(+)-Nootkatone, the flavor of grapefruit

Abstract Nootkatone is one of the most valuable citrus flavors. Originally isolated from the heartwood of the Nootka cypress ( Callitropsis nootkatensis ), it was probably the identification of nootkatone as a minor component of grapefruit oil that catapulted this sesquiterpene into the focus of flavor research and made it a highly sought-after citrus aroma in recent decades. The odors of ( +)-nootkatone and (−)-nootkatone are perceptible in the air at threshold concentrations of 30 ppm and 66,000 ppm of saturated vapor, respectively. While ( +)-nootkatone embodies a strong grapefruit scent and has a bitter taste, (−)-nootkatone has a faint woody vetiver note and is virtually tasteless. In 2020, nootkatone was registered by the US Environmental Protection Agency as an insect repellent and natural insecticide that may repel and kill mosquitoes, fleas, ticks, mites, lice, and termites. Moreover, numerous pharmacological activities of nootkatone have been thoroughly investigated. As expected, a wealth of synthetic approaches, which are essentially based on the oxidation of valencene and on total syntheses, have been published in the last 60 years since its discovery. However, in addition to extraction from natural sources (e.g., grapefruit peel), the enzymatic oxidation of valencene and fermentative processes are the preferred production technologies today. The market is expected to grow considerably over the next 10 years, not least owing to the wide range of potential applications in the pharmaceutical, personal, and home care sector. How the reader may benefit : learn more about the total synthesis of natural products, allylic oxidation, and Robinson annulation, gain deeper insights into the biosynthesis of sesquiterpenes and finally discover how enantiopure compounds, such as ( +)-nootkatone, are produced at an industrial scale. Graphical Abstract