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: 8787351
• 负责人: Maria White
• 金额: $ 28万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8787351
• 关键词: Address; Alcohols; Alkaloids; Alkenes; Alkylation; Amination; Amines; Biological; Biological Availability; Biological Factors; Biomimetics; Catalysis; Characteristics; Chemistry; Complex; Cytochrome P450; Development; Electronics; Electrons; Elements; Enzymes; Ethers; Event; Future; Goals; Hydrogen Bonding; Hydroxylation; Iron; Knowledge; Manganese; Metals; Methods; Modeling; Molecular; Nature; Oxygen; Peptides; Pharmacologic Substance; Property; Reaction; Relative (related person); 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; public health relevance; 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)：使易于获得的天然产物和相关化合物多样化以用于药物开发是21世纪的前沿目标。由这类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的作用模式。目前的合成方法在能力上受到限制 将新的功能引入有机框架，因此，这些结构作为候选药物仍然没有得到充分利用。大自然经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)，将功能引入复杂的分子支架上，通常具有精细的位置、化学和立体选择性。这一建议旨在开发具有小分子催化的高底物通用性和操作简易性的催化剂，以实现对SP3C-H氧化、胺化、烷基化和卤化反应的类似酶的选择性。这些催化剂将使用铁和锰，高度丰富，无毒，相对未开发的金属，这为发现与广泛开发的贵金属催化剂(Rh，Ru)垂直的反应性提供了令人兴奋的机会。为了实现这一目标，我们将提供新的催化剂和设计策略，以评估非血红素铁配合物(Fe(PDP))的电子、手性和立体结构等控制元素，这些元素已经证明能够在复杂分子环境中影响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氧化中显著的突出问题，如化学选择性(容忍更富电子的不饱和官能团和杂原子官能团)、对映体选择性和实现不同模式的位置选择性。我们将继续为选择性C(SP3)-H胺化和烷基化提供新型催化剂平台，利用金属硝烯和卡宾与金属氧的等电子性质和机理相似之处。观察到的Fe(PDP)的仿生反应活性将被进一步探索，以实现脂肪族3o C-H位的立体选择性卤化。此外，目前的催化剂将进行精炼，以延长催化剂的使用寿命。总而言之，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，该模型通过添加新的底物类别(芳烃、烯烃、杂环、胺、醚)，将底物的电子、立体和立体电子性质与作为催化剂的位置选择性的函数进行定量关联。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，并将为未来的催化剂和反应设计提供信息。