Stereochemistry in Asymmetric Reduction of Bulky-Bulky Ketones by Alcohol Dehydrogenases

Biocatalyzed asymmetric reduction of ketones is one of the most cost-effective and environmentally friendly approaches for preparing chiral alcohols. However, few natural ketone reductases (KREDs) or alcohol dehydrogenase (ADHs) with high activity and stereoselectivity toward bulky-bulky ketones have yet been reported due to the strong steric hindrance of these substrates. Recent developments in protein engineering have led to biocatalysts capable of producing chiral alcohols with high efficiency and stereoselectivity. This review discusses recent advances in several approaches for the manipulation of stereoselectivity, including engineering of the binding pocket and active site loops to accommodate bulky-bulky ketones, modulating the electronic effects on attraction and repulsion between binding pocket residues and substituents of ketone substrates, and adding traceless directing groups to substrates to alter their orientation. Microbial sources of KREDs and ADHs, screening techniques, and future outlooks for the field are also discussed.