An Efficient Route to Synthesizing Key Intermediates In the Chemical Synthesis of Nootkatone

Author

Ademola A. Akanbi, Louisiana State University and Agricultural and Mechanical CollegeFollow

Semester of Graduation

Fall 2025

Degree

Master of Science in Chemical Engineering (MSChE)

Department

Chemical Engineering

Document Type

Thesis

Abstract

The global burden of arthropod-borne diseases, transmitted by vectors such as mosquitoes and ticks, necessitates innovative, safe, and cost-effective repellents to mitigate public health risks. Nootkatone, a naturally occurring sesquiterpene with potent insect-repellent and acaricidal properties, offers a promising alternative to synthetic repellents like DEET due to its low toxicity, pleasant fragrance, and EPA registration as a biopesticide. However, its high production costs and limited scalability hinder widespread adoption. Herein, we present a synthetic route towards an optimized, scalable, and economical eight-step chemical synthesis of (+)-nootkatone, starting from the inexpensive and GRAS natural product β-pinene, as developed at Louisiana State University (LSU). By addressing key challenges in stereoselectivity, reagent costs, and hazardous solvent use, this work enhances the industrial viability of nootkatone production for insect repellent applications. Specific advancements include the optimization of β-pinene ozonolysis at commercially feasible temperatures (–20°C to –29°C) using methanol, achieving a 94% yield of nopinone without dichloromethane (DCM), and the development of heterogeneous catalysts for the critical anionic oxy-Cope (AOC) rearrangement to reduce reliance on expensive and hazardous reagents like potassium hydride (KH) and 18-crown-6 ether.

The research focuses on replacing KH and 18-crown-6 in the AOC rearrangement with cost-effective heterogeneous catalysts (e.g., KF/Al₂O₃, Cs₂CO₃/SiO₂), utilizing higher reaction temperatures compatible with commercial chillers, substituting costly or toxic solvents (THF, DCM, benzene) with toluene or methanol, and minimizing chromatographic separations through telescopic strategies and vacuum distillation. Model studies using a homoallylic alcohol analog (PPEH) demonstrated that catalysts like 9 wt% Cs₂CO₃/MCM-41 SiO₂ in THF achieved the highest yields, while 29 wt% KF/SAS 200 Al₂O₃ showed robust activity, paving the way for scalable AOC conditions. Additionally, our use of a 20% toluene-THF blend in the Grignard reaction for nootkatone synthesis reduced costly THF reliance while maintaining high yields and stereoselectivity. This approach unlocks opportunities for toluene in other ethereal solvent-dependent reactions, enhancing scalability and sustainability.

Date

11-19-2025

Recommended Citation

Akanbi, Ademola A., "An Efficient Route to Synthesizing Key Intermediates In the Chemical Synthesis of Nootkatone" (2025). LSU Master's Theses. 6236.
https://repository.lsu.edu/gradschool_theses/6236

Committee Chair

Dooley, Kerry