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

## TL;DR

Scientists engineered an enzyme to efficiently and selectively add hydrogen cyanide to unsaturated aldehydes, creating valuable nitriles under mild conditions.

## Contribution

A redesigned enzyme enables asymmetric conjugate hydrocyanation of aromatic enals, a previously challenging reaction in biocatalysis.

## Key findings

- The evolved DERA-CN enzyme achieves up to 99% conversion and 98% enantioselectivity in forming C4-nitriles.
- The reaction tolerates various electron-donating and electron-withdrawing groups on the substrate.
- The process involves enzyme-catalyzed hydrocyanation followed by spontaneous cyanide addition.

## Abstract

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.

The power of catalytic promiscuity: The enantioselective conjugate hydrocyanation of enals remains a long‐standing challenge for biocatalysis. Here, we report the redesign of 2‐deoxy‐D‐ribose‐5‐phosphate aldolase for the asymmetric conjugate hydrocyanation of aromatic enals, expanding the reaction scope of iminium‐based enzyme catalysis to include an additional new‐to‐nature reaction.