Enantiospecific synthesis of crotogoudin and crotobarin

In this project we seek to achieve the chemical synthesis of two natural products, crotobarin and crotogoudin. Both molecules have been shown to be active in stopping tumor progression and may offer new ways of treating cancer. Bioactive secondary metabolites (natural products) continue to serve as a basis for over 50% of the medicines currently on the market. However to develop a drug from a natural product, chemical synthesis is often essential. As such, strategies and methods for the preparation of natural products possessing complex structures remain important as the basis for discovering new medicinal entities. In this project we want to achieve the synthesis of both products in a short and efficient way and we will apply, as well as develop where necessary modern methodology. In order to obtain these the structurally challenging polycyclic molecules, we propose the synthesis of an advanced intermediate, which will then serve as a starting point to obtain the two structurally related, desired products. The syntheses of crotogoudin and crotobarin would be competitive with the existing syntheses, as it would require less steps as previously published and both natural products would be obtained in a selective manner. Given the short syntheses and the efficiency of our proposed approach to these molecules, we believe that our work will facilitate bioactivity studies and may lead to the identification of new anti-cancer compounds.

This project was focused on the construction of the structural framework of a family of molecules, called phleghenrines, isolated from a small plant in rural China. These molecules had shown be possible new leads in the treatment of the early effects of Alzheimer's disease. In addition, they are unique in a chemical sense, as their three-dimensional framework has until then not been seen in any other molecules. So far, chemists had not made any similar structure therefore no procedure on how to make them was known. The ability to create any kind of molecules is important for medicine, agriculture and engineering and for many molecules a tried and tested procedure exists. For some new scaffolds however, as in these molecules, their creation in the lab is not as straight forward and often involves the development of new methodologies or testing to see if existing methodologies are versatile enough to be adapted. In this project three different approaches were studied to discover, which would yield the most amount of material and the most convenient mode of production. In the end a straightforward procedure was developed that not only allows for the creation of these specific molecules, but also enables the creation of similar molecules with different or additional parts. This was made possible by first creating two building blocks and in a chemical addition reaction these parts were joined in a specific manner to create the scaffold that makes up the phleghenrine compounds. One of the methodologies studied in the course of this project was then evaluated for its application in the recreation of a bacterial cell wall components, a research area important for the development of vaccines and antibiotics. The molecules that make up part of the cell-wall are very challenging to work with and it was attempted to improve on the existing methods by shortening procedures and by eliminating loss of material. Initial experiments proved successful and this research endeavor will be carried on in the future.