Selective C(sp3)-H Oxidations and Functionalizations with Tunable Metal Catalysts for Synthesis

使用可调金属催化剂进行选择性 C(sp3)-H 氧化和官能化合成

• 批准号: 9918921
• 负责人: Maria White
• 金额: $ 50.09万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918921
• 关键词: Alkylation; Amination; Biological; Carbon; Chemicals; Complex; Coupling; Development; Effectiveness; Foundations; Goals; Hydrocarbons; Hydrogen Bonding; Hydroxylation; Iron; Manganese; Mediating; Medicine; Metals; Methods; Molecular Structure; Natural Products; Nature; Nitrogen; Organic Synthesis; Oxides; Oxygen; Palladium; Pharmaceutical Preparations; Pharmacologic Substance; Reaction; Scientist; Site; Source; Structure; Sulfoxide; System; Therapeutic; Transition Elements; base; biological research; catalyst; drug candidate; drug discovery; functional group; metal complex; novel; oxidation; physical property; programs; scaffold; small molecule; tool

Project Summary The biological activity of organic molecules is strongly impacted by the oxygen, nitrogen and carbon functional groups on their hydrocarbon scaffolds. Classically, the practice of organic synthesis has focused on building these scaffolds while concurrently introducing this functionality. We hypothesized that, analogous to nature, a late stage oxidation strategy, i.e., direct introduction of oxidized functionality into C(sp3)-H bonds of molecule scaffolds, would provide opportunities to diversify molecular structures and streamline syntheses. Our preliminary studies using novel transition metal catalysts have validated late stage C-H oxidation as a powerful approach for streamlining synthetic sequences and directly diversifying natural products and other complex structures. Building on this strong foundation, we plan to discover new catalysts to expand the scope of C(sp3)-H functionalizations possible. These reactions will broaden the functionality that can be introduced, sites that can be accessed, and classes of natural products and medicinal compounds that can be derivatized and synthesized. The key to our approach is to develop transition metal catalysts that mediate C(sp3)-H bond cleavage and functionalization, enabling tunable control over reactivity, as well as site-, chemo-, and stereoselectivity. We have discovered and commercialized palladium/sulfoxide catalysts for allylic C-H functionalizations, iron catalysts for aliphatic C-H hydroxylations, and manganese catalysts for intramolecular C(sp3)-H aminations. These catalysts proceed with unprecedented levels of reactivity and tunable selectivities in complex molecule settings, without the need for directing groups. These reactions and the late stage derivatization approach have already begun to be utilized by pharmaceutical companies in drug discovery and metabolite identification. The major challenges in the application of this strategy as a comprehensive C(sp3)-H functionalization approach to enable drug discovery are the development of new intermolecular methods and the expanded capacity for site-, chemo-, and stereoselectivities. To overcome these challenges, we will develop 1) new palladium/sulfoxide complexes for catalyst-controlled asymmetric induction and complex fragment couplings; 2) new base metal complexes for aliphatic C-H hydroxylations that proceed with alternate catalyst-controlled, predictable site selectivities and increased tolerance of π-systems and nitrogen-containing compounds; and 3) new base metal complexes for intra- and intermolecular C-H amination and alkylations. Analogous to the impact of cross-coupling methods on C(sp2)-C(sp2) bond formation in drug discovery, these reactions will ultimately empower scientists to form C(sp3)-O, -N, and -C bonds from ubiquitous C(sp3)-H bonds in complex molecule scaffolds. This will reinvigorate efforts to explore natural products and other complex molecules as sources of medicines and biological research tools.

项目概要 有机分子的生物活性受到氧、氮和碳的强烈影响 其碳氢化合物支架上的官能团。传统上，有机合成的实践集中于 构建这些脚手架，同时引入此功能。我们假设，类似于 本质上，后期氧化策略，即将氧化官能团直接引入到C(sp3)-H键中 分子支架，将为分子结构多样化和简化合成提供机会。 我们使用新型过渡金属催化剂的初步研究已经验证了后期 C-H 氧化作为一种 简化合成序列并直接使天然产物和其他产品多样化的强大方法 复杂的结构。在此坚实的基础上，我们计划发现新的催化剂来扩大范围 C(sp3)-H 功能化成为可能。这些反应将扩大可以引入的功能， 可访问的站点以及可衍生的天然产物和药物化合物的类别 并合成。 我们方法的关键是开发介导 C(sp3)-H 键断裂的过渡金属催化剂 和功能化，实现对反应性以及位点、化学和立体选择性的可调控制。 我们发现并商业化了用于烯丙基 C-H 官能化、铁 用于脂肪族 C-H 羟基化的催化剂，以及用于分子内 C(sp3)-H 胺化的锰催化剂。 这些催化剂在复杂分子中具有前所未有的反应活性和可调选择性 设置，无需指导组。这些反应和后期衍生化方法 制药公司已经开始将其用于药物发现和代谢物鉴定。 应用该策略作为全面的 C(sp3)-H 功能化的主要挑战 实现药物发现的方法是开发新的分子间方法和扩展 位点、化学和立体选择性的能力。为了克服这些挑战，我们将开发 1) 新的 用于催化剂控制的不对称诱导和复杂片段偶联的钯/亚砜络合物； 2）用于脂肪族C-H羟基化的新型贱金属配合物，采用交替催化剂控制进行， 可预测的位点选择性和增强的 π 系统和含氮化合物的耐受性；和 3) 用于分子内和分子间 C-H 胺化和烷基化的新型贱金属配合物。类似于 药物发现中交叉偶联方法对 C(sp2)-C(sp2) 键形成的影响，这些反应将 最终使科学家能够从复合物中普遍存在的 C(sp3)-H 键形成 C(sp3)-O、-N 和 -C 键 分子支架。这将重振探索天然产物和其他复杂分子的努力 药物和生物研究工具的来源。