Total syntheses of (–)-fragin and valdiazen, and synthetic studies towards complex neuritogenic terpenoids

Daeppen, Christophe. Total syntheses of (–)-fragin and valdiazen, and synthetic studies towards complex neuritogenic terpenoids. 2016, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_12490

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This thesis is divided in five chapters, highlighting natural products as valuable sources for the treatment of mankind diseases. The first chapter gives a general introduction into the early research and development of natural products and their history as suitable drugs in the past time. For a long time, a common strategy was the use of small molecules. Often, natural products proved to be valuable sources or were the initial step or the fundament for the development of drugs.
The second chapter is based on a long-known but poorly investigated natural product named fragin. The structurally fascinating and rare diazeniumdiolate moiety captured our attention. An enantioselective synthesis was elaborated to clarify the unknown stereogenic center. Furthermore, a racemic intermediate in the biosynthesis of fragin, named valdiazen, was isolated and confirmed via chemical synthesis. SAR-studies on fragin identified the activity-driven part of the molecule and the influence of the substituents on the antibacterial activity.
Neurodegenerative diseases are affecting increasing numbers of people worldwide and will become a serious problem for our health system. The third chapter shows the current state of the art in neurodegenerative disease treatment and how chemists were providing small molecules with potent activity to this research field. The genus Illicium is known to deliver natural products with potent neurite outgrowth inducing activity. One of these molecules is (2R)-hydroxynorneomajucin, which comprises a rare nor-type structure. We aimed to provide a total synthesis and SAR-studies to this synthetically challenging scaffold. An advanced intermediate was successfully synthesized in 18 steps.
Malaria is one of the deadliest diseases since ages and the uprising problem of strain resistance makes the future outlook even less promising. The fourth chapter describes the serendipity of a reaction to access novel endoperoxides. The formation of the endoperoxidal structure was first achieved in the presence of pure oxygen and further improved by the addition of a catalyst to induce this formal [2 + 2 + 2] cycloaddition. SAR-studies on these potent antimalarials provided a first insight into the active parts of the compounds.
The fifth chapter is dedicated to the field of antibiotics research. Natural products showed their value in the early development steps of antibiotics, but became then an almost forgotten research field. Nevertheless, emerging bacterial strain resistance becomes more of a problem worldwide, and the discovery of novel antibiotics is desperately needed. The chapter reports on our synthetic efforts towards the antibiotic striatal A. The goal of this project is to provide a synthetic entry into the striatal family. However, the first attempt was not fruitful and led to several problems such as low yields or by-product formation. A new strategy was evaluated, that targets the synthesis of a bis- diazoketone precursor to form the tricyclic core structure.
Advisors:Gademann, Karl and Pfaltz, Andreas
Faculties and Departments:05 Faculty of Science > Departement Chemie > Former Organization Units Chemistry > Organische Chemie (Gademann)
UniBasel Contributors:Daeppen, Christophe and Gademann, Karl and Pfaltz, Andreas
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12490
Thesis status:Complete
Number of Pages:1 Online-Ressource (X, 358 Seiten)
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Last Modified:08 Feb 2020 14:48
Deposited On:13 Mar 2018 13:40

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