Total Synthesis of Resiniferatoxin Enabled by Radical-Mediated Three-Component Coupling and 7-endo Cyclization

Abstract

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. Here we report the development of a novel radical-based strategy for assembling 1 from three components: A-ring 9, allyl stannane 18b, and C-ring 17b. The 6-membered 17b, prepared from d-ribose derivative 19, was designed to possess the caged orthoester structure with α-alkoxy selenide as a radical precursor. Upon treatment of 17b with 18b, 9, and V-40, the potently reactive α-alkoxy bridgehead radical was generated from 17b and then sequentially coupled with 9 and 18b to yield 16b. This first radical reaction formed the hindered C9,10-linkage between the A and C-rings and extended the C4-chain on the A-ring in a stereoselective fashion. After derivatization of 16b into 15, the remaining 7-membered B-ring was cyclized in the presence of n-BuSnH and V-40 by utilizing the xanthate on the C-ring as the radical precursor and the allylic dithiocarbonate as the terminator. The second radical reaction thus enabled not only the 7-endo cyclization but also construction of the C8-stereocenter and the C6-exo olefin. Tricycle 14 was elaborated into the targeted 1 by a series of highly optimized chemoselective reactions. The present total synthesis of 1 demonstrates the advantages of radical reactions for linking hindered bonds within carbocycles without damaging preexisting functionalities, thereby offering a new strategic design for multistep target-oriented synthesis.

Total Synthesis of 1‐Hydroxytaxinine

“…Radical reactions are compatible with diverse oxygen functionalities and applicable to the formation of sterically hindered C−C bonds, thereby serving as methods to forge the complex architectures of highly oxygenated terpenoids . In this context, we developed a series of powerful coupling reactions of α‐alkoxy carbon radicals . Our continued interest in these reactions motivated us to devise an efficient radical‐based convergent route to 1 from chiral 5 and achiral 6 (Scheme ) .…”

Radicals in natural product synthesis

“…In 2017, Inoue and co-workers completed the total synthesis of the resiniferatoxin ( 47 ), a daphnane diterpenoid that is a potent ion channel protein agonist (Scheme 6). 23 It presents a unique synthetic challenge as it features a trans -fused 5/7/6-tricyclic core as well as a cage-like orthoester component. The authors sought to develop a radical coupling strategy for the synthesis of this densely oxygenated natural product, recognizing that radical reactivity can be highly tolerant of polar functional groups.…”

Fragmentverknüpfungen in der Totalsynthese – Bildung von C‐C‐Bindungen über intermediäre Carbanionen oder freie Radikale

“…Die analgetische Wirkung des Diterpenoids 226 beruht auf einer Desensibilisierung der nozizeptiven Neurone. Obwohl Daphnan‐Terpenoide seit Jahrzehnten bekannt sind, [129] haben die Arbeitsgruppen von Wender [130] und Inoue [131] die einzigen vollständigen Synthesen von (+)‐Resiniferatoxin ( 226 ) beschrieben. Die von Inoue et al.…”