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

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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).