Synthesis of Biologically Significant Cyclopropanes

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This renewal project centers on the development of synthetic methodology and its application towards the synthesis of biologically relevant cyclopropane-containing targets including histone deacetylase inhibitors, histamine H3 antagonists, and the anti-fungal natural product ambruticin. Cationic cyclopropanation reactions with benzylic and cyclopropylmethyl alcohol derivatives will be investigated, including a detailed study of the stereochemical integrity of the ring closure reaction, with emphasis on the effect of reaction conditions (solvent polarity and leaving group effects). This methodology will be applied in the synthesis of novel cyclopropyl-substituted histone deacetylase inhibitors. The effect of alpha-heteroaromatic substitution on the stereochemical integrity of the cation cyclization process will be investigated, and this chemistry will be applied toward the synthesis of a series of H3 receptor antagonists. The activation and ring closure of allylic alcohols will be investigated, and this chemistry will be applied toward the synthesis of the architecturally complex anti-fungal polyketide ambruticin.With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Dr. Richard E. Taylor of the Department of Chemistry and Biochemistry at the University of Notre Dame. Professor Taylor and his students will devise and develop new methods for the controlled synthesis of organic molecules containing cyclopropane (three-membered ring) units. Such compounds often require special techniques for their synthesis, given the strain present in the three-membered ring, yet form the basis of a number of interesting naturally occurring compounds as well as potential pharmaceutical agents, including therapeutic agents for disorders involving sleep, food intake, thermoregulation, and memory formation. The PI's initial discoveries in this area are already transitioning into the chemical industry, where they are being used to facilitate the discovery of new drug candidates.