Development of selective enzyme catalysed phenol couplings

点击翻译按钮获取中文摘要

"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."