Palladium-Catalyzed Tsuji-Trost Reaction in Complex Mixtures

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In this project funded by the Chemical Structure, Dynamics, and Mechanisms B Program of the Chemistry Division, Professor Kazunori Koide of the Department of Chemistry at University of Pittsburgh will investigate new classes of chemical reagents for trace metal analysis and for developing a chemical technology that can make non-cell-permeable molecules cell permeable. Both objectives are important in human health, as they can lead to the development of new pharmaceuticals. The project lies at the interface of organic, inorganic, and biological chemistry, and is therefore well suited to the education of scientists at all levels. This group is also well-positioned to provide the highest level of education and training for undergraduate and graduate students and post-doctoral researchers. The research group is active in outreach activities that involve recruiting under-representative minority students for summer research and participation in undergraduate research symposium. Palladium catalyzed deallylation (Tsuji-Trost reaction), a widely used reaction in organic synthesis, had been attempted for chemosensing and chemical biology. Although promising results were obtained, further improvements are essential. As a platform for Pd quantification using a fluorogenic Tsuji-Trost reaction, the dynamic range is not yet sufficiently broad. As a means in chemical biology, although the reaction is efficient in neutral phosphate buffer, it is more than one order of magnitude slower in cell culture media. In this project, two specific aims will be pursued: (1) to develop a fluorometric or colorimetric method to quantify palladium in a high throughput manner, and (2) to develop a biocompatible Tsuji-Trost reaction to uncage bioactive molecules in cultured human cells. For specific aim 1, the research group will use Eyring plots and measure the activation energy of enthalpy to rationally adjust the kinetic profile. For specific aim 2, the research group will leverage their recent finding that hydroxymethylated analogs of tris(2-furyl)phosphine are superior to commercial phosphines in cell culture media. These two aims will expand the applications of Palladium catalysis into research areas in which it has not been used extensively.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.