UC Davis

Macrocyclic musk ketones are popular base notes in a diverse array of fragrance products ranging from perfumes and colognes to candles and air fresheners. Today, most musk odorants used in the aroma industry are produced synthetically due to ethical and sustainability concerns related to the extraction of natural musk from animal sources. For this reason, extensive computational and synthetic efforts have focused on elucidating the structure-odor relationship of various musk ketones to effectively propose and design novel analog structures. In this work, the green and practical syntheses of four macrocyclic musks were investigated utilizing a renewable and readily available monounsaturated Ω-9 fatty acid, oleic acid, as the starting material. Two of the compounds, muscone (3-MCP 1a) and dihydrocivetone (15), are known aroma chemicals of commercial relevance whereas the two others, 3-methylcyclononadecanone (3-MCN 2) and 3-methylcycloheptadecanone (3-MCH 17), are novel macrocyclic analogs of ring sizes 19 and 17, respectively. Guided by structural optimization tools and drug-protein docking software, (R)-2 and (R)-17 were predicted to bind to human olfactory receptor 5AN1 with affinities that are 11% and 10%, respectively, higher than those of (R)-muscone. Based on this analysis, efforts toward the total syntheses of 3-MCN 2 and 3-MCH 17 were initiated. Even though this experimental work was not concluded, a series of useful advances was made and the reported results may serve as a framework for future studies. Similarly, a novel, three-step synthesis of dihydrocivetone, starting from oleic acid, is described in this work and utilizes a pyrolysis-mediated cyclization approach. Additional research should focus on further optimization of the reaction conditions to improve the conversion, yield, and industrial application of the method. Lastly, a six-step, eco-efficient, and green conversion of oleic acid to (R)-muscone was theoretically devised, and translation of this developed route into experimental advances is currently being investigated.