摘要：

The sulfonamide metathesis reaction became of interest to my research group after use of electron-poor benzylic sulfonamides in a palladium-catalyzed coupling with aryl halides. The scope and mechanism of the reaction were of critical interest in developing this coupling reaction into a useful synthetic handle for complex molecule synthesis. The scope of the reaction was explored both for the possible metathesis substrates--it was found that benzylic group next to the sulfur is essential for reasonable reactivity, and the use of heterocyclic sulfonamides rather than those of primary or secondary amines are stable to acids and neutral nucleophiles, but were extremely sensitive to basic conditions. This result scales with the pKa of the nitrogenous leaving group. The mechanism of the reaction was elucidated using chemical kinetics experiments--the possible mechanisms include the nucleophilic displacement of the protonated leaving group or the elimination of the leaving group across the benzylic position to create a sulfene. The rate law for the reaction was found, the reaction is first order in both reactants. A secondary kinetic isotope effect was measured for the reaction of the sulfonamide deuterated at the benzylic position. Chemogenetic and proteomic techniques are of great utility for the greater study of proteins through the small molecules that interact with them, providing valuable insights both into their function in the cell and in the phenotype induced by their potentiation or inhibition. The synthetic efforts performed at Novartis were focused on creating effective affinity probes for identification of the protein target, and in synthesis of chimeric compounds that would probe the SAR between the many different SMIMs. These syntheses were not brought to their logical conclusion due to difficulties inherent within the synthetic route. A SMIM bioconjugate for use in biological assays was also synthesized. It was noted that when performing a [3+2] copper(I)-catalyzed nitrile oxide-alkyne cyclization, upon the incidental addition of palladium, a new intermediate ""ynoxime"" was formed as an initial product, which was shown by NMR to slowly convert to the isoxazole formed under Cu(I) catalysis. This observation reveals a heretofore-unanticipated mechanistic pathway within catalyzed [3+2] isoxazole forming reactions, though its scope is unknown. To date, investigations into this mechanistic pathway fall into three categories: identification and isolation of ynoxime under catalytic conditions, synthesis of ynoxime protected from further cyclization, and synthesis of unprotected ynoxime under non-catalytic conditions. For the first category, various electronically diverse oximoyl chlorides, alkynes, and catalyst and solvent

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