Asymmetric α-benzylation of cyclic ketones enabled by concurrent chemical aldol condensation and biocatalytic reduction
Abstract Chemoenzymatic cascade catalysis has emerged as a revolutionary tool for streamlining traditional retrosynthetic disconnections, creating new possibilities for the asymmetric synthesis of valuable chiral compounds. Here we construct a one-pot concurrent chemoenzymatic cascade by integrating...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44452-z |
| _version_ | 1797363054183186432 |
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| author | Yunting Liu Teng Ma Zhongxu Guo Liya Zhou Guanhua Liu Ying He Li Ma Jing Gao Jing Bai Frank Hollmann Yanjun Jiang |
| author_facet | Yunting Liu Teng Ma Zhongxu Guo Liya Zhou Guanhua Liu Ying He Li Ma Jing Gao Jing Bai Frank Hollmann Yanjun Jiang |
| author_sort | Yunting Liu |
| collection | DOAJ |
| description | Abstract Chemoenzymatic cascade catalysis has emerged as a revolutionary tool for streamlining traditional retrosynthetic disconnections, creating new possibilities for the asymmetric synthesis of valuable chiral compounds. Here we construct a one-pot concurrent chemoenzymatic cascade by integrating organobismuth-catalyzed aldol condensation with ene-reductase (ER)-catalyzed enantioselective reduction, enabling the formal asymmetric α-benzylation of cyclic ketones. To achieve this, we develop a pair of enantiocomplementary ERs capable of reducing α-arylidene cyclic ketones, lactams, and lactones. Our engineered mutants exhibit significantly higher activity, up to 37-fold, and broader substrate specificity compared to the parent enzyme. The key to success is due to the well-tuned hydride attack distance/angle and, more importantly, to the synergistic proton-delivery triade of Tyr28-Tyr69-Tyr169. Molecular docking and density functional theory (DFT) studies provide important insights into the bioreduction mechanisms. Furthermore, we demonstrate the synthetic utility of the best mutants in the asymmetric synthesis of several key chiral synthons. |
| first_indexed | 2024-03-08T16:16:20Z |
| format | Article |
| id | doaj.art-6c95bcee20e245c99385a40a80515b93 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T16:16:20Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-6c95bcee20e245c99385a40a80515b932024-01-07T12:34:59ZengNature PortfolioNature Communications2041-17232024-01-011511910.1038/s41467-023-44452-zAsymmetric α-benzylation of cyclic ketones enabled by concurrent chemical aldol condensation and biocatalytic reductionYunting Liu0Teng Ma1Zhongxu Guo2Liya Zhou3Guanhua Liu4Ying He5Li Ma6Jing Gao7Jing Bai8Frank Hollmann9Yanjun Jiang10School of Chemical Engineering and Technology, Hebei University of TechnologySchool of Chemical Engineering and Technology, Hebei University of TechnologySchool of Chemical Engineering and Technology, Hebei University of TechnologySchool of Chemical Engineering and Technology, Hebei University of TechnologySchool of Chemical Engineering and Technology, Hebei University of TechnologySchool of Chemical Engineering and Technology, Hebei University of TechnologySchool of Chemical Engineering and Technology, Hebei University of TechnologySchool of Chemical Engineering and Technology, Hebei University of TechnologyCollege of Food Science and Biology, Hebei University of Science & TechnologyDepartment of Biotechnology, Delft University of TechnologySchool of Chemical Engineering and Technology, Hebei University of TechnologyAbstract Chemoenzymatic cascade catalysis has emerged as a revolutionary tool for streamlining traditional retrosynthetic disconnections, creating new possibilities for the asymmetric synthesis of valuable chiral compounds. Here we construct a one-pot concurrent chemoenzymatic cascade by integrating organobismuth-catalyzed aldol condensation with ene-reductase (ER)-catalyzed enantioselective reduction, enabling the formal asymmetric α-benzylation of cyclic ketones. To achieve this, we develop a pair of enantiocomplementary ERs capable of reducing α-arylidene cyclic ketones, lactams, and lactones. Our engineered mutants exhibit significantly higher activity, up to 37-fold, and broader substrate specificity compared to the parent enzyme. The key to success is due to the well-tuned hydride attack distance/angle and, more importantly, to the synergistic proton-delivery triade of Tyr28-Tyr69-Tyr169. Molecular docking and density functional theory (DFT) studies provide important insights into the bioreduction mechanisms. Furthermore, we demonstrate the synthetic utility of the best mutants in the asymmetric synthesis of several key chiral synthons.https://doi.org/10.1038/s41467-023-44452-z |
| spellingShingle | Yunting Liu Teng Ma Zhongxu Guo Liya Zhou Guanhua Liu Ying He Li Ma Jing Gao Jing Bai Frank Hollmann Yanjun Jiang Asymmetric α-benzylation of cyclic ketones enabled by concurrent chemical aldol condensation and biocatalytic reduction Nature Communications |
| title | Asymmetric α-benzylation of cyclic ketones enabled by concurrent chemical aldol condensation and biocatalytic reduction |
| title_full | Asymmetric α-benzylation of cyclic ketones enabled by concurrent chemical aldol condensation and biocatalytic reduction |
| title_fullStr | Asymmetric α-benzylation of cyclic ketones enabled by concurrent chemical aldol condensation and biocatalytic reduction |
| title_full_unstemmed | Asymmetric α-benzylation of cyclic ketones enabled by concurrent chemical aldol condensation and biocatalytic reduction |
| title_short | Asymmetric α-benzylation of cyclic ketones enabled by concurrent chemical aldol condensation and biocatalytic reduction |
| title_sort | asymmetric α benzylation of cyclic ketones enabled by concurrent chemical aldol condensation and biocatalytic reduction |
| url | https://doi.org/10.1038/s41467-023-44452-z |
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