Total Synthesis of Resiniferatoxin.

From both structural and functional perspectives, the large family of daphnane diterpene orthoesters (DDOs) represent a truly remarkable class of natural products. As potent lead compounds for the treatment of pain, neurodegeneration, HIV/AIDS, and cancer, their medicinal potential continues to be heavily investigated, yet synthetic routes to DDO natural products remain rare. Herein we report a distinct approach to this class of complex diterpenes, highlighted by a 15-step total synthesis of the flagship DDO, resiniferatoxin.

Enantiospecific Solvolytic Functionalization of Bromochlorides.

Herein, we report that under mild solvolytic conditions, enantioenriched bromochlorides can be ionized, stereospecifically cyclized to an array of complex bromocyclic scaffolds, or intermolecularly trapped by exogenous nucleophiles. Mechanistic investigations support an ionic mechanism wherein the bromochloride serves as an enantioenriched bromonium surrogate. Several natural product-relevant motifs are accessed in enantioenriched form for the first time with high levels of stereocontrol, and this technology is applied to the scalable synthesis of a polycyclic brominated natural product. Arrays of nucleophiles including olefins, alkynes, heterocycles, and epoxides are competent traps in the bromonium-induced cyclizations, leading to the formation of enantioenriched mono-, bi-, and tricyclic products. This strategy is further amenable to intermolecular coupling between cinnamyl bromochlorides and a diverse set of commercially available nucleophiles. Collectively, this work demonstrates that enantioenriched bromonium chlorides are configurationally stable under solvolytic conditions in the presence of a variety of functional groups.

A Unified Approach for the Enantioselective Synthesis of the Brominated Chamigrene Sesquiterpenes.

The brominated chamigrene sesquiterpenes constitute a large subclass of bromocyclohexane-containing natural products, yet no general enantioselective strategy for the synthesis of these small molecules exists. Herein we report a general strategy for accessing this family of secondary metabolites, including the enantioselective synthesis of (-)-α- and (-)-ent-ß-bromochamigrene, (-)-dactylone, and (+)-aplydactone. Access to these molecules is enabled by a stereospecific bromopolyene cyclization initiated by the solvolysis of an enantiomerically enriched vicinal bromochloride.