| Small molecules have become powerful tools for biological discovery, especially their systematic use in chemical genetic studies. As a result, the search for new bioactive molecules has become a major focus of synthetic organic chemistry. In this context, and motivated by an initial interest in molecules from natural sources, we have developed synthetic methods for accessing natural product-like structures of actual or potential biological relevance, and have used them to deliver collections of new molecules for biological screening. This dissertation describes those synthetic efforts.; A versatile total synthesis of psammaplysenes A and B, two bromotyrosine-derived marine alkaloids recently found to inhibit FOXO1a nuclear export in cells deficient in tumor suppressor PTEN, is included. Following Nature's guidelines, the pseudosymmetric character of the compounds was taken into account, and their two similar-looking constituents were synthesized via distinct pathways, from a common precursor.; This synthetic design formed the basis for constructing a 28-member collection of psammaplysene analogues, in an effort to explore psammaplysene's activities in several assays. These were formed in a semi-combinatorial manner from a pool of synthetic building blocks, slightly different from the two halves of the most potent parent compound, psammaplysene A.; A synthetic library resembling molecules isolated in the Clardy lab from environmental DNA (eDNA) heterologous expression (employed to access bacterial metabolites from uncultured microorganisms) was also prepared. Counting more than 100 members, some prepared in solution and others on solid support, the library included long chain N-acyl tyrosines (structurally similar to autoinducers N-acyl homoserine lactones), along with (biosynthetically) related long chain enamides and enol esters.; Finally, we describe progress in developing the chemistry for a diversity-oriented synthesis (DOS) library of heterocycle-containing alkaloid-like molecules. Library design used a strategy that includes skeletal transformations as a contribution to the overall structural diversity. A key step, the 1,3-dipolar cycloaddition of resin-bound nitrile oxides to enamine dipolarophiles, leads to rigid polycyclic systems assembled from the resulting isoxazoline. Conditions were investigated for electrophile-induced C-N bond fragmentation that converts these systems to flexible isoxazole-associated macrocycles. |
