Asymmetric Reduction Of Ethyl4-chloro-3-oxobutanoate Using Baker's Yeast

Ethyl (S)-4-chloro-3-hydroxybutanoate ((S)-CHBE) is an important intermediate for the synthesis of Slagenins B and C and statin drugs (HMG-CoA) reductase inhibitors. It can also be reduced to β blocker of1,4-2-hydrogen pyridine derivatives. Study on the asymmetric reduction of ethyl4-chloro-3-oxobutanoate (ECOB) is of great importance in potential industrial applications and theoretical aspects. Compared with the chemical method, biological method had received great attention for environmentally friendly, mild reaction condition, high efficiency and high stereoselectivity. In the present work, baker's yeast was applied to catalyze ECOB to (S)-ECHB in the three systems, such as aqueous system, aqueous-organic solvent biphasic system and aqueous-ionic liquid biphasic system, respectively. The major results obtained in this study were as follows: Baker's yeast of Meishan brand showed the best result for the reduction of ECOB in the aqueous system. In the reduction, the main product was (S)-ECHB. Wet yeast had a higher value of e.e.(S), but the yield of product and conversion rate of reactant were significantly lower than dried yeast. Considering convenience of the actual operation, dried yeast was chosen as the catalyst in this study. Under the optimum conditions:dried baker's yeast40g/L, glucose0.5mol/L, temperature30℃, pH7.0, and shaking speed180r/min, the yield and the e.e.(S) value of (S)-ECHB reached42.9%and66.6%, respectively, after24h reaction.In order to improve the stereoselectivity of the asymmetric reduction of ECOB to (S)-ECHB, the queous-organic solvent biphasic systems were employed as reaction media in place of aqueous system. Based on the consideration of the yield and the e.e.(S) influenced by the organic solvent, the aqueous-isooctane biphasic system was chosen for the further experiments. Allyl bromide as an inhibitor was added to enhance the stereoselectivity of (S)-ECHB. Under the optimum conditions:Vaq/Vorg3/1(total volume30mL), dried baker's yeast50g/L, glucose0.6mol/L, allyl bromide0.12mol/L, ECOB0.08mol/L, temperature30℃, pH7.0, and shaking speed180r/min, the yield and the e.e. value of (S)-ECHB reached93.5%and92.3%, respectively, after24h reaction.Compared with the queous-organic solvent biphasic system, the aqueous-ionic liquid biphasic system could eliminate toxicity of organic solvent and make the convenience of product separation. Baker's yeast showed the best catalytic activity and enantioselectivity in the aqueous-[Bmim]PF6biphasic system among the biphasic systems. Under the optimum conditions:[Bmim]PF6180g/L, dried baker's yeast60g/L, glucose0.8mol/L, ECOB0.08mol/L, temperature30℃, pH7.0, and shaking speed180r/min, the yield and the e.e. value of (S)-ECHB reached92.6%and95.4%, respectively, after24h reaction.