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

在未来，高价值的分子必须在不使用昂贵、有毒和供应风险的金属催化剂的情况下高效地制备。此外，随着药物的立体化学信息变得更加丰富，有效地控制产品的3D形状(对映体控制)是至关重要的。作为新药和农用化学品以及合成试剂中的基元，装饰性苯并噻吩类化合物享有特殊的地位。然而，它们的制备方法往往需要不可持续的程序。为了应对这一挑战，我们最近学会了在无金属方法中将苯并噻吩类S氧化物用作无金属方法中的中间体，以及作为光催化无金属合成的试剂。关键的是，我们的研究和其他人的工作涉及外消旋苯并噻吩类S氧化物，因此利用硫基立体化学的对映选择性过程是不可能的。我们提出，最先进的酶催化氧化将允许以富对映体的形式获得苯并噻吩类S-氧化物，从而首次使它们能够用于反选择性无金属交叉偶联过程，从而可持续地构建用于工业开发的高价值产品。格林集团在生物催化方面的专业知识将使使用加氧酶将苯并噻吩酶氧化成富对映体的S氧化物的稀有文献先例发展成为一般的、可扩展的生物催化过程。然后，富含对映体的S氧化物将以两种方式进行利用(以宝洁集团的技术为基础)；首先，通过多种中间体，通过三组分耦合/脱芳烃序列将它们转化为具有丰富立体化学成分的产品。其次，它们将被用作底物的可回收激活剂，如炔烃，以提供富含对映体的硫盐8，用于与前手性亲核试剂的对映选择性无金属交叉偶联。我们的方法将结合生物/化学催化来提供固定定义的复杂的苯并噻吩类和小片段支架，如果不使用昂贵的、有毒的和供应风险的金属催化剂(和昂贵的手性配体)，这些材料目前无法获得或无法制备。总体项目的目标将以几项研究成果为基础：i)开发新的生物催化氧化；ii)更好地理解苯并噻吩类S氧化物的化学及其构型稳定性；iii)旨在了解酶催化S氧化中选择性来源的计算力学研究。在计算化学的关键支持下，无金属偶联和生物催化领域的领先者将首次联合起来，汇集他们互补的专业知识。学生将接受独特的培训：生物催化(Green)和有机硫化学(Procter)。

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).