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I. Applications of Cyclobutenes as Click Reagents; II. Investigations of Modified Fatty Acids as Potential Antimycobacterials; III. Investigations into Photoredox Activation of Peroxides Using New Alkoxy Radical Clocks

Boone Evans, University of Nebraska - Lincoln

Abstract

The Inverse Electron Demand Diels-Alder (IEDDA) reaction has been recently adapted for use in biological systems. Cyclobutenes, which combine good levels of chemical stability with a small molecular cross-section, have been largely overlooked in this area. Previous work in our lab observed that fatty acid-related cyclobutenes readily undergo IEDDA reaction with 1,2,4,5-tetrazines. We now demonstrate the ability to prepare a cyclobutene-labeled amino acid which can be biosynthetically installed within proteins and subsequently modified, within cells, via IEDDA reaction. We also demonstrate chemoselective reaction between a cyclobutene-functionalized alkane thiol and functionalized tetrazines at the solution interface of self-assembled monolayers. Overall this work shows the cyclobutene is a useful bioorthogonal reagent with enhanced stability relative to other IEDDA dienophiles.Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb). is the number cause of adult death worldwide from infectious disease. Previous reports from our group showed fatty acids incorporating cyclobutanes and related structures possessed useful levels of activity against these bacteria. In partnership with collaborators, we have explored several approaches elucidating the mechanism of action, including multiomics studies with a cyclobutane-containing fat, investigations of the use of a cyclobutene-substituted fat with a goal of applying the IEDDA reaction to monitor the localization of metabolites or conjugates, and preparations of isosteres of the most active leads from the earlier studies. Ongoing work has involved development of new tools to investigate processes which cleave the O-O bond of peroxides via one-electron reduction. SET has been achieved via chemical methods, electrochemical reduction, and via photoredox. There is currently a limited understanding of how these processes compare in terms of peroxide reactivity as well as regioselectivity of radical vs. alkoxide formation in the initially generated products. Here we develop a new alkoxy radical clock reagent and use it to compare the cleavage products of a range of organic peroxides from both photochemical SET and SET via Fe (II).

Subject Area

Chemistry|Energy|Morphology

Recommended Citation

Evans, Boone, "I. Applications of Cyclobutenes as Click Reagents; II. Investigations of Modified Fatty Acids as Potential Antimycobacterials; III. Investigations into Photoredox Activation of Peroxides Using New Alkoxy Radical Clocks" (2021). ETD collection for University of Nebraska - Lincoln. AAI28713398.
https://digitalcommons.unl.edu/dissertations/AAI28713398

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