RUI: Stereocontrolled Synthesis of Phantasmidine and Analogs

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In this project funded by the Chemical Synthesis Program of the Chemistry Division, Professor Richard Fitch of the Department of Chemistry and Physics at Indiana State University will develop a convergent enantioselective method for the synthesis of phantasmidine, a novel alkaloid and a potential nicotinic receptor agonist from the Ecuadoran poison frog Epipedobates anthonyi. Phantasmidine possesses a unique condensed tetracyclic structure incorporating pyridine, furan, pyrrolidine, and cyclobutane rings. An improved synthesis of cyclobutene, its epoxide and the corresponding cis- and trans-2-aminocyclobutanols will be developed, whose stereochemistry will control installation of the remaining stereocenter. A transannular ring closure involving rhodium-catalyzed carbene C-H insertion will be used to close the tetracycle. This work should produce a sufficient amount of material for a full biological evaluation of phantasmidine and provide initial structure-selectivity relationships among nicotinic receptors to aid the development of selective biological probes. The synthetic methodology that will be developed should be applicable to other related heterocycles as well as the synthesis of cyclobutane-based polymers and other structured materials. These methods and materials can impact several chemical industries, including pharmaceuticals, fine chemicals and polymers. The broader impacts involve the training of undergraduate students and a postdoctoral fellow at a predominantly undergraduate institution. The undergraduate students will participate in the Summer Undergraduate Research Experiences (SURE) program at Indiana State University, aimed at fostering a research culture among students including groups underrepresented in the sciences.