Total Synthesis of (+)-Shearilicine

Herein we report the first total synthesis of the indole diterpenoid natural product shearilicine by an 11-step sequence. This synthesis features the development of a generalizable core precursor to the highly oxidized subclass of indole diterpenoids that are particularly notable for their potent and selective inhibition of Big Potassium (BK) ion channels. In order to access the target molecule in an enantiospecific fashion, a native chiral auxiliary strategy was employed by exploiting the directing ability of the isopropylidene moiety of (R)-carvone, followed by the subsequent cleavage of this functionality. The formation of the key carbazole substructure was accomplished through a mild intramolecular Heck cyclization. Computational evaluation of the relevant transition state revealed a complex network of non-covalent interactions between the substrate and ligands.