Stereoselective Reduction of α‐Fluoro‐β‐keto Esters by NADH and NADPH‐Dependent Ketoreductases

• Published in: European journal of organic chemistry Vol. 2019; no. 25; pp. 4080 - 4084
• Main Authors: Green, Thomas K., Damarancha, Anil, Vanagel, Matthew, Showalter, Brandon, Kolberg, Sandra, Thompson, Alexander
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 07.07.2019
• Subjects: Enantioselectivity; Enzymes; Esters; Ketoreductases; Nicotinamide adenine dinucleotide; NMR spectroscopy; Stereoselectivity; Substrates; Synthesis design
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201900644

Racemic α‐fluoro‐β‐keto esters were stereoselectively transformed to α‐fluoro‐β‐hydroxy esters through dynamic reductive kinetic resolution (DYRKR) using commercially available NAD(P)H‐dependent ketoreductases. Aromatic, alkenyl, and alkyl substrates were all reduced in high optical purities and yields. For most substrates, either anti or syn diastereomers could be produced with high enantiomeric excess, depending on the enzyme employed. The enzyme reactions with ethyl α‐fluoroacetoacetate were conveniently monitored in real time by in situ 19F NMR spectroscopy. These commercially available enzymes provide convenient access to stereoisomers of α‐fluoro‐β‐hydroxy esters from easily accessible racemic substrates. Dynamic reductive kinetic resolution is applied toward the synthesis of α‐fluorinated‐β‐hydroxy esters using a set of commercially available ketoreductases. In many examples, the reactions are rapid (<1 h) and quantitative with high de and ee. 19F NMR spectroscopy proves useful for analysis of stereochemistry using in‐tube Mosher ester derivatization.