Novel Reactions of Electrophilic Nitrogen for Preparing Bioactive Molecules - Nitrogen-rich small molecules are critical to human health as they constitute the vast majority of all known pharmaceutical agents. As the requirements for new drugs become stricter, and as the diseases that are targeted become more complex, the chemical structures of those compounds are also becoming more complex. This is driving the need for more efficient means to prepare ever more complex nitrogen-containing small molecules. Typically, in synthetic chemistry, most chemical reactions of nitrogen centers involve low valent, nucleophilic nitrogen atoms. Over the past 100 years, countless synthetic transformations have been developed to prepare nitrogen-containing molecules using this paradigm. In contrast, this proposal seeks to leverage nitrogen compounds in higher oxidation states to seek new reactivity and chemical processes that can prepare complex nitrogen-containing molecules in new ways. Specifically, based upon a strong set of published preliminary results, we will develop new Heck-like reactions of electrophilic nitrogen centers as a means to construct highly substituted stereochemically and topologically complex nitrogen heterocycles. Our studies will discover new nitrogen electrophiles that can participate in these aza-Heck cyclizations, develop novel routes to important classes of biologically active heterocycles, design asymmetric entries into these compounds to control absolute stereochemistry, and dig deeper into the fundamental mechanisms of the reactions to enable further understanding of the processes. To demonstrate the importance of aza-Heck cyclizations, we will also prepare several highly complex natural products with interesting biological profiles in highly expedient ways. Each synthesis will feature aza-Heck technologies as the key enabling reaction. As reflected in our support letters, we are well positioned for follow-up studies at the completion of these synthetic efforts. We will also continue to develop new catalytic methods to prepare complex nitroalkanes and seek to use those compounds in novel transformation for preparing bioactive molecules. Overall, we expect that the development of this chemistry will positively impact human health by providing synthetic, medicinal, and process chemists valuable new tools for the construction of nitrogen-rich bioactive small molecules. At the same time, this study will provide fundamental advances in transition metal-catalyzed cross-coupling chemistry. Modified Specific Aims Nitrogen-rich small molecules are critical to human health as they constitute the vast majority of all known pharmaceutical agents. As targeted diseases are more complex and the requirements for new drugs become stricter to increase safety, the requirements and structures of the drug compounds have also become more complex. In particular, the need for increased selectivity and improved pharmacokinetics is driving a move away from traditional “flat” pharmaceuticals towards those that are chiral and rich in sp3 centers.1 In turn, this has driven the need to develop new methods that can efficiently prepare complex and highly substituted stereogenic nitrogen-containing small molecules. The proposed research will focus on new methods for preparing topologically complex, nitrogen-containing small molecules. We will focus on two strategies that are thematically related in the utilization of high-valent nitrogen precursors. These reactions are a departure from the vast majority of synthetic transformations that rely on low-valent nucleophilic nitrogen centers and will allow rapid access to compounds that traditional methods struggle to prepare. First, we will develop cyclizations of stable, readily prepared nitrogen electrophiles to prepare highly substituted stereogenic aza-heterocycles. These aza-Heck cyclizations will allow facile access to biologically and medicinally relevant heterocycles that other methods struggle to access. Second, we will develop new reactions of nitroalkanes to pre
