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

这一创新-技术转化伙伴关系(PFI-TT)项目的更广泛影响/商业潜力是开发一种天然化合物系列，可用作各种携带疾病的蚊子、跳蚤、白蚁、各种扁虱和鹿扁虱的驱虫剂，这些蚊子、跳蚤、白蚁、不同的扁虱和鹿扁虱是莱姆病的携带者。这一系列化合物基于从葡萄柚和阿拉斯加黄柏树皮中提取的天然产品，已经被证明比现有的商业驱避剂更安全、更有效。这一系列化合物目前是通过发酵过程生产的，被用作风味/香味成分，但对于消费驱虫剂来说，它仍然太贵了。该提案提出了该家族母体化合物(Nootkatone)的现有八步化学合成，以及大幅精简、优化和降低与此合成相关的成本的计划。该项目的成功完成将导致生产成本降低，接近其他商业驱虫剂的价格范围。此外，这一过程将扰乱这种化合物家族的香精/香料市场，可能会导致更广泛的采用。两名博士生将通过参加NSF i-Corps和其他培训活动来接受创新和创业方面的培训。拟议的项目将在现有实验室规模合成的基础上实现商业化，方法是：首先，大幅修改八步合成中最昂贵的一步，目前认为这一反应需要一种一次性、高度昂贵和强碱性的可溶催化剂系统。这个系统将被取代，使用过去40年开发的多相催化技术，用一种更便宜的催化剂取代，这种催化剂也更容易从反应产物中分离出来。这一单一行动可以反过来应用于降低其他合成(例如，制药中间体)的制造成本。在许多其他方面，这种合成中其他过于复杂或昂贵的步骤将得到优化，以降低试剂和溶剂成本，在某些情况下，通过使用商用臭氧发生器和冷冻机，通过溶剂替代，通过在选择性氧化反应中更好地控制氧化剂(臭氧)，以及通过减少某些工艺分离步骤中的溶剂负荷，这将通过使用现代自动闪蒸色谱分离装置来实现。所有这些对合成的修改都是为了简化和优化化合物的合成，并产生更纯粹的诺卡酮产品。该项目由创新伙伴关系(PFI)计划和既定的激励竞争研究计划(EPSCoR)联合资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.