I. Enhanced synthesis and diversification of the phorboxazole chemotype. II. Synthetic studies towards the marine natural product isoobtusadiene

This thesis is composed of two parts. Part I deals with the enhanced synthesis and diversification of the phorboxazole chemotype. Phorboxazoles A and B are marine natural products that were isolated off the coast of Western Australia from the sea sponge Phorbas sp. These unique secondary metabolites are among the most potent cytostatic compounds ever discovered, demonstrating remarkable activity against the National Cancer Institute's panel of 60 human tumor cell lines (GI₅₀ = 1.58 × 10 −9 M). In 1998 our research group reported the first total synthesis of phorboxazole A and since then has embarked on a research program aimed at defining the relationships between structure and potent anti-cancer activity of these natural products.; The first goal of this project is to develop an optimized synthesis of the phorboxazole architecture. The second goal is to determine the biological mode and mechanism of action. Accomplishing this goal will rely, in part, on our ability to synthesize a biotinylated derivative of phorboxazole A or B and employing phage display affinity chromatography. The third goal is to determine the minimal structural features required for potent biological activity through Structure Activity Relationship (SAR) studies. This will involve the use of our streamlined laboratory synthesis to generate structural analogs.; Part II of this thesis deals with synthetic efforts towards the marine natural product isoobtusadiene. Natural products from the chamigrene skeletal class ([6.6]-spirocycles) offer a challenging opportunity to synthetic chemists. The recent interest in these cytotoxic natural products have prompted much interest in the synthetic community. Described here is an efficient synthesis of a major intermediate of isoobtusadiene.