Chemo- and enantioselective routes to chiral fluorinated hydroxyketones using ketoreductases
Brendan T Grau1, Paul N Devine, Lisa N DiMichele
1Department of Process Research, Merck Research Laboratories, Merck and Co., Inc., PO Box 2000, Rahway, New Jersey 07065, USA. brendan_grau@merck.com
Abstract:
Chiral fluorinated hydroxyketones were synthesized with excellent ee (>98%) and yield by a chemo- and stereoselective reduction of prochiral methyl/trifluoromethyl diketones using commercially available ketoreductase enzymes. By using p- and m-trifluoroacetyl substituted acetophenones, we demonstrate that ketoreductases can selectively differentiate between methyl and trifluoromethyl ketones within the same molecule. As a result, useful catalysts were identified that eliminated the need for costly and time-consuming protection/deprotection of the ketone moiety, enabling a more convergent synthesis of hydroxyketones. Further, a route to chiral methyl hydroxyketones is provided where an enzyme selectively reduces the unactivated ketone.
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