Asymmetric synthesis of tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate using a self-sufficient biocatalyst based on carbonyl reductase and cofactor co-immobilization

Abstract tert -Butyl (3 R ,5 S ) - 6-chloro-3,5-dihydroxyhexanoate [(3 R ,5 S )-CDHH] is the key chiral intermediate to synthesize the side chain of the lipid-lowering drug rosuvastatin. Carbonyl reductases showed excellent activity for the biosynthesis of (3 R ,5 S )-CDHH. The requirement of cofactor NADH/NADPH leads to high cost for the industrial application of carbonyl reductases. In this study, a self-sufficient biocatalyst based on carbonyl reductase and NADP + co-immobilization strategy was developed on an amino resin carrier LX-1000HAA (SCR-NADP + @LX-1000HAA). The self-sufficient biocatalyst achieved in situ cofactor regeneration and showed the activity recovery of 77.93% and the specific activity of 70.45 U/g. Asymmetric synthesis of (3 R ,5 S )-CDHH using SCR-NADP + @LX-1000HAA showed high enantioselectivity (> 99% e.e.) and yield (98.54%). Batch reactions were performed for ten cycles without extra addition of NADP + , and the total yield of (3 R, 5 S )-CDHH achieved at 10.56 g/g biocatalyst. The present work demonstrated the potential of the self-sufficient biocatalyst for the asymmetric biosynthesis of rosuvastatin intermediate. Graphic abstract