PROJECT SUMMARY-ABSTRACT The understanding of normal cognitive function and the development of treatments for neurodegenerative diseases have been enabled by the study of natural products and their synthetic congeners. The extensive discoveries made in this realm have been limited primarily to the specific activities of abundantly available natural products or simple derivatives thereof. The long-term goal of this proposal is to develop laboratory routes to complex molecules that act on proteins associated with neurological disease. This proposal outlines approaches to limonoids that act on PTP1B and mitigate neuronal dysfunction. Departing from conventional strategies using second- and third-row metals, this proposal describes the development of first-row metal catalyzed transformations to empower laboratory routes to complex molecules that contain heterocycles. This state-of-the- art approach to multistep synthesis will result in broadly useful chemical transformations for carbon-carbon bond formation, and highly step-efficient routes to access complex small molecules. Powerful medicinal chemistry approaches will be used to make deep-seated structural modifications to limonoids, which will be used to interrogate molecular mechanisms of action. Novel analogs produced by these routes will be used to evaluate small molecule inhibition of PTP1B, which has been implicated in neurodegeneration. Through structure activity relationship studies and investigations into the binding mechanism on a molecular level, the therapeutic potential of PTP1B inhibition to improve neurodegeneration will be readily investigated.