Improved methods for the synthesis of trans-cyclooctenes and their applications in synthetic and bioorthogonal chemistry
Date
2016
Authors
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Journal ISSN
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Publisher
University of Delaware
Abstract
My doctoral research under the advisement of Joseph Fox at the University of Delaware has focused on exploiting the unique reactivity of trans-cyclooctenes (TCOs) in synthetic design, reaction method development, and bioorthogonal applications.
Chapter 1 is focused on the importance of trans-cyclooctenes in synthesis and biorthogonal chemistry. I have outlined a concise history of the synthesis of trans-cyclooctene and more complex derivatives. I have also briefly described the more recent development of select bioorthogonal reactions. In this chapter, I have focused on the TCO-tetrazine ligation, a bioorthogonal reaction first described by the Fox group in 2008. This reaction has been utilized in a variety of applications spanning cell imaging, nuclear medicine, and materials science.
Synthesizing trans-cyclooctenes has not always been a trivial process. Within the past 10 years, the Fox group has developed a closed-loop flow system to produce multi-gram quantities of a variety of trans-cyclooctene derivatives. The requirement of expansive and non-conventional equipment, however, has limited adoption by a broader audience. I sought to develop a system that could be used globally by the wider scientific community, in particular those involved in the biological applications of these useful molecules. In Chapter 2, I discuss improvements to the current flow chemistry system as well as a novel ‘no-flow’ photochemistry apparatus. The molecules synthesized have been used in a variety of reactions described in Chapter 1. I have also employed UV-Vis stopped-flow kinetics to measure reaction rates of various TCO-tetrazine partners under aqueous conditions. Understanding reaction rates continues to provide the tools necessary to improve molecular design. I also discuss the development of a one-pot diastereoselective reduction used to selectively synthesize axial substituted trans-cyclooctenes. Lastly, I briefly describe utilizing Trolox to prevent trans-cyclooctene isomerization in the presence of thiols.
Finally, trans-cyclooctene derivatives have proven to be useful intermediates for target-directed synthesis due to the strain-driven reactivity of the trans alkene. trans-Cyclooctenes possess an inherent sense of planar chirality which I have exploited in two different reaction methodology developments. In Chapter 3, I describe the development of a transannular etherification reaction. This method has shown to be both regio- and diastereoselective, providing efficient access to more complex bicyclic moieties. One complication is accessing the necessary trans-cyclooctene diastereomer in useful quantities. To this end, I have developed a diastereoselective photoisomerization process that uses catalytic chiral sensitizer and takes advantage of the inherent sense of planar chirality. Efforts towards the natural product laureoxanyne are briefly described. I conclude with the development of new trans -cyclooctene reagents used to probe oxidative stress in proteins.