Bifunctional foldamer catalysis

点击翻译按钮获取中文摘要

With funding from the Macromolecular, Supramolecular and Nanochemistry Program of the Chemistry Division, Professor Samuel H. Gellman of the University of Wisconsin-Madison is developing new types of protein-like molecules. This fundamental research is biologically inspired. All organisms contain sequence-specific oligomers and polymers that fold into particular shapes, and these shapes enable complex functions. Many of these folded molecules, such as enzymes, carry out crucial chemical transformations within the cells in the human body. Gellman's laboratory creates unnatural oligomers, or "foldamers", that adopt discrete shapes and catalyze chemical reactions. The foldamers are prepared using beta- and gamma-amino acids as alternative building blocks to the natural alpha-amino acids found in proteins. The folding of natural proteins causes key subunits to be arranged into the precise three-dimensional arrays that are essential for binding to other molecules and catalyzing chemical reactions. A central aim of this research is to develop synthetic foldamers that exhibit protein-like binding and/or catalytic properties. These artificial foldamers might ultimately surpass proteins in terms of specific functions. The basic research associated with this award could ultimately lead to development of new types of drug molecules or new types of manufacturing capabilities at the molecular level. This work provides excellent training in interdisciplinary research. It also enables young scholars to undertake productive careers in academics, industry or other settings. Gellman and his research team participate in the "Chemistry Opportunities" program intended to introduce undergraduate students to graduate-level opportunities at the University of Wisconsin-Madison. This research focuses on cutting-edge challenges in terms of molecular design, with the specific goal of developing new types of foldamer catalysts that facilitate important chemical transformations. The foldamer scaffolds contain beta- and/or gamma-amino acid residues and adopt diverse and stable helical secondary structures. Particular emphasis is placed on bifunctional catalysis of aldol reactions that produce macrocycles. Synthesizing large molecular rings via carbon-carbon bond formation is difficult because of entropic barriers that enable intermolecular reactions to compete with cyclization. Olefin metathesis has been a widely used and powerful method for macrocycle formation, and this research aims to develop complementary methods based on foldamer catalysis. Other cyclization reactions under exploration include conjugate additions of aldehydes to enoate esters. Novel products from the catalytic processes under pursuit include a class of detergents in which the hydrophobic portion is the macrocyclic alkyl unit, rather than a more familiar linear alkyl unit. The behavior of these novel detergents could provide fundamental insights on structure-property relationships, and this effort may generate useful tools for membrane protein studies. Transformative chemistry associated with this research offers opportunities for invention in terms of basic research and practical development.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.