Total synthesis and chemical modification of small molecules: a study of axonal regeneration and aryl oxidation

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2015-05

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Eliasen, Anders Mikal

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Abstract

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.

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