Protoglobin-Catalyzed Formation of cis-Trifluoromethyl-Substituted Cyclopropanes by Carbene Transfer
© 2022 Wiley-VCH GmbH..
Trifluoromethyl-substituted cyclopropanes (CF3 -CPAs) constitute an important class of compounds for drug discovery. While several methods have been developed for synthesis of trans-CF3 -CPAs, stereoselective production of corresponding cis-diastereomers remains a formidable challenge. We report a biocatalyst for diastereo- and enantio-selective synthesis of cis-CF3 -CPAs with activity on a variety of alkenes. We found that an engineered protoglobin from Aeropyrnum pernix (ApePgb) can catalyze this unusual reaction at preparative scale with low-to-excellent yield (6-55 %) and enantioselectivity (17-99 % ee), depending on the substrate. Computational studies revealed that the steric environment in the active site of the protoglobin forced iron-carbenoid and substrates to adopt a pro-cis near-attack conformation. This work demonstrates the capability of enzyme catalysts to tackle challenging chemistry problems and provides a powerful means to expand the structural diversity of CF3 -CPAs for drug discovery.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:62 |
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| Enthalten in: |
Angewandte Chemie (International ed. in English) - 62(2023), 4 vom: 23. Jan., Seite e202208936 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Schaus, Lucas [VerfasserIn] |
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| Links: |
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| Themen: |
2465-56-7 |
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| Anmerkungen: |
Date Completed 18.01.2023 Date Revised 24.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/anie.202208936 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM350457484 |
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| 520 | |a © 2022 Wiley-VCH GmbH. | ||
| 520 | |a Trifluoromethyl-substituted cyclopropanes (CF3 -CPAs) constitute an important class of compounds for drug discovery. While several methods have been developed for synthesis of trans-CF3 -CPAs, stereoselective production of corresponding cis-diastereomers remains a formidable challenge. We report a biocatalyst for diastereo- and enantio-selective synthesis of cis-CF3 -CPAs with activity on a variety of alkenes. We found that an engineered protoglobin from Aeropyrnum pernix (ApePgb) can catalyze this unusual reaction at preparative scale with low-to-excellent yield (6-55 %) and enantioselectivity (17-99 % ee), depending on the substrate. Computational studies revealed that the steric environment in the active site of the protoglobin forced iron-carbenoid and substrates to adopt a pro-cis near-attack conformation. This work demonstrates the capability of enzyme catalysts to tackle challenging chemistry problems and provides a powerful means to expand the structural diversity of CF3 -CPAs for drug discovery | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Biocatalysis | |
| 650 | 4 | |a Carbenes | |
| 650 | 4 | |a Cyclopropanes | |
| 650 | 4 | |a Organofluorines | |
| 650 | 4 | |a Protoglobins | |
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| 700 | 1 | |a Das, Anuvab |e verfasserin |4 aut | |
| 700 | 1 | |a Knight, Anders M |e verfasserin |4 aut | |
| 700 | 1 | |a Jimenez-Osés, Gonzalo |e verfasserin |4 aut | |
| 700 | 1 | |a Houk, K N |e verfasserin |4 aut | |
| 700 | 1 | |a Garcia-Borràs, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Arnold, Frances H |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Xiongyi |e verfasserin |4 aut | |
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