Volume 64, Issue 30 e202500572

Communication

Imine Reductase–Catalyzed Remote Stereocontrol for Enantiodivergent Synthesis of Cyclohexylidene-Based Axially Chiral Amines

Keting Li

NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050 China

Both authors contributed equally to this work.

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Zhen Liu,

Zhen Liu

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032 China

Both authors contributed equally to this work.

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Dr. Bin Wang,

Dr. Bin Wang

NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050 China

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Dr. Ling Huang,

Dr. Ling Huang

NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050 China

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Luyao Yu,

Luyao Yu

NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050 China

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Zitian Zhou,

Zitian Zhou

NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050 China

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Prof. Liang Lin,

Corresponding Author

Prof. Liang Lin

[email protected]

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032 China

E-mail: [email protected]; [email protected]; [email protected]

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Prof. Pengfei Fang,

Corresponding Author

Prof. Pengfei Fang

[email protected]

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032 China

E-mail: [email protected]; [email protected]; [email protected]

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Prof. Haigen Fu,

Corresponding Author

Prof. Haigen Fu

[email protected]

orcid.org/0000-0002-4993-0570

NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050 China

E-mail: [email protected]; [email protected]; [email protected]

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Keting Li,

Keting Li

NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050 China

Both authors contributed equally to this work.

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Zhen Liu,

Zhen Liu

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032 China

Both authors contributed equally to this work.

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Dr. Bin Wang,

Dr. Bin Wang

NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050 China

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Dr. Ling Huang,

Dr. Ling Huang

NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050 China

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Luyao Yu,

Luyao Yu

NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050 China

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Zitian Zhou,

Zitian Zhou

NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050 China

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Prof. Liang Lin,

Corresponding Author

Prof. Liang Lin

[email protected]

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032 China

E-mail: [email protected]; [email protected]; [email protected]

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Prof. Pengfei Fang,

Corresponding Author

Prof. Pengfei Fang

[email protected]

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032 China

E-mail: [email protected]; [email protected]; [email protected]

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Prof. Haigen Fu,

Corresponding Author

Prof. Haigen Fu

[email protected]

orcid.org/0000-0002-4993-0570

NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050 China

E-mail: [email protected]; [email protected]; [email protected]

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First published: 20 May 2025

https://doi.org/10.1002/anie.202500572

Citations: 1

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Graphical Abstract

A biocatalytic route for the enantiodivergent synthesis of cyclohexylidene-based axially chiral amines was developed. This method features imine reductase catalyzed remote stereocontrol in establishing the unusual axial chirality arising from the restricted double bond, providing both enantiomers of chiral products in high yield with high enantioselectivity.

Abstract

Cyclohexylidene-based amines exhibit unique axial chirality arising from the restricted double bond and have shown great potential in medicinal chemistry. However, their asymmetric synthesis remains challenging due to the long distance between the chirally relevant groups. Herein, we report a highly efficient and asymmetric synthesis of cyclohexylidene-based axially chiral amines from 4-substituted cyclohexanones and primary amines catalyzed by imine reductases (IREDs). Enantiodivergent IREDs were identified to provide convenient access to both enantiomers of chiral products with high yields and enantioselectivity (up to 99% yield, 99:1 or 1:99 enantiomeric ratio). A gram-scale synthesis of cyclohexylidene-based amines was also achieved. Moreover, protein X-ray crystallography and molecular modeling studies were conducted to provide structural insight into the remote stereocontrol of IREDs in generating cyclohexylidene-based axial chirality.

Conflict of Interests

The authors declare no conflict of interest.

Open Research

Data Availability Statement

The data that support the findings of this study are available in Supporting Information of this article.

Supporting Information

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Volume64, Issue30

July 21, 2025

e202500572

Imine Reductase–Catalyzed Remote Stereocontrol for Enantiodivergent Synthesis of Cyclohexylidene-Based Axially Chiral Amines

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Abstract

Conflict of Interests

Open Research

Data Availability Statement

Supporting Information

References

Citing Literature

References

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Imine Reductase–Catalyzed Remote Stereocontrol for Enantiodivergent Synthesis of Cyclohexylidene-Based Axially Chiral Amines

Graphical Abstract

Abstract

Conflict of Interests

Open Research

Data Availability Statement

Supporting Information

References

Citing Literature

References

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