Chemo- and Enantioselective Routes to Chiral Fluorinated Hydroxyketones Using Ketoreductases

• Published in: Organic letters Vol. 9; no. 24; pp. 4951 - 4954
• Main Authors: Grau, Brendan T, Devine, Paul N, DiMichele, Lisa N, Kosjek, Birgit
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.11.2007; Amer Chemical Soc
• Subjects: Catalysis; Chemistry; Chemistry, Organic; Hydrocarbons, Fluorinated - chemical synthesis; Hydrocarbons, Fluorinated - chemistry; Ketones - chemical synthesis; Ketones - chemistry; Oxidoreductases - chemistry; Physical Sciences; Science & Technology; Stereoisomerism; Time Factors; KETONES; DIKETONES; STEREOSELECTIVE REDUCTION; DEHYDROGENASE
• ISSN: 1523-7060; 1523-7052
• DOI: 10.1021/ol701810v

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.