Abstract:
This thesis describes the synthetic endeavours towards berkelic acid, an extremophile derived bioactive natural product. Penicillium sp. Pitna 4 is a fungus isolated from Berkeley Pit Lake, a metal laden, pH 2.5 lake which formed when an abandoned copper mine in Butte, Montana filled with infiltrating ground water. Berkelic acid is one of several bioactive natural products isolated from this unlikely source and has been found to have desirable selective activity against the ovarian cancer cell line OVCAR-3, as well as inhibitory activity against caspase-1 and matrix metalloprotease-3. Synthetic access to this molecule is highly desirable due to its bioactivity and novel tetracyclic structure as well as the fact that the planned bioremediation of Berkeley Pit Lake may eliminate its natural source. The synthetic studies undertaken have focused on developing a flexible strategy for the synthesis of berkelic acid that allows for future modification to structure to allow investigation of biological activity. The strategy is based on the use of a novel one-pot Horner-Wadsworth-Emmons/oxa-Michael cascade to couple two advanced intermediates – a phosphonate and a lactol. A final deprotection/spiroketalisation step then furnishes the spiroketal moiety. Careful functional group manipulations and key introduction of chirality were pivotal in the successful synthesis of a series of coupling partners which allowed the successful synthesis of a series of tricyclic analogues of berkelic acid as well as the entire tetracyclic core, with and without full substitution on the aromatic ring. The formal total synthesis of berkelic acid faltered at the penultimate step, but this project has none the less established a sound approach to this molecule which will build the foundations for a future total synthesis.