Catalyst- and Reagent-Guided Selective Alkyl C-H Bond Functionalization

催化剂和试剂引导的选择性烷基 C-H 键官能化

• 批准号: 10607409
• 负责人: Kyan Anthony D'Angelo
• 金额: $ 6.91万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2026-02-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607409
• 关键词: Alcohols; Amides; Binding; Binding Sites; Boranes; Carbon; Complex; Development; Disease; Docking; Elements; Evaluation; Exhibits; Family; Goals; Hydrogen Bonding; Intuition; Iridium; Laboratories; Lead; Ligand Binding; Ligands; Medicine; Mentors; Metabolism; Methods; Modification; Organic Synthesis; Positioning Attribute; Property; Reaction; Reagent; Research; Route; Scientist; Site; Solubility; Structure; Technology; Testing; Time; Transition Elements; Work; catalyst; clinical candidate; design; diborane; experimental study; functional group; human disease; improved; innovation; lead optimization; method development; preference; programs; three dimensional structure

PROJECT SUMMARY Identifying just one new clinical candidate for the treatment of human disease usually requires the design, synthesis, testing, and redesign of thousands upon thousands of organic compounds. Improvements to synthetic technologies therefore have a major impact on the time required to identify clinical candidates by maximizing the number of compounds that can be accessed from a single precursor. In particular, adjusting key properties such as bioactivity, solubility, metabolism, and stability are best accomplished by methods that are capable of preparing a wide variety of new compounds with a minimal number of steps. Late-stage functionalization of carbon-hydrogen bonds offers medicinal chemists this coveted opportunity by facilitating the introduction of numerous types of functional groups into a given lead structure. Recent efforts have demonstrated that transition- metal catalysts can enable the diverse functionalization of strong alkyl C–H bonds within organic compounds via the intermediacy of an organoboron compound. However, methods to achieve control over the site- and stereoselectivity of alkyl C–H bond functionalization are limited by their strength and ubiquity in complex molecules. The proposed research focuses on the development of a broadly applicable strategy to achieve selectivity in the functionalization of C(sp3)–H bonds that is independent of inherent substrate preferences. The impact of this work is to enable practitioners to make precise structural edits to bioactive compounds without lengthy synthetic manipulation. The proposed approach converts a major challenge in complex molecule functionalization, the presence of potentially intervening groups, into an opportunity to localize reactivity of a transition metal catalyst to convert specific C–H bonds into C–B bonds. Specifically, the proposed research will create catalysts and reagents that bind an existing polar functional group, such an alcohol or amide, thereby guiding functionalization to an adjacent site. Synthetic routes are presented to access a suite of catalysts and reagents. In conjunction with experiments to evaluate their suitably for guided functionalization, they will be refined iteratively for application to target structures. Subsequent studies of the functionalization of complex, biologically active compounds will demonstrate the applicability and generality of the proposed method to lead optimization. To control stereoselectivity, a key consideration in alkyl C–H bond functionalization, chiral diborane reagents derived from readily available precursors will be employed. By differentiating the energies of diastereomeric intermediates and transition states en route to the alkylboronate products, new derivatives can be accessed with well-defined three-dimensional structures. An integrated component of the proposed research program are mechanistic experiments that will form the basis of informed improvements to the overall approach, as defined by metrics that include reaction efficiency, site-selectivity, and stereo-selectivity. Achieving the specific aims of the proposed research will expand the opportunities available to scientists to make precise edits to complex organic compounds at alkyl C–H bonds, facilitating access to new bioactive compounds.

项目摘要 仅确定一个新的治疗人类疾病的临床候选者通常需要设计， 成千上万的有机化合物的合成，测试和重新设计。改进合成 因此，技术对确定临床候选者所需的时间有重大影响 可以从单个前体访问的化合物数量。特别是，调整关键属性这样 作为生物活性，可溶性，代谢和稳定性，最好通过能够的方法来完成 准备各种新化合物，并以最少的步骤数量。后期功能 碳 - 氢键通过促进引入的碳质化学家这个令人垂涎的机会 多种类型的官能团成到给定的铅结构中。最近的努力表明了过渡 - 金属催化剂可以通过有机化合物中强烷基C -H键的潜水功能化。 有机体化合物的中间体。但是，实现对站点和地点的控制的方法 烷基C – H键功能化的立体选择性受复合物中的强度和无处不在的限制 分子。拟议的研究重点是制定广泛适用的策略以实现 与继承底物偏好无关的C（SP3） - H键功能化的选择性。这 这项工作的影响是使从业人员能够精确的结构编辑，以便没有生物活性化合物 冗长的合成操作。提出的方法转化了复杂分子的重大挑战 功能化，潜在的干预组的存在，成为一个本地化反应性的机会 过渡金属催化剂将特定的C -H键转换为C – B键。具体而言，拟议的研究将 创建结合现有极性功能组（例如酒精或酰胺）的催化剂和试剂，从而 指导功能化到相邻站点。提出合成路线以获取一套催化剂和 试剂。结合实验以评估其适当的指导功能化，它们将是 迭代以迭代为目标结构。随后研究复合物的功能化， 生物活性化合物将证明所提出的方法的适用性和一般性 优化。为了控制立体选择性，烷基C -H键功能化的关键考虑因素 将采用源自可用的前体的试剂。通过区分 非对映异构体中间体和过渡状态在到达烷基硼酸酯产品的途中，新的衍生物可以 使用明确的三维结构访问。拟议研究的综合组成部分 程序是机械实验，将构成对整体方法的明智改进的基础， 由包括反应效率，位点选择性和立体定义的指标定义。实现 拟议研究的具体目标将扩大科学家可用的机会进行精确编辑 在烷基C – H键处进行复杂的有机化合物，以支持获得新的生物活性化合物。