Development of selective enzyme catalysed phenol couplings

“该项目的目的是开发酶催化的酚类分子间和分子内偶联，以获得天然产物样支架，用于天然产物合成和药物发现。该项目将涉及新酶的产生和它们在酚类偶联中的功效评估。特别是，区域选择性和对映体选择性的耦合问题将是这项工作的一个主要焦点。苯酚偶联反应是酶用于制备次生代谢产物（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。化学空间作图研究表明，天然产物和药物占据相似的化学空间，因此开发新的合成方法以获得新的类天然产物化合物对药物发现的未来至关重要。合成化学家在酚氧化偶联反应领域取得了许多进展，并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使用高负载的昂贵的过渡金属催化剂、金刚石电极或化学计量的氧化剂，这些氧化剂不是原子经济的。重要的是，许多苯酚偶联模式仍然无法实现，单取代苯酚的偶联特别困难。酶的定向进化是一项获得诺贝尔奖的技术，它允许快速产生新的酶。在本计画中，我们将利用序列饱和突变技术来产生新的酵素。这些酶将在酚类的区域选择性偶联中进行评价，以开发一系列联芳基化合物的简便途径。特别是，具有不容易通过化学催化获得的偶联模式的化合物的产生将是有针对性的。"

"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."