Regioselective preparation of 5-hydroxypropranolol and 4´-hydroxydiclofenac with a fungal peroxygenase

Abstract

An extracellular peroxygenase of Agrocybe aegerita catalyzed the H₂O₂-dependent hydroxylation of the multi-function beta-adrenergic blocker propranolol (1-naphthalen-1-yloxy-3-(propan-2-ylamino)-propan-2-ol) and the non-steroidal anti-inflammatory drug diclofenac (2-[2-[(2,6-dichloro-phenyl)amino]phenyl]acetic acid) to give the human drug metabolites 5-hdroxypropranolol (5-OHP) and 4'-hydroxydiclofenac (4'-OHD). The reactions proceeded regioselectively with high isomeric purity and gave the desired 5-OHPand 4'-OHD in yields up to 20% and 65% respectively. ¹⁸O-labeling experiments showed that the phenolic hydroxyl groups in 5-OHP and 4'-OHD originated from H₂O₂ which establishes that the reaction is mechanistically a peroxygenation. Our results raise the possibility that fungal peroxygenases may be useful for versatile, cost-effective, and scalable syntheses of drug metabolites.

Citation

Kinne, Matthias; Poraj-Kobielska, Marzena; Aranda, Elisabet; Ullrich, Rene; Hammel, Kenneth E.; Scheibner, Katrin; Hofrichter, Martin. 2009. Regioselective preparation of 5-hydroxypropranolol and 4´-hydroxydiclofenac with a fungal peroxygenase. Bioorganic & medicinal chemistry letters. Vol. 19, no. 11 (June 1, 2009): p. 3085-3087.