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 developed during the program[unreadable]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[unreadable]s two halves. The 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 a class of lycopodium alkaloids that have exhibited acetylcholine esterase inhibition and anticancer activity. The synthesis route allows general access to these members and unnatural derivatives through a common skeletal construction. General methods development during this granting period will focus on new piperidine annulation methods. This heterocycle is common to numerous pharmaceuticals and biologically active natural products. Chemical synthesis of antitumor and potential Alzheimer[unreadable]s therapeutic leads will result from these studies. Additionally, new synthetic methods with broad application in pharmaceutical synthesis will be developed.