Merging transition metal-catalysis and electrochemistry for late stage functionalization of biologically active molecules

Lead Research Organisation: University of Manchester
Department Name: Chemistry

Abstract

A 2018 joint pharma report identified organic synthesis as one of the major bottlenecks in drug discovery today.1 In the highly competitive discovery environments, only fast-to-synthesise molecules are targeted, which has led to only a small portion of the chemical shape space being explored: a factor that has been blamed for the recent low success rates in new drug development. The report emphasises the need for ideal tools such as late stage C-H functionalisation, allowing simple replacement of any C-H bond in a bioactive molecule with any desired functionality, and thus greatly accelerating the synthesis of new candidates from a lead compound. However, the field of C-H activation is significantly behind in achieving this aim: most biologically active molecules contain several polar and/or delicate functionalities ('real world' molecules), whereas most C-H activation methods use harsh conditions, incompatible with delicate groups, and catalysts that tend to poison in the presence of polar groups. The group of supervisor 1 (Larrosa) is tackling these challenges through the design of novel catalysts capable of overcoming current limitations. This is achieved through a combination of thorough mechanistic studies, leading to the understanding of the key catalytic steps, and informed novel ligand design, followed by fast reaction optimization.
While the use of electrochemistry has its origins in the early 1800s, it has had little impact on the way chemists synthesise organic molecules.2 This has changed in recent years, where new technological advances and new ideas have led to a resurgence of the field.3 Indeed, not only can electrons be a cheap replacement for stoichiometric oxidants/reductants, electrochemistry may be used to manipulate oxidation states of metals, thus controlling their reactivity.
The proposed project aims at combining transition metal-catalysis with electrochemistry in order to open up novel reactivity pathways that are not available with only transition metal catalysis or only electrochemistry (Figure 1).
Recent mechanistic developments in the Larrosa group have led to significant progress in the understanding of the operation of ruthenium catalysts in C-H functionalization, and the role of the ruthenium oxidation state in determining reactivity and selectivity.4,5 In the initial phase of this project, we will study the electrochemical modification of a number of key organometallic ruthenium-complexes, and their reactivity. In the second phase of the project, we will develop a combined chemo/electro-catalytic process for the directed C-H functionalization of aromatic compounds with green and readily available coupling partners, under unprecedentedly mild conditions. We will prioritize developing conditions compatible with 'real world' molecules, in order to maximize the impact and applicability of this novel methodology.
The project will involve construction of a dedicated electrochemical cell to optimise the reactions exemplified above.6 This will introduce the student to elements of chemical engineering, including the design of cells and membranes to achieve the correct speciation for the desired process, and the use of electrochemical flow, as well as batch, reactors.
The student will be trained in state-of-the-art chemo-catalysis, including organometallic chemistry, organic chemistry and physical organic chemistry approaches towards mechanistic understanding, within the Larrosa group. The student will receive training on electrosynthesis, electrochemical fundamentals, cell design and electrochemical approaches to reaction kinetics in the Dryfe group.

1) Nature Chem. 2018, 10, 383-394
2) Chem. Rev. 2017, 117, 13230-13319
3) Nature 2019, doi: 10.1038/s41586-019-1539-y
4) Nature Chem. 2018, 10, 724-731
5) J. Am. Chem. Soc. 2018, 140, 11836-11847
6) Adv. Func. Mater. 2018, 28, 1804357

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/S023755/1 01/04/2019 30/09/2027
2279370 Studentship EP/S023755/1 01/10/2019 30/09/2023 Jacob Luke Kenyon