Bond-Forming Methods via Dual-Metal Catalysis with Organogold Intermediates

描述（由申请人提供）：从简单的结构单元快速有效地构建复杂分子是一种基本需求。该计划的长期目标是通过有机金中间体的双金属催化，从容易获得的起始材料构建此类分子。这种双重催化策略的价值在于，它减少了所需的合成步骤的数量，同时还提供了新的合成键断开和独特的化学选择性和区域选择性。因此，这种策略大大丰富了药物开发中可用的键形成策略的工具包。这种方法是创新的，因为它结合了金催化剂重新排列和活化底物的能力，以及其他金属催化剂形成新键的选择性。这种方法的基本原理是证明了金和钯的协同催化作用，PI通过该催化作用建立了这些双催化方法在构建丁烯内酯、异香豆素和含氮杂环（三类具有已知生物活性的分子）中的合成潜力。这一概念首先将应用于在一个合成转化中构建碳-氧键和碳-碳键的反应，以合成其他生物相关的杂环。这种策略是有效的，因为它不 需要单独的合成制备和化学计量的有机金属试剂的操作;相反，反应性化合物在原位产生，允许更快和更经济地开发药物靶点。一旦这种策略通过其应用于含氧杂环得到证明，我们将应用它来开发各种其他重要的双催化反应。预计将产生以下预期结果：首先，反应的独特键断和化学选择性预计将提供通过传统途径不易获得的生物活性化合物。第二，双催化途径有望通过消除对化学计量的有机金属试剂的单独合成制备的需要来提高用于治疗人类疾病的治疗剂的合成效率。这些结果预计将产生重要的积极影响，因为它们显着加快药物发现的同时，不需要的化学废物副产品被最小化。随着化学生物学的进步不断刺激新的治疗靶点的发现，这种通过双重催化快速有效地组装复杂分子的能力将确保及时开发新药，造福人类健康。 公共卫生相关性：从拟议的研究中产生的新的催化方法将提供从简单的构建块到生物活性化合物的有效途径，大大促进这些化合物的制备用于药物发现。这些候选药物的可获得性增加将允许快速开发改善人类健康的化合物。

DESCRIPTION (provided by applicant): There is a fundamental need to rapidly and efficiently build complex molecules from simple building blocks. The long-term goal of this program is to construct such molecules from readily accessible starting materials through dual-metal catalysis with organo Gold intermediates. The value of this dual-catalytic strategy is that it reduces the number of synthetic steps required, while also giving access to new synthetic bond disconnections and unique chemo- and regioselectivities. This strategy therefore substantially enriches the toolkit of bond- forming strategies available in pharmaceutical development. This approach is innovative because it combines the power of gold catalysts to rearrange and activate substrates with the selectivity of other metal catalysts to form new bonds. The rationale for this approach is the demonstrated cooperative catalysis of gold and palladium, through which the PI established the synthetic potential of these dual-catalytic methods in the construction of butenolides, isocoumarins, and nitrogen-containing heterocycles, three classes of molecules with known biological activity. This concept first will be applied to reactions that construct carbon-oxygen and carbon-carbon bonds in one synthetic transformation in order to synthesize other biologically relevant heterocycles. This strategy is efficient because it does not require the separate synthetic preparation and manipulation of a stoichiometric organometallic reagent; instead, the reactive compounds are generated in situ, allowing for faster and more economical development of pharmaceutical targets. Once this strategy is demonstrated through its application to oxygen-containing heterocycles, we will apply it to develop a variety of other significant dual-catalyzed reactions. The following expected outcomes are anticipated: First, the unique bond disconnections and chemoselectivities of the reactions are expected to provide access to biologically active compounds not easily available through traditional pathways. Second, the dual-catalytic pathways are expected to increase the efficiency of the synthesis of therapeutic agents used to treat human disease by removing the need for separate synthetic preparation of stoichiometric organometallic reagents. These outcomes are expected to have an important positive impact because they significantly expedite drug discovery at the same time that undesired chemical waste byproducts are minimized. As advances in chemical biology continue to spur the identification of new therapeutic targets, this ability to quickly and efficietly assemble complex molecules through dual catalysis will ensure the timely development of new pharmaceuticals for the benefit of human health. PUBLIC HEALTH RELEVANCE: The new catalytic methods that will result from the proposed research will provide efficient routes from simple building blocks to biologically active compounds, significantly facilitating the preparation of these compounds for drug discovery. The increased accessibility of these pharmaceutical candidates will permit the rapid development of compounds that improve human health.