New Tools for Absolute Molecular Structure Assignment

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Through this award, funded by the Chemical Synthesis Program of the Division of Chemistry, Prof. Scott Rychnovsky and his research group from the University of California, Irvine, are developing a straightforward method to assign the absolute configuration of molecules. Complex molecules may exist in two possible mirror-image forms, and the two mirror-image molecules interact with proteins, carbohydrates and other biological molecules to produce different results. Most modern pharmaceutical agents are composed of only a single mirror image molecule with the best properties, and similarly natural products are isolated as one of two possible mirror images. Assigning molecules to the correct mirror image structure (configuration) is an important step in the developing new pharmaceutical agents, studying new natural product molecules, and in understanding their interactions with cells, animals, humans and other living creatures.The award supports development of the Competing Enantioselective Conversion (CEC) strategy for assigning the configuration of molecules. The new molecule is evaluated by measuring rates of reaction against two enantiomeric (mirror image) catalysts or reagents. Kinetic resolution catalysts are ideal because they react with high enantioselectivity, showing significant rate differences between a matched case and a mismatched case. By measuring the rate or conversion of an enantiopure molecule against the two enantiomers of the reagent, the fast-reacting reagent can be identified. Comparison with known examples allows the absolute configuration of the molecule to be assigned. The program focuses on developing a highly sensitive method for alcohols, a high-throughput method for alcohols, and an improved method for amines. A new reaction is being investigated to assign the configuration of oxiranes. The complementary methods that are being developed for amines, oxiranes and alcohols will make the determination of absolute configuration a straightforward process in organic chemistry.