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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

基本信息

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
项目类别：
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

项目摘要

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）：药物开发中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的作用方式。目前的合成方法在能力上是有限的

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.