Photoenzymatic C-H radical alkylation of arenes using S-adensoyl methionine analogues

In a future where sustainability will be a key driver, high value molecules must be selectively prepared from simple feedstocks in an expedient fashion. So called 'C-H activation' will be a key strategy in future synthesis as it allows C-H bonds present in almost every feedstock chemical to be converted to more valuable C-C bonds, for example. Unfortunately, most methods for C-H activation currently involve expensive/toxic metal catalysts and solvents and controlling the electivity for a particular C-H bond, in feedstocks where there are many, remains a grand challenge.
Two leaders in their respective fields will join forces for the first time and pool their complementary expertise in supervising the project. The Procter group has recently exploited visible light-photocatalysis to generate radicals by cleaving C-S bonds in sulfonium salts and the resultant radicals have been used in the metal-free C-H functionalization of aromatic substrates. The Micklefield group use S-adenosylmethionine (SAM) analogues - Nature's sulfonium salts - in biocatalysis and has recently reported several applications of SAM analogues in biology.
We propose that the innovative marriage of biocatalysis and visible light photocatalysis will allow the selective formation of C-C bonds at the expense of C-H bonds in important aromatic feedstocks, thus facilitating the sustainable synthesis of high-value products of industrial relevance. Our approach will use enzymes to control the selectivity of C-H functionalization, organic photocatalysts to generate radicals, and bioinspired sulfonium salts as radical precursors. A suite of sulfonium salts will be accessed using either chemo- or bio-catalysis and will allow a wide range of high value products to be prepared using the proposed photoenzymatic approach. The redox properties and reactivity of the sulfonium salt SAM analogues, in the presence of organic photocatalysts, will be assessed, and effective conditions for selective radical generation and trapping developed. Wild-type and engineered methyltransferase enzymes will then be used to control
the selectivity of C-H alkylation in aromatic substrates; methyltransferases will bind the SAM analogues and engage the substrate, before an organic visible light-photocatalyst - either in solution or immobilized in the enzyme active site - will lead to selective radical generation and trapping. We will initially focus on the development of photoenzymatic C-H allylation, propargylation, trifluoromethylation, and carboxymethylation processes that allow aromatic/heteroaromatic substrates to be converted into high-value products by C-C bond formation. Finally, we will examine innovative new approaches for the recycling of SAM analogues.
The project fuses chemocatalysis and biocatalysis in an integrated photoenzymatic approach that will deliver methods for selective C-H alkylation far beyond the current state-of-the-art in synthesis. The photoenzymatic C-H alkylation will also be employed for the late-stage functionalization of complex substrates. The Procter group have used sulfonium salts for the late-stage modification of drugs and agrochemicals. The Micklefield group have used SAM analogues for the late-stage biocatalytic alkylation of the potent immunosuppressive agent rapamycin.

iCAT will work with industry partners to create an holistic approach to the training of students in biocatalysis, chemocatalysis, and their process integration. Traditional graduate training typically focuses on one aspect of catalysis and this approach can severely restrict innovation and impact. Advances in technology and fundamental reaction discovery are rendering this silo-approach obsolete, and a new training modality is needed to produce the next generation of chemists and engineers who can operate across a far broader chemical continuum. iCAT will meet this challenge with a state-of-the-art CDT, equipping the next generation of scientists and engineers with the skills needed to develop future catalytic processes and create the functional molecules of tomorrow.

The UK has one of the world's top-performing chemical industries, achieving outstanding levels of growth, exports, productivity and international investment. The UK's chemical industry is a significant provider of jobs and creator of wealth, with a turnover in excess of £50 billion and a contribution of over £15 Billion of value to the UK economy [2015 figures]. iCAT will deliver highly skilled people to lead this industry across its various sectors, achieving impact through the following actions:

1. Equip the next generation of science and engineering leaders with the interdisciplinary skills and knowledge needed to work across the bio and chemo catalytic remit and build the functional molecules we need to structure society.

2. Provide a highly skilled workforce and research base, skilled in the latest methodologies, strategies and techniques of catalysis and engineering that is crucial for the UK's Chemical Industry.

3. Build the critical mass necessary to support effective cohort-based training in a world-class research environment.

4. Develop and disseminate new catalytic technologies and processes that will be taken up by industrial and academic teams around the world.

5. Encourage Industry to promote research challenges within the CDT that are of core relevance to their business.

6. Provide cohesion in the integration of biocatalysis, engineering and chemocatalysis to create a more unified voice for strategic dialogue with industry, funders and policy makers, and more generally outreach and public engagement.

7. Draw-in and bring together Industrial partners to facilitate future Industrial collaborations.

8. Benefit Industrial scientists through interactions with the CDT (e.g. training and supervisory experience, exposure to cutting-edge synthesis and catalysis etc).

9. Link with other activities in the landscape: bringing unique expertise in catalysis to, for example, externally-funded University-led initiatives, EPRSC Grand Challenge Networks, and the National Catalysis Hub.