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The natural product fijiolide A is a secondary metabolite isolated from a marine-derived actinomycete of the genus Nocardiopsis. It displays inhibitory activity against TNF-α-induced activation of NFκB, an important transcription factor and a potential target for the treatment of different cancers and inflammation related diseases. Structurally, fijiolide A impresses by its highly complex molecular architecture, featuring a polychlorinated and rotationally restricted [2.6]paracyclophane core. The embedded highly unsaturated cyclopenta[a]indene framework is glycosylated with an amino ribopyranose unit. Fijiolide A is related to the Bergman cycloaromatization product of the C-1027 chromophore and is proposed to stem from a similar biosynthetic enediyne precursor. This thesis outlines a total synthesis of fijiolide A. Our synthetic approach features an intermolecular ruthenium-catalyzed [2+2+2] cycloaddition of three different alkynes to assemble the heavily substituted central arene core. Only 10 further steps were required to build up the strained [2.6]paracyclophane core of the fijiolide A aglycone. For this purpose we engineered an unprecedented macroetherification process that proceeds with remarkably high regio- and atropselectivity via a templated nucleophilic substitution. A late-stage glycosylation of the sterically encumbered tertiary alcohol enabled, for the first time, access to fijiolide A. Overall, the natural product fijiolide A was synthesized in a longest linear sequence of 18 steps from commercially available starting material.
Didier Trono, Françoise Gisou van der Goot Grunberg, Laurence Gouzi Abrami, Béatrice Kunz, Audrey Geneviève Chuat, Joana Carlevaro Fita, Nattawadee Panyain