Modern Approaches for Asymmetric Construction of Carbon–Fluorine Quaternary Stereogenic Centers: Synthetic Challenges and Pharmaceutical Needs

Chemical Reviews, Journal Year: 2018, Volume and Issue: 118(7), P. 3887 - 3964

Published: April 2, 2018

New methods for preparation of tailor-made fluorine-containing compounds are in extremely high demand nearly every sector chemical industry. The asymmetric construction quaternary C-F stereogenic centers is the most synthetically challenging and, consequently, least developed area research. As a reflection this apparent methodological deficit, pharmaceutical drugs featuring constitute less than 1% all medicines currently on market or clinical development. Here we provide comprehensive review current research activity area, including such general directions as electrophilic fluorination via organocatalytic and transition-metal catalyzed reactions, elaboration substrates alkylations, Mannich, Michael, aldol additions, cross-coupling biocatalytic approaches.

Language: Английский

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Difluoromethylation Reactions of Organic Compounds

Chemistry - A European Journal, Journal Year: 2017, Volume and Issue: 23(59), P. 14676 - 14701

Published: June 20, 2017

Abstract The relevance of the ‐CF 2 H moiety has attracted considerable attention from organic synthetic and medicinal chemistry communities, because this group can act as a more lipophilic isostere carbinol, thiol, hydroxamic acid, or amide groups. Being weakly acidic, CF establish hydrogen‐bonding interactions to improve binding selectivity biologically active compounds. Therefore, hydroxyl, amino, thio substituents lead structures are routinely replaced by motif in drug discovery, with great benefits pharmacological activity drugs candidates agrochemicals. Consequently, late‐stage introduction is sought‐after strategy designing bioactive Secondly, but nonetheless relevant meaningful, study pathways introduce −Y (Y≠H, F) into substrates compounds that contain functionality have also found vast applications other areas, such fungicides, insecticides, etc., thus, deserves special attention. Although emphasis made on difluoromethylation strategies functionalize different families compounds, three main methodological protocols will be presented review article for Y moieties substrates: i) metal‐photoredox catalysis; ii) through transition metal‐catalyzed thermal protocols; iii) transition‐metal‐free strategies.

Language: Английский

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Development of Synthetic Methodologies via Catalytic Enantioselective Synthesis of 3,3-Disubstituted Oxindoles

Accounts of Chemical Research, Journal Year: 2018, Volume and Issue: 51(6), P. 1443 - 1454

Published: May 29, 2018

3,3-Disubstituted oxindoles are widely distributed in natural products, drugs, and pharmaceutically active compounds. The absolute configuration the substituents on fully substituted C3 stereocenter of oxindole often significantly influence biological activity. Therefore, tremendous efforts have made to develop catalytic enantioselective syntheses this prominent structural motif. Research area is further fueled by ever-increasing demand for modern probe- drug-discovery programs synthetic libraries chiral compounds that derived from privileged scaffolds with high diversity. Notably, efficient construction stereocenters oxindole, tetrasubstituted or all-carbon quaternary, spirocyclic not, also becomes a test ground new methodologies. We been engaged developing methods diversity-oriented synthesis 3,3-disubstituted readily available starting materials. systematically developed prepare 3-substituted 3-hydroxyoxindoles, 3-aminooxindoles, 3-thiooxindoles, quaternary oxindoles, oxindoles. These protocols can be classified into six approaches: (1) addition nucleophiles isatins isatin ketimines; (2) unprotected as nucleophiles; (3) functionalization oxindole-derived alkenes; (4) desymmetrization oxindole-based diynes; (5) spirocyclopropyl donor-acceptor (D-A) cyclopropanes; (6) elaboration diazooxindoles. By use these methods, rich diversity accessed excellent enantioselectivity. Some used formal total bioactive compounds, their analogues. On basis studies, we methodologies potential application. designed phosphoramide-based bifunctional catalysts oxindoles: cinchona-alkaloid-derived phosphoramide Michael nitroolefins broad substrate scope 1,2-cyclohexanediamine-derived activation fluorinated enol silyl ethers isatylidene malononitrile. achieved better enantiofacial control than analogous H-bond-donor-derived reactions, suggesting former catalyst development. identified Au(I) Hg(II) olefin cyclopropanation disclosed effective using electron-withdrawing N-protecting groups [3 + 3] cycloaddition, offering promise constructing diverse range such monoactivated D-A cyclopropanes. tandem sequences allow facile simple materials one-pot operation, including Morita-Baylis-Hillman/bromination/[3 2] annulation sequence, hydrogenation/ketimine formation/asymmetric 6π electrocyclization C-H functionalization/Michael amination an aza-Wittig/Strecker sequence. diynes realize highly Cu-catalyzed alkyne-azide cycloaddition (CuAAC), outlining prochiral strategy exploit asymmetric CuAAC. This Account focuses our group provides overview research design, development, applications will provide useful insights exploration reactions.

Language: Английский

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Selectivity of C–H Activation and Competition between C–H and C–F Bond Activation at Fluorocarbons

Chemical Reviews, Journal Year: 2017, Volume and Issue: 117(13), P. 8710 - 8753

Published: June 27, 2017

Partially fluorinated alkanes, arenes, and alkenes can be transformed by a variety of transition metal lanthanide systems. Although the C-H bond is weaker than C-F regardless hybridization carbon, reaction at usually more exothermic corresponding bonds. Both bonds are activated systems, but preference for activating these depends on nature hydrocarbon system, so that directed exclusively toward or yield mixture products. Additionally, presence fluorine differentiates between different positions resulting in regioselective activation; paradoxically, strongest reacts preferentially. The purpose this review to describe field reactions partially substrates with atoms, ions, molecular complexes. controlling physical properties (thermodynamics kinetics) described first, followed description stoichiometric reactions, competition activations as focus. A few representative catalytic systems discussed. also highlights benefit combining experimental theoretical studies.

Language: Английский

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Late-stage difluoromethylation: concepts, developments and perspective

Chemical Society Reviews, Journal Year: 2021, Volume and Issue: 50(14), P. 8214 - 8247

Published: Jan. 1, 2021

This review describes the conceptual advances that have led to multiple difluoromethylation processes making use of well-defined CF₂H sources.

Language: Английский

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Fluorinated Vitrimer Elastomers with a Dual Temperature Response

Journal of the American Chemical Society, Journal Year: 2018, Volume and Issue: 140(41), P. 13272 - 13284

Published: Sept. 19, 2018

Vitrimers are an emerging new class of permanently cross-linked polymeric materials that show a liquid behavior upon heating wherein the macroscopic deformation is controlled by rate internal chemical bond exchange reactions. Thus, quite uniquely among materials, flow rates and material viscosities can be enhanced or addition catalysts additives. We now report catalyst-free vitrimer system, prepared from mixing two simple components, competing mechanisms coexist, each showing strikingly different temperature dependence, related to large difference in activation energy for pathways (60 vs 130-170 kJ/mol). The low barrier process predominant at lower temperatures, but outcompeted high becomes dominant higher temperatures because its much more pronounced dependence. result interesting highly unusual dual viscosity profile this materials: very gradual decrease intercepted sharper drop temperatures. counterintuitive effect where pathway over rationalized involve reactive species, lead overall same exchange. observed promising first fluorinated elastomers, aimed performance was also shown hold nonfluorinated elastomers. A way control design rheological vitrimers toward finely tuned precisely processing applications has thus been provided.

Language: Английский

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Contemporary synthetic strategies in organofluorine chemistry

Nature Reviews Methods Primers, Journal Year: 2021, Volume and Issue: 1(1)

Published: July 8, 2021

Language: Английский

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Photochemical and electrochemical strategies in C–F bond activation and functionalization

Organic Chemistry Frontiers, Journal Year: 2021, Volume and Issue: 9(3), P. 853 - 873

Published: Dec. 7, 2021

The recent advances in photochemical or electrochemical C–F bond activation and functionalization have been summarized discussed.

Language: Английский

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Photoredox‐Catalyzed Defluorinative Functionalizations of Polyfluorinated Aliphatic Amides and Esters

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 61(9)

Published: Dec. 10, 2021

Abstract Selective C−F bond functionalization of perfluoalkyl units has huge potential towards accessing functionalized organofluorinated compounds, but remains challenging due to the high strength and inherent selectivity challenges. We report a new catalytic approach selective strong bonds in polyfluorinated aliphatic esters amides. This simple reaction proceeds mild operational fashion with divergent conversions, including hydrodefluorination, defluoroalkylation, defluoroalkenylation, affording diverse array important partially fluorinated motifs. Straightforward downstream chemistry alcohols, amines drug derivatives highlights protocol.

Language: Английский

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The interplay of polar effects in controlling the selectivity of radical reactions

Nature Synthesis, Journal Year: 2022, Volume and Issue: 1(9), P. 682 - 695

Published: Aug. 1, 2022

Language: Английский

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