著者

彦根 悠人 長友 優典 井上 将行

出版者

公益社団法人 有機合成化学協会

雑誌

有機合成化学協会誌 (ISSN:00379980)

巻号頁・発行日

vol.81, no.12, pp.1136-1149, 2023-12-01 (Released:2023-12-13)

参考文献数

95

---

Resiniferatoxin (1) belongs to a daphnane diterpenoid family, and has strong agonistic effects on TRPV1, a transducer of noxious temperature and chemical stimuli. The densely oxygenated trans-fused 5/7/6-tricarbocycle (ABC-ring) of 1 presents a daunting challenge for chemical synthesis. We accomplished three radical-based total syntheses of 1 to streamline the overall route. In the first-generation synthesis, we implemented a novel radical three-component coupling reaction. This transformation formed the hindered linkage between the A and C-rings and extended the carbon chain in a stereoselective fashion. The 7-membered B-ring was cyclized by the second radical reaction. In the second-generation synthesis, we improved the efficacy and practicality by reorganizing the reaction sequence and retaining the intermediates of the first route. Thus, we utilized intermolecular radical allylation, Stille coupling, and photocatalytic decarboxylative radical cyclization as the three key transformations. In the third-generation synthesis, we designed a specific intermediate based on the common substructure of not only 1, but also structurally related diterpenoids, and established a unified strategy. The common intermediate was efficiently built by exploiting the bridgehead radical cyclization and derivatized into 1 through efficient C-ring functionalizations. These three total syntheses of 1 together demonstrate the advantages of radical reactions for linking hindered bonds within carbocycles without damaging preexisting functionalities, thereby offering a new strategic design for multi-step target-oriented synthesis.