Gram-Scale Synthesis of Brevianamide Alkaloids.

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With our rapidly increasing global population we must endeavor to reduce the economic and environmental cost associated with producing organic substances; our medicines, agrochemicals and high-tech materials. This project aims to mimic biological processes in an effort to improve the way in which we can make these highly important substances. This is akin to how engineers take inspiration from birds and other flying animals when developing better and more efficient planes. Through this "biomimetic" approach we will investigate and learn about the highly sophisticated way Nature utilizes predisposed, highly selective, chemical reactivity to rapidly construct complex molecules. We will demonstrate the power of this biomimetic strategy by synthesizing the brevianamide alkaloids, secondary metabolites isolated from various Aspergillus and Penicillium fungi. These alkaloids have only been isolated in milligram quantities, which has thus hampered full investigation into their biological function. The chemical syntheses proposed in this research project will produce gram-scale quantities of these highly important and complex molecules, which will enable further collaborative investigations into their biological profiles. Brevianamide S, for example, has been reported to exhibit selective antibacterial activity against Bacille Calmette-Guérin (a screening surrogate for Mycobacterium tuberculosis), suggestive of a new mechanism of action that could inform the development of next-generation TB drugs. Unfortunately, the quantity of natural brevianamide S that can be isolated from fermentation and extraction of Aspergillus versicolor has impeded greater investigation into this very promising biological activity. In summary, the expected outcome of this research will be uniquely efficient synthetic strategies that significantly surpass all previous approaches to this family of natural products, new synthetic methodology that will be of wider use in organic synthesis, and practical quantities of the target natural products for biological/medicinal research.