One-pot and Telescoped Semisynthesis of (+)-Nootkatone

Due to its distinct grapefruit aroma and low perception threshold, (+)-nootkatone (5) is a high-value compound widely utilized within the flavor and fragrance industry.^1,2 Additionally, (+)-nootkatone (5) is used as a food additive and possesses insecticidal activity,³ which highlights its versatility and contributes to its significant commercial value, especially given its low natural abundance.⁴ Herein, we describe the semisynthesis of (+)-nootkatone (5) from commercial (+)-valencene (1) under telescoped continuous flow conditions. Our semisynthesis involves the photooxidation of (+)-valencene (1) with O₂ and meso-tetraphenylporphyrin (TPP), followed by a Schenk rearrangement, acetylation of the hydroperoxides, and HOAc elimination for the formation of (+)-nootkatone (5), using an adapted methodology previously developed in our laboratory.⁵ (+)-Nootkatone (5) was successfully synthesized in overall yields of up to 45% under batch conditions and 35% in a telescoped continuous flow setup.