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

Brian R. Linton, College of the Holy Cross

This is the final report for the PRF grant entitled “Hydrogen bonding peptides as asymmetric organocatalysts.”  This grant described our efforts to use conformationally-defined peptides to control the stereoselectivity of nitroalkane reactions.  Recent efforts have resulted in a quantitative analysis of the strength of hydrogen bonding employed in these organocatalysts, the development of new catalyst scaffolds, and application of hydrogen bonding organocatalysts to ester cleavage.

            Hydrogen bonding has been shown to be quite useful for a variety of endeavors, but determining the strength of a hydrogen bonding interaction has proven to be difficult.  With this in mind, our group has explored the use of hydrogen/deuterium exchange as a measure of hydrogen bond strength.  We have utilized a series of small molecules that exhibit intramolecular hydrogen bonding and compared their rates of H/D exchange with similar controls that can not exhibit hydrogen bonding.  This permits an estimation of the robustness of each individual hydrogen bonding interaction and permits conclusions regarding te overall structures as they exist in solution.  This work has been published in Chemistry a European Journal.

            We have also expanded upon our peptide catalysts to develop new scaffolds that will be able to control aspects of chemical reactivity.  This approach involves more of a design aspect to position hydrogen bonding groups to make specific interactions with anionic guests.  These have been shown to modulate the reates of reactions for Michael additions of nitroalkenes and the Henry reaction of nitroalkanes.  This work is being prepared for publication.

            Additionally, our efforts have lead us to use similar organocatalysts to effect changes in the reactions of ester cleavage.  We have shown that our organocatalysts can change the regiochemistry of nucleophile attack on cyclic esters that can undergo either alkylation or acylation reactions.  Presumably the hydrogen bonds in the catalysts can stabilize the development of electron density that occurs in the transition state of one path more that the other, leading to regiocontrol. 

            Since the last report, four students have been involved in this project, with two 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.