Resiniferatoxin (RTX) is the flagship member of the daphnane diterpenoid orthoesters (DDOs), a class of natural products with highly complex structures and pharmaceutically relevant biological properties such as anti-HIV and antitumor bioactivities. RTX itself is a potent analgesic that has been granted Orphan Drug Status by the FDA. Despite their biochemical potential, no general synthetic route to the DDOs exists owing to the topological and stereochemical complexity of these molecules. Herein we disclose a new retrosynthetic logic, orthogonal to exiting efforts toward these natural products, to rapidly access the daphnane diterpene core in a convergent and stereoselective manner. These efforts culminated in the successful 15-step total synthesis of resiniferatoxin.

The synthetic route disclosed herein centers on the late-stage assembly of the stereochemically dense 6-membered ring of the daphnanes in stark contrast to previous syntheses of RTX and related natural products, wherein this part of the molecule is constructed early on. Forging the 6-membered ring last allows for a more convergent and hence more rapid synthetic route, via which the daphnane diterpenoid orthoester core can be accessed in only 12 steps from commercially available materials. Key synthetic sequences are an allylation/Pd-catalyzed 7-exo-trig cyclization to construct the 7-membered ring of the diterpene scaffold as well as a series of a highly diastereoselective aldol reaction followed by SmI2-mediated 6-exo-trig cyclization. Using these two reactions the complex 6-membered ring of the natural product, which is decorated with 5 contiguous stereocenters, can be quickly and stereoselectively constructed. In the latter of the two steps a halide atom at the cyclization terminus was successfully used to modulate the inherent stereochemical preference in order to access the desired diastereomer of the tricyclic product. Given the rapid assembly of the DDO scaffold and the modular nature of the route, this new retrosynthetic logic has a lot of future potential for synthesizing previously inaccessible daphnane natural products.