A wide variety of natural products have been isolated from Didemnum species of ascidians, and a survey of such compounds is presented. The didemnaketals are the only spiroacetal containing natural products to be elaborated by this genus, with didemnaketal A showing the greatest activity against HIV-1 protease. General synthetic approaches to the spiroacetal moiety are discussed, and then applied in retrosynthetic analyses of the spiroacetal portion of didemnaketal A. Synthesis towards this spiroacetal portion is reported, with the products being characterised by detailed 2D NMR spectroscopy and other methods. The relative stereochemistry at C12, C14, C16, C18 and C20 in the natural product is established. Further extensions of the synthesis are discussed. Two models of the E,F bicyclic portion of the shellfish poison, pinnatoxin D, are synthesised, and characterised by detailed 2D NMR analysis. The relative stereochemistry at C27, C29 and C30 is established by this synthetic work, and is in agreement with that based only on NMR analyses. This work has been published. {Suthers, B.D., Jacobs, M.F., Kitching, W. Tetrahedron Letters 39, 2621-2624 (1998)}

A series of small molecules was synthesized to probe three protein targets in order to elucidate the key small molecule-protein interactions required for potency. Triclosan is an antibacterial compound that has surfaced as a potential environmental hazard and is hypothesized to cause perturbations in the thyroid hormone response of frogs. Using a C-fin assay and a GH3 cell line, our work suggests that triclosan itself may not in fact be the cause of the observed endocrine disruptions. Instead, methyl triclosan (a result of biological methylation during waste water treatment) was shown to disrupt the thyroid hormone response in tadpoles. Secondly, a set of probes was designed based on a cyclopentane scaffold derived from the known neuraminidase inhibitor peramivir. Kinetic assays using both a recombinant neuraminidase protein and an inactivated sample of influenza virus showed that the guanidine group contributes a 10 fold increase in potency while the α-hydroxyl group was observed to have little to no effect. This result suggests that future neuraminidase drug design based on a cyclopentane scaffold may forgo the use of both the guanidinium group and the hydroxyl group to potentially increase the oral availability of these drugs while sacrificing little in the way of potency. Finally, a series of truncated analogues related to the western half of the natural product didemnaketal A was synthesized. These compounds will be used as probes to better understand the mechanism of didemnaketal-mediated protease inhibition. It is hypothesized that a more rigid structure (due to molecular gearing enforced by the presence of additional methyl groups, relative to previously examined analogues) will increase the potency of these molecules toward HIV-1 protease and may lead to new information for designing next-generation dissociative inhibitors. Work was also begun toward the total synthesis of the natural product itself. / Graduate

The ascidian isolation artifact didemnaketal A is a highly oxygenated polyisoprenoid capable of inhibiting HIV-1 protease through an unusual dissociative mechanism. However, recent synthetic efforts have cast doubt on stereochemical assignments in the originally published structure. In the interest of elucidating the true structure of didemnaketal A through total synthesis, we present a strategy for rapidly accessing the putative spiroketal fragment by exploiting its latent symmetry. In a single step, double Sharpless asymmetric dihydroxylation reactions (SAD) allowed us to simultaneously set all seven stereogenic centers and assemble this complex fragment from non-chiral material. The precursor was obtainable through a racemic synthesis in which the geometric isomers of a nine-membered cyclic enone converged in a ring-opening cross metathesis reaction (ROCM). / Graduate / 0490 / jdavy@uvic.ca