In this project funded by the Chemical Synthesis Program of the Chemistry Division, Professor Scott Rychnovsky of the Department of Chemistry at University of California Irvine will develop a new strategy to assign the configuration of optically pure amines and alcohols. The strategy uses kinetic resolution catalysts and reagents, which are reactive compounds that are known to react faster with one mirror image of a molecule than the other. Reactions will be investigated with amines and alcohols to identify structural features that correlate with rate differences between mirror-image (enantiomeric) molecules. Understanding of the relationship between structure and rate could lead to a general tool to predict the absolute configuration of molecules based on the rates of reaction with benchmark reagents.
Amines and alcohols are very common structural elements in biologically active natural products and in new pharmaceutical agents. Assigning the complete three-dimensional structure to these molecules is the first step in understanding their activity. This project will facilitate research in many fields related to chemistry including pharmaceutical development, agricultural chemistry, medicinal chemistry and natural product isolation and structure assignment. The project will be developed with the participation of a wide variety of undergraduate and graduate students, including those from groups historically underrepresented in the sciences.
Complex three-dimensional objects are found in two different forms that are mirror images of each other. For example, a left-hand is the mirror image of a right hand. This property of handedness is found in real world objects such as gloves and shoes, but it is also found in microscopic object such at sugar molecules or amino acid molecules. Most of the molecules of life—peptides, carbohydrates, proteins, RNA and DNA—are only found with one "handedness," and the interactions between these molecules are determined by matching the appropriate handedness of each component. To develop and understand molecules that interact predictably with biological systems, one must choose the appropriate handedness of the molecule. We have developed a new way to distinguish left-handed and right-handed molecules. The Competing Enantioselective Conversion (CEC) method is used to assign handedness to molecules. The strategy operates by trying to react the molecule of interest with a right-handed and left-handed reactive molecule that we will call a reagent. In this test, we have found that a left-handed molecule reacts rapidly with the right-handed reagent, but reacts poorly with the left-handed reagent. Conversely, and right-handed molecule reacts best with the left-handed reagent. By testing a new molecule against the right-handed and left-handed reagents, we can determine its handedness. The method is simple and effective. It takes about an hour, requires minimal equipment, and has been used in our undergraduate laboratory courses. It promises to be important in the analysis of new molecules from natural sources, and in the development of new drugs to treat a variety of diseases such as cancer and heart disease.
