Informatics-driven Catalyst Design towards Enhanced Iridum(I) Catalysts for Radiolabelling Applications

分子的同位素标记对于制药工业中的admet研究和反应机理的阐明是至关重要的。最重要的同位素标记方法是氢同位素交换(HIE)。在Lewis碱性基团指导下的Csp2-H HIE方面，我们开发了一系列IrNHC/膦配合物，这些配合物容纳了广泛的导向基团，并展示了良好的氚和氚掺入水平。在这项工作的延伸中，我们将我们的新催化剂应用于定向C-H活化和分子内C-C键的形成。更具体地说，在一系列苯甲酸衍生物中使用羧酸盐导向基团，C-H活化和烯烃芳基化，使用我们特别设计的NHC-膦配合物，促进了具有三和四个苄基立体中心的双和三环的合成。这个项目的目标将是：-进一步优化这种C-C键的形成过程，并扩大底物范围；-使用计算技术和配体参数来加深我们对体系的了解，并指导催化剂设计；以及-将这些数据驱动的方法扩展和组合到相关的C-C、C-X和C-D键形成过程中。总体而言，这种方法将预备研究与动力学、机理研究、参数化和广泛的计算技术相结合，从而允许使用数据驱动的方法来设计新型催化剂和进行反应优化。

The isotopic labelling of molecules is crucial to ADMET studies within the pharmaceutical industry, and for the elucidation of reaction mechanisms. Foremost amongst the methods for isotope labelling is hydrogen isotope exchange (HIE). In terms of Csp2-H HIE directed by Lewis basic groups, we have developed an extensive range of iridium(I) NHC/phosphine complexes, which accommodate a broad range of directing groups and demonstrate excellent levels of deuterium and tritium incorporation.In an extension of this work, we have applied our emerging catalysts to directed C-H activation and intramolecular C-C bond formation. More specifically, using the carboxylate directing group in a range of benzoic acid derivatives, C-H activation and alkene arylation, using our specifically designed NHC-phosphine chelated complex, has facilitated the synthesis of bi- and tricycles featuring tertiary and quaternary benzylic stereocentres.The objectives of this project will be to:- Further optimise this C-C bond forming process, and expand the substrate scope;- Employ computational techniques and ligand parameterisation to enhance our understanding of the system and guide catalyst design; and- Extend and combine these data driven approaches to related C-C, C-X and C-D bond formation processes.Overall, this approach combines preparative studies with kinetics, mechanistic studies, parameterisation, and a broad range of computational techniques, to allow a data-driven approach to novel catalyst design and reaction optimisation.