Biocatalytic, Enantioenriched Primary Amination of Tertiary C–H Bonds
Intermolecular functionalization of tertiary C–H bonds to construct fully substituted stereogenic carbon centers represents a formidable challenge: without the assistance of directing groups, the state-of-the-art catalysts struggle to introduce chirality to racemic tertiary sp3-carbon centers. Direct asymmetric functionalization of such centers is a worthy reactivity and selectivity goal for modern biocatalysis. Here we present an engineered nitrene transferase (P411-TEA-5274), derived from a bacterial cytochrome P450, that is capable of aminating tertiary C–H bonds to provide chiral α-tertiary primary amines with high efficiency (up to 2300 total turnovers) and selectivity (up to >99% enantiomeric excess (e.e.)). The construction of fully substituted stereocenters with methyl and ethyl groups underscores the enzyme’s remarkable selectivity. A comprehensive substrate scope study demonstrates the biocatalyst’s compatibility with diverse functional groups and tertiary C–H bonds. Mechanistic studies, incorporating both experimental and computational data, elucidate how active-site residues distinguish between the enantiomers and enable the enzyme to perform this transformation with excellent enantioselectivity..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
chemRxiv.org - (2023) vom: 13. Dez. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mao, Runze [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
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| doi: |
10.26434/chemrxiv-2023-8d2tc |
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| 520 | |a Intermolecular functionalization of tertiary C–H bonds to construct fully substituted stereogenic carbon centers represents a formidable challenge: without the assistance of directing groups, the state-of-the-art catalysts struggle to introduce chirality to racemic tertiary sp3-carbon centers. Direct asymmetric functionalization of such centers is a worthy reactivity and selectivity goal for modern biocatalysis. Here we present an engineered nitrene transferase (P411-TEA-5274), derived from a bacterial cytochrome P450, that is capable of aminating tertiary C–H bonds to provide chiral α-tertiary primary amines with high efficiency (up to 2300 total turnovers) and selectivity (up to >99% enantiomeric excess (e.e.)). The construction of fully substituted stereocenters with methyl and ethyl groups underscores the enzyme’s remarkable selectivity. A comprehensive substrate scope study demonstrates the biocatalyst’s compatibility with diverse functional groups and tertiary C–H bonds. Mechanistic studies, incorporating both experimental and computational data, elucidate how active-site residues distinguish between the enantiomers and enable the enzyme to perform this transformation with excellent enantioselectivity. | ||
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