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Aminothiazole-based inhibitors designed for HCV polymerase display low micromolar potencies in biochemical assays. These compounds show a stringent preference for a cyclohexyl ...hydrophobe at the 2-amino position. The composition of these compounds suggests that they may be interacting at a recently discovered allosteric site on the polymerase.
Interaction with aromatic π systems has become recognized as an important mode of stabilization of carbocation intermediates in biological reactions. To gain insight into such carbocation-π ...interactions, we have undertaken a study of intramolecular model systems, one being a benzobicyclo4.2.1nonene model system. Our goal is to compare, for example, the stabilities of a syn carbocation, in which π complexation is possible, vs. an isomeric anti carbocation, in which π complexation is precluded. Syntheses of alkenes as carbocation precursors, and the results of the NMR studies of the kinetics of protonation of these alkene precursors will be presented. Computational results for the optimized geometries and relative energies of alkenes and carbocations will be discussed to explain the experimental data. In another model system that was proposed for investigation, a benzobicyclo3.2.1octenyl ketone was needed as an important intermediate for the synthesis of the corresponding model system. Attempts to develop an efficient synthesis that would provide gram quantities of this intermediate ketone will be presented in this thesis. Finally, during the synthesis of a naphthalene diol needed for the synthesis of a naphthalene bridged model system, initially proposed for the study of carbocation-π interaction, a novel benzonorcaradiene derivative was discovered in the lithium aluminum hydride reduction of 1,8-naphthalic anhydride. Experiments designed to elucidate the mechanism of the benzonorcaradiene formation, and results of deuterium labeling experiments and molecular modeling will be discussed in this thesis.
Reduction of 1,8-naphthalic anhydride (
1) with LiAlH
4 in THF (or DME, but not Et
2O) affords, in addition to diol
2, benzonorcaradiene
3. Extended treatment of
2 or lactone
4 also leads to
3, in ...66% and 65% yield, respectively. Reduction of
4 with LiAlD
4 established that formation of
3 proceeds via a symmetrical intermediate. No significant norcaradiene formation is observed upon comparable LiAlH
4 treatment of
14, 15, 16 or
17. This novel reduction of a naphthalene derivative to a benzonorcaradiene appears to be unique to
2 or its precursors.
Reduction of anhydride
1 with LiAlH
4 in THF yields, in addition to diol
2, benzonorcaradiene
3. Extended LiAlH
4 treatment of
2 or lactone
4 affords ∼65% of
3.
