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

描述(由申请人提供)：从简单的构建块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这样的分子。这种双催化策略的价值在于它减少了所需的合成步骤，同时还提供了新的合成键断开以及独特的化学和区域选择性。因此，这一策略大大丰富了药物开发中可用的成键策略工具包。这种方法是创新的，因为它将金催化剂重新排列和激活底物的能力与其他金属催化剂的选择性结合在一起，形成新的键。这种方法的基本原理是金和钯的协同催化，PI通过这种双催化方法建立了构建丁烯内酯、异香豆素和含氮杂环的合成潜力，这三类分子具有已知的生物活性。这一概念首先将应用于在一次合成转化中构建碳-氧和碳-碳键的反应，以合成其他生物相关的杂环。这一策略是有效的，因为它没有 需要单独的化学计量有机金属试剂的合成制备和操作；取而代之的是，反应性化合物在现场产生，从而允许更快和更经济地开发药物靶标。一旦这一策略通过对含氧杂环的应用得到证明，我们将应用它来开发其他各种重要的双催化反应。预计将出现以下预期结果：首先，这些反应独特的键断开和化学选择性有望提供通过传统途径不易获得的生物活性化合物。其次，双催化途径有望通过消除单独合成化学计量比有机金属试剂的需要，提高用于治疗人类疾病的治疗剂的合成效率。预计这些结果将产生重要的积极影响，因为它们大大加快了药物发现的速度，同时最大限度地减少了不受欢迎的化学废物副产品。随着化学生物学的进步继续推动新的治疗靶点的确定，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的药物，造福人类健康。

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.