Ru-based metalloenzymes for asymmetric C-H functionalization

Transition-metal catalysis has been at the heart of tremendous advances in synthetic organic chemistry over the last half century. Developments such as Pd-cross-couplings (Nobel 2010), Ru-metathesis (Nobel 2005), asymmetric Ru-hydrogenations and Fe-epoxidations (Nobel 2001), Cu-click chemistry and, more recently, C-H activation chemistry have provided extremely powerful tools for chemists. However, with some exceptions, small molecule transition-metal catalysts are unable to provide the exquisite selectivity and extremely high reactivity that enzymes are generally capable of. On the other hand, the range of transformations possible from naturally occurring enzymes is but a fraction of what has been developed for small molecule transition-metal catalysts.
Artificial metalloenzymes (AMs) are metalloproteins where an abiotic metal cofactor is installed within a protein scaffold. Over the last two decades, rapid progress in the development of AMs has revealed enormous potential for the expansion of the toolset of reactions available to enzymes. In principle, one could dream of drawing from the vast breadth of reactivities afforded by homogeneous transition-metal catalysts, and harnessing the selectivity control, fine tuning and robustness of enzymes, to afford the ultimate synthetic tools. However, the range of genetically available aminoacids that can be used as ligands is small and not suitable for most desired applications. As an alternative, researchers have resorted to anchoring pre-assembled cofactors, but in this approach the accurate placement of the cofactor is challenging resulting in AMs of lower activity than the free cofactor. Thus the techniques allowing the move from a well-defined small molecule transition-metal catalyst to a next generation AM version are still in their infancy.
In the Larrosa group we have recently developed a novel class of small molecule Ru-catalysts that are able to mediate the C-H activation of aromatic compounds and functionalize them with aryl and alkyl electrophile coupling partners. However, while in many cases chiral compounds are generated in these reactions (either through the formation of a chiral centre or atropisomers) inducing enantioselectivity has not been possible, leading in all cases to racemic products. Furthermore, regio and/or chemoselectivity is often not achieved when two or more very similar positions are available for reaction in the coupling partners.
In this project we aim at developing a novel AM, containing a well-defined Ru-catalyst in its active site, that will be able to catalyse asymmetric C-H functionalization of aromatic compounds with a variety of coupling partners. To develop such a Ru-AM, we aim at exploring a novel approach towards AMs: moving away from natural aminoacids, we will employ advanced protein engineering methods to expand the type of ligands available to AMs. In particular, we will install in the protein a genetically encoded non-natural aminoacid bearing a suitable 'direct' ligand for Ru, which will allow for the formation of a AM where the position of the Ru in the active site is controllable through genetic manipulation. Such a AM will be amenable of optimization of its catalytic activity through directed evolution (Nobel 2018) of the enzyme on which the Green group specialises. Ultimately, these novel AMs will be used for catalysing the C-H arylation, alkylation and other functionalizations with control on regioselectivity and enantioselectivity, of substrates of importance from small building blocks for synthesis to larger biologically active molecules such as drugs.
The student will be trained in state-of-the-art chemocatalysis, including organometallic chemistry, organic chemistry and physical chemistry techniques for the design, synthesis and investigation of small molecule ruthenium based transition-metal catalysts & enzymology, genetically encoding of unnatural aminoacids, directed evolution and assessment of enzymatic reactions

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.