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

Ir催化的碳-氢活化和氢同位素交换的新方法，用于标记的寡核苷酸和其他在药物发现中非常重要的杂环。最近从Strathclyde的Kerr实验室建立的Ir物种已经成为同位素标记化学中最活跃的物种之一，这是药物设计和合成中非常重要的一个领域。在这些研究的基础上，现在建议，作为与阿斯利康扩展合作的一部分，这一领域在催化剂结构、关键底物范围和标记方式方面进一步和广泛地多样化。这项研究项目的目标是：-将最近开发的SP3标记扩大到与阿斯利康直接重要和相关的寡核苷酸单位；-将定向SP2标记扩大到更广泛的具有药学意义的重要N-杂环；以及-开发一种目前广受欢迎的非定向C-2标记吡啶的方法。利用Strathclyde实验室的新兴技术，各种标记的新化学实体将通过这一合作研究项目获得。更具体地说，这将包括极有价值的和选择性标记的寡核苷酸单元，以及一系列具有更高药用价值和在生物结合过程中潜在应用的杂环。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械模型和动力学研究相结合，将构成这一方案的核心组成部分。

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.