Selective C(sp3)-H Oxidations and Functionalizations with Tunable Metal Catalysts for Synthesis

皮埃尔·怀特，福特汽车，R35，通用汽车：122525。 -- 1.项目总结 2个月 C(SP3)-H到C(SP3)-O、-N或-C的原子化变化可以深刻地影响生物功能和 4.小分子的物理性质。传统上，引入这些功能依赖于官能团 5.预氧化碳-杂原子前体的转化。此方法限制了直接安装新的 6将官能团转化为复杂的分子，通常需要从头合成，而这对于快速探索 7.生物学功能。我们的建议旨在提供选择性的C(SP3)-H官能化反应，这些反应安装了O，N和 8℃，在复杂分子的碳氢化合物骨架中。这将使后期功能化能够加速药物 9改进发现过程，简化全合成，并使作为候选药物的天然产物的探索成为可能。 我们的小组已经证明，复杂分子中的C(SP3)-H键可以根据它们的 11电子、立体和立体电子性质，导致化学界内的范式转变， 12在2007年之前，人们认为脂肪族C-H键在准备阶段是无法区分的。为此，我们发现并 用于C(SP3)-H氧化的商用铁和锰PDP基催化剂；钯(II)/亚砜催化剂 14位用于烯丙基C-H官能化；以及用于分子内和分子间C(SP3)-的锰酞菁催化剂- 他有15次性行为。这些催化剂在复杂的分子环境中具有极好的反应性和选择性， 16，而不需要指导小组。从这项工作中出现的后期功能化方法 17已在工业和学术环境中使用。在这个可观的基础上，我们将致力于 18.扩大后期功能化在化学合成和药物中的应用所需的主要挑战 19.发现。我们将创新用于脂肪族C-H氧化的新的贱金属络合物，以提高化学选择性 20%的π官能团和未受保护的醇的耐受性，以及探索通过非 21.建立联系互动。这些进展将使氧化烷基化和催化剂等新反应成为可能。 22控制了不对称诱导和位置发散。我们将开发新的碱金属络合物用于分子间 23个具有前所未有的选择性的C-H胺化和烷基化反应，并发现了新的配体类型 24.不对称诱导。将发明新的钯(II)/亚砜催化剂，重点是介绍 25提供复杂环境中的功能。将开发交叉偶联反应，其中O和N被引入作为 26个是复杂的碎片。此外，以催化剂控制为特征的不对称C-H官能化 27在具有预先存在的立体产生中心的基质中的非对映选择性将被提高。总而言之，这个项目 28将改变合成化学家制造复杂分子的方式，并使其多样化，以追求疗法、代谢物、 29个DNA和生物探针。

PI, White, M.C.    R35 GM 122525    1  Project Summary 2  3  The atomistic change of C(sp3)–H to C(sp3)–O, –N, or –C can profoundly impact the biological function and 4  physical properties of small molecules. Traditionally, introducing these functionalities relies on functional group 5  transformations from pre-oxidized carbon-heteroatom precursors. This approach limits the direct installation of new 6  functionality into complex molecules, often necessitating de novo synthesis that is impractical for rapid exploration of 7  biological function. Our proposal aims to provide selective C(sp3)–H functionalization reactions that install O, N and 8  C in the hydrocarbon scaffold of complex molecules. This will enable late-stage functionalizations that expedite drug 9  discovery processes, streamline total syntheses, and empower exploration of natural products as drug candidates. 10  Our group has shown that C(sp3)–H bonds in complex molecules can be distinguished based on their 11  electronic, steric, and stereoelectronic properties, resulting in a paradigm shift within the chemistry community that 12  prior to 2007 viewed aliphatic C–H bonds as preparatively indistinguishable. To do this, we have discovered and 13  commercialized iron and manganese PDP-based catalysts for C(sp3)–H oxidations; palladium(II)/sulfoxide catalysts 14  for allylic C–H functionalization; and manganese phthalocyanine catalysts for both intra- and intermolecular C(sp3)– 15  H aminations. These catalysts proceed with excellent levels of reactivity and selectivity in complex molecule settings, 16  without the need for directing groups. The late-stage functionalization approach that has emerged from this work has 17  been utilized in both industrial and academic settings. Building on this considerable foundation, we will undertake 18  major challenges required to broaden the application of late-stage functionalization in chemical synthesis and drug 19  discovery. We will innovate new base-metal complexes for aliphatic C–H oxidations that increase chemoselectivity 20  for tolerance of π-functionality and unprotected alcohols, as well as explore catalyst chiral recognition through non- 21  bonding interactions. These advances will make possible new reactions such as oxidative alkylations and catalyst- 22  controlled asymmetric induction and site-divergence. We will develop new base-metal complexes for intermolecular 23  C–H aminations and alkylations with unprecedented selectivities, and discover new ligand types amenable to 24  asymmetric induction. New palladium(II)/sulfoxide catalysts will be invented with an emphasis on introducing 25  functionality in complex settings. Cross-coupling reactions will be developed where O and N are introduced as part of 26  complex fragments. Additionally, asymmetric C–H functionalizations that feature catalyst-controlled 27  diastereoselectivities in substrates with pre-existing stereogenic centers will be advanced. Collectively, this program 28  will change the way synthetic chemists make and diversify complex molecules in pursuit of therapeutics, metabolites, 29  and biological probes.