Synthesis of (R)-bambuterol based on asymmetric reduction of 1-[3,5-bis(dimethylcarbamoyloxy)phenyl]-2-chloroethanone with incubated whole cells of Williopsis californica JCM 3600

• W. californica reduced 1-[3,5-bis(dimethylcarbamoyloxy)phenyl]-2-chloroethanone to give (R)-alcohol.
• Substrate for the reduction was easily prepared by chemo-enzymatic procedure from commercially available 1-(3,5-diacetoxyphenyl)ethanone.
• Addition of glycerol (10%, v/v) assisted the co-factor regeneration as well as the dissolution of the crystalline substrate.
• The product was transferred to enantiomerically pure (R)-bambuterol, a prodrug of (R)-terbutalin.
• Seven-step synthesis of (R)-bambuterol was achieved from commercially available material in total 30% yield.

To achieve the synthesis of (R)-bambuterol, a prodrug of (R)-terbutaline, asymmetric reduction of 1-[3,5-bis(dimethylcarbamoyloxy)phenyl]-2-chloroethanone with whole cells of Williopsis californica JCM 3600 pre-incubated on glycerol as a carbon source was examined. Initially, the insolubility of this crystalline substrate (mp 126–127 °C) in the incubation broth was an obstacle that needed to be overcome. To solve the problem, the concentration of glycerol was increased to 10% during reduction. Glycerol worked well for recycling oxido-reduction cofactors and for enhancing the water solubility of the substrate. The reduction proceeded smoothly to give enantiomerically pure (R)-alcohol in 81% isolated yield.

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