Studies toward the synthesis of celastrol and the late-stage hydroxylation of arenes mediated by 4,5-dichlorophthaloyl peroxide

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.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Chemistry

Grantor

The University of Texas at Austin

Year dc:date.issued

2014

Author dc:creator

• Camelio, Andrew Michael

Advisor dc:contributor.advisor

• Siegel, Dionicio R.

• Total synthesis of celastrol
• Triterpenoid
• Natural products polyene cascade
• Polyolefin cyclization
• Arene hydroxylation
• Arene oxidation
• Peroxides
• Phthaloyl peroxide
• 4,5-dichlorophthaloyl peroxide
• Late-stage

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/2152/25022

OAI identifier oai:identifier

oai:repositories.lib.utexas.edu:2152/25022