Integrated Bio-photocatalysis for Asymmetric sp3-Arylation

The integration of chemo- and biocatalysis offers a sustainable approach to making molecules which enables waste-free synthesis, catalytic or metal-free alternatives to current reagents, and a new way of building up molecular complexity whilst simplifying process complexity and cost. Approaching synthesis from this perspective will be critical to future chemistry, where all inter-related factors (reagents, solvent, yields, intermediates, catalysts etc) can be systemically optimized for the best synthetic route. The challenges, however, are substantial - how can we create mutually compatible reaction conditions for both enzymes and chemo systems, given the often vastly different requirements (notably of temperature and solvent)?
This project will invent new, integrated arylation technologies that exploit readily available sulfonamides as powerful amphiphilic synthons for metal free arylation [1]. These transformations have a number of notable aspects: They are transition metal free, operating under very simple, user-friendly conditions; the sulfonamide starting materials are cheap and widely commercially available; they form two pivotal connections for functional molecules (C-N and C-Ar bonds), and conceptually represent a new way of looking at the sulfonamide structure as a synthon in chemistry - the SO2 moiety as a traceless linker for an electrophilic arene and a nucleophilic nitrogen atom.
We will develop this chemistry as a general tool for simultaneous C-N and C-Aryl bond formation, an extremely powerful combination. We will conduct a full survey of electrophilic coupling partners that can react in this domino process, building on preliminary results with alkyl halides (A), biaryl synthesis via functionalized aryne precursors (B), photoredox arylation via decarboxylation (C) and electron donor-acceptor complexes (D). We will introduce new electrophiles (e.g. alkenes, diazos, carbonyls) to further grow this chemistry into a portfolio of arylation transformations that are amenable to asymmetric biocatalysis.
sp3-Aryl structures are privileged motifs in medicinal chemistry and represent high-value building blocks in enantioenriched form. The metal free quality of the Smiles presents exciting possibilities for integrated processes, as many will proceed under simple, mildly basic conditions, and thus may not require the membrane compartmentalisation that is often required for merging TM-chemocatalysis with biocatalysis. e.g. desymmetrising biohalogenation [2] is well-suited to the benzyhydryl derivatives we plan to produce from photoredox radical Smiles chemistry. Integrated SN2 Smiles / arylmalonate decarboxylase (AMD) desymmetrisation [3] would deliver chiral phenylglycine derivatives, whilst acyl chloride Smiles reaction would give a symmetrical benzyhydryl, that could be hydrolyzed to the primary amide using a nitrile hydratase. These enzymes are particularly robust, being employed on kiloton scale in industry,[4] and have great potential in chemo-biocatalytic transformations that can create new asymmetric transformations. The sp2 Smiles route to biaryls and enaminoate structures sets up a powerful route to chiral beta amino acids through reduction. We have achieved this using chemical hydrogenation, using an expensive Pt catalyst - we will study an integrated process using ene reductase enzymes.
Overall the project will deliver a powerful asymmetric arylation method having broad scope, with the integrated catalysis approach enabling transformations that would not be possible using chemo- or bio-catalysis alone. The potential range of electrophile, and simplicity of reaction conditions, creates a sustainable synthetic method to produce the molecules of tomorrow in medicine, materials and agroscience.
** References and scheme available on request **

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.