Efficient Catalytic and Asymmetric and Cycloaddition Routes to Future Medicines

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The transformation of raw materials into high value goods by synthesis is a fundamental act of wealth creation and a barometer of economic activity. This proposal involves development of new reactions that can be used to quickly assemble high value molecules from simple, cheap starting materials using relatively benign conditions. The results of this research program will lead to more efficient synthesis, a key objective for environmentally responsible manufacturing.Specifically, we have developed cycloaddition reactions that give molecules that closely resemble alkaloid natural products with medicinal value. We anticipate that such cycloadducts will be useful for modulation of novel biological targets and may have direct value for development of future agrochemicals and pharmaceuticals. The broad utility of this synthesis therefore offers lasting economic and scientific value from its application in future.Molecules with specific symmetry, or handedness, are very important for obtaining selective pharmaceutical molecules. There are no examples of an asymmetric version of the proposed cycloaddition reactions, thus we have set out to investigate and invent reactions that efficiently deliver cycloadducts as individual stereoisomers.We plan to showcase these new, powerful reactions by completing a very concise synthesis of a complex alkaloid natural product called securinine. Essentially, we plan to break the record for efficient production of this alkaloid. Securinine is particularly interesting because it has been reported to cause selective controlled shut-down (apoptosis) of colon cancer cells. A reliable, high yielding route to analogues may help identification of the biological pathway by which this compound works and ultimately inform future discovery of novel therapies for the treatment of cancer.This proposal will generate know-how that can be easily transferred to high value industries and will train the next generation of innovators in this vital economic sector.