PFI-TT: Chemical Synthesis of a Natural Product Family of Compounds for Tick-Targeted Prevention and Control

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The broader impact/commercial potential of this Partnerships for Innovation - Technology Translation (PFI-TT) project is the development of a natural product family of compounds that can serve as insect repellent for various disease-carrying strains of mosquitos, fleas, termites, diverse ticks, and deer ticks, which are carriers of Lyme disease. This family of compounds, based on natural products derived from grapefruit and Alaskan yellow cedar bark, is already proven to be both safer and more effective than existing commercial repellents. This family of compounds is currently produced by fermentation processes and is used as flavor/fragrance components, but it is still too expensive for consumer insect repellents. The proposal presents an existing eight-step chemical synthesis for the parent compound of the family (nootkatone), along with a plan to greatly streamline, optimize and reduce the costs associated with this synthesis. The successful completion of this project will lead to the reduction of the production costs close to the price range of other commercial insect repellents. Furthermore, this process will disrupt the flavor/fragrance market for this compound family, possibly leading to wider adoption. Two Ph.D. students will be trained in innovation and entrepreneurship by participating in the NSF I-Corps and other training activities. The proposed project would enable commercialization based on the existing bench-scale synthesis by, first, greatly modifying the most expensive of the eight synthetic steps, a reaction currently thought to require a throwaway, highly expensive and strongly basic soluble catalyst system. This system would be replaced, using heterogeneous catalytic technology developed over the last 40 years, with a far cheaper catalyst that would also be easier to separate from the reaction products. This single action could in turn be applied to reduce manufacturing costs in other syntheses (e.g., pharma intermediates). In many other ways, other overly complex or expensive steps in this synthesis will be optimized to reduce reagent and solvent costs, in some cases by the use of a commercial ozonizer and chiller, by solvent substitutions, by better oxidant (ozone) control in the selective oxidation reactions, and by the reduction in solvent loadings in certain process separation steps, which will be made possible by the use of a modern automated flash chromatographic separation unit. All these modifications to the synthesis have been designed to streamline and optimize the synthesis of the compound, and to generate purer nootkatone products.This project is jointly funded by Partnerships for Innovation (PFI) program and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.