Synthetic studies directed towards topoisomerase II inhibitors: UCT4B and clerodane diterpenes analogs

The present research has been carried out as part of a project involving the dimerization studies of the topoisomerase II inhibitor UCT4B. The antitumor activity of these agents is believed to be due to biologically active dimmers. The focus of this research is to explore synthetic methods towards UCT4B analogs.; At present all the reported methods for the decalin portion originate from the chiral pool, this does not allow for manipulations to be made onto the decalin ring. The UCT4B consists of an angular methyl group at C-5 position on the decalin ring core. In the first part of this research investigations using acyl radical cyclizations were carried out to construct the trans fused decalin ring core.; Model studies showed that acyl radical cyclization without stabilizing groups occur without regioselectivity. However in the presence of a thioketene acetal group, these cyclizations occur selectively favouring the smaller ring size. Results obtained with the cyclization studies showed that the use of a radical stabilizing group like dithiane offers a regio and diastereoselective method for the construction of cis fused bicyclic systems possessing angular methyl groups. The regioselective control observed in acyl radical cyclization has merit and holds promise as a method in the synthesis of cyclic compounds possessing quaternary carbon centers. Application of the methodology has been demonstrated in a formal synthesis of rac-cuparene.; The second part of this thesis describes the synthetic studies carried out towards spirocardin and UCT 413 analogs. These model compounds contain all of the sidechain functionality, therefore all of the chemistry developed in their synthesis is expected to be directly applicable to the total synthesis of the natural products. Studies using Brown's homoallenylation chemistry as well enyne metathesis (developed in The Diver lab) were carried out to prepare dienyl alcohols on a multigram scale, these alcohols are important interrmediates for the model compounds. Investigations have also been carried out to prepare analogs which contain a side chain that is not fully oxidized. The last chapter describes attempts to prepare reduced analogs of UCT4B via a selective oxidation of the terminal hydroxyl group.