Asymmetric Synthesis of Both Enantiomers of Dimethyl 2-Methylsuccinate by the Ene-Reductase-Catalyzed Reduction at High Substrate Concentration
Chiral dimethyl 2-methylsuccinate (<b>1</b>) is a very important building block for the manufacturing of many active pharmaceutical ingredients and fine chemicals. The asymmetric reduction of C=C double bond of dimethyl citraconate (<b>2</b>), dimethyl mesaconate (<b>3&...
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MDPI AG
2022-09-01
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| Series: | Catalysts |
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| Online Access: | https://www.mdpi.com/2073-4344/12/10/1133 |
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| author | Jiacheng Li Jianjiong Li Yunfeng Cui Min Wang Jinhui Feng Peiyuan Yao Qiaqing Wu Dunming Zhu |
| author_facet | Jiacheng Li Jianjiong Li Yunfeng Cui Min Wang Jinhui Feng Peiyuan Yao Qiaqing Wu Dunming Zhu |
| author_sort | Jiacheng Li |
| collection | DOAJ |
| description | Chiral dimethyl 2-methylsuccinate (<b>1</b>) is a very important building block for the manufacturing of many active pharmaceutical ingredients and fine chemicals. The asymmetric reduction of C=C double bond of dimethyl citraconate (<b>2</b>), dimethyl mesaconate (<b>3</b>) or dimethyl itaconate (<b>4</b>) by ene-reductases (ERs) represents an attractive straightforward approach, but lack of high-performance ERs, especially (<i>S</i>)-selective ones, has limited implementing this method to prepare the optically pure dimethyl 2-methylsuccinate. Herein, three ERs (Bac-OYE1 from <i>Bacillus</i> sp., <i>Se</i>ER from <i>Saccharomyces eubayanus</i> and <i>Af</i>ER from <i>Aspergillus flavus</i>) with high substrate tolerance and stereoselectivity towards <b>2</b>, <b>3</b> and <b>4</b> have been identified. Up to 500 mM of <b>3</b> was converted to (<i>S</i>)-dimethyl 2-methylsuccinate ((<i>S</i>)-<b>1</b>) by <i>Se</i>ER in high yields (80%) and enantioselectivity (98% <i>ee</i>), and 700 mM of <b>2</b> and 400 mM of <b>4</b> were converted to (<i>R</i>)-<b>1</b> by Bac-OYE1 and <i>Af</i>ER, respectively, in high yields (86% and 77%) with excellent enantioselectivity (99% <i>ee</i>). The reductions of diethyl citraconate (<b>5</b>), diethyl mesaconate (<b>6</b>) and diethyl itaconate (<b>7</b>) were also tested with the three ERs. Although up to 500 mM of <b>5</b> was completely converted to (<i>R</i>)-diethyl 2-methylsuccinate ((<i>R</i>)-<b>8</b>) by Bac-OYE1 with excellent enantioselectivity (99% <i>ee</i>), the alcohol moiety of the esters had a great effect on the activity and enantioselectivity of ERs. This work provides an efficient methodology for the enantiocomplementary production of optically pure dimethyl 2-methylsuccinate from dimethyl itaconate and its isomers at high titer. |
| first_indexed | 2024-03-09T20:30:00Z |
| format | Article |
| id | doaj.art-479c150a72dd495ebc5bb73d82150626 |
| institution | Directory Open Access Journal |
| issn | 2073-4344 |
| language | English |
| last_indexed | 2024-03-09T20:30:00Z |
| publishDate | 2022-09-01 |
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| series | Catalysts |
| spelling | doaj.art-479c150a72dd495ebc5bb73d821506262023-11-23T23:24:11ZengMDPI AGCatalysts2073-43442022-09-011210113310.3390/catal12101133Asymmetric Synthesis of Both Enantiomers of Dimethyl 2-Methylsuccinate by the Ene-Reductase-Catalyzed Reduction at High Substrate ConcentrationJiacheng Li0Jianjiong Li1Yunfeng Cui2Min Wang3Jinhui Feng4Peiyuan Yao5Qiaqing Wu6Dunming Zhu7Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, ChinaNational Center of Technology Innovation for Synthetic Biology, National Engineering Research Center of Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin 300308, ChinaNational Center of Technology Innovation for Synthetic Biology, National Engineering Research Center of Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin 300308, ChinaKey Laboratory of Industrial Fermentation Microbiology, Ministry of Education, College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, ChinaNational Center of Technology Innovation for Synthetic Biology, National Engineering Research Center of Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin 300308, ChinaNational Center of Technology Innovation for Synthetic Biology, National Engineering Research Center of Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin 300308, ChinaNational Center of Technology Innovation for Synthetic Biology, National Engineering Research Center of Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin 300308, ChinaNational Center of Technology Innovation for Synthetic Biology, National Engineering Research Center of Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin Airport Economic Area, Tianjin 300308, ChinaChiral dimethyl 2-methylsuccinate (<b>1</b>) is a very important building block for the manufacturing of many active pharmaceutical ingredients and fine chemicals. The asymmetric reduction of C=C double bond of dimethyl citraconate (<b>2</b>), dimethyl mesaconate (<b>3</b>) or dimethyl itaconate (<b>4</b>) by ene-reductases (ERs) represents an attractive straightforward approach, but lack of high-performance ERs, especially (<i>S</i>)-selective ones, has limited implementing this method to prepare the optically pure dimethyl 2-methylsuccinate. Herein, three ERs (Bac-OYE1 from <i>Bacillus</i> sp., <i>Se</i>ER from <i>Saccharomyces eubayanus</i> and <i>Af</i>ER from <i>Aspergillus flavus</i>) with high substrate tolerance and stereoselectivity towards <b>2</b>, <b>3</b> and <b>4</b> have been identified. Up to 500 mM of <b>3</b> was converted to (<i>S</i>)-dimethyl 2-methylsuccinate ((<i>S</i>)-<b>1</b>) by <i>Se</i>ER in high yields (80%) and enantioselectivity (98% <i>ee</i>), and 700 mM of <b>2</b> and 400 mM of <b>4</b> were converted to (<i>R</i>)-<b>1</b> by Bac-OYE1 and <i>Af</i>ER, respectively, in high yields (86% and 77%) with excellent enantioselectivity (99% <i>ee</i>). The reductions of diethyl citraconate (<b>5</b>), diethyl mesaconate (<b>6</b>) and diethyl itaconate (<b>7</b>) were also tested with the three ERs. Although up to 500 mM of <b>5</b> was completely converted to (<i>R</i>)-diethyl 2-methylsuccinate ((<i>R</i>)-<b>8</b>) by Bac-OYE1 with excellent enantioselectivity (99% <i>ee</i>), the alcohol moiety of the esters had a great effect on the activity and enantioselectivity of ERs. This work provides an efficient methodology for the enantiocomplementary production of optically pure dimethyl 2-methylsuccinate from dimethyl itaconate and its isomers at high titer.https://www.mdpi.com/2073-4344/12/10/1133dimethyl citraconatedimethyl itaconatedimethyl mesaconatedimethyl 2-methylsuccinateenantioselective enzymatic reductionene-reducase |
| spellingShingle | Jiacheng Li Jianjiong Li Yunfeng Cui Min Wang Jinhui Feng Peiyuan Yao Qiaqing Wu Dunming Zhu Asymmetric Synthesis of Both Enantiomers of Dimethyl 2-Methylsuccinate by the Ene-Reductase-Catalyzed Reduction at High Substrate Concentration Catalysts dimethyl citraconate dimethyl itaconate dimethyl mesaconate dimethyl 2-methylsuccinate enantioselective enzymatic reduction ene-reducase |
| title | Asymmetric Synthesis of Both Enantiomers of Dimethyl 2-Methylsuccinate by the Ene-Reductase-Catalyzed Reduction at High Substrate Concentration |
| title_full | Asymmetric Synthesis of Both Enantiomers of Dimethyl 2-Methylsuccinate by the Ene-Reductase-Catalyzed Reduction at High Substrate Concentration |
| title_fullStr | Asymmetric Synthesis of Both Enantiomers of Dimethyl 2-Methylsuccinate by the Ene-Reductase-Catalyzed Reduction at High Substrate Concentration |
| title_full_unstemmed | Asymmetric Synthesis of Both Enantiomers of Dimethyl 2-Methylsuccinate by the Ene-Reductase-Catalyzed Reduction at High Substrate Concentration |
| title_short | Asymmetric Synthesis of Both Enantiomers of Dimethyl 2-Methylsuccinate by the Ene-Reductase-Catalyzed Reduction at High Substrate Concentration |
| title_sort | asymmetric synthesis of both enantiomers of dimethyl 2 methylsuccinate by the ene reductase catalyzed reduction at high substrate concentration |
| topic | dimethyl citraconate dimethyl itaconate dimethyl mesaconate dimethyl 2-methylsuccinate enantioselective enzymatic reduction ene-reducase |
| url | https://www.mdpi.com/2073-4344/12/10/1133 |
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