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Abstract

The synthesis of natural products has been a core discipline of organic chemistry for almost 200 years. Complex molecules offer boundless challenges for synthetic chemists and demand new solutions. Marine (micro-) organisms have proven to be an especially rich source of various chemically as well as biologically interesting natural products.
The present thesis describes the total synthesis of belizentrin methyl ester. The parent compound belizentrin was isolated from the dinoflagellate Prorocentrum belizeanum in 2014. Already during the isolation, belizentrin proved to be a very unstable compound; this was corroborated during our campaign towards its synthesis. We also found that the corresponding methyl ester was sufficiently stable, albeit still sensitive. Our efforts eventually resulted in a highly convergent total synthesis of this compound in a longest linear sequence of 19 steps.
This work was conducted in collaboration with Dr. Sylvester Größl, who synthesized the polyhydroxyated sidechain; his contributions are acknowledged and described in the relevant sections of the following thesis.
The key steps during the synthesis of the macrocyclic portion of the molecule were two palladium catalyzed cross coupling reactions to assemble three fragments, followed by the intramolecular aminolysis of a spirolactone to close the macrolactam ring. After a few protecting group and redox manipulations, the macrocycle and the sidechain were connected by an Eselective Julia-Kocienski olefination. Finally, global deprotection yielded the aforementioned belizentrin methyl ester.
Additionally, an enantiodivergent approach to chiral allenes starting from propargylic alcohols was developed. This project was conducted in collaboration with Karin Radkowski and Dr. Macarena Corro Moron. Chiral allenes play an interesting role as structural element in both natural products and synthetic pharmaceutical agents. Furthermore, they are valuable synthetic intermediates.
Different strategies for the stereospecific conversion of propargylic alcohols to allenes have been reported. The concept harnesses the stereochemical information of chiral propargylic alcohols to construct chiral allenes. A drawback of the known methods is that one enantiomer of the starting alcohol leads to only one enantiomer of the product allene. As the enantiomers of allenes can be viewed as geometrical isomers at one of the double bonds, we envisioned that the stereospecific construction of the “second” double bond from “E/Z”-isomeric precursors would provide access to both enantiomers of the allene in question.
We found isomeric alkenylsilanes, which were accessed via the cis- or trans-selective hydrosilylation of propargylic alcohols, to be suitable precursors. In the presence of a base and a Cu^(I) source, these compounds undergo a facile and stereospecific Brook rearrangement with consecutive elimination to produce allenes. Due to the stereocontrolled hydrosilylation, both enantiomers of an allene are accessible from a single enantiomer of the starting alcohol. This method has been successfully tested on a selection of propargylic alcohols.