Metal-Catalysed Reductive Functionalisation of Heterocycles

Lead Research Organisation: University of Oxford
Department Name: Synthesis for Biology & Medicine CDT

Abstract

This project falls within the EPSRC Physical Sciences research areas of Catalysis and Synthetic Organic Chemistry

By the end of the drug discovery process, less than 10% of potential drug candidates that reached the clinical trial stage actually make it to the market. This attrition rate represents a significant and costly limitation to the process and limits progress of modern pharmacotherapy. Recent analysis has shown that the 3-dimensionality of drug candidates correlates with their efficacy, and thus a refinement of the drug development process, focussing on 3D targets would potentially result in a greater proportion of prospective drugs making it to the market.
The main issue synthetic medicinal chemists face is that while a chemist wishing to make a 2D molecule has a wealth of prior research to build upon, however the synthesis of 3D molecules is less well documented and routinely more challenging. Chemical reactions that take 2D molecules and transform them into 3D molecules would provide a convenient solution to this problem and are the overall focus of this DPhil research project. More specifically, we are interested in dearomative functionalization reactions of aromatic heterocycles, which are a commonly found motif in the majority of commercial drugs. A recent study found 59% of all commercial drugs feature a nitrogen containing ring.
While dearomatization reactions are well established in the literature, achieving this transformation simultaneously to a carbon-carbon bond forming process presents a greater challenge and synthetically useful examples in literature are rare. The Donohoe group has made significant progress on this front and have developed reactions that complete this transformation, from 2D to 3D, with high yield and utilising the carbon-carbon bond formation to install a new functional group in the molecule that enables future derivatisation. The reaction also uses a low loading of the metal catalyst and readily available, low molecular weight reagents such as methanol and formaldehyde, resulting in greater atom economy. These factors are vital in the face of the rising need for sustainable and more efficient chemistry.
The work we are currently undertaking expands the scope of substrates that are able to participate in the reaction. This will make the process more generalizable and thus more viable for industrial application. Following the completion of this task we will move on to development of new functionalisation reactions to incorporate alongside the dearomatization process, expanding its potential to more varied drug candidates or alternatively move on to other nitrogen containing heterocycles.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/S513866/1 30/09/2018 29/09/2023
2112482 Studentship EP/S513866/1 30/09/2018 30/03/2023 Bruno Marinic