Cyanide‐free Enantioselective Synthesis of Nitriles: Synthetic Proof of a Biocatalytic Concept and Mechanistic Insights

The first (“by definition”) cyanide‐free enantioselective synthetic approach towards chiral α‐ and β‐branched nitriles is reported. This process is based on a biocatalytic dehydration of racemic aldoximes by using an aldoxime dehydratase and proceeds with high conversion and excellent enantioselectivity (up to 98 % ee) with water as the only side‐product when starting from a racemic substrate with a high E/Z ratio. Thus, in combination with the facile generation of aldoximes through condensation of readily accessible aldehydes with hydroxylamine, this methodology offers an attractive and efficient path to chiral nitriles with excellent atom economy in aqueous solution. Furthermore, this study shows a surprising enzymatic dependency of the enantiopreference on the E or Z configuration of the aldoxime moiety. Notably, the whole stereochemical course of this enzymatic reaction has been rationalized by means of a computational study.