Regio- and enantiodivergent oxidations performed with cryptic Baeyer-Villiger monooxygenases from Aspergillus flavus

FELIX M FERRONI

Port Edward

Congreso; 24th Anual Conference. Catalysis Society of South Africa; 2013

Catalysis Society of South AFrica

Baeyer-Villiger monooxygenases (BVMOs) are valuable oxidative biocatalysts that catalyze the oxidation of ketones to esters or lactones using NAD(P)H as electron donor and molecular oxygen as oxidative reactant [1]. These enzymes are also able to catalyze epoxidation [2] and sulfoxidiation reactions [3]. Due to the mild reaction conditions and often high chemo, regio- and enantioselectivity displayed by BVMOs, their use in synthetic chemistry offers a versatile alternative for the synthesis of optically pure esters or lactones through desymmetrization of prochiral ketones and oxidative kinetic resolution of racemic substrates. Herein we describe the identification and characterization of the products of 4 putative genes that code for BVMOs from the fungus Aspergillus flavus. We have cloned and expressed the 4 BVMOs (AFL210, AFL456, AFL619 and AFL838) in Escherichia coli and performed activity screening against a wide range of substrates including several cyclic, bicyclic and linear ketones. AFL210 showed the broadest substrate scope, accepting several cyclic, aliphatic, aromatic and bicyclic ketones. The regio-selectivity of AFL210 was investigated using 2- and 3-methyl substituted cyclohexanone. Unlike the well-characterized cyclohexenone monoxygenase from Acinetobacter, AFL210 produce only the ?normal? lactone from 3-methylcyclohexanone. It was also able to give a mixture of sulfoxide and sulfone by sulfoxidation of thioanisole, whereas AFL456 only produced the sulfoxide. Desymmetrization of prochiral 4-substituted cyclohexanone substrates by AFL210 proceeded to high enantiomeric excesses. AFL456 and AFL838 proved to be excellent catalysts for the BV conversions of various aromatic ketones, including phenylacetone, acetophenone and hydroxyacetophenone, and linear ketones up to 2-undecanone. Regio- and enantiodivergent oxidation of rac-bicyclo[3.2.0]hept-2-en-6-one was observed between the different BVMOs, with kinetic resolution of the substrate achieved with 3 of the 4 BVMOs. References [1] H. Leisch, K. Morley and P.C.K.Lau, Chem Rev 111 (2011) 4165-4222. [2] S. Colonna, N. Gaggero, G. Carrea, G. Ottolina, P. Pasta, F. Zambiachini, Tet Lett 43 (2002) 1797-1799. [3] P.B. Brondani, G. De Gonzalo, M.W. Fraaije, L.H. Andrade, Adv Synth Catal 353 (2011) 2169-2173.