Catalysts and Reagents for Amide Bond Synthesis

New York University, New York NY

Investigators

Abstract

In this project funded by the Chemical Catalysis program of the Chemistry Division, Professor Paramjit Arora of New York University is developing new catalysts for the synthesis of the amide bond, the linchpin bond in peptides, which are a basic structural building block of proteins. Biological systems make heavy use of peptides and proteins to carry out complex tasks at the molecular level, and they are composed multiple amide bond subunits linked together in a long chain. The use of peptides and proteins as chemical reagents and therapeutics necessitates their production in large amounts; however, the synthesis of these compounds remains inefficient and wasteful. This project is building upon classical and contemporary methods for amide bond formation to enable a more efficient and greener synthesis of proteins and other important compounds that contain amide bonds. This research should yield valuable strategies and reagents for studying chemical processes in biology and for medicinal chemistry. The project also includes teaching activities to train students at the interface of organic chemistry and chemical biology. Students engaged in this work are gaining a broad experience in fundamental chemical and biochemical techniques with potential future applications in biomedical technologies. A collaboration with Professor Amy Brown of Neumann University, Department of Chemistry is making progress on establishing a one-semester research-oriented capstone course at that university. Professor Arora is developing new organocatalysts for amide bond formation that are based upon a chemoselective ligation strategy for the synthesis of native amide bonds in proteins. Chemoselective reactions for amide bond formation have transformed the ability to access synthetic proteins and other bioconjugates through ligation of fragments. In these ligations, amide bond formation is accelerated by transient enforcement of an intramolecular reaction between the carboxyl and the amine termini of two fragments. Building on this principle, Professor Arora is developing aldehyde capture ligation that parlays the high chemoselective reactivity of aldehydes and amines to enforce amide bond formation between amino acid residues and peptides that are difficult to ligate by existing technologies. Aldehyde capture ligation utilizes an o-benzaldehyde selenoester to enforce an intramolecular reaction between the carboxyl and the amine partners. The key advantage of aldehyde capture ligation is that the method is applicable, in principle, to most any N-terminal amino acid residue for amide bond formation, because the capture step is changed from thioester exchange, as in native chemical ligation, to aldehyde-amine condensation. The methodologies are being applied to the synthesis of small ring, cyclic peptides.