Volume 63, Issue 7 e202318550
Research Article

Enzymatic Synthesis of Noncanonical α-Amino Acids Containing γ-Tertiary Alcohols

Rui Zhang

Corresponding Author

Rui Zhang

State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203 China

These authors contributed equally to this work.

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Chenghua Zhang

Chenghua Zhang

Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308 China

School of Pharmacy, North Sichuan Medical College, Nanchong, 637100 P. R. China

These authors contributed equally to this work.

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Jiamu Tan

Jiamu Tan

State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203 China

University of Chinese Academy of Sciences, Beijing, 100049 China

These authors contributed equally to this work.

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Yifan He

Yifan He

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203 China

University of Chinese Academy of Sciences, Beijing, 100049 China

These authors contributed equally to this work.

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Dan Zhuo

Dan Zhuo

School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China

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Jingxuan Zhang

Jingxuan Zhang

State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203 China

University of Chinese Academy of Sciences, Beijing, 100049 China

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Zhenzhen Luo

Zhenzhen Luo

School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China

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Qiaoqiao Li

Qiaoqiao Li

School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China

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Jiaying Yao

Jiaying Yao

Graduate School, Jiangxi University of Chinese Medicine, Nanchang, 330004 China

Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 China

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Changqiang Ke

Changqiang Ke

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203 China

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Chunping Tang

Chunping Tang

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203 China

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Yang Ye

Yang Ye

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203 China

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Shijun He

Corresponding Author

Shijun He

Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 China

University of Chinese Academy of Sciences, Beijing, 100049 China

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Xiang Sheng

Corresponding Author

Xiang Sheng

Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308 China

National Center of Technology Innovation for Synthetic Biology, National Engineering Research Center of Industrial Enzymes and Key Laboratory of Engineering Biology for Low-Carbon Manufacturing, Tianjin, 300308 P. R. China

University of Chinese Academy of Sciences, Beijing, 100049 China

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Cangsong Liao

Corresponding Author

Cangsong Liao

State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203 China

School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China

University of Chinese Academy of Sciences, Beijing, 100049 China

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First published: 28 December 2023
Citations: 8

Graphical Abstract

An enzymatic decarboxylative aldol reaction was developed for the synthesis of noncanonical α-amino acids containing γ-tertiary alcohol groups. The modularity of the electrophile enabled access to four classes of ncAAs with high efficiency as well as excellent regioselectivity and stereoselectivity.

Abstract

Noncanonical amino acids (ncAAs) containing tertiary alcohols are valuable as precursors of natural products and active pharmaceutical ingredients. However, the assembly of such ncAA scaffolds from simple material by C−C bond formation remains a challenging task due to the presence of multiple stereocenters and large steric hindrance. In this study, we present a novel solution to this problem through highly selective enzymatic decarboxylative aldol addition. This method allows for the streamlined assembly of multifunctionalized ncAAs with γ-tertiary alcohols from readily available materials, such as L-aspartatic acid and isatins, vicinal diones and keto esters. The modularity of electrophiles furnished four classes of ncAAs with decent efficiency as well as excellent site and stereocontrol. Computational modeling was employed to gain detailed insight into the catalytic mechanism and to provide a rationale for the observed selectivities. The method offers a single-step approach to producing multifunctionalized ncAAs, which can be directly utilized in peptide synthesis and bioactivity assessment.

Conflict of Interests

The authors declare no conflict of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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