Total Synthesis of Physalin A and B

Proteasome inhibitors have profound effects on tumor growth, tumor spread and sensitize cancer cells to apoptosis. Recently several constituents of Physalis plants, like Physalin A and B, have been identified as proteasome inhibitors and therefore as potential candidates for cancer therapy. Both highly oxygenated compounds possess an unprecedented 13,14-seco-16,24-cyclo-steroidal skeleton with eleven stereogenic centers, making Physalin A and B exceptional beautiful and complex molecules. Although the structures of Physalin A and B have long been known and their extremely interesting biological profiles as well as their challenging structural features make them ideal targets for natural product synthesis, so far no total synthesis of either compound has been reported. This fellowship application represents the detailed description of a concise and flexible synthetic approach towards Physalin A and B utilizing latest methodologies in organic chemistry as well as the incorporation of a complex tandem reaction as designated key step. The proposed plan should not only be suitable for the synthesis of both natural products, but also provide various derivatives not accessible via semi-synthetic routes. These derivatives are needed for extensive investigations about the mode of action and to get a better understanding of this important class of proteasome inhibitors. The proposed synthetic route towards Physalin A and B is based on: Synthesis of the eastern fragment by an Ireland-Claisen rearrangement. Preparation of the sterol fragment via an organocatalytic Diels Alder reaction and an ene-yne ring closing metathesis rearrangement (or desymmetrization of a symmetric precursor). Coupling of both fragments by a pyrrolidine mediated Tsuji-Trost reaction. A spectacular tandem reaction as key step of the proposed synthesis combining an Eschenmoser fragmention and a [2+2] cycloaddition in a single step. Oxidation and modification of the carbon skeleton to finally provide Physalin A and B.

To understand and more importantly to cure cancer is one of the most important challenges in modern science. The reasons, why, when and how this fatal dysregulation of cells starts, are very complex and still not fully understood. Therefore, it's crucial to gain new insights and to get a better understanding of the underlying concepts and mechanisms, which are involved.Already in 2006 Kobayashi and coworkers isolated several structurally related natural products from marine sponges, which were called cortistatins. Not just because of their interesting and challenging structures, but more importantly because of their unprecedented activity against cancer, several research groups immediately became interested in these compounds. Also the Shair group at the Harvard University started to elucidate the still unknown mode of action of cortistatin A, which is the most potent natural product of this class. However, it soon became apparent that larger quantities of this compound were needed, than could be provided by already known synthetic routes. During this project a novel, very concise, and high yielding synthesis of a general precursor for the preparation of derivatives of cortistatin A was established. The new route avoids expensive reagents and catalysts and is based on the conversion of inexpensive reagents instead. More importantly, all steps seem to be robust, easy to handle and can be performed on a larger scale. Additional steps to prepare a variety of derivatives, starting from this general precursor, are closely related to known transformations, which have previously been used in the synthesis of the natural product itself. As consequence, this new approach has already been used to prepare first derivatives, shortly after this postdoctoral study was concluded. The activity and potency of these compounds is currently tested.