Exploiting Biocatalysis for the Scalable Synthesis of Enantiopure γ‐Hydroxynitrile Building Blocks

We report the scalable biocatalyzed synthesis of γ‐hydroxynitriles from their corresponding prochiral ketone precursors. Screening of a panel of alcohol dehydrogenases (ADHs) identified RRADH as an ( S )‐selective ADH yielding the desired products in e.e. values of 99%, whereas LSADH gave ( R )‐configured γ‐hydroxynitriles (e.e. up to 95%). Optimization of this transformation allowed for reaction scale‐up to 5 mmol, affording the targets in gram quantities. Moreover, the absolute configuration of the ( S )‐configured products was unambiguously established by single‐crystal diffraction. This study showcases how chiral γ‐hydroxynitriles can be generated from readily available γ‐ketonitriles in an efficient and scalable manner, providing a robust and sustainable access to these valuable entities.