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，White，M.C。 R35 GM 122525   1个项目摘要 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学功能和 4小分子的物理特性。传统上，引入这些功能依赖于功能组 5从预氧化的碳杂原植物前体转化。这种方法限制了新的直接安装 6个复杂分子的功能，通常是从头合成所必需的，这对于快速探索是不切实际的 7生物功能。我们的建议旨在提供安装O，N和 在复合分子的烃支架中8 C。这将实现加快药物的后期功能化 9发现过程，简化总合成和赋予对毒品候选天然产品的能力探索。 10我们的小组表明，可以根据它们的C（SP3） - H键来区分复合分子中的H键 11电子，空间和立体电子特性，导致化学界的范式转移 12之前，12之前将脂肪族C – H键视为无法区分。为此，我们发现了 13个商业化的铁和锰PDP催化剂用于C（SP3） - H氧化；钯（II）/亚氧化催化剂 14用于Allic C – H功能化；以及用于分子间和分子间C（SP3）的锰邻苯胺催化剂 - 15 h氨化。这些催化剂在复杂分子环境中以极高的反应性和选择性水平进行， 16无需指导小组。这项工作已经出现的后期功能化方法 在工业和学术环境中使用了17个。在这个考虑基础的基础上，我们将承担 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。我们将为脂肪族C – H氧化创新新的基准配合物，以提高化学选择性 20用于容忍π功能和未受保护的酒精，并通过非 - 探索催化剂手性识别 21个粘结相互作用。这些进步将使可能的新反应，例如氧化酒精和催化剂 - 22受控的不对称诱导和现场差异。我们将开发新的碱基络合物用于分子间 23具有前所未有的选择性的C – H氨和烷基化，并发现适合的新配体类型 24不对称诱导。将发明新的钯（II）/硫化催化剂，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作为一部分 26个复杂片段。此外，具有催化剂控制的不对称C – H功能化 27在具有先前存在的立体中心的底物中的非映异构才能得到前进。总体而言，这个程序 28将改变合成化学家在追求治疗剂，代谢物，代谢物中的复杂分子的方式和多样化的方式。 29和生物学问题。