Photoenzymatic catalysis enables enantioselective radical dearomative spirocyclization
Changtong Zhu1, Yan Zhang2, Zhiwei Deng1
1Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, PR China.
Nature Communications
|December 23, 2025
Summary
This study introduces a novel photoenzymatic method for creating complex chiral spirocycles using engineered enzymes and visible light. This green chemistry approach enables efficient synthesis of valuable pharmaceutical building blocks.
Area of Science:
- Organic Chemistry
- Biocatalysis
- Synthetic Chemistry
Background:
- Dearomatization is key for synthesizing 3D spirocyclic structures vital in pharmaceuticals.
- Biocatalytic dearomatization for these frameworks under mild conditions is underexplored.
- Enantioselective construction of congested quaternary spirocenters is challenging.
Purpose of the Study:
- To develop a mild and green biocatalytic method for dearomative spirocyclization.
- To engineer nicotinamide-dependent ketoreductase (KRED) for enhanced enantioselectivity.
- To synthesize chiral spirocyclohexadienones, including ortho-isomers.
Main Methods:
- Utilizing a photoenzymatic platform combining visible-light activation and engineered KRED catalysis.
- Employing semi-rational engineering of KRED P2-D12.
- Applying the method to N-hydroxyphthalimide esters.
Main Results:
- Achieved highly enantioselective dearomative spirocyclization (>99% ee).
- Synthesized diverse chiral spirocyclohexadienones with excellent functional group tolerance.
- Successfully synthesized the cytotoxic natural product (+)-denobilone A with 93% ee.
Conclusions:
- Established a powerful chemobiocatalytic platform for complex chiral spiroarchitecture synthesis.
- Expanded the biocatalytic toolbox for sustainable synthetic chemistry.
- Demonstrated high enantioselectivity and stereocontrol in KRED-catalyzed reactions.
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