Synthetic C-H Oxidations and Functionalizations with Sustainable Metal Catalysts

描述（由申请人提供）：用于药物开发的易于获得的天然产物和相关化合物的多样化是世纪的前沿目标。由这些化合物提供的新型支架通常富含立体中心，赋予期望的生物学特性和选择性作用模式。目前的合成方法在以下方面的能力有限： 在有机框架上引入新的功能，结果，这些结构作为候选药物仍然没有得到充分利用。 自然界通常使用可持续的铁基P450酶，其氧化sp3-杂交的C-H键（即脂肪族、烯丙基和苄基），以将功能性引入复杂的分子支架上，通常具有精确的位点选择性、化学选择性和立体选择性。该提议寻求开发催化剂，其实现对sp3 C-H氧化、胺化、烷基化和卤化反应的酶样选择性，具有小分子催化的高底物通用性和操作容易性特征。这些催化剂将采用铁和锰，高度丰富，无毒，和相对未开发的金属，目前令人兴奋的机会，发现反应性是正交的广泛探索贵金属催化剂（Rh，Ru）。为了实现这一目标，我们将贡献新的催化剂和设计策略，评估控制元素，如电子，手性和非血红素铁络合物（Fe（PDP））的空间位阻，已经证明了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氧化的能力。这些新型催化剂将解决脂肪族C-H氧化中的显著突出问题，例如化学选择性（耐受更富电子的不饱和官能团和杂原子官能团）、对映选择性和实现位点选择性的交替模式。我们将继续为选择性C（sp3）-H胺化和烷基化提供新的催化剂平台，这些平台利用了金属氮烯和卡宾与金属氧代的等电子性质和机理相似性。Fe（PDP）的仿生反应性将被进一步探索以实现脂肪族3 o C-H位点的立体选择性卤化。此外，目前的催化剂将被精炼，以增加催化剂的寿命。 总的来说，我们期望这些脂肪族、烯丙位和苄基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，空间和立体电子性质与催化剂的位点选择性定量相关。该模型还将探索其告知催化剂设计的能力。从这些研究中获得的基本知识将有助于重新定义“惰性”C-H键的物理有机性质，并将为未来的催化剂和反应设计提供信息。

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.