overall synthesis cost below $500/kg, making nootkatone economically viable for widespread tick and mosquito control and significantly expanding access to a safe, effective, pollinator-friendly repellent.
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