Preparative Asymmetric Synthesis of 4,4-Dimethoxytetrahydro-2H-pyran-3-ol with a Ketone Reductase and in Situ Cofactor Recycling using Glucose Dehydrogenase

The asymmetric enzymatic ketone reduction of 4,4-dimethoxytetrahydro-2H-pyran-3-one provided the ( R )-α-hydroxyketal, an important chiral precursor for a pharmaceutical intermediate, with high enantioselectivity (>99% ee). An economical process including in situ NADPH-cofactor regeneration using glucose dehydrogenase has been developed to produce the desired material in high yield (96–98%). The two-enzyme process was employed at pilot-plant scale to produce 80 kg of ( R )-4,4-dimethoxytetrahydro-2H-pyran-3-ol. Critical factors for scale-up were found to be pH control and agitation speed.