New Tools for Absolute Molecular Structure Assignment

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The Rychnovsky lab is supported by the Chemical Synthesis Program in the Chemistry Division to develop a new strategy to assign the absolute configuration of molecules. Molecules may exist in two possible mirror-image forms, which are commonly described as right-handed and left-handed molecules. The new strategy involves testing the molecule in question by reacting it with two mirror-image reagents specially chosen to differentiate right-handed and left-handed molecules. Determining the more reactive reagent leads to identification of the handedness (configuration) of the molecule in question. Two mirror-image molecules interact with proteins, carbohydrates and other biological molecules differently, with one of the mirror-image molecules often having more favorable properties than the other. Most modern pharmaceutical drugs are composed of only a single mirror image molecule as often only one of the two forms are beneficial to human health. 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. Undergraduate and graduate students carry out the research for this project. UC Irvine is a Hispanic Serving Institution, which provides ample opportunities to recruit talented Hispanic (and other minority) students to participate in this project. Professor Rychnovsky works with the faculty at Santiago Community College providing their students with an avenue to develop their research skills and expertise. This project benefits society by advancing human health as well as improving student training/employment in the pharmaceutical industries and medical sector.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 allow the absolute configuration of the molecule to be assigned. The program focuses on developing new reagents for differentiating alkenes and dienes with adjacent stereogenic centers. The method for assigning secondary alcohol configuration is being adapted to identify a wider variety of structures. The research is well suited for the training of new undergraduate scientists, and students with diverse backgrounds are recruited to participate in this project. Santiago Community College has many students who transfer to the UC system, but they rarely have the opportunity to participate in research projects. Professor Rychnovsky works with the faculty there to recruit summer students to take part in this research program, thus providing an avenue for community college students to develop research skills and experience.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.