開催日: 2017/09/20 - 2017/09/22
Resiniferatoxin (1) is a daphnane diterpenoid, isolated from the latex of Euphorbia resinifera. Compound 1 was revealed to exhibit strong analgesic properties by acting as a potent activator of transient receptor potential vanilloid 1 (TRPV1). The structure of 1 consists of a fused 5/7/6-membered carbocyclic framework and a unique orthoester moiety. The promising therapeutic activities and the highly complex architecture have gained intense interest in the chemical community. A number of synthetic efforts have been reported, but the only total synthesis of a daphnane diterpenoid disclosed to date is that of 1 by Wender and co-workers. Herein, we describe the asymmetric synthesis of 1 by employing a novel radical-based strategy. To simplify the retrosynthetic dissection of 1, we have developed radical-based approach to assemble a highly oxygenated carbon skeleton. The caged orthoester structure of 1 motivated us to utilize a three-component radical coupling. Accordingly, 1 was retrosynthetically disassembled into A-ring 6, allyl stannane 7 and C-ring 5, which would be derived from D-ribose (10). First, 5 was synthesized from D-ribose (10). The six-membered C-ring structure of 1 was assembled by a ring-closing metathesis of diene 12, which was derived from 10 via installation of two carbon chains. Stereoselective functionalization of the C-ring provided α-alkoxy selenide 5 as a radical precursor. The key three-component radical coupling reaction between 5-7 enabled us to elongate the nine-carbon unit and introduce the three stereocenters in a single step. Then, the following seven-step transformation, including stereoselective C4-hydroxylation, afforded bisxanthate 34. B-ring formation by a 7-endo radical cyclization built the C8-stereocenter, and produced ABC-ring framework 2. Finally, the total synthesis of 1 was accomplished from 2 through the orthophenylacetate formation, the C7-allylic oxidation, and the installation of homovanilloyl group by SN2 displacement as the key transformations. In conclusion, we have developed a novel radical-based synthetic route to 1. The present approach demonstrated the power and versatility of the radical reactions to realize the construction of highly oxygenated structures.