The bakers' yeast reduction of 3-oxo-3-phenylpropanenitrile (1) has been difficult to achieve due to a dominant alkylating mechanism. A library of 18 bakers' yeast reductases, that are overexpressed in E. coli, were screened against (1). Four enzymes were found to reduce this substrate and by varying the enzyme both enantiomers of 3-hydroxy-3-phenylpropanitrile (2) could be prepared with high enantiomeric excess. In addition, the E. coli whole-cell system can be optimized to nearly eliminate the competing alkylating mechanism. By using this system, a formal biocatalytic synthesis of both antipodes for the serotonin reuptake inhibitors Prozac®, atomoxetine, and nisoxetine has been demonstrated.