Marine-derived heterocycles : structural, synthetic and biological investigations

This dissertation describes synthetic, structural and biological studies on three different groups of heterocyclic marine natural products. Chapter 2 describes the assignment of the absolute configuration of phorbasides A and B, cytotoxic macrolide glycosides from the marine sponge Phorbas sp. The synthesis of a series of ene-yne chlorocyclopropane model compounds is described; the circular dichroism spectrum for each model is presented and compared to the spectra obtained for the natural products. The relationship between configuration and structure of the extended ene-yne chromophore and the observed Cotton effect is discussed. Chapter 3 describes i) The characterization of three new antazirine analogues from the marine sponge Dysidea fragilis; ii) The total synthesis of (Z)-dysidazirine, a related 2H-azirine natural product isolated in 1988 from Dysidea fragilis, and iii) The synthesis of a series of dysidazirine analogues. The antifungal activity of all compounds against a panel of clinically-relevant pathogenic fungi is reported. The data is used to develop a basic Structure- Activity-Relationship for antifungal activity of long- chain 2H-azirine carboxylates. Implications for the mechanism of action of (Z)-dysidazirine are discussed. Chapter 4 details the first total synthesis of the cytotoxic polyketide macrololide enigmazole A, isolated from the marine sponge Cynachyrella enigmatica. Enigmazole A was synthesized in 22 steps (longest linear sequence) and 0.41% overall yield from known compounds. The development of a method for preparation of functionalized oxazol-2-yl zinc reagents by direct zinc insertion is described. Oxazol-2-yl zincates were found to undergo palladium catalyzed Negishi coupling and copper catalyzed acylation reactions. The application of this methodology to the preparation of the oxazole-containing side chain of enigmazole A is presented