Discovery of a novel intramolecular double cyclization for the construction of the cortistatin pentacyclic core

A number of small molecule agents that target growth factor receptors and their signaling pathways have been identified as inhibitors of angiogenesis. As a result, the quest for the isolation and discovery of new families of natural products with anti-angiogenic activity continues. The cortistatins, a novel family of rearranged steroidal alkaloids, have recently been identified. All eleven family members exhibit varying levels of anti-angiogenic activity. The most potent member of the family is cortistatin A. It is distinguished by a highly functionalized A ring, an oxabicyclo[3.2.1] octene B ring, and an isoquinoline moiety at C17. In our quest toward the total synthesis of cortistatin A, we identified a novel intramolecular double cyclization. As a result, the enantioselective synthesis of the cortistatin pentacyclic core is described. The cornerstone of our approach is a hypervalent iodine induced intramolecular oxidative dearomatization nitrile oxide cycloaddition.