Scaling-Up of “Smart Cosubstrate” 1,4-Butanediol Promoted Asymmetric Reduction of Ethyl-4,4,4-trifluoroacetoacetate in Organic Media

Biocatalytic asymmetric reduction of ethyl-4,4,4-trifluoroacetoacetate under water-deficient reaction conditions using a “smart cosubstrate” 1,4-butanediol was demonstrated up to a 2 L scale. Substrate concentrations of 100 g/L were applied by using half-molar equivalent of 1,4-butanediol in methyl-tert-butylether (MTBE). Using this approach, full conversion of ethyl-4,4,4-trifluoroacetoacetate to the corresponding (S)-alcohol with an excellent enantiomeric excess (ee) of ≥99% was accomplished in 5 days. 150 g of isolated enantiopure product with high purity (94%) was obtained.