Innovative Transformations of Fundamental Synthetic Building Blocks

项目摘要：化学合成在健康相关研究中的价值与以下能力密切相关 从容易获得的材料中高效地产生药剂。此Mira应用程序寻求合并 NIGMS资助的两个生产性项目，重点是开发创新的综合转型 基本的构建块。该计划的长期目标是确定有希望的新模式 化学反应性促进生物医学小分子的快速发现和发展 申请。此应用程序的总体目标是开发一组不同的启用转换 使用未活化的脂肪族C-H键或烷基亲电体。脂肪族化合物的位置选择性转化 C-H键在简化药物合成和加快获得新的类似物方面具有巨大的前景 通过后期官能化的生物相关化合物。尽管有这种潜力，但很少有分子间C-H 准备价值的功能化是存在的。我们寻求开发实用的分子间脂肪族C-H 引入多种化学官能团并具有高水平的位置选择性的官能化。 这项研究是基于这样一个假设，即自由基介导的分子间C-H官能化提供了 与替代方法相比，具有更高的部位选择性和化学选择性的潜力，使 新的、通用的C-H变换的发展。我们的方法将涉及识别新的N- 功能化试剂以及光氧化还原催化中的创新途径，以解锁一系列不同的 有价值的，目前无法使用杂原子为中心的自由基的C-H变换。 另一个主要目标是开发过渡金属催化的立体选择性结构过程 C-C债券，否则将是具有挑战性的。除了少数例外，使用未激活的 在催化的C-C键形成反应中，烷基卤化物涉及活性自由基中间体。这一限制 防止在立体选择性的C-C键形成反应中使用烷基卤化物，该反应将使药物流线化 合成并提供获得具有医学价值的功能化小分子的途径。我们寻求建立 非活化烷基立体选择性直接偶联金属催化新范式 亲电剂和广泛使用的化学原料。我们假设烷基的双电子活化 亲电性将解锁一系列立体选择性的C-C结构。我们的目标包括发展 未活化烷基的立体专一性、羰化转化和立体选择性碳环化反应 亲电者。拟议研究的基本原理是，产生的实际和选择性反应将 便于获得各种具有合成和药用价值的小分子。我们建议的研究是 创新是因为它涉及未被充分利用的化学反应模式，以产生新的、强大的键- 形成反应。这些贡献意义重大，因为它们将为 新一代生物活性天然产物和医药制剂的发现和开发。

Project Summary: The value of chemical synthesis in health-related research is closely tied to the ability to efficiently generate medicinal agents from readily available materials. This MIRA application seeks to merge two productive NIGMS-funded projects centered on the development of innovative synthetic transformations of fundamental building blocks. The long-term goal of this program is to identify promising new modes of chemical reactivity to facilitate the rapid discovery and development of small molecules for biomedical applications. The overall objective of this application is to develop a diverse set of enabling transformations using either unactivated aliphatic C–H bonds or alkyl electrophiles. Site-selective transformations of aliphatic C–H bonds hold enormous promise in streamlining drug synthesis and expediting access to novel analogs of biologically relevant compounds via late-stage functionalization. Despite this potential, few intermolecular C–H functionalizations of preparative value exist. We seek to develop practical, intermolecular aliphatic C–H functionalizations that introduce diverse chemical functionality and proceed with high levels of site selectivity. This research is based on the hypothesis that radical-mediated intermolecular C–H functionalizations offer the potential for superior site selectivities and chemoselectivities as compared to alternative approaches, enabling the development of new, general C–H transformations. Our approach will involve the identification of new N- functionalized reagents as well as innovative pathways in photoredox catalysis to unlock a diverse set of valuable, currently inaccessible C–H transformations using heteroatom-centered radicals. Another major goal is to develop transition metal catalyzed processes for the stereoselective construction of C–C bonds that would otherwise be challenging to accomplish. With few exceptions, the use of unactivated alkyl halides in catalytic C–C bond-forming reactions involves reactive radical intermediates. This limitation prevents the use of alkyl halides in stereoselective C–C bond-forming reactions that would streamline drug synthesis and provide access to medicinally valuable, functionalized small molecules. We seek to establish new paradigms in metal catalysis that enable the stereoselective direct coupling of unactivated alkyl electrophiles and widely available chemical feedstocks. We hypothesize that two-electron activation of alkyl electrophiles will unlock a range of stereoselective C–C constructions. Our objectives include the development of stereospecific, carbonylative transformations and stereoselective carbocyclizations of unactivated alkyl electrophiles. The rationale of the proposed research is that the practical and selective reactions produced will facilitate access to diverse synthetically and medicinally valuable small molecules. Our proposed research is innovative because it involves underutilized modes of chemical reactivity to generate new, powerful bond- forming reactions. These contributions are significant because they will offer a range of transformations for the discovery and development of next generation, biologically active natural products and medicinal agents.