Enzymatic Nitrogen Insertion into Unactivated C–H Bonds

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(41), С. 19097 - 19105

Опубликована: Окт. 4, 2022

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

Язык: Английский

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Strategies and Mechanisms of First-Row Transition Metal-Regulated Radical C–H Functionalization

Chemical Reviews, Год журнала: 2024, Номер 124(17), С. 10192 - 10280

Опубликована: Авг. 8, 2024

Radical C–H functionalization represents a useful means of streamlining synthetic routes by avoiding substrate preactivation and allowing access to target molecules in fewer steps. The first-row transition metals (Ti, V, Cr, Mn, Fe, Co, Ni, Cu) are Earth-abundant can be employed regulate radical functionalization. use such is desirable because the diverse interaction modes between metal complexes species including addition center, ligand complexes, substitution single-electron transfer radicals hydrogen atom noncovalent complexes. Such interactions could improve reactivity, diversity, selectivity transformations allow for more challenging reactions. This review examines achievements this promising area over past decade, with focus on state-of-the-art while also discussing existing limitations enormous potential high-value regulated these metals. aim provide reader detailed account strategies mechanisms associated

Язык: Английский

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Thioether-Directed NiH-Catalyzed Remote γ-C(sp³)–H Hydroamidation of Alkenes by 1,4,2-Dioxazol-5-ones

Journal of the American Chemical Society, Год журнала: 2021, Номер 143(37), С. 14962 - 14968

Опубликована: Сен. 8, 2021

A NiH-catalyzed thioether-directed cyclometalation strategy is developed to enable remote methylene C–H bond amidation of unactivated alkenes. Due the preference for five-membered nickelacycle formation, chain-walking isomerization initiated by NiH insertion an alkene can be terminated at γ-methylene site from moiety. By employing 2,9-dibutyl-1,10-phenanthroline (L4) as ligand and dioxazolones reagent, occurs γ-C(sp3)–H bonds afford amide products in up 90% yield (>40 examples) with remarkable regioselectivity (up 24:1 rr).

Язык: Английский

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On the Origin of Rh-Catalyzed Selective Ring-Opening Amidation of Substituted Cyclopropanols to Access β²-Amino Ketones

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(8), С. 3667 - 3675

Опубликована: Фев. 15, 2022

β2-Amino carbonyls, an α-substituted β-amino scaffold, hold a prominent place in the development of new pharmaceuticals and peptidomimetics. Herein, we report highly efficient Rh-catalyzed ring-opening amidation substituted cyclopropanols, which turned out to serve as linchpin for selective synthesis β2-amino ketones outcompete formation β3-isomers. Instead generally accepted rationale consider steric factors β2-selectivity, orbital interaction was elucidated play more critical role amidative cyclopropanols generate key Rh–C intermediate. Subsequent inner-sphere acylnitrene transfer achieved excellent efficiency (TON > 5000) by using readily accessible dioxazolones amino source afford with broad applicability.

Язык: Английский

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Transition Metal-Catalyzed Regioselective Direct C–H Amidation: Interplay between Inner- and Outer-Sphere Pathways for Nitrene Cross-Coupling Reactions

Accounts of Chemical Research, Год журнала: 2022, Номер 55(15), С. 2123 - 2137

Опубликована: Июль 19, 2022

ConspectusCatalytic C–N bond cross-coupling reactions have been a subject of fundamental importance in synthetic organic and medicinal chemistry because amides amines are ubiquitous motifs natural products, functional materials, pharmaceuticals. Since the pioneering works Breslow Mansuy on metalloporphyrin-catalyzed direct hydrocarbon amidation using sulfonyliminoiodinane reagents, substantial development has achieved toward practical selective amination protocols. Notably, Du Bois's group developed dirhodium(II,II) carboxylate catalytic system for C(sp3)–H amidations via Rh-sulfonyl nitrene intermediates. Yet, this protocol suffers from competitive alkene aziridination is limited to electron-rich tertiary ethereal C–H bonds; analogous arenes remained ineffective.This Account discusses our early effort explore cyclopalladated complexes ortho-selective C(aryl)–H amidations. While Buchwald–Hartwig cannot be directly applied arenes, effective 2-arylpyridines occurred when an external oxidant such as K2S2O8 was employed. Preliminary studies suggested that may proceed through reactive Pd-nitrene Aiming develop more diversified protocols, we employed nosyloxycarbamates precursors Pd-catalyzed ortho-amidation N-pivalanilides. Likewise, benzoic acids produce anthranilic acids, which versatile many medicinally valuable heterocycles. In attempt expand C(aryl)–N coupling amines, studied d6 piano-stool Cp*Rh(III) systems [Cp* = pentamethylcyclopentadienyl]. Our work established sound reaction platform based electrophilic aminating reagents including N-chloroamines, hydroxyamides, N-carboxyhydrazides formation aryl–metal complexes.Building upon metal-nitrene platform, moved forward examine γ-lactam synthesis by intramolecular carbonyl insertion. Noted nitrenes prone undergo Curtius-type rearrangement form isocyanate; found π-basic Ru(II) center effectively decomposes dioxazolones afford regioselective γ-C(sp3)–H With chiral diphenylethylenediamines (dpen) ligands bearing electron-withdrawing arylsulfonyl substituents, [(p-cymene)Ru(dpen)] complex catalyzed decomposition γ-lactams formal Enantioselective insertion allylic propargylic bonds also with remarkable tolerance C═C C≡C bonds. selectivity [(p-cymene)Ru] switched give dihydroquinolinones l-proline ligand. Recently, aimed address regiocontrolled unactivated methylene NiH catalyst. benzyl can differentiated their dissociation energies steric properties, groups making up skeleton display similar electronic properties. context, exploited five-membered nickelacycle terminate NiH-mediated chain-walk isomerization, reacted furnish C(sp3)–N at γ-methylene position.This summarizes contribution activation. By exploiting inner-sphere outer-sphere pathways, successfully protocols target The mechanistic underpinning different related affiliated will discussed.

Язык: Английский

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Iron-Catalyzed Intermolecular Amination of Benzylic C(sp³)–H Bonds

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(48), С. 21858 - 21866

Опубликована: Ноя. 23, 2022

A catalytic system for intermolecular benzylic C(sp3)-H amination is developed utilizing 1,2,3,4-tetrazole as a nitrene precursor via iron catalysis. This method enables direct installation of 2-aminopyridine into the and heterobenzylic position. The selectively aminates 2° bond over 3° 1° bonds. Experimental studies reveal that undergoes formation radical intermediate. study reports discovery new 2-pyridine substituted benzylamine synthesis using inexpensive, biocompatible base metal catalysis should have wide application in context medicinal chemistry drug discovery.

Язык: Английский

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Intermolecular Enantioselective Benzylic C(sp³)−H Amination by Cationic Copper Catalysis**

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(24)

Опубликована: Апрель 14, 2023

Chiral benzylic amines are privileged motifs in pharmacologically active molecules. Intramolecular enantioselective radical C(sp3 )-H functionalization by hydrogen-atom transfer has emerged as a straightforward, powerful tool for the synthesis of chiral amines, but methods intermolecular amination remain elusive. Herein, we report cationic copper catalytic system with peroxide an oxidant. This mild, straightforward method can be used to transform array feedstock alkylarenes and amides into high enantioselectivities, it good functional group tolerance broad substrate scope. More importantly, synthesize bioactive molecules, including drugs. Preliminary mechanistic studies indicate that reaction involves radicals generated transfer.

Язык: Английский

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Controlling Radical-Type Single-Electron Elementary Steps in Catalysis with Redox-Active Ligands and Substrates

JACS Au, Год журнала: 2021, Номер 1(8), С. 1101 - 1115

Опубликована: Июль 6, 2021

Advances in (spectroscopic) characterization of the unusual electronic structures open-shell cobalt complexes bearing redox-active ligands, combined with detailed mapping their reactivity, have uncovered several new catalytic radical-type protocols that make efficient use synergistic properties substrates, and metal to which they coordinate. In this perspective, we discuss tools available study, induce, control reactions ligands and/or contemplating recent developments field, including some noteworthy tools, methods, developed our own group. The main topics covered are (i) characterize ligands; (ii) novel synthetic applications carbene nitrene substrates at cobalt–porphyrins; (iii) development take advantage purely ligand- substrate-based redox processes, coupled cobalt-centered spin-changing events a manner; (iv) utilization influence spin state metal. Redox-active emerged as useful generate reactive metal-coordinated radicals, give access methodologies intricate (electronic) structures, yet be exposed.

Язык: Английский

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Catalytic Intermolecular C(sp³)–H Amination: Selective Functionalization of Tertiary C–H Bonds vs Activated Benzylic C–H Bonds

Journal of the American Chemical Society, Год журнала: 2021, Номер 143(17), С. 6407 - 6412

Опубликована: Апрель 26, 2021

A catalytic intermolecular amination of nonactivated tertiary C(sp3)–H bonds (BDE 96 kcal·mol–1) is reported for substrates displaying an activated benzylic site 85 kcal·mol–1). The bond selectively functionalized to afford α,α,α-trisubstituted amides in high yields. This unusual site-selectivity results from the synergistic combination Rh2(S-tfpttl)4, a rhodium(II) complex with well-defined pocket, tert-butylphenol sulfamate (TBPhsNH2), which leads discriminating rhodium-bound nitrene species under mild oxidative conditions. system very robust, and reaction was performed on 50 mmol scale only 0.01 mol % catalyst. TBPhs group can be removed conditions corresponding NH-free amines.

Язык: Английский

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Iron-Catalyzed Intermolecular C–N Cross-Coupling Reactions via Radical Activation Mechanism

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(27), С. 14599 - 14607

Опубликована: Июнь 30, 2023

A concept for intermolecular C-N cross-coupling amination has been discovered using tetrazoles and aromatic aliphatic azides with boronic acids under iron-catalyzed conditions. The follows an unprecedented metalloradical activation mechanism that is different from traditional metal-catalyzed reactions. scope of the reaction demonstrated by employment a large number tetrazoles, azides, acids. Moreover, several late-stage aminations short synthesis drug candidate have showcased further synthetic utility. Collectively, this should wide applications in context medicinal chemistry, discovery, pharmaceutical industries.

Язык: Английский

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