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。特别地，芳香胺被发现于药物、农用化学品和功能材料中。因此，用于形成C-N键的选择性方法是珍贵的合成工具。最常用的C-N键形成反应之一是Buchwald-Hartwig胺化反应。然而，该方法需要偶联配偶体的预官能化，限制了对含有合适的C-X键的基底的应用。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，则可以导致任何芳香胺的形成。直接C-H胺化在过去十年中受到了极大的关注，然而，仍然存在许多挑战。例如，大多数胺化反应仅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，当使用导向基团来控制C-H活化步骤时，大多数方法仅限于邻位选择性胺化，而间位选择性过程非常罕见。在Larrosa组中，我们最近开发了一类新型的小分子Ru催化剂，其可以介导带有氮基导向基团的复杂分子的后期芳基化和烷基化。这些催化剂通过形成关键的高度富电子的双环钌化物质进行，从而比以前的Ru催化剂带来大的反应性改进。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，邻位和Meta区域选择性转化都是可能的。绿色团队专注于开发工程酶来催化合成过程，直到现在都是均相催化剂的专属领域。这些新的酶联合收割机结合了化学催化的合成多功能性和酶提供的精确控制。Larrosa和绿色的工作也在合作开发基于过渡金属的金属酶，可以用于精确控制C-H官能化过程。在这个项目中，我们的目标是开发新的Ru基催化体系，能够进行带有N基导向基团的芳烃的区域选择性C-H胺化，重点在于开发能够对复杂分子进行操作的方法（后期官能化）和控制邻位胺化和间位胺化区域选择性。为了实现这些雄心勃勃的目标，我们计划结合联合收割机最先进的有机金属化学，电化学和电化学方法，使我们能够微调催化中间体的反应性，在原位。此外，我们将探索由Larrosa和绿色小组开创的用于形成和使用Ru基金属酶的酶促方法，目的是进行不对称C-H胺化。学生将接受最先进的化学催化的培训，包括有机金属化学，有机化学和物理化学技术的设计，Larrosa集团内小分子钌基过渡金属催化剂的合成和研究。学生将在绿色小组内接受酶学、非天然氨基酸的遗传编码、定向进化和酶反应评估方面的培训。

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.