Aziridinomitosenes (AZMs) are similar in structure and function to the clinically-used DNA alkylating agent mitomycin C (MC). Initial experiments examining anticancer activity of several synthetic AZMs demonstrate that the substitution pattern at the C6 and C7 positions significantly influence potency. Specifically, C7-methyl analogs are up to 5400 times more potent than corresponding unsubstituted compounds against a variety of cancer cell lines. In order to investigate the relevancy of these positions, this study aims to prepare additional AZM analogs substituted with ethyl or benzyl groups at C6 (5a  and 5b  ), as well as a C6/C7 dimethyl analog (5c  ). The synthesis, summarized in Figure 1, relies upon preparation of a 2,5-disubstituted oxazole (3  ) that is then subjected to an oxazolium salt/azomethine ylide cycloaddition sequence that generates the AZM tetracyclic core (4  ). Protecting group removal, oxidation, and carbamate installation will generate the desired final products. Thus far, the 17 steps required for compound 4c  , as well as 7 steps towards oxazoles 3a  and 3b  , have been completed. Key transformations completed thus far include a) conversion of commercially available 1,2-propanediol or ?-butyrolactone to ester 1  and lactone 2  , respectively; b) treatment with lithiated methyl isocyanide to produce C5-substituted oxazoles; c) aziridine incorporation via elaboration of a serine-derived aldehyde; and d) preparation of cycloaddition precursor 3  by addition of a protected propargyl alcohol. Progress to date and details of the syntheses will be presented.

Synthesis of C6/C7 substituted aziridinomitosene analogs

247th National Meeting (2014)

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