Design, Preparation, And Applications Of Novel N-Vinyliminium Salts in Organic Synthesis. Design and Synthesis of Tau Aggregate-specific Fluorescent Probes for Postmortem Imaging of Brains with Tauopathies
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PART I Efforts to optimize the electrophilic coupling partners for the Suzuki reaction by electronically and sterically tuning the pyridinium moiety are described. Both reaction temperature and catalyst loading have been significantly reduced, resulting in a practical advance in Suzuki coupling. N-vinylpyridinium salts are easily prepared from various activated acetylenes to form crystalline, air-stable, and non-hygroscopic solid, and represent a practical improvement over the analogous vinyl halides and vinyl triflates. New mechanistic interpretations of aza-Michael additions with substituted pyridinium tetrafluoroborate salts to activated alkynes have been made. It is understood that the stereochemical outcome of such nucleophilic additions depends upon the intrinsic ability of neighboring electron-withdrawing groups to stabilize an adjacent negative charge. This view may no longer be valid in light of new data that shows a remarkable dependence on the concentration of free base present that favors trans isomers. Previous work with N-vinyliminium and N-trialkylammonium salts suggested that they would also be ideally suited for the efficient total synthesis of certain classes of alkaloid natural products. We have demonstrated, a one-pot synthesis of the alkaloid mesembrine, that relies on a Diels-Alder cycloaddition, followed by a novel thermal SO2 extrusion/radical recombination of an additional arylsulfonyl activating group. The unexpected and serendipitous synthesis of an important member of the piperidine class of the hemlock alkaloid, coniine, was completed by means of an electrocyclic ring closure of N-vinylpyridinium tetrafluoroborate followed by an MgO nanoscale particle catalyzed transfer hydrogenation. PART II We prepared a series of 6-azaindole derivatives, designed for use as a tau-specific fluorescent probes, was prepared. The short synthetic routes utilizes transition metal-free N-arylation reactions linked via PEGylated units to the fluorescent dye (e.g., rhodamine). The putative tau binding unit (6-azaindole) is linked to the fluorescent unit via a copper-catalyzed [3+2] Huisgen cylcoaddition of a terminal acetylene to an azide (i.e., “click” chemistry). This approach offers a simple and efficient method for synthesizing a small library of potential tau-specific probes for further study (e.g., staining post-mortem brain tissue).
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Part I. Introduction ; Background and significance ; Results and discussion ; Conclusions and future directions ; Experimental section -- Part II. Introduction ; Background and significance ; Results and discussion ; Experimental section
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M.S. (Master of Science)