Enantio- and Diastereoenriched Enzymatic Synthesis of 1,2,3-Polysubstituted Cyclopropanes from (Z/E)-Trisubstituted Enol Acetates
In nature and synthetic chemistry, stereoselective [2+1] cyclopropanation is the most prevalent strategy for the synthesis of chiral cyclopropanes, a class of key pharmacophores in pharmaceuticals and bioactive natural products. One of the most extensively studied reactions in the organic chemist's arsenal, stereoselective [2+1] cyclopropanation, largely relies on the use of stereodefined olefins, which require elaborate laboratory synthesis or tedious separation to ensure high stereoselectivity. Here we report engineered hemoproteins derived from a bacterial cytochrome P450 that catalyze the synthesis of chiral 1,2,3-polysubstituted cyclopropanes, regardless of the stereopurity of the olefin substrates used. Cytochrome P450 BM3 variant IC-G3 exclusively converts ( Z )-enol acetates to enantio- and diastereoenriched cyclopropanes and in our model reaction delivers a leftover ( E )-enol acetate with 98% stereopurity, using whole Escherichia coli cells. IC-G3 was further engineered with a single mutation to enable the biotransformation of ( E )-enol acetates to α -branched ketones with high levels of enantioselectivity while simultaneously catalyzing the cyclopropanation of ( Z )-enol acetates with excellent activities and selectivities. We conducted docking studies and molecular dynamics simulations to understand how active-site residues distinguish between the substrate isomers and enable the enzyme to perform these distinct transformations with such high selectivities. Computational studies suggest the observed enantio- and diastereoselectivities are achieved through a stepwise pathway. These biotransformations streamline the synthesis of chiral 1,2,3-polysubstituted cyclopropanes from readily available mixtures of ( Z/E )-olefins, adding a new dimension to classical cyclopropanation methods.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2023 |
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| Enthalten in: |
Research square - (2023) vom: 12. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mao, Runze [VerfasserIn] |
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Date Revised 26.07.2023 published: Electronic UpdateIn: J Am Chem Soc. 2023 Jul 11;:. - PMID 37433085 Citation Status PubMed-not-MEDLINE |
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| doi: |
10.21203/rs.3.rs-2802333/v1 |
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| PPN (Katalog-ID): |
NLM355943786 |
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| 245 | 1 | 0 | |a Enantio- and Diastereoenriched Enzymatic Synthesis of 1,2,3-Polysubstituted Cyclopropanes from (Z/E)-Trisubstituted Enol Acetates |
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| 500 | |a Date Revised 26.07.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a UpdateIn: J Am Chem Soc. 2023 Jul 11;:. - PMID 37433085 | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a In nature and synthetic chemistry, stereoselective [2+1] cyclopropanation is the most prevalent strategy for the synthesis of chiral cyclopropanes, a class of key pharmacophores in pharmaceuticals and bioactive natural products. One of the most extensively studied reactions in the organic chemist's arsenal, stereoselective [2+1] cyclopropanation, largely relies on the use of stereodefined olefins, which require elaborate laboratory synthesis or tedious separation to ensure high stereoselectivity. Here we report engineered hemoproteins derived from a bacterial cytochrome P450 that catalyze the synthesis of chiral 1,2,3-polysubstituted cyclopropanes, regardless of the stereopurity of the olefin substrates used. Cytochrome P450 BM3 variant IC-G3 exclusively converts ( Z )-enol acetates to enantio- and diastereoenriched cyclopropanes and in our model reaction delivers a leftover ( E )-enol acetate with 98% stereopurity, using whole Escherichia coli cells. IC-G3 was further engineered with a single mutation to enable the biotransformation of ( E )-enol acetates to α -branched ketones with high levels of enantioselectivity while simultaneously catalyzing the cyclopropanation of ( Z )-enol acetates with excellent activities and selectivities. We conducted docking studies and molecular dynamics simulations to understand how active-site residues distinguish between the substrate isomers and enable the enzyme to perform these distinct transformations with such high selectivities. Computational studies suggest the observed enantio- and diastereoselectivities are achieved through a stepwise pathway. These biotransformations streamline the synthesis of chiral 1,2,3-polysubstituted cyclopropanes from readily available mixtures of ( Z/E )-olefins, adding a new dimension to classical cyclopropanation methods | ||
| 650 | 4 | |a Preprint | |
| 700 | 1 | |a Wackelin, Daniel J |e verfasserin |4 aut | |
| 700 | 1 | |a Jamieson, Cooper S |e verfasserin |4 aut | |
| 700 | 1 | |a Rogge, Torben |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Shilong |e verfasserin |4 aut | |
| 700 | 1 | |a Das, Anuvab |e verfasserin |4 aut | |
| 700 | 1 | |a Taylor, Doris Mia |e verfasserin |4 aut | |
| 700 | 1 | |a Houk, K N |e verfasserin |4 aut | |
| 700 | 1 | |a Arnold, Frances H |e verfasserin |4 aut | |
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| 856 | 4 | 0 | |u http://dx.doi.org/10.21203/rs.3.rs-2802333/v1 |3 Volltext |
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