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

• Published in: Journal of the American Chemical Society 2017-11, Vol.139 (45), p.16420-16429
• Main Authors: Hashimoto, Satoshi, Katoh, Shun-ichiro, Kato, Takehiro, Urabe, Daisuke, Inoue, Masayuki
• Format: Article
• Language: English
• Subjects: Cyclization; Diterpenes - chemical synthesis; Diterpenes - chemistry; Free Radicals - chemistry; Molecular Conformation; Ribose - chemistry; Stereoisomerism
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.7b10177

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-Bu3SnH 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.