Synthesis and Use of Selenonic Acids as Epoxidation Catalysts and Mechanistic Investigation of the Antioxidant Drug Ebselen
Date
2023-08
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Abstract
Selenium and selenium dioxide have long been known to effect the oxidation of organic substrates, first appearing in the early 20th century as a method of dehydrogenating hydrocarbons. Little progress was made in the use of organoselenium reagents in organic synthesis until the early 1970’s when the selenoxide syn-elimination was shown to be a general method for the installation of double bonds. This reinvigorated the field of organoselenium chemistry, and over the ensuing decade several new selenium-mediated oxidations were developed, including the epoxidation and dihydroxylation of alkenes, Baeyer-Villiger oxidations and the oxidation of phenols to quinones. Many studies of these reactions have invoked a peroxyseleninic acid as the active oxidant, though little evidence was provided at the time to support these claims. Contrary to these early reports, we found that the peroxyseleninic acid is a relatively poor epoxidizing agent due to its facile decomposition to a mixed selenonium-selenonate salt. This salt is stable in the solid state, but generates the corresponding selenonic acid in the presence of hydrogen peroxide. The selenonic acid itself is inactive towards epoxidations; however, in the presence of excess peroxide, rapid epoxidation occurs. This shows that the selenonic acid must be further activated, presumably to the benzeneperoxyselenonic acid. Although selenonic acids were first reported more than a century ago, they have been studied far less frequently and have found little application as synthetic reagents when compared to their seleninic acid analogues. This is in large part due to difficulties in their preparation and characterization, which led to errors in their structure identification in earlier work. Given the newfound importance of selenonic acids in oxidation reactions, a new protocol for the efficient and expedient synthesis of selenonic acids was needed. This was achieved in a one-pot reaction starting from readily available aryl bromides to furnish a range of aryl selenonic acids bearing electron-donating and -withdrawing groups in good to high yields. Finally, organoselenium compounds can mimic the selenoenzyme glutathione peroxidase, which protects cells against oxidative stress by reducing peroxides in the presence of the tripeptide thiol glutathione. Ebselen is arguably the most studied such mimetic; however, there is still considerable uncertainty in its mechanism of action. The final portion of this thesis is a systematic reinvestigation of several key reactions of the proposed catalytic cycles in order to gain further insight into its mechanism which may allow for the design of better glutathione peroxidase mimetics.
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Keywords
Organoselenium chemistry, Antioxidants, Ebselen, Selenonic acids, Oxidation, Epoxidation, Peroxides, Benzeneperoxyselenonic aicd, Benzeneperoxyseleninic acid
Citation
Sands, K. N. (2023). Synthesis and use of selenonic acids as epoxidation catalysts and mechanistic investigation of the antioxidant drug Ebselen (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.