Total synthesis and structure-activity studies of marine natural products

The first chapter describes the synthesis of analogs of the antimitotic agent curacin A. A first generation library of analogs was prepared from geraniol by solution phase parallel synthesis. Lead structures from this library were further refined in a focused mixture library synthesis. Purification of mixtures was effectively accomplished using a novel fluorous alkoxyethyl ether protecting group. A second generation library resulted in an oxime ether analog which demonstrates superior inhibition of tubulin polymerization relative to curacin A. This analog also displays decreased lipophilicity and a simplified structure compared with curacin A.; The second chapter describes the discovery of a novel glycosylation methodology. The synthesis and applications of a fluorous THP protecting group are outlined. The use of Cp₂ZrCl₂/AgClO₄ for activation of anomeric sulfoxides was first employed for attachment of the fluorous THP. This new methodology was subsequently extended to carbohydrate glycosylation chemistry, specifically glucose and mannose derived sulfoxide donors.; The third chapter describes synthetic efforts towards the marine natural product leucascandrolide A. A novel and convergent synthesis of the macrocycle of the molecule is described. Highlights of the synthetic approach are the bidirectional synthesis of a dithiane fragment, an efficient dithiane alkylation, and a Mitsunobu macrolactonization.