Computation and Development of New, Enabling Synthetic Methods

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PROJECT SUMMARY/ABSTRACT Summary The overall objective of this research program is to develop analyses, tools, and methods to achieve new, more effective reagents, catalysts, and biological ligands. One focus will be on state-of-the-art computation methods to understand stereoselectivity, chemoselectivity, and reactivity at the molecular level with the aim of designing new, more effective reagents, catalysts, and biological ligands. The control of selectivity and reactivity are essential features of efficient synthesis, yet our molecular level understanding of how fundamental interactions perturb these aspects is only rudimentary. Further, many aspects of how these same fundamental interactions govern binding in a biological context are incompletely understood. Another focus will be on oxidative coupling of fragments via C-C, C-O, and C-N bond formation by means of C–H activation chemistry. Catalyst libraries will be designed for study of biomimetic reactions using two guiding principles: 1) matching catalyst oxidation potentials with the oxidation potentials of the substrates under consideration and 2) selecting metals that can utilize oxygen to regenerate the catalytic species. These libraries will be deployed in a high-throughput microscale format to discover reactivity patterns heretofore unimagined. From the data obtained, reaction “profiles” will be constructed and new inferences about reactivity, selectivity, and mechanism will be made, which will be tested experimentally. The fundamental hallmark of this proposal is the ability to access new reaction patterns to construct important organic structures in an efficient and rational manner. Computation and mechanistic understanding gives us the tools to solve problems and posit hypotheses. High throughput microscale experimentation permits rational hypotheses to be interrogated broadly and to facilitate optimization of the many interdependent variables in the possible reaction space. Relevance The fundamental hallmark of this proposal is the ability to design new reactions and catalysts via computation and mechanistic study. The goal is to construct important organic structures in an efficient and rational manner. New synthetic methods greatly increase access to untapped chemical space, leading to materials and pharmaceuticals that benefit society. To achieve this goal, investigations will focus on obtaining an improved understanding of reactivity and selectivity. The development of new oxidative coupling chemistry is a particular focus due to increases in efficiency from lower step counts and smaller waste streams. The challenge in this area is selectivity in any given transformation due the numerous C–H bonds present in a typical organic molecule. Use of biomimetic processes leads to bioactive natural products and natural product-like cores, desirable entities in medicinal chemistry. Invaluable training, absent outside of industrial settings, will be afforded to graduate students and other coworkers.