Abstract
Small ring synthesis via ene-reductase mediated reductive cyclization
Frieß M.1, Heckenbichler K. 1, Macheroux P. 2, Gruber K. 3, Breinbauer R. 1
1Technical University of Graz, Institute of Organic Chemistry, Graz, Austria
2Technical University of Graz, Institute of Biochemistry, Graz, Austria
3Univeristy of Graz, Institute of Molecular Biosciences, Graz, Austria
Small carbocycles like cyclopropanes are structural elements that are frequently occurring in valuable products like active pharmaceutical ingredients. Thus, efficient methods for their preparation are in high demand, especially when they manage to meet high standards of sustainability. Since biocatalysis is always at the forefront of methods when it comes to sustainability, it was our desire to develop an ene-reductase based method for the synthesis of small rings.
To utilize ene-reductases for the biosynthesis of small cycloalkanes, substrate as well as enzyme engineering is required. In terms of substrates, halogenated enals were used. The substrates should be converted by ene-reductase variants, which lack protic residues in their active sites. Due to missing protic side chains, the enolate intermediate of the commonly accepted ene-reductase mechanism is not protonated as fast as it would happen in the wild-type enzyme. The higher persistence of the enolate intermediate within the active site of the ene-reductase variants, leads to the possibility of a nucleophilic attack at the terminal alkyl halide of the utilized substrate. Based on this intramolecular halide displacement the intended carbocycle is generated [1]. So far the concept of ene-reductase mediated cyclization could be successfully employed for the biosynthesis of cyclopropane-carbaldehyde derivatives in good disatereo- and excellent enantioselectivities. Currently the expansion of this method to four- and five-membered rings is under investigation.
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[1] Heckenbichler et. al., Angewandte Chemie Int. Ed. 2018, 57, 7240-7244
Frieß M.1, Heckenbichler K. 1, Macheroux P. 2, Gruber K. 3, Breinbauer R. 1
1Technical University of Graz, Institute of Organic Chemistry, Graz, Austria
2Technical University of Graz, Institute of Biochemistry, Graz, Austria
3Univeristy of Graz, Institute of Molecular Biosciences, Graz, Austria
Small carbocycles like cyclopropanes are structural elements that are frequently occurring in valuable products like active pharmaceutical ingredients. Thus, efficient methods for their preparation are in high demand, especially when they manage to meet high standards of sustainability. Since biocatalysis is always at the forefront of methods when it comes to sustainability, it was our desire to develop an ene-reductase based method for the synthesis of small rings.
To utilize ene-reductases for the biosynthesis of small cycloalkanes, substrate as well as enzyme engineering is required. In terms of substrates, halogenated enals were used. The substrates should be converted by ene-reductase variants, which lack protic residues in their active sites. Due to missing protic side chains, the enolate intermediate of the commonly accepted ene-reductase mechanism is not protonated as fast as it would happen in the wild-type enzyme. The higher persistence of the enolate intermediate within the active site of the ene-reductase variants, leads to the possibility of a nucleophilic attack at the terminal alkyl halide of the utilized substrate. Based on this intramolecular halide displacement the intended carbocycle is generated [1]. So far the concept of ene-reductase mediated cyclization could be successfully employed for the biosynthesis of cyclopropane-carbaldehyde derivatives in good disatereo- and excellent enantioselectivities. Currently the expansion of this method to four- and five-membered rings is under investigation.
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[1] Heckenbichler et. al., Angewandte Chemie Int. Ed. 2018, 57, 7240-7244
| Originalsprache | englisch |
|---|---|
| Publikationsstatus | Veröffentlicht - 31 Aug. 2022 |
| Veranstaltung | 10th International Congress on Biocatalysis: Biocat 2022 - Hamburg University of Technology, Hamburg, Deutschland Dauer: 28 Aug. 2022 → 1 Sept. 2022 https://www.biocat-conference.de/ |
Konferenz
| Konferenz | 10th International Congress on Biocatalysis |
|---|---|
| Kurztitel | Biocat 2022 |
| Land/Gebiet | Deutschland |
| Ort | Hamburg |
| Zeitraum | 28/08/22 → 1/09/22 |
| Internetadresse |
Fields of Expertise
- Human- & Biotechnology