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. / text

Injuries to the central nervous system are irreversible and debilitating due to the limited regrowth of damaged or severed neurons. Two small molecules, xanthofulvin and vinaxanthone, isolated from P. vinaceum and P. glabrum promote spinal cord regeneration in animal models. It is speculated that these natural products inhibit semaphorin 3A, a chemorepellent that mitigates axonal growth-cone formation. In addition to promoting axonal growth, rats treated with vinaxanthone and xanthofulvin following complete spinal cord transection experienced greater remyelination, increased angiogenesis, attenuated apoptosis, and depressed scaring of the lesion site. The only prior synthesis of vinaxanthone speculated that the xanthone core is constructed via enzyme-catalyzed intermolecular Diels-Alder reaction. We have demonstrated, however, that warming a functionalized acetoacetyl chromone in water, furnishes vinaxanthone in good yield, providing an alternative biosynthetic pathway. With a robust syntheses of both natural products, we determined the protein target of the observed regeneration: succinate receptor 1, providing a new therapeutic target to promote neuronal regeneration. Among the various methods of incorporating oxygen into aryl rings, the direct conversion of a C-H bond into a C-OH bond is ideal. The metal-free hydroxylation of arenes developed in our laboratory, utilizing phthaloyl peroxide, marks the first disclosure of this transformation using mild conditions. Computational and experimental evidence obtained thus far has supported a mechanism involving a diradical intermediate. The reactivity of phthaloyl peroxide was increased by the incorporation of two chlorine atoms onto the ring. To minimize the accumulation of large quantities of peroxide, the optimization of the preparation of the peroxide in flow has been developed. This protocol immediately consumes the peroxide as it is generated. Finally, a new dearomatization reaction has been optimized. This reaction forms two carbon-oxygen bonds and dearomatizes the ring system.

The debilitating effects of spinal cord injury can be attributed to a lack of regeneration in the central nervous system. Identification of growth-promoting pathways, particularly ones that can be controlled by small molecules, could provide significant advancements in regenerative science and lead to potential treatments for spinal cord injury. The biological investigations of neuroregenerative small molecules, specifically the natural products clovanemagnolol and vinaxanthone, have been expanded to a whole organism context using the nematode Caenorhabditis elegans (C. elegans) as a tool for these studies. A straightforward assay using C. elegans was developed to screen for compounds that promote neuronal outgrowth in vivo. This outgrowth assay was then used to guide the design of chemically edited analogs of clovanemagnolol that maintained biological activity while possessing structures amenable to further modification for mechanism of action studies. Pull-down experiments using affinity reagents synthesized from a neuroactive structural derivative, clovanebisphenol, and the C. elegans proteome combined with mass spectrometry-based protein identification and genetic recapitulation using mutant C. elegans identified the putative protein target of the small molecule as a kinesin light chain, KLC-1. Furthermore, the small molecule-promoted regeneration of injured neurons in vivo was studied using laser microsurgery to cut specific axons in C. elegans followed by treatment with a library of analogs of the growth-promoting natural product vinaxanthone. Enhanced axonal regeneration was observed following small molecule treatment and the results were used to determine the structure-activity relationship of vinaxanthone, which may guide future development of potential drug candidates for the treatment of spinal cord injury. / text