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

Author:

Zhang Rui1,Zhang Chenghua23,Tan Jiamu14,He Yifan54,Zhuo Dan6,Zhang Jingxuan14,Luo Zhenzhen6,Li Qiaoqiao6,Yao Jiaying78,Ke Changqiang5,Tang Chunping5,Ye Yang5,He Shijun84,Sheng Xiang294,Liao Cangsong164ORCID

Affiliation:

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

2. Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences Tianjin 300308 China

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

4. University of Chinese Academy of Sciences Beijing 100049 China

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

6. School of Chinese Materia Medica Nanjing University of Chinese Medicine Nanjing 210023 China

7. Graduate School Jiangxi University of Chinese Medicine Nanchang 330004 China

8. Innovation Research Institute of Traditional Chinese Medicine Shanghai University of Traditional Chinese Medicine Shanghai 201203 China

9. 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

Abstract

AbstractNoncanonical 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.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

General Chemistry,Catalysis

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