Intramolecular Aryne Cycloadditions and Rearrangements

描述（由申请人提供）：本提案的长期目标是了解导致各种类型的有趣和新颖的分子内芳炔环加成（IMAC）和重排的结构、电子、构象和空间参数，并将这些过程开发成用于构建复杂和重要天然产物的强大应用程序集。为了实现这些目标，我们将设计，合成和研究各种系统，导致一些重要类别的IMAC，如[4+2]，[2+2]和[2+2]与重排，II型[4+2]和烯反应流形。除了我们自己的工作外，文献中只报道了另外六个分子内芳炔环加成化学的例子，所有这些都局限于[4+2]反应流形，然后只与芳族二烯反应。因此，探索这一系列反应的必要性是迫切的，具有很高的学术价值。我们将研究这些环加成流形从合成以及机械的角度。值得注意的是，我们认为这一建议代表了有史以来第一次系统地尝试评估的全面反应概况的芳基就其分子内环加成行为。此外，这些过程有可能产生新的和令人兴奋的结构基序，这将是困难的或不可能通过现有的技术和方法制备。本研究将为芳炔环加成化学的理解提供重要基础并做出重大贡献。我们发表的和初步的研究[4+2]，串联[2+2]环加成重排，烯过程清楚地表明，除其他外，概念的证明和内在价值，进一步追求这条研究路线。我们还将合成选择性胆碱酯酶抑制剂加兰他敏，作为分子内芳炔环加成化学在构建各种复杂和结构多样的天然产物中的合成潜力的示范。

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.