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

Lead Research Organisation: University of Manchester
Department Name: Chemistry

Abstract

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. (...)

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/S023755/1 01/04/2019 30/09/2027
2279405 Studentship EP/S023755/1 01/10/2019 30/09/2023 Stanley Anselm Sowerby Thomas