Ruthenium-catalyzed Late Stage Amination of arenes

胺在生物活性化合物中普遍存在，具有广泛的基序和构型。特别是，芳香胺存在于药品、农用化学品和功能材料中。因此，形成碳氮键的选择性方法是宝贵的合成工具。最常用的C-N键形成反应之一是Buchwald-Hartwig胺化反应。然而，这种方法需要耦合伙伴的预官能化，限制了含有合适C-X键的基板的应用。相反，直接C-H胺化代表了一种强大的策略，如果我们能够选择性地激活任何C-H键，就可以形成任何芳香胺。在过去的十年中，直接碳氢胺化受到了极大的关注，然而，仍然存在许多挑战。例如，大多数胺化反应只在简单的底物中进行，更复杂的分子导致没有反应性或副反应。此外，当使用定向基团来控制C-H激活步骤时，大多数方法仅限于正选择性胺化，而元选择性过程非常罕见。在Larrosa小组中，我们最近开发了一类新型的小分子ru催化剂，可以介导含有氮基导向基团的复杂分子的晚期芳基化和烷基化。这些催化剂通过形成关键的高富电子双环化物质来进行，比以前的钌催化剂带来了很大的反应性改进。虽然这些反应通常会导致邻位官能化，但我们已经发现，对于某些类型的反应（例如与仲烷基卤化物的烷基化），通过简单地修饰催化剂中的配体球体，邻位和间位区域选择性转化都是可能的。格林集团专门从事工程酶的开发，以催化合成过程，到目前为止，这一直是均相催化剂的专属领域。这些新的酶结合了化学催化的合成多功能性和酶所提供的精确控制。Larrosa和Green的工作还共同致力于基于过渡金属的金属酶的开发，这种金属酶可用于精确控制碳氢化合物的功能化过程。在这个项目中，我们的目标是开发新的基于ru的催化系统，能够对含有n基导向基团的芳烃进行区域选择性的C-H胺化，重点是开发能够在复杂分子（后期功能化）上操作的方法，以及控制邻胺化和间胺化区域选择性的方法。为了实现这些雄心勃勃的目标，我们计划结合最先进的有机金属化学、光催化和电化学方法，这将使我们能够在原位微调催化中间体的反应性。此外，我们将探索Larrosa & Green小组开创的酶促方法，用于形成和使用基于ru的金属酶，目的是进行不对称C-H胺化。该学生将在Larrosa集团内接受最先进的化学催化方面的培训，包括有机金属化学、有机化学和物理化学技术，用于设计、合成和研究小分子钌基过渡金属催化剂。该学生将接受有关酶学、非天然氨基酸遗传编码、定向进化和评估格林集团内酶促反应的培训。

Amines are ubiquitous in biologically active compounds, with a vast range of motifs and configurations. In particular, aromatic amines are found in pharmaceuticals, agrochemicals and functional materials. Thus selective methods for the formation of C-N bonds are prized synthetic tools. One of the most commonly used C-N bond forming reactions is the Buchwald-Hartwig amination. However, this method requires the prefunctionalization of the coupling partner, limiting application to substrates containing a suitable C-X bond. Instead, direct C-H amination represents a powerful strategy that could lead to the formation of any aromatic amine if we were able to selectively activate any C-H bond.Direct C-H amination has received significant attention over the last decade, however, many challenges remain. For example, most amination reactions operate just in simple substrates, with more complex molecules leading to no reactivity or side reactions. Furthermore, when using directing groups to control the C-H activation step, most methods are limited to ortho-selective amination, with meta-selective processes being very rare.In the Larrosa group, we have recently developed a novel class of small molecule Ru-catalysts that can mediate the late stage arylation and alkylation of complex molecules bearing nitrogen-based directing groups. These catalysts proceed via the formation of key highly electron-rich biscycloruthenated species, bringing large reactivity improvements over previous Ru-catalysts. While these reactions normally lead to ortho-functionalization, we have uncovered that for some classes of reactions (eg alklyations with secondary alkyl halides) both ortho and meta regioselective transformations are possible, by simply modifying the ligand sphere in the catalyst.The Green group specialises on the development of engineered enzymes to catalyze synthetic processes that have until now been the exclusive domain of homogeneous catalysts. These new enzymes combine the synthetic versatility of chemo-catalysis with the precise control afforded by enzymes. The Larrosa and the Green work are also working together on the development of transition metal based metalloenzymes, that could be used for the precise control of C-H functionalization processes.In this project, we aim at developing novel Ru-based catalytic systems capable of performing regioselective C-H amination of arenes bearing N-based directing groups, with emphasis on developing methods capable of operating on complex molecules (late stage functionalization) and on controlling access to both ortho- and meta-amination regioselectivities. To achieve these ambitious aims, we plan to combine state-of-the-art organometallic chemistry, photocatalysis and electrochemical approaches that will allow us to fine tune the reactivity of catalytic intermediates, in situ. In addition, we will explore enzymatic approaches being pioneered by the Larrosa & Green groups for the formation and use of Ru-based metalloenzymes with the objective of carrying out asymmetric C-H aminations.The student will be trained in state-of-the-art chemocatalysis, including organometallic chemistry, organic chemistry and physical chemistry techniques for the design, synthesis and investigation of small molecule ruthenium based transition-metal catalysts, within the Larrosa group. The student will receive training on enzymology, genetically encoding of unnatural aminoacids, directed evolution and assessment of enzymatic reactions within the Green group.