Advances in the Development of Synthetic Methods for Complex Molecule Synthesis

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The proposed research program is aimed at the development of novel strategies and new synthetic methods and reagents for the efficient formation of carbon-carbon and carbon-heteroatom bonds. Methods that can generate products in a selective manner, whether in a site-selective, chemoselective or stereoselective fashion are of particular importance, since they can then be used for the controlled and predictable synthesis of complex molecules. Specific projects outlined in the current proposal include the development of cycloaddition, electrocyclization and sigmatropic reactions. The scope of these methods and, where appropriate, the mechanism of the reactions will be determined. In addition, obtaining an understanding of the parameters which control reactivity and selectivity will allow the development of predictive models. Reaction sequences and domino reactions that allow for the rapid construction of molecular complexity using practical conditions and stable reagents are of particular value. The synthetic methods that are developed will be applied directly to the syntheses of biologically relevant and structurally complex target molecules, including natural products which display anticancer or antibiotic activity, such as macrocyclic depsipeptides and alkaloids. Example targets are the marine sponge alkaloids agelamadin and nagelamide which we aim to synthesize through an electrocyclization approach. General methods, reactions, and reagents that are of broad applicability ultimately result in practical benefits to other synthetic organic chemists, both in academic labs and commercial labs. Overall the proposed program will not only advance basic research in science and technology, but will also provide a training and research environment for students interested in research and development careers in the pharmaceutical, biotechnology, medicinal, agrochemical, and high-tech materials sectors.