Highly Efficient Chemoenzymatic Synthesis of Methyl (R)‐o‐Chloromandelate, a Key Intermediate for Clopidogrel, via Asymmetric Reduction with Recombinant Escherichia coli

Methyl (R)‐o‐chloromandelate [(R)‐1], which is an intermediate for a platelet aggregation inhibitor named clopidogrel, was obtained in >99% ee by the asymmetric reduction of methyl o‐chlorobenzoylformate (2) with recombinant Escherichia coli overproducing a versatile carbonyl reductase. A remarkable temperature effect on productivity was observed in the whole‐cell reduction of 2, and the optimum productivity as high as 178 g/L was attained at 20 °C on a 2‐g scale (1.0 M). The optimized reaction could be scaled up easily to transform 20 g of 2 in 100 mL of buffer. Three synthetic methods for 2 are compared.