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

分子的同位素标记对于制药行业的ADMET研究和反应机制的阐明至关重要。最重要的同位素标记方法是氢同位素交换（HIE）。在由Lewis碱性基团引导的Csp2-H HIE方面，我们已经开发了广泛的铱(I) NHC/膦配合物，它容纳了广泛的指导基团，并表现出优异的氘和氚结合水平。在这项工作的扩展中，我们已经将我们的新兴催化剂应用于定向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导向基团，C-H活化和烯烃芳化，使用我们专门设计的nhc -膦螯合配合物，有助于合成具有叔苯基和季苯基立体中心的双环和三环。该项目的目标将是：-进一步优化这种C-C键形成过程，并扩大基板范围；-运用计算技术和配体参数化来提高我们对系统的理解和指导催化剂设计；扩展并结合这些数据驱动的方法到相关的C-C， C-X和C-D键形成过程。总体而言，该方法将准备研究与动力学、机理研究、参数化和广泛的计算技术相结合，以允许数据驱动的方法进行新型催化剂设计和反应优化。

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.