Reports: B147589-B1: Hydrogen Bonding Peptides as Asymmetric Catalysts

Brian R. Linton , College of the Holy Cross

To: Petroleum Research FundFrom: Brian R. LintonRe: Supplementary report for grant #47589-B1 This is the third report for the PRF grant entitled ÒHydrogen bonding peptides as asymmetric organocatalysts.Ó This grant described our efforts to use conformationally-defined peptides to control the stereoselectivity of nitroalkane reactions. Our efforts this year have been to expand the substrate scope of these catalysts and discern the mechanistic insights gathered from the use of HOBt in catalytic peptide synthesis. The construction of the Holy Cross integrated science complex has resulted in some delays, and therefore an extension to the grant timeframe was granted. During the course of the synthesis of our catalytic peptides we encountered curious results in the use of coupling reagents and hydroxybenzotriazole (HOBt). When acylated HOBt derivatives were isolated, a doubling was observed where two products were observed instead of the anticipated one. We were able to show that the product ratios were determined by a combination of steric and Curtin-Hammett effects. Some acylated HOBt derivatives were difficult to form due to steric repulsions in larger acyl groups. Reactivity of some acylated HOBt derivatives was governed by a balance of product stability and transition state energies. This provided resolution of existing confusion regarding HOBt reactivity, as well as providing another example of the Curtin-Hammett effect. This work recently appeared in the Journal of Organic Chemistry. We continue to expand our investigations into the control of nitroalkane reactions. We have created a series of nucleophiles or electrophiles that are similar to substrates that have been successful with established catalysts. We continue to perform reactions that are combinations of these substrates to determine which show selectivity with our catalysts. Additionally we have been designing novel scaffolds that will permit the orientation of multiple hydrogen bonds into one binding pocket. The hope is that these designed receptors will serve as bifunctional catalysts, binding to both nucleophile and electrophile. We will also apply these new catalysts to nitroalkane reactions, again looking for enantioselectivity. This past year, three students have been involved in this project, with one summer stipend being directly funded from this grant. Results have been presented at national meetings and Holy Cross college symposia. As in previous years, this grant has been instrumental in supporting our work on novel organocatalysts as well as supporting the preparation of undergraduate researchers. Sincerely,Brian R. LintonDepartment of Chemistry * One College Street * Worcester, MA 01610-2395 * (508) 793-3560 * Fax (508) 793-3550
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