Abstract:
This thesis is concerned with the development of novel synthetic routes towards the highly substituted tetracyclic core of berkelic acid, a novel bioactive natural compound isolated from an extremophile found in Berkeley Pit Lake. This highly acidic (pH = 2.5-2.7), metal laden lake, formed through infiltration of an abandoned copper mine in Montana, USA, is the source of the Penicillium sp. Pitna 4 from which berkelic acid was isolated in 2006. Bioassays on berkelic acid have shown selective activity against OVCAR-3, an ovarian cancer cell line, as well as inhibitory activity towards the matrix metalloproteinase MMP-3 and the cysteine protease caspase-1. Due to its bioactivity and the complex structure, berkelic acid represents an interesting target for synthetic chemists. This study describes two approaches towards the tetracyclic core of berkelic acid. The first approach is concerned with the synthesis of the benzannulated spiroacetal moiety using a styrene derivative for a Kulinkovich reaction to form a cyclopropanol. Further studies of the selective ring opening of the cyclopropanol and acidic spiroacetalisation afforded the tricyclic benzannulated spiroacetal moiety of berkelic acid. To further examine the scope of the synthetic strategy, a series of analogous benzannulated spiroacetals were synthesised using the established approach. A second approach describes extensive studies on the synthesis of the tricyclic isochromane core of berkelic acid employing an oxa-variant of the Hofmann-Löffler-Freytag reaction to construct the isochromane ring. Use of Au(I)-catalysed hydroarylation to establish the precursor for the key Hofmann-Löffler-Freytag reaction and Pd-catalysed carbonylation to introduce the carboxylic acid completed the novel synthetic approach towards this tricyclic moiety. To demonstrate the scope of the developed strategy, the synthesis of the tetracyclic spiroacetal core was next achieved, making use of a second oxidative radical cyclisation step to introduce the spiroacetal moiety.