Evaluation of a Convergent Approach to Aziridinomitosenes

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Student Presentation

Presentation Date


Faculty Sponsor

Don Warner


Aziridinomitosenes (AZMs), like the structurally similar anti-tumor agent mitomycin C (MC), are known to covalently cross link complementary CG-sequences within the minor groove of the DNA helix, which halts mitosis and results in cell death. Unlike MC, however, AZMs possess additional electrophilic centers on the quinone ring that presumably play a role in cytotoxicity. Positions C6 and C7 are of particular interest due to an observed increase in cytotoxicity against several different cancer cell lines. To better understand the importance of these positions, facile entry to a library of AZM analogs is required. To this end, we are exploring an adaptation of a linear synthesis that is more convergent and potentially affords more flexibility. In the new route, a substituted β- acetoxy, γ-alkynyl carbonyl is prepared and subsequently treated with a C5-lithio oxazole species. After protection, the product contains the necessary components required for the oxazolium salt/azomethine ylide cycloaddition sequence that generates the AZM tetracyclic core. To evaluate this new approach, a simple model system has been synthesized and subjected to the reaction conditions. Specifically, an appropriately functionalized β-acetoxyhex-γ-ynal was prepared and treated with C2-phenyl substituted oxazole. Upon addition of the oxazole moiety to the aldehyde, the basicity of the C5-lithio-oxazole was found to be problematic. Enolization and subsequent elimination of the acetate-protected alcohol was determined to be the major reaction pathway. Attempts to circumvent this problem are underway, but initial studies with the desired product suggest that the azomethine ylide cycloaddition sequence and subsequent quinone generation have been successful. These results, as well as the synthesis of relevant compounds, will be presented.

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