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

在未来，可持续性将是最重要的，高价值分子必须有选择地以权宜之计的方式制备，而不是求助于使用昂贵、有毒和供应风险的金属催化剂。此外，有效控制产品的三维形状（“对映体控制”）是至关重要的，例如，药物的立体化学信息变得更丰富（更多的三维）。修饰苯并噻吩，特别是那些在C3位置上有芳基的苯并噻吩，在新药、农用化学品和分子电子学材料的开发中享有特殊地位。不幸的是，在苯并噻吩的C3位置引入芳基取代基的方法——所谓的“交叉偶联”反应的例子——很少，而且目前最先进的方法需要昂贵的铂族金属，而铂族金属的供应存在风险，因此它们的使用是不可持续的。为了解决这一挑战，我们最近开发了一种金属费方法，通过氧化硫原子来激活苯并噻吩支架，得到苯并噻吩s -氧化物。我们已经证明，这些很少被研究的亚砜中间体与苯酚偶联产生重要的C3芳基苯并噻吩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，将利用加氧酶将苯并噻吩酶氧化为对映体富集s -氧化物的稀疏文献先例转化为一般的、可扩展的生物催化过程。然后，我们的化学催化技术将被用于将富集对映体的s -氧化物转化为含有手性轴的重要C3芳基苯并噻吩产品或三组分偶联/脱芳化的立体化学富集产品。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，酶氧化和无金属化学交叉耦合方法的创新结合将首次允许在工业开发的高价值苯并噻吩产品的构建过程中控制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.