Synthetic C-H Oxidations and Functionalizations with Sustainable Metal Catalysts

使用可持续金属催化剂进行合成 C-H 氧化和官能化

• 批准号: 9113946
• 负责人: Maria White
• 金额: $ 27.87万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9113946
• 关键词: Address; Alcohols; Alkaloids; Alkenes; Alkylation; Amination; Amines; Biological; Biological Availability; Biomimetics; Catalysis; Characteristics; Chemistry; Complex; Cytochrome P450; Development; Electronics; Electrons; Elements; Enzymes; Ethers; Event; Future; Goals; Health; Hydrogen Bonding; Hydroxylation; Iron; Knowledge; Manganese; Metals; Methods; Modeling; Molecular; Natural Products; Nature; Oxygen; Peptides; Pharmacologic Substance; Property; Reaction; Research; Site; Specificity; Structure; Terpenes; Time; base; carbene; catalyst; chlorination; design; drug candidate; drug development; frontier; functional group; halogenation; mathematical model; molecular recognition; novel; oxidation; scaffold; small molecule

DESCRIPTION (provided by applicant): Diversification of readily accessible natural products and related compounds for drug development is a frontier goal in the 21st century. The novel scaffolds provided by such compounds, often rich with stereocenters, confer desirable biological properties and selective modes of action. Current synthetic methods are limited in their ability to introduce new functionality onto organic frameworks and as a result, these structures remain underutilized as drug candidates. Nature routinely uses sustainable iron-based P450 enzymes that oxidize sp3-hybridized C-H bonds (i.e. aliphatic, allylic, and benzylic) to introduce functionality onto complex molecular scaffolds, often with exquisite site-, chemo-, and stereoselectivity. This proposal seeks to develop catalysts that achieve enzyme-like selectivity for sp3 C-H oxidation, amination, alkylation, and halogenation reactions with the high substrate generality and operational ease characteristic of small molecule catalysis. These catalysts will employ iron and manganese, highly abundant, non-toxic, and relatively unexplored metals that present the exciting opportunity to discover reactivity that is orthogonal to extensively explored noble metal catalysts (Rh, Ru). To achieve this goal we will contribute novel catalysts and design strategies that evaluate control elements like electronics, chirality, and sterics for non-heme iron complexes (Fe(PDP)) that have already demonstrated the ability to effect preparative and predictably selective aliphatic C-H oxidations in complex molecule settings. These novel catalysts will address significant outstanding problems in aliphatic C-H oxidation such as chemoselectivity (tolerance of more electron rich unsaturated and heteroatom functionality), enantioselectivity, and achieving alternate modes of site-selectivity. We will continue to contribute novel catalyst platforms for selective C(sp3)-H aminations and alkylations that exploit the isoelectronic nature and mechanistic similarities of metal nitrenes and carbenes with metal oxos. The observed biomimetic reactivity of Fe(PDP) will be further explored to achieve stereoselective halogenations of aliphatic 3o C-H sites. Additionally, current catalysts will be refined to increase catalysts lifetimes. Collectively, we expect these aliphatic, allylic, and benzylic C-H functionalization reactions to enable the rapid synthesis and diversification of complex biologically relevant molecules that were otherwise inaccessible as pharmaceutical scaffolds. Additionally, we will continue refine our mathematical model, which quantitatively correlates the electronic, steric, and stereoelectronic properties of a substrate to site-selectiviy as a function of catalyst, via addition of new substrate classes (arenes, olefins, heterocycles, amines, ethers). The model will also be explored for its ability to inform catalyst design. The fundamental knowledge that will be gained from these studies will serve to redefine the physical organic properties of "inert" C-H bonds and will inform future catalyst and reaction designs.

描述（由申请人提供）：用于药物开发的易于获取的天然产物和相关化合物的多样化是 21 世纪的前沿目标。这些化合物提供的新型支架通常富含立体中心，具有理想的生物学特性和选择性作用模式。目前的合成方法的能力有限 将新的功能引入有机框架中，因此，这些结构作为候选药物仍未得到充分利用。 大自然通常使用可持续的铁基 P450 酶来氧化 sp3 杂化的 C-H 键（即脂肪族、烯丙基和苄基），以将功能引入复杂的分子支架上，通常具有精致的位点选择性、化学选择性和立体选择性。该提案旨在开发能够实现 sp3 C-H 氧化、胺化、烷基化和卤化反应的类酶选择性的催化剂，并具有底物通用性高和小分子催化操作简便的特点。这些催化剂将采用铁和锰，这些储量丰富、无毒且相对未开发的金属，为发现与广泛探索的贵金属催化剂（Rh、Ru）正交的反应性提供了令人兴奋的机会。为了实现这一目标，我们将贡献新颖的催化剂和设计策略，以评估非血红素铁络合物 (Fe(PDP)) 的电子、手性和空间等控制元素，这些元素已经证明能够在复杂的分子环境中实现制备和可预测的选择性脂肪族 C-H 氧化。这些新型催化剂将解决脂肪族C-H氧化中的重大突出问题，例如化学选择性（耐​​受更多富电子不饱和和杂原子官能团）、对映选择性和实现位点选择性的替代模式。我们将继续为选择性 C(sp3)-H 胺化和烷基化贡献新型催化剂平台，利用金属氮烯和卡宾与金属氧代的等电子性质和机械相似性。将进一步探索观察到的 Fe(PDP) 的仿生反应性，以实现脂肪族 3o C-H 位点的立体选择性卤化。此外，现有的催化剂将得到改进，以延长催化剂的使用寿命。 总的来说，我们期望这些脂肪族、烯丙基和苄基 C-H 官能化反应能够快速合成和多样化复杂的生物学相关分子，否则这些分子无法作为药物支架。此外，我们将继续完善我们的数学模型，通过添加新的底物类别（芳烃、烯烃、杂环化合物、胺、醚），该模型将底物的电子、空间和立体电子性质与催化剂的位点选择性相关联。该模型还将探索其为催化剂设计提供信息的能力。从这些研究中获得的基础知识将有助于重新定义“惰性”C-H 键的物理有机性质，并为未来的催化剂和反应设计提供信息。

项目成果

Oxidative diversification of amino acids and peptides by small-molecule iron catalysis.

• DOI: 10.1038/nature18941
• 发表时间: 2016-09-08
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Osberger, Thomas J.;Rogness, Donald C.;Kohrt, Jeffrey T.;Stepan, Antonia F.;White, M. Christina
• 通讯作者: White, M. Christina

Remote Oxidation of Aliphatic C-H Bonds in Nitrogen-Containing Molecules.

• DOI: 10.1021/jacs.5b10299
• 发表时间: 2015-11-25
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Howell JM;Feng K;Clark JR;Trzepkowski LJ;White MC
• 通讯作者: White MC

A manganese catalyst for highly reactive yet chemoselective intramolecular C(sp(3))-H amination.

• DOI: 10.1038/nchem.2366
• 发表时间: 2015-12
• 期刊: Nature chemistry
• 影响因子: 21.8
• 作者: Paradine SM;Griffin JR;Zhao J;Petronico AL;Miller SM;Christina White M
• 通讯作者: Christina White M