Synthesis of Complex Molecular Architectures Using Strategic 1,4-Sigmatropic Rearrangements

点击翻译按钮获取中文摘要

Organic synthesis plays an essential role in the fine chemical, agrochemical, and pharmaceutical industries. The synthesis of molecules containing multiple stereocenters in close proximity is one of the major challenges in synthetic chemistry and many classes of biologically important natural products contain stereocenters. One strategy to rapidly access these complex frameworks is through "one-pot" tandem reactions - where the product of one reaction is the substrate for the next transformation. Research in the Derksen group is focused on developing asymmetric, tandem reactions that incorporate a 1,4-sigmatropic rearrangement (1,4-SR). We have recently discovered a synthetic strategy to access important biologically active terpene natural product frameworks using a tandem photo-cyclization/1,4-SR reaction process. This work has shown that solvent effects and even the wavelength of light used to initiate the reaction play an important role in the overall yield of targeted terpene frameworks and the formation of byproducts. This research proposal aims to advance the utility of this process by identifying novel strategies of controlling the regio- and stereoselectivity of the 1,4-SR using substrate control as well as catalytic methods - reducing the overall number of steps and the cost of synthesis. This proposal also aims to expand the substrate scope of the tandem cyclization/1,4-SR process by completing systematic evaluations of ring sizes, heteroatoms, and substituents that are compatible with the reaction. A clear understanding of the factors that dictate reaction selectivity will provide a powerful tool for use of this methodology in complex molecule synthesis. Although the 1,4-SR is known in the literature, it has been underutilized due to challenges in controlling regio- and stereoselectivity. The proposed research program improves on existing methods in the literature by developing new ways to control product selectivity, improve yields, and to expand the substrate scope of tandem 1,4-SR reactions. With the knowledge of how to control the tandem 1,4-SR selectivity, the Derksen group has demonstrated that a common intermediate can be used to synthesize the framework of three classes sesquiterpene natural products - the cubebane, sprioaxane, and most importantly, the guaiane sesquiterpenes. With the diverse array of bioactivity reported for these natural products, including anticancer, antifungal, and as antiinflammatory agents, the work described in this proposal will not only impact the synthetic chemistry community, but will also provide valuable materials for biologists eager to understand how these compounds interact with their natural receptors. The skills developed by students within this research program will provide highly-trained chemists for the Canadian workforce who are comfortable engaging in complex, interdisciplinary research challenges.