Enzymatic Activation Of Benzothiophenes For 3D Shape-Selective Metal-Free Cross-Coupling

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In a future where sustainability will be paramount, high-value molecules must be selectively prepared in an expedient fashion, without recourse to the use of expensive, toxic and supply-risk metal catalysts. Furthermore, efficient control of the 3D shape of products ('enantiocontrol') is crucial as drugs - for example - become richer in stereochemical information (more 3D). Decorated benzothiophenes - in particular those bearing an aryl group at the C3 position - enjoy a privileged status in the development of new medicines, agrochemicals, and materials for molecular electronics. Unfortunately, methods for the introduction of aryl substituents at the C3 position in benzothiophenes - examples of so-called 'cross-coupling' reactions - are scarce and the current-state-of-the-art requires expensive, platinum group metals whose supply is at risk, and their use, therefore, is unsustainable. To address this challenge, we recently developed a metal-fee approach that exploits activation of the benozthiophene scaffold by oxidation of the sulfur atom to give benzothiophene S-oxides. We have shown that these little-studied sulfoxide intermediates undergo cross-coupling with phenol partners to give important C3 aryl benzothiophenes.1,2,3 In this project, we will use our expertise in biocatalysis and enzyme engineering to transform sparse literature precedent for the enzymatic oxidation of benzothiophenes to enantioenriched S-oxides using oxygenases into general, scalable biocatalytic processes. Our chemocatalytic technology will then be adapted to convert the enantioenriched S-oxides into important C3 aryl benzothiophene products containing a chiral axis or stereochemically-rich products of three-component coupling/dearomatisation. Crucially, our complementary expertise in bio- and chemocatalysis will be underpinned by leading computational (bio)chemistry. Thus, the innovative marriage of enzymatic oxidation and metal-free chemical methods for cross-coupling will allow - for the first time - control of 3D shape during construction of high-value benzothiophene products for industrial exploitation.