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: 10330708
• 负责人: Maria White
• 金额: $ 54.95万
• 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 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330708
• 关键词: 3-Dimensional; Alcohols; Alkylation; Amination; Area; Biological; Biological Process; Carbon; Chemistry; Communities; Complex; Coupling; Foundations; Hydrocarbons; Hydrogen Bonding; Individual; Industrialization; Iron; Ligands; Manganese; Metals; Natural Products; Outcome; Oxides; Palladium; Pharmaceutical Preparations; Preparation; Process; Property; Reaction; Site; Sulfoxide; Therapeutic; Work; base; catalyst; chemical synthesis; drug candidate; drug discovery; functional group; innovation; metal complex; novel; oxidation; phthalocyanine; physical property; programs; scaffold; small molecule

PI, White, M.C.    R35 GM 122525    1  Project Summary 2  3  The atomistic change of C(sp3)–H to C(sp3)–O, –N, or –C can profoundly impact the biological function and 4  physical properties of small molecules. Traditionally, introducing these functionalities relies on functional group 5  transformations from pre-oxidized carbon-heteroatom precursors. This approach limits the direct installation of new 6  functionality into complex molecules, often necessitating de novo synthesis that is impractical for rapid exploration of 7  biological function. Our proposal aims to provide selective C(sp3)–H functionalization reactions that install O, N and 8  C in the hydrocarbon scaffold of complex molecules. This will enable late-stage functionalizations that expedite drug 9  discovery processes, streamline total syntheses, and empower exploration of natural products as drug candidates. 10  Our group has shown that C(sp3)–H bonds in complex molecules can be distinguished based on their 11  electronic, steric, and stereoelectronic properties, resulting in a paradigm shift within the chemistry community that 12  prior to 2007 viewed aliphatic C–H bonds as preparatively indistinguishable. To do this, we have discovered and 13  commercialized iron and manganese PDP-based catalysts for C(sp3)–H oxidations; palladium(II)/sulfoxide catalysts 14  for allylic C–H functionalization; and manganese phthalocyanine catalysts for both intra- and intermolecular C(sp3)– 15  H aminations. These catalysts proceed with excellent levels of reactivity and selectivity in complex molecule settings, 16  without the need for directing groups. The late-stage functionalization approach that has emerged from this work has 17  been utilized in both industrial and academic settings. Building on this considerable foundation, we will undertake 18  major challenges required to broaden the application of late-stage functionalization in chemical synthesis and drug 19  discovery. We will innovate new base-metal complexes for aliphatic C–H oxidations that increase chemoselectivity 20  for tolerance of π-functionality and unprotected alcohols, as well as explore catalyst chiral recognition through non- 21  bonding interactions. These advances will make possible new reactions such as oxidative alkylations and catalyst- 22  controlled asymmetric induction and site-divergence. We will develop new base-metal complexes for intermolecular 23  C–H aminations and alkylations with unprecedented selectivities, and discover new ligand types amenable to 24  asymmetric induction. New palladium(II)/sulfoxide catalysts will be invented with an emphasis on introducing 25  functionality in complex settings. Cross-coupling reactions will be developed where O and N are introduced as part of 26  complex fragments. Additionally, asymmetric C–H functionalizations that feature catalyst-controlled 27  diastereoselectivities in substrates with pre-existing stereogenic centers will be advanced. Collectively, this program 28  will change the way synthetic chemists make and diversify complex molecules in pursuit of therapeutics, metabolites, 29  and biological probes.

PI，怀特，M.C.    R35 通用汽车 122525    1 项目概要 2  3 C(sp3)–H 到 C(sp3)–O、–N 或 –C 的原子变化可以深刻影响生物功能和 4 小分子的物理性质。传统上，引入这些功能依赖于功能组 5 预氧化碳杂原子前体的转化。这种方法限制了直接安装新的 6 复杂分子的功能，通常需要从头合成，这对于快速探索是不切实际的 7 生物学功能。我们的建议旨在提供选择性 C(sp3)–H 官能化反应，安装 O、N 和 复杂分子的碳氢化合物支架中的 8 C。这将使后期功能化成为可能，从而加速药物的开发 9 发现流程，简化全合成，并促进天然产物作为候选药物的探索。 10 我们的小组已经证明，复杂分子中的 C(sp3)–H 键可以根据它们的性质来区分 11 电子、空间和立体电子特性，导致化学界发生范式转变 12 2007 年之前，人们认为脂肪族 C-H 键是难以区分的。为此，我们发现并 13 商业化的基于铁和锰的 PDP 催化剂，用于 C(sp3)–H 氧化；钯(II)/亚砜催化剂 14 用于烯丙基 C–H 官能化；和锰酞菁催化剂，用于分子内和分子间 C(sp3)– 15 H 胺化。这些催化剂在复杂的分子环境中具有优异的反应活性和选择性， 16 无需指导小组。这项工作中出现的后期功能化方法已经 17 已在工业和学术环境中使用。在此基础上，我们将开展 扩大后期功能化在化学合成和药物中的应用所需的 18 个主要挑战 19 发现。我们将创新用于脂肪族 C-H 氧化的新型贱金属络合物，以提高化学选择性 20 对 π 官能团和未受保护的醇的耐受性，以及通过非-探索催化剂手性识别 21  粘合互动。这些进步将使新的反应成为可能，例如氧化烷基化和催化剂- 22 控制不对称诱导和位点发散。我们将开发用于分子间相互作用的新型贱金属配合物 23 具有前所未有的选择性的 C–H 胺化和烷基化，并发现适合的新配体类型 24  不对称感应。将发明新型钯(II)/亚砜催化剂，重点是引入 25 复杂设置中的功能。将开发交叉偶联反应，其中引入 O 和 N 作为 26 个复杂的片段。此外，具有催化剂控制特征的不对称C-H官能化 27  具有预先存在的立体中心的底物的非对映选择性将得到提高。总的来说，这个程序 28 将改变合成化学家制造复杂分子并使复杂分子多样化的方式，以追求治疗方法、代谢物、 29 和生物探针。