New Foldamer Catalysts

With the support of the Macromolecular, Supramolecular and Nanochemistry program in the Division of Chemistry, Professor Samuel H. Gellman of the University of Wisconsin-Madison will develop foldamer catalysts that are inspired by the structural diversity of enzymes. Enzymes are large protein-based macromolecules that act as biological catalysts by accelerating numerous chemical reactions in living organisms. Some of the most well known reactions catalyzed by enzymes include conversion of cane sugar into glucose and fructose, breaking of glucose into ethyl alcohol and carbon dioxide, and hydrolysis of fats. Foldamers, on the other hand, are unnatural scaffolds that mimic protein-like conformational behavior and potentially also the catalytic properties of enzymes. In this project, foldamers will be prepared using β-amino acids in addition to the usual α-amino acid building blocks for natural peptides. During the protein folding process, key subunits are arranged into the precise three-dimensional arrays that are essential for binding to other molecules and catalyzing chemical reactions. In this project, organic and supramolecular chemistries specifically tailored to enable efficient functional group incorporation into helical foldamer scaffolds will be utilized to prepare bifunctional and trifunctional foldamer catalysts. The synthesized catalysts will then be utilized in variety of metal and non-metal catalyzed carbon-carbon bond forming reactions. This project will provide excellent training in interdisciplinary research and enable young scholars to undertake productive careers in academia, industry, or other settings. Additionally, Professor Gellman will continue to support expansion of diversity, equity, and inclusion in the scientific community through his involvement in graduate student recruitment and through his activities as a Trustee of the Gordon Research Conferences. This project will seek to expand the range of bifunctional foldamer catalysis by examining α/β-peptides containing new types of reactive diads. Three paths will be pursued under the first general goal, focusing on bifunctional catalysis. In the first path, side chains containing new types of reactive groups that function via covalent activation of substrates, specifically, hydrazides for electrophilic activation of α-substituted enals, and thiazolium systems or related heterocycles for activation of aldehydes toward Stetter reactions, will be incorporated into foldamer scaffolds. In the second path, side chains intended to activate substrates noncovalently either through H-bonding or cation-π-interactions will be explored. The third path will focus on adding bipyridine or terpyridine units that will be used for complexation with nickel and subsequently α-arylation of aldehydes. In the second goal, the team will seek to harness the modularity of foldamer scaffolds to allow three functional groups to work in coordination to promote a single transformation. This project seeks to enable the development of new catalysts that are inspired by the structural diversity of enzymes. The ability to precisely control the location of multiple reactive sites within foldamers could additionally provide exciting opportunities of using these enzyme mimics for synergistic catalysis. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.