Dynamic kinetic resolution of α-substituted β-ketoesters catalyzed by Baeyer-Villiger monooxygenases: access to enantiopure α-hydroxy esters.

Biocatalytic procedures can circumvent some of the drawbacks that classical methodologies present in chemical synthesis. One example is shown by the Baeyer-Villiger (BV) reaction, a process discovered more than 100 years ago that consists in the nucleophilic insertion of one atom of oxygen in the adjacent position of a carbonyl moiety affording esters or lactones. This reaction proceeds using peroxides or peracids as oxidants with, in general, low selectivity, employing labile and shock-sensitive compounds that do not match with the principles of the Green Chemistry. Baeyer-Villiger monooxygenases (BVMOs, 1.14.13.x) represent an effective alternative to perform the BV reaction. These biocatalysts are nicotinamide dependent flavoenzymes that convert linear or cyclic ketones into esters and lactones, respectively, using molecular oxygen as mild oxidant. In general, BVMOs display excellent chemo-, regioand/or enantioselectivities while using environmentally friendly reaction conditions. BVMOs have been widely used in the desymmetrisation or the kinetic resolution of cyclic and bicyclic ketones, as well as linear aliphatic and alkyl aryl ketones. Recently, several BVMOs from different bacterial origin were employed in the enzymatic kinetic resolution of a set of aliphatic β-hydroxyketones and βaminoketones, valuable synthons in the preparation of optically active diols and amino acids, respectively, via regioselective Baeyer–Villiger oxidation. Herein we investigate whether aliphatic acyclic racemic α-alkyl-β-ketoesters are accepted as substrates by BVMOs. Interestingly, since spontaneous racemisation of the starting material occurs, this allowed us to perform an effective BVMO-catalysed dynamic kinetic resolution (DKR). Such effective BVMO-based DKR provides a new catalytic pathway for the synthesis of high-valuable enantiopure α-acylated hydroxy esters (Scheme 1). These compounds are important intermediates that can easily be turned into enantioenriched α-hydroxy acids, very interesting derivatives well-known for their use in the cosmetic industry. They can also be selectively hydrolysed into the corresponding αhydroxy esters, versatile products that find application in the chemical, food and pharmaceutical industry, as e.g. anticancer drugs, antibiotics and other bioactive natural derivatives. Alkyl hydroxy esters are also employed as useful building blocks of numerous highly valuable compounds. Three BVMOs were selected to perform the selective BaeyerVilliger reaction of the starting material: phenylacetone monooxygenase (PAMO) from Thermobifida fusca, its M446G mutant and 4-hydroxyacetophenone monooxygenase (HAPMO) from Pseudomonas fluorescens ACB, being achieved the best results with the two wild-type enzymes. It is worth noting that these biocatalysts are primarily active on aromatic compounds and have been mainly employed in the synthesis of enantioenriched aromatic sulfoxides, ketones and esters. In this study, we show that these biocatalysts also accept non-aromatic substrates.