Flow chemistry-enabled asymmetric synthesis of cyproterone acetate in a chemo-biocatalytic approach
Abstract Flow chemistry has many advantages over batch synthesis of organic small-molecules in terms of environmental compatibility, safety and synthetic efficiency when scale-up is considered. Herein, we report the 10-step chemo-biocatalytic continuous flow asymmetric synthesis of cyproterone aceta...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56371-2 |
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| author | Yajiao Zhang Minjie Liu Xianjing Zheng Liang Gao Li Wan Dang Cheng Fener Chen |
| author_facet | Yajiao Zhang Minjie Liu Xianjing Zheng Liang Gao Li Wan Dang Cheng Fener Chen |
| author_sort | Yajiao Zhang |
| collection | DOAJ |
| description | Abstract Flow chemistry has many advantages over batch synthesis of organic small-molecules in terms of environmental compatibility, safety and synthetic efficiency when scale-up is considered. Herein, we report the 10-step chemo-biocatalytic continuous flow asymmetric synthesis of cyproterone acetate (4) in which 10 transformations are combined into a telescoped flow linear sequence from commercially available 4-androstene-3, 17-dione (11). This integrated one-flow synthesis features an engineered 3-ketosteroid-Δ1-dehydrogenase (ReM2)-catalyzed Δ1-dehydrogenation to form the C1, C2-double bond of A ring, a substrate-controlled Co-catalyzed Mukaiyama hydration of 9 to forge the crucial chiral C17α-OH group of D ring with excellent stereoselectivity, and a rapid flow Corey-Chaykovsky cyclopropanation of 7 to build the cyclopropyl core of A ring. By strategic use of these three key reactions and fully continuous-flow operations, cyproterone acetate (4) is produced in an overall yield of 9.6% in 3 h of total reaction time, this is the highest total number of chemical transformation performance in any other continuous-flow synthesis reported to date. |
| format | Article |
| id | doaj-art-c0699a16b6624cccb1664e255a85a373 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c0699a16b6624cccb1664e255a85a3732025-02-02T12:33:25ZengNature PortfolioNature Communications2041-17232025-01-0116111210.1038/s41467-025-56371-2Flow chemistry-enabled asymmetric synthesis of cyproterone acetate in a chemo-biocatalytic approachYajiao Zhang0Minjie Liu1Xianjing Zheng2Liang Gao3Li Wan4Dang Cheng5Fener Chen6Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan UniversityEngineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan UniversityEngineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan UniversityEngineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan UniversityEngineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan UniversityEngineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan UniversityEngineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan UniversityAbstract Flow chemistry has many advantages over batch synthesis of organic small-molecules in terms of environmental compatibility, safety and synthetic efficiency when scale-up is considered. Herein, we report the 10-step chemo-biocatalytic continuous flow asymmetric synthesis of cyproterone acetate (4) in which 10 transformations are combined into a telescoped flow linear sequence from commercially available 4-androstene-3, 17-dione (11). This integrated one-flow synthesis features an engineered 3-ketosteroid-Δ1-dehydrogenase (ReM2)-catalyzed Δ1-dehydrogenation to form the C1, C2-double bond of A ring, a substrate-controlled Co-catalyzed Mukaiyama hydration of 9 to forge the crucial chiral C17α-OH group of D ring with excellent stereoselectivity, and a rapid flow Corey-Chaykovsky cyclopropanation of 7 to build the cyclopropyl core of A ring. By strategic use of these three key reactions and fully continuous-flow operations, cyproterone acetate (4) is produced in an overall yield of 9.6% in 3 h of total reaction time, this is the highest total number of chemical transformation performance in any other continuous-flow synthesis reported to date.https://doi.org/10.1038/s41467-025-56371-2 |
| spellingShingle | Yajiao Zhang Minjie Liu Xianjing Zheng Liang Gao Li Wan Dang Cheng Fener Chen Flow chemistry-enabled asymmetric synthesis of cyproterone acetate in a chemo-biocatalytic approach Nature Communications |
| title | Flow chemistry-enabled asymmetric synthesis of cyproterone acetate in a chemo-biocatalytic approach |
| title_full | Flow chemistry-enabled asymmetric synthesis of cyproterone acetate in a chemo-biocatalytic approach |
| title_fullStr | Flow chemistry-enabled asymmetric synthesis of cyproterone acetate in a chemo-biocatalytic approach |
| title_full_unstemmed | Flow chemistry-enabled asymmetric synthesis of cyproterone acetate in a chemo-biocatalytic approach |
| title_short | Flow chemistry-enabled asymmetric synthesis of cyproterone acetate in a chemo-biocatalytic approach |
| title_sort | flow chemistry enabled asymmetric synthesis of cyproterone acetate in a chemo biocatalytic approach |
| url | https://doi.org/10.1038/s41467-025-56371-2 |
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