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 natural product celastrol (1) possesses a wide array of promising biological activities related to diseases characterized by protein misfolding including those associated with neuronal degradation, inflammation, and cancer. Relevant to cancer, celastrol functions as a non-ATP-competitive inhibitor of heat shock protein-90, providing a potential lead for the development of new inhibitors with improved pharmacology. A laboratory preparation of the small molecule was undertaken to provide access to the unnatural enantiomer of celastrol. The lack of understanding of the chemistry and biology of the growing class of celastroids is attributed to the incompatibility of biologically inspired polyene cyclization strategies to assemble friedelin triterpenoids. As a result of these problems residing at the interface of chemistry and biology, a purely synthesis-based strategy for polyene cyclizations to rapidly construct the pentacyclic core of the friedelin and celastroid natural products has been developed. This efficient strategy is gram scalable culminating in the first total synthesis of wilforic acid (127) and an advanced intermediate capable of delivering celastrol (1) as well as numerous celastroid natural products. Phenols possess broad utility serving as key materials in all facets of chemical industries, especially the pharmaceutical industry. The ideal synthesis of a phenolic compound entails the direct oxidation of an aryl C-H bond remains to be a difficult synthetic challenge. Following our initial report describing the hydroxylation of arenes using phthaloyl peroxide, new peroxide derivatives were investigated to probe their reactivity in an effort to hydroxylate aromatics which were previously unreactive. Electronically poor to moderately rich arenes were successfully hydroxylated with a broad functional group tolerance using 4,5-dichlorophthaloyl peroxide. This protocol has been applied toward the rapid synthesis of phenolic analogs and metabolites of current pharmaceuticals as well as biocides. Mechanistic studies using kinetic isotope effect, competition, and benzylic oxidation experiments indicate that a novel diradical reverse-rebound mechanism is the likely pathway. Further examination of the transition-state using linear free energy relationships with sigma vs. sigma+ values established a linear trend with a low negative rho value (- 3.92) corresponding best using sigma values supporting a diradical reverse-rebound addition. / text