Synthesis of a library of antiviral silvestrol analogues and development of novel methodologies in the field of radical chemistry

Abstract

The first part of this dissertation deals with the design and synthesis of silvestrol and rocaglamide derivatives exhibiting antiviral properties. These two natural products, which belong to the Flavagline group, were isolated from different species of the genus Aglaia. Due to their activity as selective translation inhibitors, they found application in previous medicinal chemistry research primarily as lead structures in cancer research, but later antiviral activity against a variety of RNA viruses was also demonstrated. In the present dissertation, several strategies for the total synthesis of this class of natural products were elaborated on the basis of previous work. This allowed the preparation of a library of 40 derivatives in total. The biological testing of 27 of these compounds against hepatitis E, which was carried out by collaborators at the Ruhr University Bochum, revealed new structure-activity relationships and confirmed that the correlations established in cancer research are also applicable to the antiviral properties. In addition, it was possible to identify candidates that exhibited both higher antiviral activity and proportionally lower cytotoxicity than both natural products.

The second part of this dissertation deals with the development of novel synthetic methodologies in the field of radical chemistry. Based on a MINISCI-type decarboxylation, an access to synthetically useful alkoxyamines was established. The relevance of this method was demonstrated by its application in the context of a new total synthesis approach for (±)-indatraline. Studies on the reactivity of a polymer-bound bis(azido)iodiate(I) complex, which releases the highly explosive iodine azide in a controlled manner, enabled the elucidation of several previously unknown radical mechanisms. Furthermore, several methods have been developed to generate bromine azide from stable precursors in situ for the use in organic solvents to accomplish 1,2-functionalization of alkenes and chemoselective oxidation of secondary alcohols.