Regioselective o-Hydroxylation of Monosubstituted Benzenes by P450 BM3

摘要

Halogenated phenols are widely used building blocks in the synthesis of vitamins, lipid-lowering agents, and other drugs. Commonly, halogenated phenols are produced in chemosynthetic processes requiring energy-intensive downstream processing steps and hazardous chemicals, for example (Hg/Ti) acetate derivatives for the synthesis of iodophenol. Chloro- and bromophenols are produced by electrophilic halogenation reactions employing Br2 and Cl2, yielding mixtures of o- and p-phenol derivatives as well as additional by-products (e.g. dichlorophenol). Consequently, purification of isomeric products is required for drug synthesis. Guaiacol and its derivatives vanillin and eugenol are intermediates in the perfume and flavor industry and common antioxidants in the treatment of cancer, cardiovascular disorders, and Parkinson's and Alzheimer's diseases. Guaiacol can be isolated from plants or synthesized from catechol by reaction with stoichiometric amounts of NaOH in the presence of other corrosive reagents. The direct chemical hydroxylation of substituted benzenes is unattractive since oxygenation reactions on nonactivated C atoms are unselective and do not occur on the aromatic ring.