New Approaches in Iridium Catalysis for Appreciably Expanded Isotope Labelling Processes

迄今为止，在Strathclyde实验室内的详细研究已经导致发现和建立了一系列新型铱催化剂，其具有N-杂环卡宾（NHC）单元以及庞大的膦配体，其能够经由邻位定向的C-H插入过程将氢的重同位素（氘和氚）递送到芳香分子。事实上，当与广泛选择的底物（包括酮、酰胺、酯和N-杂环）一起使用时，这些催化剂已经成为全球范围内标记化学领域中最活跃的物种。在此基础上，2016年10月与默克（美国）合作启动了一项研究计划，目标是将我们开发的铱催化剂应用于更罕见，更具挑战性的氨基酸和肽的sp3标记。作为该研究伙伴关系的一部分，初步研究集中在一系列NHC/膦催化剂标记甘氨酸衍生物，具有多种N-和C-末端保护基团，并为本工作计划中的详细研究提供了基础。作为本计划的一部分，与默克公司（美国）的合作将进一步扩展到开发更广泛有效的氨基酸和肽标记方法。具体而言，基于我们正在进行的研究所建立的重要理解，该项目的目标将是：-通过新的催化剂设计，进一步开发氨基酸中sp3杂化C-H键的氢同位素交换，并以计算研究为基础;-将方法扩展到更复杂的氨基酸和肽的标记;及─探索在固相上标记氨基酸和肽。本工作计划中描述的研究将推动一系列新的用于一系列新颖的C-H活化和C-H sp3键的氘/氚同位素交换过程的稳定且高活性的催化剂。利用我们实验室的新兴技术，将出现一系列经过调整的铱基催化剂系统，通过溶液和固相技术提供各种标记的氨基酸和肽。事实上，关于后者，在固相上标记肽是一个有吸引力的提议：当裂解后纯化将递送纯的标记肽时，它简化了溶解度问题，并允许从产物中分离催化剂和任何标记的废物。

To date, detailed studies within Strathclyde laboratories have led to the discovery and establishment of a family of novel iridium catalysts, possessing N-heterocyclic carbene (NHC) units alongside bulky phosphine ligands, which are capable of delivering heavy isotopes of hydrogen (deuterium and tritium) to aromoatic molecules via an ortho-directed C-H insertion process. Indeed, when employed with a broad selection of substrates including ketones, amides, esters, and N-heterocycles, these catalysts have emerged to become some of the most active species in this area of labelling chemistry on a global scale. Following on from this, a research programme was initiated in October 2016, in collaboration with Merck (USA), with the goal of applying our developed iridium catalysts in the much rarer, and more challenging, sp3 labelling of amino acids and, in turn, peptides. As part of this research partnership, initial investigations focused on a range of NHC/phosphine catalysts in the labelling of glycine derivatives, with a board variety of N- and C-terminus protecting groups, and have provided the foundations for the research detailed as part of this programme of work.As part of this programme the collaboration with Merck (USA) will be further extended to develop even more broadly effective methods for the labelling of amino acids and peptides. Specifically, and based on the significant understanding established through our ongoing studies, the project objectives will be to:- Further develop the hydrogen-isotope exchange of sp3 hybridised C-H bonds in amino acids through novel catalyst design, underpinned by computational studies;- Extend the methodology to the labelling of more complex amino acids and peptides; and- Explore the labelling of amino acids and peptides on solid phase.The research described in this programme of work will drive the development of an appreciable range of new stable and highly active catalysts for application within a series of novel C-H activation and deuterium/tritium isotope exchange processes of C-H sp3 bonds. Capitalising on emerging techniques from our laboratories, a series of tuned iridium-based catalyst systems will emerge to deliver access to a variety of labelled amino acids and peptides via both solution and solid phase techniques. Indeed, regarding the latter, the labelling of peptides on solid phase is an attractive proposition: it simplifies solubility issues, and allows separation of catalyst and any labelled waste from the product, when post-cleavage purification would deliver a pure labelled peptide.