UC San Diego

Actinomycetes are microbes found in terrestrial soil and marine sediment that produce a rich variety of secondary metabolites. These natural products have diverse biological activity including antifungal, insecticidal, antibacterial, and antitumor activities. Although in most cases we can only speculate why the producer microbes make these natural products, they have been in use throughout human history. Some of these secondary metabolites and their semi-synthetic derivatives have proven to be indispensible to modern medicine, and others are highly desirable for non-essential uses such as food additives, fragrances and dyes. Our laboratory became interested in the actinomycetes produced pladienolide natural products when they were originally reported due to their potent antitumor activity and unique cell-cycle arrest profile. The novel assay used in their discovery, and the reported biological data indicated that these natural products probably had a unique mechanism of action against tumor cells. Herein is described research toward the synthesis and structural elucidation of the pladienolides and their close structural relative FD-895. This research was accompanied by efforts to isolate authentic samples of the pladienolides from their producer organism, Streptomyces platensis MER 11107. These efforts led to the isolation and structural elucidation of novel spirotetronate polyketides from this organism, the spirohexenolides. Chapter 1 describes attempts toward the synthesis of the core macrolactone ring of the pladienolides and FD-895, the synthesis of the sidechain of FD-895, and the synthesis of two models of FD-895 which demonstrate the feasibility of our end-game strategy toward this family of natural products. Chapter 2 describes the isolation efforts directed toward the pladienolides, and the isolation and structural elucidation of the spirohexenolides. An intramolecular Diels-Alder (IMDA) approach to (±) - spirohexenolide A, and a Lewis-acid catalyzed Diels-Alder approach to (±) - spirohexenolide B are described