Nickel-Catalyzed Ligand-Controlled Selective Reductive Cyclization/Cross-Couplings

Accounts of Chemical Research, Journal Year: 2023, Volume and Issue: 56(5), P. 515 - 535

Published: Jan. 23, 2023

ConspectusThe use of quaternary stereocenters during lead candidate optimization continues to grow because improved physiochemical and pharmacokinetic profiles compounds with higher sp3 fraction. Pd-catalyzed redox-neutral alkene difunctionalization involving carbopalladation alkenes followed by nucleophilic-trapping σ-alkyl-palladium intermediates has been developed as an efficient method construct stereocenters. However, the low chemoselectivity air sensitivity organometallic nucleophiles, well their availability accessibility, limit scope application this elegant strategy. Recently, Ni-catalyzed reductive cross-coupling evolved into a privileged strategy easily valuable C(sp3)-C bonds. Despite great progress, enantioselective coupling C(sp3) electrophiles still relies on activated or functionalized alkyl precursors, which are often unstable require multiple steps prepare. Therefore, via selective cyclization/cross-coupling was developed. This not only offers robust practical alternative for traditional but also provides strategic complementarity electrophiles. In Account, we summarize latest results from our laboratory topic. These findings mainly include explorations in modulating enantioselectivity cyclization mode cyclization/cross-couplings.We will first discuss chiral heterocycles focus effects ligands, reductants, additives roles cross-coupling. A wide range have explored, including aryl halides, vinyl alkynyl gem-difluoroalkenes, CO2, trifluoromethyl alkenes, cyano The synthetic potential approach demonstrated synthesis biologically active natural products drug molecules. Second, detail how tune steric nickel catalysts modifying bipyridine ligands regiodivergent cyclization/cross-couplings. Specifically, bidentate favors exo-selective cyclization/cross-coupling, while carboxylic acid-modified ligand permits endo-selective cyclization/cross-coupling. We show activate amide substrate altering electronic properties substituents nitrogen, thereby enabling nucleophilic addition halides carbonyls. Further investigation led tunable cyclization/cross-couplings (addition carbonyl vs 7-endo-cyclization) divergent pharmacologically important 2-benzazepine frameworks. Finally, serendipitously discover that changing oxidation state can control migratory aptitude different groups, thus providing switchable skeletal rearrangement transformation is high value it represents conceptually unprecedented new C-C bond activation. Thus, Account summarizes methods allow formation using variety insight relationship between structure, substrate, selectivity.

Language: Английский

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The Landscape of Potential Small and Drug Substance Related Nitrosamines in Pharmaceuticals

Journal of Pharmaceutical Sciences, Journal Year: 2022, Volume and Issue: 112(5), P. 1287 - 1304

Published: Nov. 17, 2022

This article reports the outcome of an in silico analysis more than 12,000 small molecule drugs and drug impurities, identifying nitrosatable structures, assessing their potential to form nitrosamines under relevant conditions challenges determine compound-specific AIs based on data available or read-across approaches for these acceptance by health authorities. Our indicate that presence pharmaceuticals is likely prevalent originally expected. In total, 40.4 % analyzed APIs 29.6 API impurities are nitrosamine precursors. Most structures identified through our workflow could complex API-related nitrosamines, so-called substance related (NDSRIs), although we also found release well-known potent NDMA, NDEA, others. Due common structural motifs including secondary tertiary amine moieties, whole essential classes such as beta blockers ACE inhibitors at risk. To avoid risk shortages even complete loss therapeutic options, it will be well-established ICH M7 principles remain applicable industry regulatory authorities keep open communication not only about science but make sure there a good balance between benefit patients.

Language: Английский

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Contemporary Approaches for Amide Bond Formation

Advanced Synthesis & Catalysis, Journal Year: 2023, Volume and Issue: 365(24), P. 4359 - 4391

Published: Nov. 7, 2023

Abstract Amide bond construction has garnered significant interest in recent decades due to amides being one of the most prevalent functional groups among bioactive molecules. Out thirty‐seven new drugs approved by FDA 2022, eleven are small molecules containing at least amide bond. Additionally, there nineteen large as drugs, some which have peptide structures, and therefore, also bear bonds. In years, multiple teams embraced challenge developing more efficient methods for formation. This dedication led numerous publications appearing monthly prestigious journals, showcasing advancements this field. The primary goal review is present viable strategies constructing It crucial differentiate between formation synthesis; hence, focus on describing specific forming C(O)−N particular, concentrates developed within last six years. There a particular emphasis approaches that consider thought process when selecting starting materials groups. approach ensures coverage all common chemical transformations yield

Language: Английский

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Challenges and Breakthroughs in Selective Amide Activation

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(49)

Published: Sept. 20, 2022

In contrast to ketones and carboxylic esters, amides are classically seen as comparatively unreactive members of the carbonyl family, owing their unique structural electronic features. However, recent decades have emergence research programmes focused on selective activation under mild conditions. past four years, this area has continued rapidly develop, with new advances coming in at a fast pace. Several novel strategies been demonstrated effective tools for amide activation, enabling transformations that once synthetically useful mechanistically intriguing. This Minireview comprises field, highlighting trends breakthroughs what could be called age activation.

Language: Английский

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Highly Chemoselective Transamidation of Unactivated Tertiary Amides by Electrophilic N−C(O) Activation by Amide‐to‐Acyl Iodide Re‐routing

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(24)

Published: March 31, 2022

The challenging transamidation of unactivated tertiary amides has been accomplished via cooperative acid/iodide catalysis. Most crucially, the method provides a novel manifold to re-route reactivity N,N-dialkyl through reactive acyl iodide intermediates, thus reverting classical order carboxylic acid derivatives. This direct route amide-to-amide bond interconversion with excellent chemoselectivity using equivalent amounts amines. combination and identified as essential factor activate amide C-N electrophilic catalytic activation, enabling production new desired transamidated products wide substrate scope both amines, including late-stage functionalization complex APIs (>80 examples). We anticipate that this powerful activation mode bonds will find broad-ranging applications in chemical synthesis.

Language: Английский

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Synthesis of Natural Products by C−H Functionalization of Heterocycless

Chemistry - A European Journal, Journal Year: 2022, Volume and Issue: 28(22)

Published: Jan. 28, 2022

Total synthesis is considered by many as the finest combination of art and science. During last decades, several concepts were proposed for achieving perfect vision total synthesis, such atom economy, step or redox economy. In this context, C-H functionalization represents most powerful platform that has emerged in years, empowering rapid complex natural products enabling diversification bioactive scaffolds based on product architectures. review, we present an overview recent strategies towards heterocyclic enabled functionalization. Heterocycles represent common motifs drug discovery marketed drugs. The implementation heterocycles enables novel tactics construction core architectures, but also changes logic design retrosynthetic permits access to with enhanced biological activities.

Language: Английский

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Ni‐Catalyzed Divergent Synthesis of 2‐Benzazepine Derivatives via Tunable Cyclization and 1,4‐Acyl Transfer Triggered by Amide N‐C Bond Cleavage

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(25)

Published: April 6, 2022

Abstract Ligand‐directed divergent synthesis can transform common starting materials into distinct molecular scaffolds by simple tuning different ligands. This strategy enables the rapid construction of structurally rich collection small molecules for biological evaluation and reveals novel modes catalytic transformation, representing one most sought‐after challenges in synthetic chemistry. We herein report a Ni‐catalyzed ligand‐controlled tunable cyclization/cross‐couplings pharmacologically important 2‐benzazepine frameworks. The bidentate ligand facilitates nucleophilic addition aryl halides to amide carbonyl, followed 1,4‐acyl transfer cross‐coupling obtain 2‐benzazepin‐5‐ones benzo[c]pyrano[2,3‐e]azepines. tridentate promotes selective 7‐ endo cyclization/cross‐coupling access 2‐benzazepin‐3‐ones. protocol operates under mild reaction conditions with cyclization patterns that be easily modulated through backbone.

Language: Английский

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Nickel-Catalyzed Three-Component Alkylacylation of Alkenes Enabled by a Photoactive Electron Donor–Acceptor Complex

Organic Letters, Journal Year: 2022, Volume and Issue: 24(22), P. 3938 - 3943

Published: May 23, 2022

An electron donor-acceptor complex-enabled, nickel-catalyzed three-component net-reductive 1,2-alkylacylation of alkenes is developed. This conjunctive reductive acyl cross-coupling process obviates the use an exogenous photocatalyst and a stoichiometric metal-based reductant, affording various synthetically useful 1,3-dicarbonyl compounds in good yields with broad substrate scope excellent functional group tolerance. Both alkyl electrophiles are derived from highly abundant readily accessible carboxylic acids, making catalytic 1,2-dicarbofunctionalization more general sustainable.

Language: Английский

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Classes of Amides that Undergo Selective N–C Amide Bond Activation: The Emergence of Ground-State Destabilization

The Journal of Organic Chemistry, Journal Year: 2022, Volume and Issue: 88(19), P. 13371 - 13391

Published: Sept. 2, 2022

Ground-state destabilization of the N–C(O) linkage represents a powerful tool to functionalize historically inert amide bond. This burgeoning reaction manifold relies on availability bond precursors that participate in weakening nN → π*C=O conjugation through N–C twisting, N pyramidalization, and electronic delocalization. Since 2015, acyl activation ground-state has been achieved by transition-metal-catalyzed oxidative addition bond, generation radicals, transition-metal-free addition. Perspective summarizes contributions our laboratory development new ground-state-destabilized enabled twist synthetic utility amides cross-coupling reactions reactions. The use as electrophiles enables plethora previously unknown transformations such coupling, decarbonylative radical coupling forge C–C, C–N, C–O, C–S, C–P, C–B bonds. Structural studies activated catalytic systems developed past decade enable view change from "traditionally inert" "readily modifiable" functional group with continuum reactivity dictated destabilization.

Language: Английский

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The Chemical Relationship Among Beta-Lactam Antibiotics and Potential Impacts on Reactivity and Decomposition

Frontiers in Microbiology, Journal Year: 2022, Volume and Issue: 13

Published: March 24, 2022

Beta-lactam antibiotics remain one of the most commonly prescribed drug classes, but they are limited by their propensity to cause hypersensitivity reactions (e.g., from allergy anaphylaxis) as well emergence bacteria with a myriad resistance mechanisms such β-lactamases. While development efforts continue focus on overcoming resistance, there ongoing concerns regarding cross-contamination β-lactams during manufacturing and compounding these drugs. Additionally, is need reduce levels drugs β-lactam in waste-water mitigate risk environmental exposure. To help address future effective remediation chemistries processes, it desired better understand structural relationship among common β-lactams. This study includes creation class-wide ordering entire series, including both United States Food Drug Association (US-FDA)-approved experimental therapies. The result relational map: “Lactamome,” which positions each substance according architecture chemical end-group. We utilized novel method compare relationships radial cladogram describe positioning respect efficacy, hydrolysis, reported hypersensitivity, Woodward height. resulting classification scheme may broad-spectrum treatments that occupational exposure negative impacts, assist practitioners avoiding adverse patient reactions, direct research.

Language: Английский

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