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UBC Theses and Dissertations

Synthesis and applications of alkyl and aryl vinyl sulfides and sidearm-substituted bisoxazolines Bichler, Paul


The presence of sulfur in numerous blockbuster drugs, natural products and other medicinally active molecules necessitates the development of efficient methods for the synthesis of carbon-sulfur bonds. Transition metal approaches towards the construction of CS bonds have largely aided in the synthesis of aryl thioethers and related functionalities. However, few examples of catalytic processes demonstrate a tolerance for less reactive aliphatic thiols, leading to a widespread belief of an incompatibility of these substrates in catalytic C-S bond formation. To this end, our group has demonstrated the first examples of rhodium-catalyzed alkyne hydrothiolation processes for the synthesis of alkyl vinyl sulfides. The work detailed in this thesis encompasses the use of Wilkinson’s catalyst in alkyne hydrothiolation for the selective formation of E-linear alkyl and aryl vinyl sulfides. The substrate scope of this process is quite general, tolerating a variety of useful functional groups capable of undergoing further elaboration. Interestingly, alkyne substrates with adjacent heteroatoms undergo a reversal of regioselectivity, often favouring the branched regioisomer relative to the expected E-linear vinyl sulfide. The use of our catalytic alkyne hydrothiolation methodology was applied to the synthesis of a promising cancer chemotherapeutic agent, ON 01910.Na, which shows broad-spectrum activity towards a large number of cancer cell lines. Additionally, the reactivity of aryl and vinyl sulfides was evaluated within the context of vinylogous thioesters capable of undergoing electrocyclizations. The development of a Sonogashira cross-coupling thio-Michael addition sequence allowed for the synthesis of a variety of heteroaromatic substituted vinylogous thioesters. The treatment of these substrates with excess triflic acid proved optimal in facilitating cyclization to thiaindanone-type products, a motif found in molecules with application towards the treatment of neurologic diseases. The observation of interesting skeletal rearrangements suggests a competition between the expected Nazarov cyclization and an intramolecular Friedel-Crafts acylation. Lastly, a series of sidearm-substituted bisoxazolines were synthesized and a preliminary investigation of their coordination chemistry is reported. The application of these complexes towards a variety of asymmetric transformations, including the Nazarov cyclization, is currently ongoing.

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