Chemo-Divergent Cationic Cascades for the Synthesis of Biologically Active Alkaloids

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Project Summary: Alkaloids are an important class of nitrogen-containing, low-molecular weight compounds that are ubiquitous in plants.1 These compounds exhibit a wide range of pharmacological activities; ranging from antineoplastics (like noscapine) to analgesics (like morphine), or stimulants (like caffeine, or nicotine).2 Given their medicinal properties, the development of new methodologies that give access to libraries of new and complex alkaloids will aid in drug discovery efforts. In addition, the newly developed strategies will represent novel synthetic disconnections, which will facilitate the efficient synthesis of natural products and drug targets. This proposal will provide a facile and efficient route for the synthesis of structurally complex alkaloids from simple and inexpensive starting materials. One of the projects uses a halide-trapped aza-Prins cyclization to form a nitrogen-containing heterocycle with vinyl halide functional handle. These products can be ionized to give a series of structurally interesting products, depending on the reaction conditions and substrate design. The second project involves an intramolecular, π-trapped aza-Prins cyclization, giving access to two new rings and a new stereocenter in a one pot process. This chemistry is attractive for asymmetric studies using chiral thioureas to obtain enantioenriched products. This would be the first example of an enantioselective, alkynyl Prins cyclization. Synthesized libraries of compounds will be analyzed using online cheminformatics tools to determine which operationally simple transformations can be performed to increase the potential for bioactivity in our substrates. These modified substrates will be submitted to a number of high throughput screening centers for testing against various cancer cell lines, as well as used in collaborations with the University of Rochester Medical Center.