New Synthetic Chemistries Enabled by Oxyallyl and 2-Aminoallyl Cations

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PROJECT SUMMARY/ABSTRACT This grant application describes our proposed research in the production of value-added compounds of synthetic and biological interests, using novel chemistries that are centralized in the intermediacy of unsymmetrical oxyallyl and 2- aminoallyl cations. Oxyallyl and 2-aminoallyl cations are structurally unique reactive species. These intermediates have been utilized extensively in the Nazarov-type cyclization as well as cycloaddition reactions to assemble various complex molecular architectures. Despite these well-known reactivity, synthetic methods that harness the nucleophilic capture of unsymmetrical oxyallyl and 2-aminoallyl cations in a regioselective manner remain underexplored. This lack of studies consequently limit the full synthetic utilities of these versatile intermediates particularly in the arena of drug discovery. The long-term goal of our research program is to investigate the synthetic applicability of unsymmetrical oxyallyl and 2-aminoallyl cation technology in generating a library of novel small molecules in the chemical space that are suitable for high throughput screening in drug discovery. These studies could lead to protecting and improving human health, which is the ultimate goal of the NIH. The objective of the proposed research is to demonstrate that unsymmetrical oxyallyl and 2-aminoallyl cations are highly versatile reactive intermediates that could be readily harnessed to produce diverse molecular scaffolds of biological and pharmaceutical relevance. Our hypothesis is that unsymmetrical oxyallyl and 2- aminoallyl cations could be generated under mild catalytic conditions and captured by a broad spectrum of nucleophiles at the α-carbon in a regioselective manner by introducing appropriate “protecting” groups in their respective heteroatom centers. We have conducted extensive preliminary studies to support this hypothesis. We expect that completion of the proposed research will enable the rapid production of structurally novel small molecules with diverse stereochemistry and functionalities, which can be then evaluated for their therapeutic applications. To screen their biological activities, we have participated in the Open Innovation Drug Discovery (OIDD) at Eli Lilly. In fact, submission of synthetic products generated during our preliminary studies to this program has yielded interesting results. For instance, several of our compounds were found to exhibit inhibitory activities against IL-17A and PCSK9 proteins. Overall, our research will lay the foundation for detailed synthetic applications of oxyallyl and 2-aminoallyl cations, enabling future studies of the resulting structurally unique small molecules as potential therapeutic agents.