Asymmetric Conjugate Hydrocyanation of <i>α</i> , <i>β</i> ‐Unsaturated Aldehydes Catalyzed by Engineered 2‐Deoxy‐D‐ribose‐5‐phosphate Aldolase

The enantioselective conjugate hydrocyanation of α,β-unsaturated aldehydes remains a long-standing challenge in synthetic chemistry. Here, we report the redesign of 2-deoxy-D-ribose-5-phosphate aldolase (DERA) into an efficient biocatalyst capable of promoting the asymmetric conjugate addition of hydrogen cyanide (generated in situ from trimethylsilyl cyanide) to aromatic enals via an iminium activation pathway. The evolved variant DERA-CN enables the efficient formation of various C4-nitriles with high conversions (up to 99%) and good enantioselectivity (up to 98% e.e.). Control experiments revealed a stepwise process involving enzyme-catalyzed conjugate hydrocyanation followed by spontaneous 1,2-addition of cyanide. Substrates with various electron-donating and electron-withdrawing groups are tolerated, providing access to various enantioenriched nitriles. This work expands the scope of DERA-promoted iminium catalysis and provides a rare enzymatic platform for asymmetric conjugate hydrocyanation under mild aqueous conditions.