Total Synthesis of Fijiolide A via an Atropselective Paracyclophane FormationReport as inadecuate

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Lausanne: EPFL, 2016

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.

Keywords: total synthesis ; natural products ; fijiolide ; [2+2+2] cycloaddition ; Pauson-Khand reaction ; paracyclophane formation ; atropselectivity ; glycosylation. Thèse École polytechnique fédérale de Lausanne EPFL, n° 6895 (2016)Programme doctoral Chimie et Génie chimiqueFaculté des sciences de baseInstitut des sciences et ingénierie chimiquesLaboratoire de catalyse et synthèse asymétriquesJury: Prof. Jieping Zhu (président) ; Prof. Nicolai Cramer (directeur de thèse) ; Prof. Jérôme Waser, Prof. Karl Gademann, Prof. Edward Anderson (rapporteurs) Public defense: 2016-1-8 Reference doi:10.5075/epfl-thesis-6895Print copy in library catalog

Author: Heinz, ChristophAdvisor: Cramer, Nicolai


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