| The trioxacarcins are structurally complex, highly oxygenated bacterial isolates that potently inhibit the growth of human cancer cells in culture as a consequence of their ability to alkylate guanosine residues of duplex DNA. This dissertation presents a component-based synthetic route to the trioxacarcin structural class, broadly defined, which resulted in fully synthetic routes to trioxacarcin A (1), DC-45-A1 (10), and a diverse collection of analogs.;Two efficient synthetic routes were developed to the deoxysugar trioxacarcinose A (2) found within most trioxacarcins. Both routes relied on diastereoselective, chelation-controlled additions of allylmetal reagents to free or protected syn-alpha,beta-dihydroxyketones. A scalable protocol provided their common syn diol starting material 32, using a p-phenylbenzyl ester as an expedient for purification and enantioenrichment by recrystallization.;Diastereoselective glycosylation reactions were developed for the coupling of activated forms of trioxacarcinose A to fully functionalized trioxacarcin core substrates. This methodology enabled the preparation of the natural product DC-45-A1 (10) in three chemical steps from synthetic precursor 23. Incorporation in tandem of an activated derivative of trioxacarcinose B (3) prepared by postdoctoral researcher Thomas Magauer resulted in an 11-step synthesis of trioxacarcin A (1) from precursor 23..;The synthetic route to trioxacarcin A (1) proceeded by the assembly of five components of similar structural complexity: epoxy diazo diketone 18, cyanophthalide 19, cyclohexenone 20, a trioxacarcinose A glycosyl donor, and a trioxacarcinose B glycosyl donor. A diverse collection of trioxacarcin analogs was prepared by variation of these modular components, both individually and in combination, to introduce deep-seated structural modifications which would have been difficult to access by other means. Through measurements of antiproliferative activity in cultured human cancer cells, this program in analog synthesis has begun to define the structural features which enable or disfavor potent growth inhibition. In particular, novel trioxacarcins such as methoxymethyl aglycon 127 have been identified which retain antiproliferative activity at levels comparable to trioxacarcin A (1) despite significant structural simplification. |
