New Synthetic Strategies and Technologies

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This research program is directed at the development of new synthetic technologies and strategies for the construction of intermediate and target molecules. A newly discovered annulation-fragmentation cascade reaction sequence involving acid-catalyzed carbon-carbon bond formation followed by an intramolecularly-induced carbon-carbon bond scission will be optimized, and its scope will be expanded and applied to the synthesis of hyperforin and perforatumone. A second recently discovered reaction, leading to substituted N-hydroxyindoles, will also be developed. These heterocyclic motifs constitute important domains of bioactive natural products like the antibiotic nocathiacin A and of a variety of medicinally active agents. Finally, a theoretical prediction will be tested regarding enhancement through structural modifications of the chemical reactivity of IBX, a hypervalent iodine reagent. In addition to a number of designed IBX reagents, the proposed research will encompass the synthesis of chiral versions of this versatile oxidizing reagent for explorations in asymmetric synthesis.With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Dr. Kyriacos C. Nicolaou, of the Department of Chemistry at the Scripps Research Institute. Dr. Nicolaou is developing new synthetic technologies and strategies for the construction of intermediate and target molecules for potential applications in several areas, including medicine and materials science. The project encompasses three related topics, each aiming to sharpen the tools of chemical synthesis and demonstrate their application and broad impact on science and technology on one hand and education and training on the other. A newly discovered cascade reaction sequence will be optimized and applied to the synthesis of constituents of St. Johns Wort, used as a folk medicine for neurodegenerative disorders and having potential as lead compounds for treatment of diseases such as depression and Alzheimers disease. A second recently discovered reaction, leading to the core structural motifs of bioactive natural products like the antibiotic nocathiacin A, will also be explored. Finally, a theoretical prediction regarding chemical reactivity will serve as the starting point for a study of the shape-selective oxidation of organic molecules. Each of these studies offers promise for the development of new strategies and tools for the synthesis of the complex organic molecules increasingly demanded by our modern manufacturing and pharmaceutical markets.