Integrated Electro-Biocatalysis for Arylation

Lead Research Organisation: University of Manchester
Department Name: Chemistry

Abstract

Despite a venerable history in synthetic chemistry, electrosynthesis has historically been regarded as the preserve of specialists and only rarely been used to discover new reactions and shape conceptual developments in molecule making. A number of developments have coincided to suggest this landscape is changing, and that electrosynthesis will be heavily influential in the immediate future of synthesis: 1) Sustainable chemistry - the availability of cheap energy sources to power new processes under very mild conditions has critical significance for the green chemistry agenda. 2) Technology - Synthetic chemists are now far more receptive to technological advances in the laboratory, with the success of flow chemistry exemplifying how process innovation can create reaction discovery. 3) Mechanism - Single electron transfer chemistry has undergone a major renaissance in the literature, with photoredox catalysis being one of the principal drivers of new synthesis over the past ten years. The conceptual overlap with electrochemistry is clear, whereby precise control of electron transfer enables new reaction pathways to be discovered in synthesis.
We will explore 'electro-bio' processes to exploit the strengths of electrosynthesis (versatile C-C bond formations and / or global redox change) and those of biocatalysis (exquisite control of absolute stereochemistry), showcasing the exceptionally mild conditions that are axiomatic to both techniques. We have established some preliminary results in the laboratory in collaboration with the Turner (biocatalysis) and Dryfe (electrochemistry) groups, on an electro-oxidation system integrated with biocatalytic reductive amination (1->2). This has established expertise and equipment in the group and surmounted parts of the steep learning curve necessary to effectively use electrochemical methods to make molecules. We will apply these techniques to the discovery of new arylation methods that can exploit electricity to create sustainable routes to enantio-enriched heteroarenes. For example, the Oxidative Nucleophilic Substitution of Hydrogen (ONSH) developed by the Makosza group is an extremely powerful transformation in concept for the alkylation of electron poor arenes and azines, but is plagued by very harsh oxidants that restrict application. We will develop an aqueous electrochemical oxidation system that will oxidize the sigma-complex 5 formed from nucleophilic addition of enolate equivalents. The resultant protected amino acid 6 can then directly undergo biocatalytic deracemization to produce valuable enantioenriched building blocks for pharma and the wider fine chemical industry.
Contrastingly, we will study electroreduction of pyridiniums (8) to enable the fundamental transformation of flat sp2 carbon residues into higher value sp3 moieties. The reduction of pyridines to piperidines is a powerful exemplification of this idea that has seen extensive research in the hydrogenation field using precious metal catalysis. We will develop a sustainable, metal-free electrochemical approach, beginning with activated substrates such as the nicotinidinium 8, that can access substituted piperidines 9 for further biocatalytic manipulation. The HDNO / IRED technology developed in the Turner group is extremely effective for de-racemizing secondary amines such as 9, and will deliver biologically-enriched piperidines 10.
The electro/bio integration presents exciting possibilities for technology development to discover new transformations. Our preliminary work was established in batch and has been extended to a prototype flow system that puts an electrochemical cell in line with an immobilized enzyme compartment. Development of these concepts will be strengthened by iCAT interactions with flow engineering to develop new collaborative approaches to integrated systems that are discovered in the course of the programme.

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
2279460 Studentship EP/S023755/1 01/10/2019 30/09/2023 Anastasios Charitou