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

在可持续发展将是最重要的未来，必须以一种权宜之计的方式选择性地制备高价值分子，而不是使用昂贵、有毒和供应风险高的金属催化剂。此外，有效控制产品的3D形状(“对映体控制”)是至关重要的，因为药物--例如--的立体化学信息变得更加丰富(更多的是3D)。修饰的苯并噻吩类化合物--尤其是那些在C3位置含有芳基的化合物--在新药、农用化学品和分子电子材料的开发中享有特殊地位。不幸的是，在苯并噻吩类化合物的C3位引入芳基取代基的方法--所谓的“交叉偶联”反应的例子--很少，而且目前的技术水平需要昂贵的铂族金属，其供应受到威胁，因此，它们的使用是不可持续的。为了应对这一挑战，我们最近开发了一种金属-FeE方法，该方法利用苯并噻吩类支架上硫原子的氧化活化来得到苯并噻吩类S氧化物。我们已经证明了这些很少研究的亚砜中间体与苯酚伙伴发生交叉偶联得到重要的C3芳基苯并硫酚。1，2，3在这个项目中，我们将利用我们在生物催化和酶工程方面的专业知识，将稀有的文献先例转化为使用加氧酶将苯并硫苯催化氧化成对映体富集型S-氧化物的一般可扩展的生物催化过程。然后，我们的化学催化技术将适用于将富含对映体的S氧化物转化为重要的C3芳基苯并噻吩类产品，这些产品包含一个手性轴或三组分偶合/脱芳烃的立体化学丰富的产品。至关重要的是，我们在生物和化学催化方面的互补专业知识将得到领先的计算(生物)化学的支持。因此，酶催化氧化和无金属化学交叉偶联方法的创新结合将首次允许在构建用于工业开发的高价值苯并噻吩类产品期间控制3D形状。

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.