Total Synthesis of Resiniferatoxin Enabled by Photocatalytic Decarboxylative Radical Cyclization

Abstract

Resiniferatoxin (1) is a complex daphnane diterpenoid with a highly oxygenated 5/7/6-membered ABC-ring system. Here we report a new synthetic route to 1 that requires 27 steps from a starting d-ribose derivative. The carbon spacer and A-ring are sequentially attached to the C-ring by radical allylation and Stille coupling reactions, respectively. An Ir­(III)-catalyzed photoinduced decarboxylative radical reaction then forged the sterically hindered bond between the tetra- and trisubstituted carbons to cyclize the central seven-membered B-ring.

The synthesis of seven- and eight-membered rings by radical strategies

“…In 2022, Inoue and co-workers described another pathway for the enantioselective synthesis of resiniferatoxin (Scheme 42). 76 Compared with the previous route, 72 this scheme subtracted 14 steps and increased the total yield by >40-fold. Meanwhile, the n Bu 3 Sn-mediated three-component coupled cyclization was replaced by the photoinitiated decarboxylation radical cyclization strategy, which is more environment-friendly and significantly reduces the energy of the reaction.…”

Tigliane and daphnane diterpenoids from Thymelaeaceae family: chemistry, biological activity, and potential in drug discovery

“…This method is also expected to be applied for synthesizing daphnanes with the same B-ring structure, which has not been achieved thus far [47]. In daphnane diterpenoids, since the first total synthesis of resiniferatoxin (2), an analgesic candidate with a 6-ene structure similar to phorbol (3), was reported in 1997, its synthetic route has been optimized and updated until 2022 [48][49][50]. The total synthesis of daphnanes with 6,7-epoxy structure has only been reported for 6,7-epi-yuanhuapin (19), but as mentioned above, the total synthesis of daphnanes with 5β-hydroxy-6α,7α-epoxy structure, which is primarily isolated from the plants of Thymelaeaceae family, has not yet been achieved (Fig.…”

Total Synthesis of Resiniferatoxin

“…Despite significant effort, and despite a number of successful syntheses of the structurally and biogenetically related tigliane and rhamnofolane diterpenes, − only two daphnane total syntheses have been accomplished during the half century following their isolation. For two decades, Wender’s landmark 1997 total synthesis of 1 remained the only route to a full DDO member until Inoue’s impressive radical-based route emerged in 2017. − Herein we report our findings in this area characterized by 12-step entry into the complex DDO core, and a 15-step total synthesis of 1 .…”