Over the past century, there has been a worldwide escalation in the prevalence of neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Huntington’s disease. There are still no cures for these disorders and current therapeutics are only palliative. More recently, emerging therapeutic approaches have focused on maintaining neuronal function in these disease models with small molecules that possess neurotrophic properties. In this multidisciplinary proposal, we plan to complete the first total synthesis of (2R)-hydroxy-norneomajucin, confirm the neurotrophic activity of this natural product and evaluate advanced intermediates, and also initiate investigations into the biological target of this compound. The key transformation of our synthetic approach involves a Transannular Diels–Alder (TADA) reaction to establish the ABC ring system of the molecule in a single step. Assembly of the Diels-Alder precursor will be achieved through the combination of four basic fragments utilizing a Yamaguchi macrolactonization, Pd-mediated coupling, Horner-Wadsworth-Emmons olefination and an alkylation. All synthetic work will be performed at the host institution (Gademann Lab, University of Basel, Switzerland). With (2R)-hydroxy-norneomajucin and analogs in hand, we then plan to perform a NGF-mediated neurite outgrowth PC-12 cellular assay on the natural product and advanced intermediates at the host institution (Gademann Lab, University of Basel, Switzerland). In addition, we plan to perform HIP-HOP assays to elucidate the biological target of this molecule in collaboration with Dominic Hoepfner (NIBR Novartis Basel). The latter collaborative project will help to establish a working partnership between academia and industry in Europe. In general, this multidisciplinary proposal will contribute to European research and the transfer of knowledge acquired by the fellow while in the United States.
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