Natural Product Synthesis of (+)-Brefeldin A

The asymmetric total synthesis of (+)-Brefeldin A, a potent anticancer agent, which has in addition several other pharmaceutically interesting activities, is outlined and proposed inhere. Within the project a new synthetic strategy is presented involving ring closing alkyne metathesis, a recently developed trans-hydrogenation as well as an elegant and simple route for the synthesis of the required alkyne from the corresponding lactone. As pharmaceutical interest in the title compound has risen due to the exquisite pharmaceutical properties of (+)- Brefeldin A, the new developed synthesis does not only aim on a short and convenient route, but also aims for high quantities of the natural product to supply medicinal studies with sufficient amounts for further testing. Therefore several routes towards the cyclopentanol core of the molecule are proposed and will be evaluated during the project with regard to their feasibility to meet the requirements outlined in the proposal below [e.g. high yields in combination with highly practicable protocols at a large batch size (multigram scale)]. These routes include biocatalytic methods, which are based on enzymatic resolution in order to install the required asymmetry at an early-stage precursor. The total synthesis is completed via ring closing alkyne metathesis (RCAM) forming the macrocylce and subsequent catalytic trans-hydrogenation to give (+)-Brefeldin A.

Natural products are a unique source for the discovery of new drugs. Isolation from natural sources has proven in many cases sufficient for the initial discovery, but further studies on the mode of action and the possibility to use the discovery for a medical treatment require certain quantities of the natural product, which often cannot be supplied by the natural source.Therefore target-oriented organic synthesis aims on the construction of these drug compounds in the laboratory and is often supplying sufficient quantities of the natural product for the second round of tests as a potential pharmaceutical. (+)-Brefeldin A, a natural product with a tremendous record of interesting properties (anticancer activity against a profound number of human cancer cells lines, antibiotic activity, etc.), has been the target of this project. A simple synthetic route has been developed, that relies on a lately developed, new synthetic methodology. This methodology enables the construction of a tedious structural feature (the introduction of a E-configured doublebond from an alkyne), which was hard to create selectively in the laboratory in previous synthetic attempts towards the target Brefeldin molecule. By the new route, about half a gram of Brefeldin A was prepared and the newly developed methodology was first applied to a real and structural complex molecule. Important new aspects were observed for the first time, leading to a reinvestigation of the chemical mode of action during this key transformation. These new studies mark a new milestone in understanding this chemical tool and allow a more detailed forecast to its application.Additionally, two biologically based processes have been developed that produce primary amines, important compounds for e.g. polymers, and cinnamic acids, which are important pharmaceutical intermediates. The total synthesis of indolizidin based alkaloids has been a major target too. These natural products possess potential to be used in the treatment of Alzheimers disease and schizophrenia. The synthesis of Monomorine A, a prominent member of this group of compounds has been established to its second key step and is currently even after the projects end worked on, to finish the biosynthetic route.