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 构建富含sp3（即高度三维）有机分子的一般方法的发展 支架是有机合成中的一个长期挑战。高sp3特性赋予有益的生物学特性 活性和药代动力学特性，但由于其复杂性， 相对于富含SP2的化合物，化合物在用于药物发现的文库中代表性不足。过渡金属 催化已经彻底改变了富含sp2的有机支架的构建，产生了一系列通用的 这些转化允许容易地合成用于开发的化合物类似物的不同文库。 新的小分子治疗剂。建立类似的合成富含sp3的有机物的通用方法 从简单的起始材料的支架，催化的创新是必要的。本文提出的研究 采用创新的配体和催化剂设计作为一种手段，发现新的和一般的支架建设 可以将简单的起始材料（即烯烃、二烯烃、芳烃）转化为官能和 结构复杂的产品。在一个领域，我们正在开发非传统的配体平台， 用于开发烯烃碳官能化的Pd催化剂的配体空间的填充不足区域 反应.我们已经发现衍生自脲的配体，其占据小的有机配体区域， 膦和N-杂环卡宾，有效地促进杂环化反应， 亲两性物和二烯。此外，具有非常规空间分布的膦配体可以发挥配体控制作用 与二烯杂环化的位点选择性相比。这一领域今后的工作将侧重于扩大这些领域， 研究结果开发了一种统一的合成方法来制备不同的脂肪族杂环，以及选择性， 烯烃的多组分碳官能化反应。这些方法的发展将能够 通过合理的配体设计和计算机辅助的配体发现。在另一个领域，我们正在建立 铜-二胺络合物作为氧化自由基加成反应的通用催化剂。我们反应的中心 设计是将Cu催化剂配位到基底上，这促进了反应性自由基的选择性产生 可以加成到烯烃和芳烃的中间体。利用这种方法，我们发现了一种有氧氨基- 内烯烃的氧化，其与不同的芳基取代的烯烃接合并在温和的 条件设计增强Cu的氧化电位并促进与底物配位的配体 将能够发现氧化自由基烯烃加成反应中的新催化反应性，并提供了一种 高对映选择性转化的发展框架。这些反应将使快速 构建多种功能基序和环状支架，具有优异的催化剂对化学选择性的控制 和立体选择性。总的来说，拟议的研究计划将导致多功能催化剂的发展， 用于有效制备与发现具有以下特征的化合物相关的功能分子的方法 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。