Application of New Amination Reactions to Natural Product and Nonnatural Heterocy

Vanderbilt University, Nashville TN

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Abstract

This program describes a chemical synthesis route to biologically active natural products. Mitomycin C is a clinically-used small molecule for chemotherapy that functions as a DNA cross-linking agent. No other known chemotherapeutic duplicates this mechanism of action. A short synthesis is being developed based on new reactions devleoped during the program's first phase: the aza-Darzens reaction of propargyl imines to produce the cis-aziridine diastereoselectively. A metal promoted amine-alkyne enamine synthesis is then paired with a quinone to conjoin the molecule's two halves. Completion of the synthesis will be accomplished via one of several intermediates this approach provides. Completion of the total synthesis of (+)-serratezomine A is also planned. Free radical-mediated vinyl amination is a key enabling reaction in this synthesis. Serratezomine A is a member of the lycopodium alkaloids;many constituents have exhibited acetycholine esterase inhibition and anticancer activity. The synthesis route allows general access to these members and unnatural derivatives through a common skeletal construction. Chemical synthesis of antitumor and potential Alzheimer's therapeutic leads will result from these studies. Additionally, new synthetic methods with more general impact in pharmaceutical synthesis are expected to result.