Strain release driven reactivity of bicyclobutanes and cyclopropenyl ketones and studies towards understanding the role of helicity in salen catalysis

Smith, Natalee Jo-Ann
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University of Delaware
My doctoral research in the laboratories of Joseph Fox at the University of Delaware has been multidisciplinary in nature. The results described in this dissertation span across streamlining multistep syntheses, synthetic methods development and exploring chemical biology. Metal-salen catalysts have emerged as an important class of catalysts in enantioselective synthesis. An ongoing area of interest in the Fox Lab has been to study in detail the mode by which the catalysts, with their chiral, helical organic frameworks impart enantioselectivity to reactions. One of these catalysts was synthesized via a 15 step synthesis and has been used as a probe to understand the mechanistic origin of asymmetric induction in metal-salen catalyzed reactions. As the synthesis of this mechanistic probe was long, I developed a method to streamline the efficiency of the synthesis. These efforts will be discussed in the first chapter. Chapter two focuses on the development of synthetic methods to allow for the enantioselective bicyclobutanation/homoconjugate addition of a range of heteroatomic nucleophiles as a method for rapidly accessing strereochemically defined cyclobutanes. Optimization of the addition of azides to bicyclobutanes led to the discovery of a new, highly soluble and nucleophilic azide source. Efforts to probe the mechanism of the azide addition reaction are discussed. Cysteine alkylation represents one of the most broadly useful methods for protein modification, combining the merits of site selectivity with the ability to modify a native protein. Cysteine-modified proteins span a broad range of applications, including protein-drug conjugation, nuclear medicine, and materials science. Chapter three details studies surrounding the development of a new class of cysteine alkylating agents based on cyclopropenyl ketones. Using strain as a design principle, it was hypothesized that the significant release of strain energy (∼27 kcal/mol) upon thiol alkylation would result in an addition reaction that is both fast and irreversible. Results detailed demonstrate that cyclopropenyl ketones are viable alternatives to maleimide reagents, which though widely used are known to form unstable thiol conjugates.