Development of a 6-endo-selective bromoetherification

The steadily increasing demand for new drugs for the treatment of various diseases and the urgent need for new antibiotic scaffolds, result in an unbroken interest in the isolation of natural products. Over decades natural products inspired synthetic chemists efforts and constituted the basis for the identification of different drugs available today. In recent years, especially marine natural products have attained growing attention, because of the frequent occurrence of uncommon structural motifs leading to novel biological mechanisms of action. As the marine environment is very hostile, these metabolites are often stable to harsh salty conditions, and exhibit extraordinary potency to circumvent the activity-diminishing diluting effect. Among the isolated maritime natural products numerous halide-containing structures can be found. Unfortunately, by now there are only very few synthetic methods available dealing with the accessibility of sp3 C-X bonds. The formation of 6-membered haloethers, in particular, represents a striking challenge in natural product synthesis. To face this challenge and be able to design short and efficient syntheses toward various halogenated natural haloethers the proposal describes the elaboration of a general protocol for a 6-endo selective bromoetherification reaction. The ambitious task to overcome the kinetically favored 5-exo bromoetherification reaction is the most exciting endeavor presented. Furthermore, the combination with a selective epoxide opening reaction will extend the scope of the bromoetherification reaction tremendously and open access to different classes of halogenated natural products. Additionally, making these natural products easier accessible will help to provide necessary quantities for comprehensive biological studies. In order to demonstrate the general applicability of the newly developed concept we will also accomplish the synthesis of microcladallene, a C15 acetogenin, isolated from red algae Laurencia microcladia. A fast and effective access to microcladallene would be additionally desirable, because due to the highly interesting structural features this bromoether will be extensively analyzed concerning its biological effectiveness within pharmacological studies at Scripps Florida. Critically, the newly developed bromoetherification reaction should be successfully applied in the total synthesis of a marine natural product, and show the general application in presence of diverse functionalities.

Biology, chemistry and medicine have always been closely linked, not only, but especially when it comes to finding new drugs. Many natural substances were isolated from herbs or medicinal plants, their structure elucidated and their biological activity tested. Some of these natural products served as the basis for the development of new drugs. Due to a steadily growing demand for new drugs for the treatment of various diseases and the urgent need for new antibiotics, there is an unbroken interest in the isolation of new natural products. In recent years, especially marine natural products have attained growing attention, because of the frequent occurrence of uncommon structural motifs leading to novel biological mechanisms of action. As the marine environment is very hostile, these metabolites are often stable to harsh salty conditions, and exhibit extraordinary potency to circumvent the activity-diminishing diluting effect. Due to the very small amount of isolated natural products, it is often necessary to create these molecules on a larger scale in the laboratory. Herein, especially the incorporation of halides represents a striking challenge to the natural product chemist. Particularly the access to 6-membered haloethers, which are a very frequent component of maritime natural products, has so far only been possible on a very cumbersome path. Over the last two years, a new method to provide faster access to this complex structural element has been successfully developed in the course of this project. In principle, the development of a new method in chemistry can be compared with the addition of a new tool to a toolbox. Not every tool is equally suitable for every task, but if you have the right tool for a given job, you can do it very efficiently. The newly developed protocol is very robust and tolerates a variety of different functional groups to allow for a broad synthetic application. In this case, the newly developed method facilitates access to the aforementioned 6-membered haloethers. This method makes it easier to provide the required amounts of different natural substances for comprehensive biological investigations, in order to identify possible active ingredients or lead structures.