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Biocatalytic engineering study demonstrates enantiodivergent C3-selective reduction of 3,5-dicarbonyl esters, highlighting a practical route to chiral pharmaceutical intermediates like pitavastatin.
Chiral arylvinyl-substituted 3-hydroxy-5-oxo esters are valuable motifs in pharmaceuticals, yet their enantiocontrolled synthesis remains challenging. Herein, we report a biocatalytic system using ketoreductases (KREDs) for the highly C3-selective reduction of arylvinyl-substituted 3,5-dicarbonyl esters. Through semirational protein engineering, RasADH-E189D afforded the representative (S)-products in 89–99% conversion and 93–99% ee. Complementary (R)-products were obtained using KmCR2 and several other variants with up to 97% conversion and >99% ee, including a key intermediate for the synthesis of pitavastatin. Preparative-scale reactions (greater than 100 mg) further demonstrated the practicality of this platform. Protein–ligand docking among the substrate, cofactor, and KREDs provided mechanistic insights for great stereoselectivity.
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Wu et al. (2026) studied this question.
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