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）：可容易获得的天然产品和药物开发相关化合物的多样化是21世纪的前沿目标。这种化合物提供的新型脚手架通常具有立体中心，赋予理想的生物学特性和选择性作用模式。当前的合成方法的能力有限 将新功能引入有机框架上，因此，这些结构仍然不足为候选药物。 自然常规使用可持续的铁基p450酶，将SP3杂交C-H键（即脂肪型，烯丙基和苯并）氧化，将功能引入功能上，通常具有精美的位点，化学，化学效果，化学，化学效果和刻度选择性。该提案旨在开发催化剂，以实现SP3 C-H氧化，胺化，烷基化和卤化反应的酶样选择性，该反应与小分子催化的高底物通用性和可操作性的特征。这些催化剂将采用铁和锰，高度丰富，无毒且相对未开发的金属，这是一个令人兴奋的机会，以发现对广泛探索贵族金属催化剂（RH，RU）的反应性。为了实现这一目标，我们将为非血红素铁配合物（FE（PDP））评估诸如电子，手性和集体的控制元素，这些催化剂和设计策略已经证明了在复杂分子设置中能够实现制备和可预测性的选择性脂肪型C-H氧化的能力。这些新型的催化剂将解决脂肪族C-H氧化中的重大出色问题，例如化学选择性（对更多电子富含电子的不饱和和杂原子功能的耐受性），对映选择性以及实现位点选择性的替代模式。我们将继续为选择性C（SP3）H氨基和烷基化提供新的催化剂平台，从而利用金属硝酸盐和金属Oxos的金属硝酸盐和卡宾斯的等值性质和机械性相似性。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位点的立体选择卤素化。此外，当前的催化剂将被完善，以增加催化剂的寿命。 总的来说，我们期望这些脂肪族，烯丙基和苯基C-H功能化反应能够快速合成和多样化复杂的生物学相关分子，这些分子原本无法作为药物支架无法访问。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（Arenes，Olefins，Olefins，Heterocycles，Amines，Ethers），定量地将基板与位点 - 选择性的电子，空间和立体电子特性相关联。该模型还将因其通知催化剂设计的能力而进行探索。这些研究将获得的基本知识将有助于重新定义“惰性” C-H键的物理有机特性，并将为未来的催化剂和反应设计提供信息。