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Progress Towards the Total Synthesis of Rugulosone and Methodologies of Alkene Isomerization and Formation of Substituted Adamantanones


In Chapter 1, potential strategies toward the synthesis of rugulosone were investigated. Although initial efforts towards forming the bicyclo[3.3.1]nonane core via a Michael addition - Dieckmann condensation reaction sequence did not prove useful for our investigations, the synthesis of the core was accomplished via a highly efficient tetraalkylation of commercially available starting materials. Using our developed methodology, we were able to isomerize unactivated alkenes to form the C2 symmetric core necessary for the natural product. Studies toward the addition of the northern side chain were conducted, and proved to be promising. Synthesis of a protected southern side chain was accomplished, and may be used in the future to couple with the functionalized core to facilitate a highly divergent synthesis of the natural product.

For our work towards the synthesis of the core of rugulosone, we developed a methodology to isomerize exo-methylene groups to their corresponding tri-substituted internal alkenes. The exo-methylene groups of 2,6-disubstituted bicyclo[3.3.1]nonan-9-ones were readily isomerized over a palladium catalyst under an atmosphere of hydrogen to form predominantly the isomer with C2 symmetry with very little formation of the analogous product with CS symmetry. A hydrogen source was essential to effect the rearrangement.

The third and last chapter outlines formation of highly substituted adamantanones. Adamantane-based small molecules are useful in the treatment of a variety of conditions, ranging from neurodegenerative disorders such as Parkinson's and Alzheimer's disease, to viral infections such as HIV. We thus desired to efficiently construct substituted adamantanones, potential precursors to the corresponding adamantanes. Trifluoromethanesulfonic acid facilitated formation of the adamantanone core from 1,5-dialkyl-3,7-dimethylenebicyclo[3.3.1]nonan-2-one, which was easily obtained in one step from commercially available starting materials. The resulting adamantyl cation was trapped with a variety of nucleophiles to form tetrasubstituted adamantanones. Aromatic and heteroaromatic nucleophiles have proven to be successful, and oxygen and nitrogen nucleophiles provide access to a wide variety of functionality at the newly formed tertiary position.

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