Discovering catalytic strategies for transition metal-catalyzed reactions to construct topologically complex organic scaffolds

发现过渡金属催化反应的催化策略以构建拓扑复杂的有机支架

• 批准号: 10714006
• 负责人: Shauna M Paradine
• 金额: $ 31.82万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714006
• 关键词: 3-Dimensional; Aerobic; Alkenes; Area; Biological; Carbon; Catalysis; Chemicals; Complex; Development; Diamines; Drug Kinetics; Future; Generations; Health; Human; Libraries; Ligands; Methodology; Methods; Organic Synthesis; Periodicity; Phosphines; Preparation; Property; Reaction; Research; Science; Site; Therapeutic; Transition Elements; Urea; Work; analog; carbene; catalyst; design; diene; drug discovery; human disease; innovation; invention; new technology; novel; programs; scaffold; small molecule; small molecule therapeutics

PROJECT SUMMARY The development of general methods for the construction of sp3-rich (i.e. highly three-dimensional) organic scaffolds is a longstanding challenge in organic synthesis. High sp3 character imparts beneficial biological activities and pharmacokinetic properties into organic molecules, but because of their complexity, such compounds are underrepresented in libraries for drug discovery relative to sp2-rich compounds. Transition metal catalysis has revolutionized the construction of sp2-rich organic scaffolds, producing an array of general transformations that allow for the facile synthesis of diverse libraries of compound analogues for developing novel small molecule therapeutics. To establish similarly versatile methods for synthesizing sp3-rich organic scaffolds from simple starting materials, innovations in catalysis are needed. The research proposed herein employs innovative ligand and catalyst design as a means to discover novel and general scaffold-building methodologies that can transform simple starting materials (i.e. alkenes, dienes, arenes) into functionally and structurally complex products. In one area, we are developing unconventional ligand platforms that occupy underpopulated regions of ligand space for Pd catalysis for the development of olefin carbofunctionalization reactions. We have found that ligands derived from urea, which occupy a region of small organic ligands that is inaccessible to phosphines and N-heterocyclic carbenes, effectively promote heteroannulation reactions of ambiphiles and dienes. In addition, phosphine ligands with unconventional steric profiles can exert ligand control over site-selectivity for heteroannulations with dienes. Future work in this area will focus on expanding on these findings to develop a unified synthetic approach to preparing diverse aliphatic heterocycles, as well as selective, multicomponent carbofunctionalization reactions of olefins. These methodological developments will be enabled by both rational ligand design and computationally-aided ligand discovery. In another area, we are establishing Cu-diamine complexes as general catalysts for oxidative, radical addition reactions. Central to our reaction design is coordinating Cu catalysts to the substrate, which promotes selective generation of reactive radical intermediates that can add to olefins and arenes. Using this approach, we have discovered an aerobic amino- oxygenation of internal alkenes that engages diverse aryl-substituted alkenes and operates under mild conditions. Designing ligands that enhance the oxidative potential of Cu and facilitate coordination to substrates will enable the discovery of new catalytic reactivity in oxidative, radical olefin addition reactions, and provides a framework for the development of highly enantioselective transformations. These reactions will enable the rapid construction of diverse functional motifs and cyclic scaffolds with excellent catalyst control over chemoselectivity and stereoselectivity. In total, the proposed research program will result in the development of versatile catalytic methods for the efficient preparation of functional molecules that are relevant for discovering compounds with therapeutic potential, and thus will have a significant impact on biomedical sciences and human health.

项目摘要 开发用于构建SP3丰富（即高三维）有机物的一般方法 脚手架是有机合成的长期挑战。高SP3特征赋予有益的生物学 活性和药代动力学特性是有机分子的，但由于其复杂性，这种特性 相对于SP2富化合物的药物发现的库中，化合物的代表性不足。过渡金属 催化彻底改变了SP2丰富的有机脚手架的构建，产生了一系列一般 转换允许易于合成复合类似物的不同库 新颖的小分子疗法。建立类似用途的方法来合成富含SP3的有机物 需要简单的起始材料的脚手架，需要催化中的创新。本文提出的研究 采用创新的配体和催化剂设计作为发现新颖和一般脚手架建造的手段 可以将简单的起始材料（即烷烃，二烯，领域）转化为功能和功能和 结构复杂的产品。在一个领域，我们正在开发占据的非常规配体平台 PD催化的配体空间较低的区域，用于开发烯烃碳功能化 反应。我们发现源自尿素的配体占据了一个小的有机配体区域 无法访问磷和N杂环碳烯，有效地促进 炮弹和迪恩斯。此外，具有非常规空间剖面的磷酸配体可以发挥配体控制 超过二烯异质的场地选择性。该领域的未来工作将重点扩展这些 开发统一合成方法来制备各种脂肪族异环的发现以及选择性 烯烃的多组分功能功能化反应。这些方法论的发展将启用 通过理性配体设计和计算辅助配体发现。在另一个领域，我们正在建立 Cu-二胺复合物作为氧化，自由基添加反应的一般催化剂。我们反应的中心 设计将CU催化剂配合到基板，该催化剂促进了反应性自由基的选择性生成 可以增加烯烃和竞技场的中间体。使用这种方法，我们发现了有氧氨基 内部烷烃的氧合能与各种芳基取代的烯烃与轻度下运行 状况。设计配体可增强Cu的氧化潜力并促进底物的配位 将在氧化，自由基烯烃添加反应中发现新的催化反应性，并提供 发展高度对映选择性转换的框架。这些反应将使快速 构建具有极好的催化剂控制化学选择性的各种功能基序和循环支架 和立体选择性。总共提出的研究计划将导致多功能催化的发展 有效制备功能分子的方法，该功能分子与发现化合物有关 治疗潜力，因此将对生物医学科学和人类健康产生重大影响。