Total Synthesis of Fijiolide A.

Fijiolide A is a secondary metabolite isolated from a marine-derived actinomycete of the genus Nocardiopsis. It was found to significantly reduce the TNF-α induced activity of the transcription factor NFκB, which is considered a promising target for the treatment of cancer and inflammation-related diseases. We disclose an enantioselective synthesis of fijiolide A enabled by a fully intermolecular, yet regioselective cyclotrimerization of three unsymmetrical alkynes to construct its tetra-substituted arene core. An atropselective macroetherification enables the assembly of the strained [2.6]paracyclophane motif. A late-stage glycosylation of the macrocyclic aglycone at its tertiary alcohol position allowed for the first total synthesis of fijiolide A.