Scale‐up and intensification of (S)‐1‐(2‐chlorophenyl)ethanol bioproduction: Economic evaluation of whole cell‐catalyzed reduction of o‐Chloroacetophenone

Escherichia coli cells co‐expressing genes coding for Candida tenuis xylose reductase and Candida boidinii formate dehydrogenase were used for the bioreduction of o‐chloroacetophenone with in situ coenzyme recycling. The product, (S)‐1‐(2‐chlorophenyl)ethanol, is a key chiral intermediate in the synthesis of polo‐like kinase 1 inhibitors, a new class of chemotherapeutic drugs. Production of the alcohol in multi‐gram scale requires intensification and scale‐up of the biocatalyst production, biotransformation, and downstream processing. Cell cultivation in a 6.9‐L bioreactor led to a more than tenfold increase in cell concentration compared to shaken flask cultivation. The resultant cells were used in conversions of 300 mM substrate to (S)‐1‐(2‐chlorophenyl)ethanol (e.e. >99.9%) in high yield (96%). Results obtained in a reaction volume of 500 mL were identical to biotransformations carried out in 1 mL (analytical) and 15 mL (preparative) scale. Optimization of product isolation based on hexane extraction yielded 86% isolated product. Biotransformation and extraction were accomplished in a stirred tank reactor equipped with pH and temperature control. The developed process lowered production costs by 80% and enabled (S)‐1‐(2‐chlorophenyl)ethanol production within previously defined economic boundaries. A simple and efficient way to synthesize (S)‐1‐(2‐chlorophenyl)ethanol in an isolated amount of 20 g product per reaction batch was demonstrated. Biotechnol. Bioeng. 2013; 110: 2311–2315. © 2013 Wiley Periodicals, Inc.