This proposal explores the utility of chromium Fischer carbenes in a new synthetic methodology to biologically important molecules, as well as the potential of thee complexes as cytotoxic agents. The synthetic methodology is based on a new application of the anions of phosphinated Fischer carbenes which are known to show markedly enhanced nucleophilicity relative to their nonphosphinated analogs. The proposal first seeks to quantify this enhanced nucleophilicity by carrying out pKa determinations on the phosphinated complexes. This knowledge will then be applied to designing a new synthetic route to 2-oxacyclopentylidenes by reaction of epoxides with an appropriate phosphinated carbene anion. Significantly, the 2- oxacyclopentylidenes may be directly converted to gamma-lactones, a nucleus which is responsible for the biological activity found in many anti-cancer agents. The synthetic methodology will be further developed through the incorporation of chiral phosphines to provide optically active gamma- lactones. This latter route will be exploited in the syntheses of optically active forms of the natural products hexanolide and trans-cognac lactone. In addition, the reactivity of alpha,beta-unsaturated lactones and alphabeta-unsaturated 2-oxacycloalkylidenes with biologically relevant thiol nucleophiles, such as cysteine, will be explored. This latter study will examine the hypothesis that increased rates of Michael additions of thiol nucleophiles lead to concomitant increases in cytotoxicity. Since alpha,beta-unsaturated 2-oxacycloalkylidenes react essentially like highly activated alpha,beta-unsaturated lactones, they are expected to show orders of magnitude increases in the rate of thiol additions over the organic analogs. Thus, these cyclic Fischer carbene structures may eventually be found to display excellent cytotoxicity. Their potential in this regard, however, will also depend on their selectivity. The Fischer carbenes will be examined for their selectivity towards sulfur versus nitrogen and oxygen nucleophiles and for the effect of phosphine substitution on this selectivity. The relationship between the structure and the kinetic reactivity of these complexes and the released organic analogs will be explored employing spectrophotometric techniques in both conventional and stopped-flow time ranges, under uniform solvent and temperature conditions.
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