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

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

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

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

Biosynthesis and Structure Activity Relationship Investigations of the Diazeniumdiolate Antifungal Agent Fragin

Only a few natural products possessing a diazeniumdiolate have been isolated and usually these compounds display a broad range of biological activities. Only recently the first diazeniumdiolate natural product biosynthetic gene cluster was identified in Burkholderia cenocepacia H111, which produces the fungicide (-)-fragin and the signal molecule (rac)-valdiazen. In this study, L-valine was identified as the initial substrate of (-)-fragin biosynthesis by feeding experiments using isotopically labeled amino acids. The formation of the diazeniumdiolate was chemically studied by several proposed intermediates. Our results indicate that the functional group is formed during an early stage of the biosynthesis. Furthermore, an oxime compound was identified as a degradation product of (-)-fragin and was also observed in the crude extract of the wild type strain. Moreover, structure-activity relationship analysis revealed that each moiety of (-)-fragin is essential for its biological activity

Preparation of antimalarial endoperoxides by a formal [2 + 2 + 2] cycloaddition

A formal [2 + 2 + 2] cycloaddition reaction between a 1,3-dione, an olefin, and molecular oxygen mediated by light is reported, which delivers endoperoxides in good yield through the formation of two C-O and one C-C bond in one step. The resulting 1,2-dioxanes are stable compounds and can be further derivatized at the hemiacetal position via alkylation or acetylation. All compounds have been evaluated against Plasmodium falciparum, and the best compound displayed an IC50-value of 180 nM. A potential mechanistic rationale for the formation of these compounds is presented

Formal Total Synthesis of (−)-Jiadifenolide and Synthetic Studies toward seco-Prezizaane-Type Sesquiterpenes

Synthetic studies toward highly oxygenated seco-prezizaane sesquiterpenes are reported, which culminated in a formal total synthesis of the neurotrophic agent (−)-jiadifenolide. For the construction of the tricyclic core structure, an unusual intramolecular and diastereoselective Nozaki–Hiyama–Kishi reaction involving a ketone as electrophilic coupling partner was developed. In addition, synthetic approaches toward the related natural product (2R)-hydroxy-norneomajucin, featuring a Mn-mediated radical cyclization for the tricycle assembly and a regioselective OH-directed C–H activation are presented