FWF - J 3466-N28 - Natural Product Synthesis of (+)-Brefeldin A

In this project an asymmetric synthesis of potential anti-cancer natural product (+)-Brefeldin will be attempted.

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.