Chemo- and enantioselective routes to chiral fluorinated hydroxyketones using ketoreductases.
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.
Grau
Brendan T
BT
Department of Process Research, Merck Research Laboratories, Merck and Co., Inc., PO Box 2000, Rahway, New Jersey 07065, USA. brendan_grau@merck.com
Devine
Paul N
PN
DiMichele
Lisa N
LN
Kosjek
Birgit
B
D002384:Catalysis; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry; D010088:Oxidoreductases / Q000737:chemistry*; D013237:Stereoisomerism; D013997:Time Factors
D006845:Hydrocarbons, Fluorinated; D007659:Ketones; D010088:Oxidoreductases