Site-selective C–H functionalization to access the arene backbone of indoles and quinolines

Chemical Society Reviews, Год журнала: 2021, Номер 50(20), С. 11249 - 11269

Опубликована: Янв. 1, 2021

The site-selective C-H bond functionalization of heteroarenes can eventually provide chemists with great techniques for editing and building complex molecular scaffolds. During the past decade, benzo-fused N-heterocycles such as indoles quinolines have been among most widely investigated organic templates. Early developments led to on pyrrole pyridine cores quinolines; however, benzenoid ring has remained a challenge in catalysis. In this review, we elaborate recent highly challenging bonds less-reactive core quinolines. These findings are mainly described selective directing group assisted strategies, remote their reaction mechanisms. underlying principle each strategy is elucidated, which aims facilitate design more advanced structure heterocycles based bioactive molecules, synthetic drugs, material aspects. Moreover, challenges perspectives catalytic access arene backbone also proposed conclusion section.

Язык: Английский

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Tunable molecular editing of indoles with fluoroalkyl carbenes

Nature Chemistry, Год журнала: 2024, Номер 16(6), С. 988 - 997

Опубликована: Март 5, 2024

Язык: Английский

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From Ground-State to Excited-State Activation Modes: Flavin-Dependent “Ene”-Reductases Catalyzed Non-natural Radical Reactions

Accounts of Chemical Research, Год журнала: 2024, Номер 57(9), С. 1446 - 1457

Опубликована: Апрель 11, 2024

ConspectusEnzymes are desired catalysts for chemical synthesis, because they can be engineered to provide unparalleled levels of efficiency and selectivity. Yet, despite the astonishing array reactions catalyzed by natural enzymes, many reactivity patterns found in small molecule have no counterpart living world. With a detailed understanding mechanisms utilized catalysts, we identify existing enzymes with potential catalyze that currently unknown nature. Over past eight years, our group has demonstrated flavin-dependent "ene"-reductases (EREDs) various radical-mediated selectivity, solving long-standing challenges asymmetric synthesis.This Account presents development EREDs as general radical reactions. While developed multiple generating radicals within protein active sites, this account will focus on examples where flavin mononucleotide hydroquinone (FMNhq) serves an electron transfer initiator. initial mechanistic hypotheses were rooted electron-transfer-based initiation commonly used synthetic organic chemists, ultimately uncovered emergent unique site. We begin covering intramolecular discussing how activates substrate reduction altering redox-potential alkyl halides templating charge complex between flavin-cofactor. Protein engineering been modify fundamental photophysics these reactions, highlighting opportunity tune systems further using directed evolution. This section highlights range coupling partners termination available reactions.The next intermolecular role enzyme-templated ternary complexes among cofactor, halide, partner gating ensure it only occurs when both substrates bound highlight applications activation mode, including olefin hydroalkylation, carbohydroxylation, arene functionalization, nitronate alkylation. also discusses favor steps elusive solution reductive nitroalkanes. aware several recent EREDs-catalyzed photoenzymatic transformations from other groups. discuss results papers context nuances substrates.These biocatalytic often complement state-of-the-art small-molecule-catalyzed making valuable addition chemist's toolbox. Moreover, underlying principles studied potentially operative cofactor-dependent proteins, opening door different types enzyme-catalyzed anticipate serve guide inspire broad interest repurposing access new transformations.

Язык: Английский

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The emergence of the C–H functionalization strategy in medicinal chemistry and drug discovery

Chemical Communications, Год журнала: 2021, Номер 57(83), С. 10842 - 10866

Опубликована: Янв. 1, 2021

Owing to the market competitiveness and urgent societal need, an optimum speed of drug discovery is important criterion for successful implementation. Despite rapid ascent artificial intelligence computational bioanalytical techniques accelerate in big pharma, organic synthesis privileged scaffolds predicted silico vitro vivo studies still considered as rate-limiting step. C-H activation latest technology added into chemist's toolbox construction late-stage modification functional molecules achieve desired chemical physical properties. Particularly, elimination prefunctionalization steps, exceptional group tolerance, complexity-to-diversity oriented synthesis, functionalization medicinal expand space. It has immense potential a library molecules, structural required pharmacological properties such absorption, distribution, metabolism, excretion, toxicology (ADMET) attachment reporters proteome profiling, metabolite etc. preclinical studies. Although heterocycle modification, 18F labelling, methylation, via have been reviewed from synthetic standpoint, general overview these protocols aspects not reviewed. In this feature article, we will discuss recent trends methodologies through activation/annulation cascade; arylation sp2-sp2 sp2-sp3 cross-coupling; borylation/silylation introduce linchpin further manipulation; amination N-heterocycles hydrogen bond acceptors; fluorination/fluoroalkylation tune polarity lipophilicity; methylation: methyl magic discovery; peptide macrocyclization therapeutics biologics; fluorescent labelling radiolabelling bioimaging; bioconjugation biology studies; drug-metabolite biodistribution excretion diversification drug-molecules increase efficacy safety; cutting-edge DNA encoded improved chemistry discovery.

Язык: Английский

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Transition metal-catalyzed C–H functionalizations of indoles

New Journal of Chemistry, Год журнала: 2021, Номер 45(31), С. 13692 - 13746

Опубликована: Янв. 1, 2021

This review summarises a wide range of transformations on the indole skeleton, including arylation, alkenylation, alkynylation, acylation, nitration, borylation, and amidation, using transition-metal catalyzed C–H functionalization as key step.

Язык: Английский

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Regioselective Radical Alkylation of Arenes Using Evolved Photoenzymes

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(21), С. 11866 - 11874

Опубликована: Май 18, 2023

Substituted arenes are ubiquitous in molecules with medicinal functions, making their synthesis a critical consideration when designing synthetic routes. Regioselective C–H functionalization reactions attractive for preparing alkylated arenes; however, the selectivity of existing methods is modest and primarily governed by substrate's electronic properties. Here, we demonstrate biocatalyst-controlled method regioselective alkylation electron-rich electron-deficient heteroarenes. Starting from an unselective "ene"-reductase (ERED) (GluER-T36A), evolved variant that selectively alkylates C4 position indole, elusive using prior technologies. Mechanistic studies across evolutionary series indicate changes to protein active site alter character charge transfer (CT) complex responsible radical formation. This resulted significant degree ground-state CT complex. on C2-selective ERED suggest evolution GluER-T36A helps disfavor competing mechanistic pathway. Additional engineering campaigns were carried out C8-selective quinoline alkylation. study highlights opportunity use enzymes reactions, where small molecule catalysts struggle selectivity.

Язык: Английский

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Recent advances in transition-metal-catalyzed directed C–H alkenylation with maleimides

Organic & Biomolecular Chemistry, Год журнала: 2022, Номер 20(24), С. 4837 - 4845

Опубликована: Янв. 1, 2022

Transition-metal-catalyzed directed C-H alkenylation with maleimides has attracted much attention in recent years, as maleimide core moieties are present various natural products and pharmaceuticals. In addition, these derivatives can be readily modified into biologically important compounds including succinimides, pyrrolidines γ-lactams. The efficient chelation-assisted inert bond activation strategy provides straightforward access to a wide array of structurally diverse molecules containing units. This review describes the major progress mechanistic investigations on Heck-type reaction/cyclization organic until early 2022.

Язык: Английский

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One‐Carbon Ring Expansion of Indoles and Pyrroles: A Straightforward Access to 3‐Fluorinated Quinolines and Pyridines

Angewandte Chemie International Edition, Год журнала: 2023, Номер 63(5)

Опубликована: Дек. 12, 2023

Abstract 3‐Fluorinated quinolines and pyridines are prevalent pharmacophores, yet their synthesis is often challenging. Herein, we demonstrate that dibromofluoromethane as bromofluorocarbene source enables the one‐carbon ring expansion of readily available indoles pyrroles to structurally diverse 3‐fluorinated pyridines. This straightforward protocol requires only a short reaction time ten minutes can be performed under air atmosphere. Preliminary investigations reveal this strategy also applied other valuable azines by using different 1,1‐dibromoalkanes bromocarbene sources.

Язык: Английский

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Iodine-dependent oxidative regioselective aminochalcogenation of indolines

Chemical Communications, Год журнала: 2024, Номер 60(9), С. 1152 - 1155

Опубликована: Янв. 1, 2024

An efficient approach for the selective construction of C2,3- or C2,5-aminochalcogenated indole derivatives has been developed, which enables oxidative regioselective aminochalcogenation indolines with amines and dichalconides.

Язык: Английский

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Ynones in dearomative spirocyclisation processes; a review

Tetrahedron Chem, Год журнала: 2024, Номер 9, С. 100055 - 100055

Опубликована: Янв. 14, 2024

This review concentrates on our research into the discovery of novel ynone-based dearomative spirocyclisation processes, whilst placing new chemistry context existing knowledge. The genesis programme, development efficient synthetic routes to prepare natural products spirobacillene A (1) and B (2), utilised indole ynones. stimulated a much wider study explore reactivity ynones in processes more generally. Routes generate wide range spirocycles were subsequently developed, with reactions tethered indoles, benzofurans, benzisoxazoles, pyrroles, pyridines, isoquinolines, pyrazines, cyclic ketimines, anisoles all discussed herein, these initiated by catalytic Ag(I), Cu(II), Pd(0), photolysis many other reagents. Asymmetric variants some are also discussed, as is further elaboration spirocyclic give carbazoles, quinolones, polycycles useful building blocks. Finally, applications methodology product synthesis (e.g. A, lasubine II indolizidine 209D) described.

Язык: Английский

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