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Enzyme-Catalyzed Intramolecular C-C Coupling Transformation of Nitriles.
Chaonan Zhu1, Dongqi Wu1, Yinhong Lai1
1State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.
Journal of the American Chemical Society
|February 27, 2026
Summary
Enzyme engineering enables nitrile C-C coupling, a novel biocatalytic transformation. This breakthrough facilitates the synthesis of 3-hydroxychromones using a ThDP-dependent enzyme under mild aqueous conditions.
Area of Science:
- Enzyme catalysis and biocatalysis
- Organic synthesis and green chemistry
Background:
- Nitrile C-C coupling is a critical transformation currently missing from the biocatalytic toolbox.
- Developing enzymatic methods for challenging organic reactions is a key objective in enzyme catalysis.
Purpose of the Study:
- To engineer a ThDP-dependent enzyme for nitrile C-C coupling.
- To establish a biocatalytic method for synthesizing 3-hydroxychromones.
- To explore enzymatic addition of aldehyde groups to triple bonds under aqueous conditions.
Main Methods:
- Engineering of a ThDP-dependent enzyme to catalyze nitrile C-C coupling.
- In situ generation of acyl anion equivalents for the coupling reaction.
- Biocatalytic hydrolysis of imine intermediates under mildly acidic aqueous conditions.
Main Results:
- Achieved nitrile C-C coupling using an engineered ThDP-dependent enzyme.
- Demonstrated the first ThDP-dependent enzymatic addition of an aldehyde to a triple bond.
- Successfully synthesized 3-hydroxychromones via an oxidant-free, enzyme-catalyzed strategy.
Conclusions:
- The engineered enzyme provides a valuable synthetic complement to existing biocatalytic transformations.
- The biocatalytic approach offers an efficient and green method for synthesizing valuable intermediates.
- This study encourages further development of biocatalysis for challenging nitrile C-C coupling reactions.
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