A new approach to the marine natural product ulapualide A

This thesis describes synthetic studies directed towards a second generation total synthesis of ulapualide A. Ulapualide A is an extraordinary bioactive tris-oxazole based macrolide which was isolated from the egg masses of the marine sponge Hexabranchus sanguineus and exhibits potent antifungal activity with inhibition of leukaemia cell proliferation. The Introduction to this thesis includes an overview of natural product chemistry and draws attention to the 'ulapualide' family of secondary metabolites including their isolation, biological activity, biosynthesis and structural determination. Also included is a summary of a total synthesis of ulapualide A by our research group in Nottingham, together with a review of oxazole containing natural products. The Results and Discussion section of this thesis details our general strategy for an alternative design for the synthesis of the tris-oxazole based macrolide core of ulapualide A. A synthesis of a model system exemplifying this strategy is then described, together with a detailed discussion of polyoxazole ring formation. This is followed by application of the model study to ulapualide A itself, and includes a total synthesis of the polyol C26-C41 side-chain of ulapualide A. The section concludes by describing our synthetic efforts towards the remaining chiral fragment of this natural product, the bottom-chain. The thesis concludes with an Experimental section containing full details of the preparative work completed and listing spectroscopic and analytical data for all new compounds synthesised during the study. An Appendix contains a description of contemporaneous synthetic studies carried out by Panek et al during the course of my PhD studies. X-ray crystallographic and spectroscopic data, together with reprints of publications resulting from our work are also included