Grant: Discovery Grants Program - Individual

Chemists fabricate new substances such as polymers and pharmaceuticals through the process of chemical synthesis. A ""toolbox"" of defined chemical reactions controls what products can be made from available starting chemicals. The most useful reactions (""tools"") at a chemist's disposal are those that are best understood. Thorough investigation of a chemical reaction to gain understanding involves testing the reaction on a variety of starting chemicals under a variety of conditions and analyzing the chemicals produced. I propose to investigate a reaction known as the Truce-Smiles rearrangement that was first reported in the 1950s but has been largely unexplored since. This reaction has not achieved the status of ""chemical tool"" because there remains a lot that is unknown or not understood about the Truce-Smiles rearrangement due to lack of investigation. The goal of my research program is to illuminate this reaction and elevate it to the position of a reliable, useful synthetic reaction. This will be achieved by examining the conditions that are used to conduct the reaction and optimizing them to maximize energy efficiency and minimize waste and environmental impact. The scope of the reaction will be investigated to determine its generality and the limits of its tolerance for starting chemicals. The usefulness of the improved Truce-Smiles rearrangement will then be demonstrated by applying the reaction to some challenges in chemical synthesis as well as to the preparation of a library of chemicals that will be tested as pharmaceuticals. In the long term, this reaction will be used to synthesize a library of small molecules that will be screened as selective cysteine protease inhibitors. This could lead to the development of new anticancer therapeutics.