Chemoenzymatic Synthesis of Apremilast: A Study Using Ketoreductases and Lipases

The key step in the chemoenzymatic synthesis of apremilast was to produce chiral alcohol (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol, (R)-3. Two enzymatic approaches were evaluated obtain (R)-3, one using ketoreductases and other lipases. Bioreduction 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (2), ketoreductase KRED‑P2-D12, led (R)-3 with 48% conversion 93% enantiomeric excess (ee). Kinetic resolution rac-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl acetate (rac-4), via hydrolysis reaction, 20% n-butanol, catalyzed by lipase from Aspergillus niger yielded > 99% ee, 50% E-value (enantiomeric ratio) 200. reaction between enantiomerically pure 4-acetylamino-isoindol-1,3-dione (8) afforded 65% yield 67% ee.