New Iridium-catalysed Methods for C-H Activation and Hydrogen-Isotope Exchange towards Labelled Oligonucleotides and Other Heterocycles

新的铱催化的方法C-H活化和氢同位素交换对标记的寡核苷酸和其他杂环的药物发现的重要性提高最近建立的铱物种从克尔实验室在斯特拉斯克莱德已经出现，成为一些最活跃的物种在同位素标记化学，在药物设计和合成领域的显着重要性。在这些研究的基础上，现在提出，作为与阿斯利康扩展合作的一部分，铱催化的这一领域在催化剂结构、关键底物范围和标记模式方面进一步广泛多样化。该研究项目的目标是：-将最近开发的sp3标记扩展到对阿斯利康直接重要和相关的寡核苷酸单元;-将定向sp2标记扩展到明显更广泛的药学上重要的N-杂环;以及-开发一种通用的、目前正在寻求的吡啶类非定向C-2标记方法。本工作方案中描述的研究将提供一系列灵活的稳定，高活性催化剂在正在进行的选择性和官能团耐受性C-H活化和氢同位素交换过程中具有可观的实用性。利用Strathclyde实验室的新兴技术，通过这个合作研究项目，将可以获得各种标记的新化学实体。更具体地，这将包括极有价值的和选择性标记的寡核苷酸单元，以及一系列具有提高的药学重要性和在生物缀合过程中的潜在应用的杂环。作为这些研究方法的一部分，并作为我们实验室在这一领域的常规应用，计算方法的应用与实验机制建模和动力学研究相结合，将形成该计划的核心组成部分。

New Iridium-catalysed Methods for C-H Activation and Hydrogen-Isotope Exchange towards Labelled Oligonucleotides and Other Heterocycles of Elevated Importance in Drug Discovery.Recently established iridium species from the Kerr laboratories at Strathclyde have emerged to become some of the most active species in isotope labelling chemistry, an area of significant importance within drug design and synthesis. Building on these studies, it is now proposed that, as part of extended collaborations with AstraZeneca, this field of iridium catalysis is further and extensively diversified, in terms of catalyst structure, key substrate scope, and mode of labelling. The objectives of this research project are to:- Extend the recently-developed sp3 labelling towards oligonucleotide units of direct importance and relevance to AstraZeneca;- Expand directed sp2 labelling to an appreciably broader range of pharmaceutically-important N-heterocycles; and- Develop a general and presently sought-after method for the non-directed, C-2 labelling of pyridines.The research described in this programme of work will deliver a flexible range of stable, highly active catalysts of appreciable utility in ongoing selective and functional group tolerant C-H activation and hydrogen isotope exchange processes. Capitalising on emerging techniques from Strathclyde laboratories, a variety of labelled new chemical entities will become accessible via this collaborative research project. More specifically, this will include extremely valuable and selectively labelled oligonucleotide units, as well as a series of heterocycles of elevated pharmaceutical importance and potential application in bioconjugation processes. As part of these research approaches and as routinely applied within our laboratory in this area, the application of computational methods combined with experimental mechanistic modelling and kinetic studies will form a core component of this programme.