The overarching goal of this research program is to discover new catalytic methods for the synthesis of biologically active targets, both natural and unnatural. We have previously reported the synthesis of phenolic lipid natural products and efforts toward two families of polycyclic terpenes, as well as a general process for the synthesis of the cobalt complexes used in the photocatalytic investigations described in Project 2. The targets described in this proposal include molecules that will serve as mechanistic probes to study neurodegeneration and viral diseases, as well as leads that may provide new therapeutic opportunities. We are investigating methods to target specific structural motifs with established biological activity, such as amino-adamantanes and limonoid natural products, as well as catalytic methods designed to apply to a broad spectrum of chemical targets. The enabling technology behind these methods is photocatalysis, which harnesses light energy to drive complex catalytic processes. Photocatalysis continues to provide new mechanisms and transformations that are difficult or impossible to access otherwise. Understanding the governing principles of these processes allows us to apply that insight to the discovery of new, broadly useful synthesis methods. Substituted adamantanes appear in a wide variety of molecules with important function including clinically approved drugs for Alzheimer?s dementia and viral diseases, however efficient synthesis remains a challenge. In Project 1, new amino-adamantane derivatives will be accessed through a new aminoalkylation reaction and new catalytic strategies that enable unique selectivity that is complementary to existing approaches. The unique strategies described here include a detailed study of the selectivity of new and established H-atom transfer methods, providing guidelines necessary for selecting the proper HAT catalyst for different substrate classes. In Project 2, a novel polar/radical crossover manifold inspired by the biochemistry of vitamin B12 will be developed for the efficient use of inexpensive and readily available alcohols for bioactive molecule construction. These methods will be applied to the synthesis of promising natural product targets such as the neuroprotective limonoids. The investigation of the neuroprotective activity of limonoids is of central importance, therefore alternative pathways will be explored to access to these molecules and derivatives for mechanism of action studies. Overall, the concepts described here will provide general platforms for the rapid construction of pharmacophores and bioactive natural product derivatives that can be immediately deployed by biomedical researchers.
The treatment of human disease, from viral infections to neurodegenerative conditions such as Alzheimer's disease, relies in large part on the discovery and development of new medicines for therapeutic intervention. This proposal seeks to develop new catalytic reactions to access known pharmacophores, diversify these scaffolds to make new derivatives for testing, and synthesize natural product families that exhibit significant neuroprotective effects to study them in greater detail. These methods will provide an increase in efficiency and generality for the synthesis of established drug molecules and promising new targets.