| Summary: | The lipase kinetic resolution (KR) of aryloxy-propan-2-yl acetates, via hydrolysis, produced enantiomerically pure/enantioenriched mexiletine intermediates and analogs. Racemic acetates <i>rac</i>-1-(2,6-dimethylphenoxy)propan-2-yl acetate (<i>rac</i>-<b>5a</b>), <i>rac</i>-1-(2,4-dimethylphenoxy)propan-2-yl acetate (<i>rac</i>-<b>5b</b>), <i>rac</i>-1-(<i>o</i>-tolyloxy)propan-2-yl acetate (<i>rac</i>-<b>5c</b>) and <i>rac</i>-1-(naphthalen-1-yloxy)propan-2-yl acetate (<i>rac</i>-<b>5d</b>) were used as substrates. A preliminary screening (24 h, phosphate buffer pH 7.0 with 20% acetonitrile as co-solvent, 30 °C and enzyme:substrate ratio of 2:1, m:m) was carried out with twelve lipases using acetate <b>5a</b> as substrate. Two enzymes stood out in the KR of <b>5a</b>, the Amano AK lipase from <i>Pseudomonas fluorescens</i> and lipase from <i>Thermomyces lanuginosus</i> (TLL) immobilized on Immobead 150. Under these conditions, both the (<i>R</i>)-1-(2,6-dimethylphenoxy)propan-2-ol [(<i>R</i>)-<b>4a</b>] and the remaining (<i>S</i>)-1-(2,6-dimethylphenoxy)propan-2-yl acetate [(<i>S</i>)-<b>5a</b>] were obtained with enantiomeric excess (<i>ee</i>) > 99%, 50% conversion and enantiomeric ratio (E) > 200. The KR study was expanded to racemic acetates <b>5b-d</b>, leading to the corresponding chiral remaining acetates with ≥95% <i>ee</i>, and the alcohols <b>4b-d</b> with ≥98% <i>ee,</i> and conversion values close to 50%. The best conditions for KRs of <i>rac</i>-<b>5b-d</b> involved the use of lipase from <i>P. fluorescens</i> or TLL immobilized on Immobead 150, 24 or 48 h and 30 °C. These intermediates had their absolute configurations determined using <sup>1</sup>H NMR spectroscopy (Mosher’s method), showing that the KRs of these acetates obeyed the Kazlauskas’ rule. Molecular docking studies corroborated the experimental results, indicating a preference for the hydrolysis of (<i>R</i>)-<b>5a-d</b>.
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