Evolution of a Synthetic Strategy for Complex Diterpenes from Euphorbiaceae and Thymelaeaceae

The biosynthetically related daphnane, tigliane, and rhamnofolane diterpenes are a fascinating collection of natural products endowed with distinct polycyclic architectures and immense therapeutic potential. Containing a common 5,7,6-fused tricyclic core with varied oxidation, these molecules have served as popular and challenging synthetic targets for over four decades. Despite much work, however, many complex members remain inaccessible by synthesis. Inspired by this, we developed a convergent coupling strategy employing two modular fragments as a gateway into this class of diterpenoids. This article details the evolution of such a strategy initially resulting in the total synthesis of the flagship daphnane diterpene orthoester (DDO), resiniferatoxin (RTX). A key trans-fused hydroazulene building block was designed and synthesized via a 7-exo-trig Heck cyclization and then coupled with an aldehyde bearing preprogrammed oxidation state for RTX via a diastereoselective aldol reaction. After extensive investigations involving many different substrates, a subsequent key SmI₂-mediated 6-exo-trig radical cyclization/1,5-hydrogen atom transfer (HAT) cascade was realized, which enabled rapid access to the 5,7,6-fused tricyclic core and, ultimately, a total synthesis of (±)-resiniferatoxin in as few as 14 steps. Here we also detail enantioselective syntheses of key building blocks relevant to these natural products. Finally, we demonstrate that a modified aldehyde fragment can be incorporated into this strategy to intercept a key tricyclic ketone thus achieving formal syntheses of rhamnofolane and tigliane diterpenes, such as crotophorbolone, phorbol, and prostratin. We believe this general strategy could prove useful in accessing various diterpenes of even higher complexity from the plant families Euphorbiaceae and Thymelaeaceae.