A convergent synthetic route to trioxacarcins.

摘要

Presented in this dissertation is the development of a highly convergent synthetic route to the trioxacarcins, a class of densely oxygenated, structurally complex bacterial isolates with potent antiproliferative effects in various human cancer cell lines grown in culture. To address the chemical synthesis of natural and unnatural trioxacarcins broadly, we targeted the differentially protected trioxacarcin precursor (17). As a strategic objective, we sought to develop a synthetic route employing strategic bond-pair constructions between components of similar structural complexity at or near the final step of the route.The oxirane ring of the epoxy diazo diketone component (22), which maps onto the DNA-reactive spiro epoxide found in the trioxacarcins, was introduced by diastereoselective epoxidation of an alpha-methylene-beta- tert-butyldimethylsilyloxy-carboxylate ester with potassium tert-butoxide--tert-butyl hydroperoxide, a transformation developed for this purpose and found to have generality. A series of experiments employing deuterium-labeled epoxidation substrates revealed that the epoxidation reaction proceeds by stereospecific oxygen-atom transfer.The densely oxygenated core of the trioxacarcins was constructed using a carbonyl ylide--aldehyde cycloaddition reaction between the epoxy diazo diketone 22 and the differentially protected aldehyde 21, which was prepared from cyanophthalide 23 and cyclohexenone 24, a sequence of just six steps. The stereochemical outcome of the cycloaddition was strongly influenced by the metal catalyst employed and by the protective groups present within each reactant (only the desired cycloadduct 19 is depicted).*The differentially protected trioxacarcin precursor 17 was transformed to the natural trioxacarcin DC-45-A2 (1) in a two-step deprotection sequence. Synthetic DC-45-A2 (1) provided spectroscopic data that were in close agreement with literature values, and the structure of the synthetic material was unequivocally established by X-ray crystallographic analysis. An unnatural stereoisomer of DC-45-A2, iso-DC-45-A2 (145), was also prepared and preliminary studies reveal that there are significant differences in reactivity between the two isomers.*Please refer to dissertation for diagrams.