Chemoenzymatic synthesis of an Odanacatib precursor through a Suzuki‐Miyaura cross coupling and bioreduction sequence

A series of 1-aryl-2,2,2-trifluoroethanones has been chemically synthesized to later study their bioreduction using stereocomplementary alcohol dehydrogenases (ADHs). Satisfyingly, (R)-alcohols were obtained in high conversions and selectivities using the ADH from Ralstonia species and the one from Rhodococcus ruber, while the (S)-enantiomers were independently produced using the ADH from Lactobacillus brevis and the commercially available evo-1.1.200. In the search for a stereoselective route towards the Odanacatib, an orally bioavailable and selective inhibitor of Cathepsin K, the development of a sequential methodology combining a palladium-catalyzed cross coupling between 1-(4-bromophenyl)-2,2,2-trifluoroethanone and 4-(methylsulfonyl)phenylboronic acid in aqueous medium with the bioreduction of the resulting 2,2,2-trifluoro-1-(4 '-(methylsulfonyl)-[1,1 '-biphenyl]-4-yl)ethanone has been extensively studied. Finally, the desired (R)-2,2,2-trifluoro-1-(4 '-(methylsulfonyl)-[1,1 '-biphenyl]-4-yl)ethanol was obtained in enantiomerically pure form and 85 % yield with a 128 g L-1 d(-1) productivity following a sequential approach.