Synthesis of Spiro-bicyclo[2.2.2]Octane Derivatives Towards the Development of Paclitaxel Mimetics

Abstract: Many of the drugs that are developed in the pharmaceutical industry have their origin in natural products. Paclitaxel, the active substance of the medicine Taxol, was found in the bark of the Pacific yew tree (Taxus brevifolia). This was discovered in the early 1960's when a screening program was initiated by the National Cancer Institute (NCI) in the US, with the aim to find new natural products that could be of use in cancer treatment. The low yield of paclitaxel from the bark and the fact that the tree dies without its bark, together with the many positive reports on different types of tumors, lead to a massive effort to find new ways of producing paclitaxel. Production via total synthesis of this complex molecule is both complicated and expensive. However, the need could be satisfied via a semi synthetic route starting from a closely related analogue, which can be isolated from the leaves of the European yew (Taxus baccata). Today, paclitaxel is produced by plant tissue cultures and is used in the treatment of a variety of cancers. However, its use is limited due to severe side effects, low water solubility and resistance. The primary intention with the work presented in this thesis was to synthesize paclitaxel mimetics and to test them for biological activity. Paclitaxel mimetics can be described as synthetic, structurally simplified compounds which share paclitaxel's mechanism of action and that ideally show the same or improved activity. Compounds of this kind might become valuable tools for further investigations aimed at addressing the various concerns of paclitaxel. For the design of our paclitaxel mimetic, we searched for simple rigid skeletons that could replace paclitaxel's complex core structure. The geometry of the new structure had to be such, that when decorated with the pharmacophores (structural parts that are of importance for activity) of paclitaxel, they should have proper spatial arrangements. By molecular modelling we identified a spiro-bicyclo[2.2.2]octane framework to be a suitable core structure. In the course of our study, we successfully developed a synthesis of novel racemic bridgehead hydroxyl bicyclo[2.2.2]octane derivatives. This methodology was subsequently modified so as to allow the synthesis of both enantiomers of the bicyclic structures in high enantiomeric excess. In addition, a methodology for the spiro-annulation was developed. Functionalisation of the spiro-bicyclic core structure with the necessary paclitaxel pharmacophores, in order to obtain a testable mimetic, still remains to be completed.