Total syntheses of the regenerative natural products vinaxanthone, xanthofulvin, and eupalinilide E.
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The fungal metabolites vinaxanthone and xanthofulvin possess the remarkable ability to restore motor function in animal models of complete spinal cord transection making them the most promising small molecules for the development of spinal cord injury (SCI) therapeutics. A concise nine-step total synthesis of vinaxanthone was accomplished utilizing a biomimetic dimerization of the putative precursor 5,6-dehydropolivione and the first reported synthesis of xanthofulvin was achieved in 15-steps highlighted by an unprecedented enaminone O-to-C carboxyl transfer to forge key carbon-carbon bonds. Both natural products were also identified as positive allosteric modulators of the G-protein coupled receptor (GPCR), GPR91, thus elucidating their modes of action accounting for their regenerative capabilities. Furthermore, a unique ynone coupling reaction was developed in order to access various vinaxanthone analogs for structure activity relationship (SAR) studies. This resulted in the preparation of a small molecule library of 25 vinaxanthone analogs that demonstrated pronounced neuronal regeneration within laser axotomy assays performed in vivo on C. elegans. The plant derived natural product eupalinilide E has been found to promote the ex vivo expansion of hematopoietic stem and progenitor cells (HSPCs) which have the potential to improve the success of medical procedures such as bone marrow transplants. In light of its promising applications, unknown mechanism of action, and scarcity in nature the total synthesis of eupalinilide E was undertaken. Efforts culminated in the first enantioselective total synthesis of the natural product in 20-steps, which showcases a Favorskii rearrangement, borylative enyne cyclization, aldehyde-ene ring closure, and a dual allylic oxidation.