Merging Photocatalysis with Biocatalysis to Access Unexplored Chemical Space (hvBIOCAT)

In this project, we aim to combine the power of enzymatic C-H bond functionalisation and photoredox/Ni dual catalysis to construct complex molecules in a single reaction providing new, more efficient and rapid routes to pharmaceuticals and other essential products. For example, bespoke engineered halogenase enzymes will be used to regioselectively install halogen substituents into complex aromatic scaffolds with in situ photoredox/Ni dual catalysis enabling concomitant construction of new C(sp2)-C(sp3) and C(sp2)-heteroatom bonds that are inaccessible via current state-of-the-art synthetic methods.
Biocatalysis and photocatalysis have emerged as the two most fruitful and dynamic catalytic approaches for creating new reactivity to enable rapid construction of complex target molecules. Enzymes typically possess exquisite enantio-, regio- and chemoselectivity, obviating the need for protecting group manipulation and operate under mild/benign/sustainable conditions. Directed evolution approaches can also be used to rapidly improve the properties of enzymes for synthetic applications [1, 2]. New photocatalytic systems, particularly metalla-photoredoxcatalysis, can also operate under mild aqueous conditions providing access to radical species and unprecedented reaction mechanisms/pathways [3,4]. Despite the power and synergy of these two catalytic regimes, the potential for integrating the two has been largely unexplored [5]. Previously, we demonstrated how highly regioselective flavin-dependent halogenase (Fl-Hal) enzymes, that use benign inorganic halides, are an attractive alternative to traditional toxic and nonselective chemical halogenation methods [6-12]. We showed that regiodivergent tryptophan halogenases (Trp-Hal) can halogenate a range of indoles, anilines and phenolic substrates [7-12] with high regioselectivity. We also used active site mutagenesis to improve catalytic activity of Trp-Hal and we were able to switch the regioselectivity of these enzymes with various non-natural substrates [8,9]. In addition, we have explored the biocatalytic potential of fungal halogenases, showing how RadH, and engineered variants, can regioselectively halogenate a wide range of aryl and heteroaryl compounds [12]. Finally, we succeeded in integrating Fl-Hal with chemocatalysts to open up new reaction pathways in vitro [7]. We demonstrated, for the first time, the integration of Fl-Hal with transition metal-catalysed cross-coupling chemistry, in one-pot, to achieve regiodivergent arylation or alkenylation of aromatic scaffolds. These tandem, regioselective biohalogenation-arylation cascades, which are not possible using solely biocatalysis or chemocatalysis, can be carried out under mild, aqueous and benign conditions generating products in good yields, using a PDMS membrane to compartmentalise the incompatible enzymes and TM-catalysts [7]. In addition, we recently developed one-pot Fl-Hal mediated cyanation reactions.
hvBIOCAT aims to build on our previous success to develop methods for combining halogenases with photoredox/Ni dual catalysis in one pot integrated reactions, delivering new C(sp2)-C(sp3) and C(sp2)-heteroatom cross coupling reactions that are not achievable using the currently available catalytic methods. Over many years, we have established a library of robust engineered Fl-Hal that can regioselectively halogenate a large range of aromatic substrates, including pharmaceutically relevant scaffolds (for a few examples see Fig 1B). Consequently, the project will initially focus on optimising the chemocatalysts for integration with Fl-Hal, screening various Ni-complexes with different organic (metal free) photocatalysts (PC), such as 4CzlPN (Fig. 1A). If there are any compatibility issues, we will implement methods for compartmentalising the biocatalysts from the chemocatalysts using membranes, catalyst immobilisation/encapsulation, addition of green organic co-solvents, or surfactants/micelles etc. (...)

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.