Chemoselective C-4 aerobic oxidation of catechin derivatives catalyzed by the trametes villosa laccase/1-hydroxybenzotriazole system: synthetic and mechanistic aspects

J. Org. Chem. 2011, 76, 820-832 Published on Web 01/04/2011 DOI: 10.1021/jo101886s r2011 American Chemical Society pubs.acs.org/joc Chemoselective C-4 Aerobic Oxidation of Catechin Derivatives Catalyzed by the Trametes villosa Laccase/1-Hydroxybenzotriazole System: Synthetic and Mechanistic Aspects Roberta Bernini,+,* Fernanda Crisante,+ Patrizia Gentili,?,* Fabio Morana,? Marco Pierini,§ and Monica Piras§ +Dipartimento di Agrobiologia e Agrochimica, Universita degli Studi della Tuscia, Via S. Camillo De Lellis, 01100 Viterbo, Italy, ?Dipartimento di Chimica and IMC-CNR Sezione Meccanismi di Reazione, Universita degli Studi La Sapienza, P. le A. Moro 5, I-00185 Roma, Italy, and §Dipartimento di Chimica e Tecnologia del Farmaco, Universita degli Studi La Sapienza, P. le A. Moro 5, I-00185 Roma, Italy berninir@unitus.it; patrizia.gentili@uniroma1.it Received October 6, 2010 Catechin derivatives were oxidized in air in the presence of the Trametes villosa laccase/1-hydroxybenzotriazole (HBT) system in buffered water/1,4-dioxane as reactionmedium. The oxidation products, flavan- 3,4-diols and the corresponding C-4 ketones, are bioactive compounds and useful intermediates for the hemisynthesis of proanthocyanidins, plant polyphenols which provide beneficial health properties for humans. Determinations of oxidation potentials excluded that catechin derivatives could be directly oxidized by laccase Cu(II), while it resulted in the H-abstraction from benzylic positions being promptly promoted by the enzyme in the presence of the mediator HBT, the parent species producing in situ the reactive intermediate benzotriazole-N-oxyl (BTNO) radical. A remarkable and unexpected result for the laccase/HBT oxidative system has been the chemoselective insertion of the oxygen atom into the C-4-H bond of catechin derivatives.Mechanistic aspects of the oxidation reaction have been investigated in detail for the first time in order to corroborate these results. Since the collected experimental findings could not alone provide information useful to clarify the origin of the observed chemoselectivity, these data were expressly supplemented with information derived by suitable molecular modeling investigations. The integrated evaluation of the dissociation energies of theC-Hbonds calculated both by semiempirical and DFT methods and the differential activation energies of the process estimated by a molecular modeling approach suggested that the observed selective oxidation at the C-4 carbon has a kinetic origin.