New Bond Disconnections in the Streamlined Synthesis of Complex Bioactive Molecules

PROJECT SUMMARY The goal of this program is the discovery of powerfully simplifying synthetic disconnections, strategies, and concepts to prepare biologically important and topologically complex molecules in rapid and diverse fashion. Multiple complex natural products from the plant families Euphorbiaceae and Thymelaeaceae have entered, or successfully completed, human clinical trials as therapeutic agents. Despite their significant documented medicinal relevance toward cancer treatment, HIV eradication, and neurodegenerative disease many complex diterpenes in these families are not available in significant quantities, and unlike many small molecule drug discovery programs, it is difficult to easily mix- and-match structural fragments embedded within these structures. We have developed a new strategy toward natural products from Euphorbiaceae and Thymelaeaceae which is both efficient and convergent. Diverse polycycles of high sp3 content are becoming increasingly important in medicinal chemistry and library screening. We have developed a new strategy to prepare many different polycyclic frameworks from a single starting material using simple reagents under mild conditions. We seek to exploit these finding towards problems in human health. From both of these activities will emerge new therapeutic lead compounds for the treatment of human diseases and new diverse screening fragments that are currently inaccessible. Through this work, trainees will be provided with rigorous and intellectually stimulating training in synthetic organic chemistry and exposure to applications in biomedicine.