Copper‐Catalyzed Dehydrogenative Amidation of Light Alkanes

Fuentes, M. Ángeles; Gava, Riccardo; Saper, Noam I.; Romero, Erik A.; Caballero, Ana; Hartwig, John F.; Pérez, Pedro J.

doi:10.1002/ange.202104737

Cited by 7 publications

(3 citation statements)

References 33 publications

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“…Both the increased bond strength and site- and stereo-differentiation among competing locations with highly similar chemical environments pose significant challenges, as can be appreciated through an examination of the synthetic C–H functionalization literature. Such differentiation is promoted by biasing reactivity toward a particular C–H bond through tethering (intramolecular reactions), the use of directing groups, or by exploiting inherent stereoelectronic preferences that direct reactions to electronically favored or sterically accessible positions − (see refs − for relevant work on C–N bond-forming reactions). Without such bias, the only demonstration of a selective, catalyst-controlled derivatization is the seminal report by Davies and co-workers − on rhodium-catalyzed asymmetric carbene insertion into hydrocarbon C–H bonds (also see ref ).…”

Section: Introductionmentioning

confidence: 99%

Enzymatic Nitrogen Insertion into Unactivated C–H Bonds

et al. 2022

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Selective functionalization of aliphatic C–H bonds, ubiquitous in molecular structures, could allow ready access to diverse chemical products. While enzymatic oxygenation of C–H bonds is well established, the analogous enzymatic nitrogen functionalization is still unknown; nature is reliant on preoxidized compounds for nitrogen incorporation. Likewise, synthetic methods for selective nitrogen derivatization of unbiased C–H bonds remain elusive. In this work, new-to-nature heme-containing nitrene transferases were used as starting points for the directed evolution of enzymes to selectively aminate and amidate unactivated C(sp3)–H sites. The desymmetrization of methyl- and ethylcyclohexane with divergent site selectivity is offered as demonstration. The evolved enzymes in these lineages are highly promiscuous and show activity toward a wide array of substrates, providing a foundation for further evolution of nitrene transferase function. Computational studies and kinetic isotope effects (KIEs) are consistent with a stepwise radical pathway involving an irreversible, enantiodetermining hydrogen atom transfer (HAT), followed by a lower-barrier diastereoselectivity-determining radical rebound step. In-enzyme molecular dynamics (MD) simulations reveal a predominantly hydrophobic pocket with favorable dispersion interactions with the substrate. By offering a direct path from saturated precursors, these enzymes present a new biochemical logic for accessing nitrogen-containing compounds.

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Section: Introductionmentioning

confidence: 99%

Enzymatic Nitrogen Insertion into Unactivated C–H Bonds

et al. 2022

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“…For the substrates tested, amidation reactions were found more tractable to product detection (Fig 3B , red and black) whereas amine functionalization could be unambiguously established for only a subset (Fig 3B , red and green). Functionalization is detected for various substituted cycloalkanes harboring alcohols (23)(24)(25), ketones (27)(28)(29), esters (32,33) and halide substitutions (36)(37)(38). Carboxylic acid 40, amide 42 and nitrile 43 were competent.…”

Section: Substrate Promiscuitymentioning

confidence: 99%

Enzymatic Nitrogen Insertion into Unactivated C–H Bonds

Athavale

Gao

Das

et al. 2022

Preprint

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Selective functionalization of aliphatic C–H bonds, ubiquitous in molecular structures, could allow ready access to diverse chemical products. While enzymatic oxygenation of C–H bonds is well established, the analogous enzymatic nitrogen functionalization is still unknown; nature is reliant on pre-oxidized compounds for nitrogen incorporation. Likewise, synthetic methods for selective nitrogen derivatization of unbiased C–H bonds remain elusive. In this work, new-to-nature heme-containing nitrene transferases were used as starting points for the directed evolution of enzymes to selectively aminate and amidate unactivated C(sp3)–H sites. The desymmetrization of methyl- and ethylcyclohexane with divergent site selectivity is offered as demonstration. The evolved enzymes in these lineages are highly promiscuous and show activity towards a wide array of substrates, providing a foundation for further evolution of nitrene transferase function. Computational studies and kinetic isotope effects (KIEs) are consistent with a stepwise radical pathway involving an irreversible, enantiodetermining hydrogen atom transfer (HAT), followed by a lower-barrier diastereoselectivity determining radical rebound step. In-enzyme molecular dynamics (MD) simulations reveal a predominantly hydrophobic pocket with favorable dispersion interactions with the substrate. By offering a direct path from saturated precursors, these enzymes present a new biochemical logic for accessing nitrogen-containing compounds.

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“…Although the p -methoxybenzylation of secondary amides might be accomplished under strongly basic conditions, such drastic conditions are not suitable for functionalized secondary amides. Considering the high functional-group compatibility of their radical chemistry, the application of various recently developed radical N -alkylations of amides might be a good choice. However, to date, only one previous intermolecular radical N -methylation approach has been applied to secondary amides with limited success, although there have been several reports on the intramolecular radical N -alkylation of secondary amides .…”

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confidence: 99%