Development of selective enzyme catalysed phenol couplings

这个项目的目的是开发酶催化的苯酚分子间和分子内偶联，以获得天然产品类支架，用于天然产品合成和药物发现。该项目将涉及新酶的产生和对其在苯酚偶联中的有效性的评估。特别是，偶联中的区域选择性和对映体选择性问题将是这项工作的主要重点。苯酚偶联反应是酶用于制备次生代谢物(即天然产物)和生物聚合物(如木质素和黑色素)的主要过程之一。化学空间图谱研究表明，天然产物和药物占据着相似的化学空间，因此开发合成方法来获得新的天然产物类化合物对未来的药物发现至关重要。合成化学家在氧化苯酚偶联反应领域取得了许多进展，制备了各种各样的手性配体和天然产物。不幸的是，这些努力主要依赖于高负载昂贵的过渡金属催化剂、钻石电极或化学计量比氧化剂的使用，这些都不是原子经济的。关键的是，许多苯酚偶联模式仍然无法获得，单取代苯酚的偶联尤其困难。酶的直接进化是一项诺贝尔奖获得者的技术，它允许快速产生新的酶。在这个项目中，我们将使用序列饱和突变技术来产生新的酶。然后，这些酶将在酚类的区域选择性偶联中进行评估，以便开发一种方便地获得一系列联芳基的途径。特别是，将针对产生具有化学催化不易获得的耦合模式的化合物。“

"The purpose of this project is to develop enzyme catalysed inter- and intramolecular couplings of phenols to access natural product-like scaffolds for natural product synthesis and drug discovery. The project will involve the generation of novel enzymes and the evaluation of their efficacy in couplings of phenols. In particular, issues of regioselectivity and enantioselectivity in the couplings will be a major focus of this work. Phenol coupling reactions are one of the main processes used by enzymes to prepare secondary metabolites (i.e. natural products) and biopolymers such as lignin and melanin. Chemical space mapping studies have shown that natural products and drugs occupy similar chemical space, therefore developing synthetic methods to access novel natural product-like compounds is of critical importance to the future of drug discovery.Synthetic chemists have made many advances in the field of oxidative phenol coupling reactions and a diverse assortment of chiral ligands and natural products have been prepared. Unfortunately, these efforts mostly rely on the use of high loadings of expensive transition metal catalysts, diamond electrodes, or stoichiometric oxidants that are not atom economical. Crucially, many phenol coupling patterns remain inaccessible, and couplings of mono-substituted phenols are particularly difficult.Directed evolution of enzymes is a Nobel prize winning technique that allows for the rapid generation of novel enzymes. In this project, we will use sequence saturation mutagenesis techniques to generate novel enzymes. These enzymes will then be evaluated in the regioselective coupling of phenols in order to develop a facile access to a range of biaryls. In particular, the generation of compounds with coupling patterns not readily accessible by chemocatalysis will be targeted."