Intramolecular Aryne Cycloadditions and Rearrangements

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DESCRIPTION (provided by applicant): The long term goals of this proposal are to understand the structural, electronic, conformational and steric parameters that lead to the various types of interesting and novel intramolecular aryne cycloadditions (IMACs) and rearrangements, and to develop these processes into a powerful set of applications for the construction of complex and important natural products. To accomplish these goals we will design, synthesize and investigate various systems that lead to some of the important classes of IMACs such as the [4+2], [2+2] and [2+2] with rearrangement, Type II [4+2], and ene reaction manifolds. With the exception of our own work just six other examples of intramolecular aryne cycloaddition chemistry have been reported in the literature, and all of these have been limited to the [4+2] reaction manifold and then only with aromatic dienes. The need to explore this suite of reactions is therefore compelling and of high intellectual merit. We will examine these cycloaddition manifolds from both synthetic as well as mechanistic perspectives. Significantly, we believe this proposal represents the first ever systematic attempt to assess the comprehensive reaction profile of arynes with respect to their intramolecular cycloaddition behavior. Moreover, these processes have the potential to generate new and exciting structural motifs that would be difficult or impossible to prepare by existing technologies and methods. This study will provide an important foundation and contribute significantly to the understanding of aryne cycloaddition chemistry. Our published and preliminary studies with respect to the [4+2], tandem [2+2]cycloaddition-rearrangement, and ene processes clearly demonstrate, inter alia, the proof of concept and the intrinsic value of pursuing this line of research further. We will also synthesize the selective cholinesterase inhibitor galanthamine as a demonstration of the synthetic potential of intramolecular aryne cycloaddition chemistry in the construction of a wide range of complex and architecturally diverse natural products.