The Total Synthesis of Bioactive Molecules and the Development of the Methodological Underpinning

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This proposal describes the development of new and useful chemical transformations and the application of those transformations to the challenge of preparing, by chemical synthesis, target molecules of biological or medicinal significance. Our research group has the long term goals of: 1) Uncovering previously unknown reactivity of existing functional groups with the aim of developing new, useful synthetic methods, 2) developing the chemistry of donor-acceptor cyclopropanes, 3) exploring new Conia-ene chemistry, 4) developing new ways to prepare and functionalize heterocyclic motifs, and 5) applying the synthetic methods above to the expedient synthesis of natural and unnatural target molecules possessing important biological activity. In this proposal we will describe our plans to address the above long term objectives as well as describing, in detail, our plans to address the following more focused shorter term objectives: 1) The development of new reactions of donor acceptor cyclopropanes including the reactions with azirines, aziridines, and diazines, 2) the exploration of unconventional dipoles such as keteneamines in useful synthetic reactions, 3) the investigation of a very recently developed pyrrole synthesis, 4) the development of a tandem Conia-ene/Diels-Alder reaction and its application in synthesis, 5) the application our Diels-Alder/ Plieninger indolization strategy to the synthesis of the natural product and 6) we will apply the methods above to the synthesis of heterocylic natural products such as tronocarpine, callosine, halichlorine and actinophyllic acid The above chemistry is anticipated to add significantly to the arsenal of chemical methodology available to the synthetic chemist. These enabling technologies will allow the synthetic chemist greater access to complex molecules by chemical synthesis. The research described in our proposal will aid in the training of chemists skilled in the synthesis of complex molecules. This will prepare them for both academic and industrial careers, particularly as pharmaceutical chemists.