Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)

Graduate Group


First Advisor

Jeffrey D. Winkler


The polyketide natural product citrofulvicin, which was isolated in 2018, presents an intriguing synthetic target due to both the structural complexity of the octacyclic ring system, which contains a 1-hydroxy-2,4,6-trioxaadamantane ring, and the reported antiosteoporotic activity of citrofulvicin. Synthetic access to this natural product would allow for further biological evaluation. This dissertation describes the synthetic efforts toward citrofulvicin. An initial approach using an isoxazole ring as a protecting group for a β-diketone on a model system targeting the core ring system of citrofulvicin led to the formation of unexpected polycyclic pyridine-containing structures. An alternative approach using a dioxolane protecting group on the model system led to the development of a concise synthesis of the key intermediate for the proposed final intramolecular cyclization cascade. Due to the observed unexpected intramolecular reactivity of this intermediate, a thioketal blocking group was introduced, which allowed for the successful cyclization cascade to occur. Removal of the thioketal blocking group led to the core ring system of citrofulvicin, which only lacked the aromatic ring substituents. Thus, the core ring system was synthesized in nine steps from readily available materials and the developed synthetic route should translate to the synthesis of citrofulvicin with a suitably substituted aromatic starting material.

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