Total Synthesis of Fijiolide A via an Atropselective Paracyclophane Formation

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.


Advisor(s):
Cramer, Nicolai
Year:
2016
Publisher:
Lausanne, EPFL
Keywords:
Other identifiers:
urn: urn:nbn:ch:bel-epfl-thesis6895-2
Laboratories:




 Record created 2015-12-30, last modified 2018-09-13

n/a:
Download fulltext
PDF

Rate this document:

Rate this document:
1
2
3
 
(Not yet reviewed)