Application of N-Oxides for the Synthesis of Nitrogen Heterocycles - Project Summary: Nitrogen heterocycles are a ubiquitous and key structural motif of bioactive natural products and pharmaceuticals with proven efficacy targeting cancer, psychiatric disorders, antimicrobials, and analgesics. However, the synthetic strategy of introducing new nitrogen heterocycles into a pharmaceutical framework is nontrivial and costly, especially when considering complex three-dimensional (3D) targets. We intend to expand upon our recent body of work that has identified N-oxide chemistry as a promising, innovative, adaptable solution for this conundrum. To create nitrogen heterocycles of pharmacological interest, we will use N-oxides, easily prepared and stable compounds, as precursors for [3+2] cycloadditions. N-oxide compounds were first used in a limited number of cycloaddition reactions in the 1980s. However, despite solid and logical reasoning at that time, the lack of mechanistic understanding on how these reactions occurred predicted electrophilic intermediates that would cause side reactions, low yields, and poor stereochemical control. Consequently, the synthetic community undervalued this reaction manifold and avoided such an approach. However, re-evaluation of the original experimental data with the perspective of high-quality density functional theory, led to us uncovering mechanistic details defining the critical role of solvent in such ionic systems, and eradicated the previously conceived synthetic barriers to efficient use. We intend to resurrect and establish this unexplored synthetic avenue forming nitrogen heterocycles from simple precursors without onerous overhead as a practical and significant protocol in medicinal chemistry. Beyond our proposed work delivering key analgesics (aza-bicycles), novel antimicrobials (imidazolines), and enantio-enriched systems, the impact of N- oxide chemistry has the potential for many new directions and discoveries including cyclic N-oxides, silyl imines, and N-chiral compounds. Aligned with NIH/R15 goals, this project has been designed to be approachable for students of all levels of experience in experimental and/or computational chemistry, adapting the educational philosophy of Universal Design. Initial experimental projects range from performing and optimizing established reactions under supervision (beginner) to running novel reactions and analyzing complex reaction mixtures (advanced/graduate). Likewise, on the computational side students can learn to build Z-matrixes and identify ground states for new analogs (beginner), progress to finding transition structures, performing energy decomposition analyses and develop critical analysis skills (advanced/graduate). Ultimately, our plan is to optimize this N-oxide chemistry to create nitrogen heterocycles as the core component for analgesics (Aim I), antimicrobials (Aim II), and stereo-defined 3D structures (Aim III). This proposal offers an innovative, adaptable strategy for creating a wide range of such compounds through a shared reaction pathway that will empower the pharmaceutical community to expand upon its efforts significantly in the discovery of novel drugs in the strategic areas of antimicrobials and analgesics.
