Cascade Cyclization Synthesis of Fused Polycyclic Ethers

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The Chemical Synthesis Program supports the research of Prof. Frank E. McDonald at Emory University, in a project exploring the stereo- and regioselective exo-mode cyclizations of acyclic polyene precursors bearing allylic oxygen substituents as stereoinduction elements. This project is the basis for a novel cascade polycyclization approach to brevenal, a non-toxic inhibitor of brevetoxin binding. Major objectives for the granting period include uncovering the diastereoselectivities of metal-catalyzed cycloisomerization and halonium-ion mediated cyclization processes, and demonstrating the feasibility and generality of bicyclization and multiple ring-forming polycyclization processes. In addressing the broader impact of meaningful inclusion of less-experienced researchers such as undergraduate researchers and K-12 science teachers, the McDonald laboratory also develops new synthetic routes for the acyclic precursors required for cascade cyclization processes, based on efficient and scalable preparations of multiply-functionalized building blocks of general interest to the synthetic community. This research focuses on discovering new strategies for the chemical synthesis of structurally complex compounds of marine origin. A critical barrier to progress in this field has been the dozens of steps required for preparing compounds of potential medicinal and commercial importance. The McDonald laboratory is addressing this challenge by developing a novel synthetic strategy, to form structurally complex compounds in a single operation, from relatively simple and easily prepared linear precursors. The potential impact of this research includes the efficient preparation of relatively complex compounds such as brevenal, which is a non-toxic inhibitor of airborne toxins naturally produced by red tide events in tropical and subtropical marine regions, including the Gulf of Mexico. Broader impacts of this research feature inclusion of undergraduate students and K-12 science teachers through several summer research programs at Emory.