Enzymatic activation of benzothiophenes for enantioselective metal-free cross-coupling

In the future, high-value molecules must be prepared efficiently without the use of expensive, toxic and supply-risk metal catalysts. Furthermore, efficient control of the 3D shape of products ('enantiocontrol') is crucial as medicines, for example, become richer in stereochemical information. Decorated benzothiophenes enjoy a privileged status as a motif found in new medicines and agrochemicals and in reagents for synthesis. However, methods for their preparation often require unsustainable procedures. To address this challenge, we have recently learned to exploit benzothiophene S-oxides as intermediates in metal-free approaches to decorated benzothiophenes and also as reagents for metal-free synthesis mediated by light Crucially, our studies, and the work of others, has involved racemic benzothiophene S-oxides and enantioselective processes exploiting stereochemistry at sulfur are therefore not possible.
We propose that state-of-the-art enzymatic oxidation will allow access to benzothiophene S-oxides in enantioenriched form, thus allowing - for the first time - their use in enantioselective metal-free cross-coupling procedures for the sustainable construction of high-value products for industrial exploitation. The Green group's expertise in biocatalysis will allow scarce literature precedent for the enzymatic oxidation of benzothiophenes to enantioenriched S-oxides using oxygenases to be developed into general, scalable biocatalytic processes. The enantioenriched S-oxides will then be leveraged in two ways (building upon Procter group technology); firstly, they will be converted, via versatile intermediates, into stereochemically-rich products through a three-component coupling/dearomatisation sequence. Secondly, they will be used as recyclable activators of substrates, such as alkynes, to give enantioenriched sulfonium salts 8 for use in enantioselective metal free cross-couplings with prochiral nucleophiles.
Our approach will integrate bio/chemo catalysis to deliver stereodefined, complex benzothiophenes and small fragment scaffolds that are either currently unavailable or cannot be prepared without recourse to the use of expensive, toxic and supply-risk metal catalysts (and expensive chiral ligands). The overarching project aims will be underpinned by several research outcomes; i) the development of new biocatalytic oxidations; ii) an improved understanding of the chemistry of benzothiophene S-oxides and their configurational stability, and; iii) computational mechanistic studies aimed at understanding the origin of selectivity in enzymatic S-oxidation. With crucial support in computational chemistry, leaders in metal-free couplings and biocatalysis will join forces for the first time and pool their complementary expertise. The student will receive a unique training: biocatalysis (Green) and organosulfur chemistry (Procter).

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.