Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

Chemical Reviews, Год журнала: 2022, Номер 122(6), С. 6634 - 6718

Опубликована: Фев. 18, 2022

Organic compounds labeled with hydrogen isotopes play a crucial role in numerous areas, from materials science to medicinal chemistry. Indeed, while the replacement of by deuterium gives rise improved absorption, distribution, metabolism, and excretion (ADME) properties drugs enables preparation internal standards for analytical mass spectrometry, use tritium-labeled is key technique all along drug discovery development pharmaceutical industry. For these reasons, interest new methodologies isotopic enrichment organic molecules extent their applications are equally rising. In this regard, Review intends comprehensively discuss developments area over last years (2017–2021). Notably, besides fundamental isotope exchange (HIE) reactions isotopically analogues common reagents, plethora reductive dehalogenative deuteration techniques other transformations incorporation emerging now part labeling toolkit.

Язык: Английский

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C–H deuteration of organic compounds and potential drug candidates

Chemical Society Reviews, Год журнала: 2022, Номер 51(8), С. 3123 - 3163

Опубликована: Янв. 1, 2022

This review summarises deuteration methods of various organic motifs containing C(sp 2 )−H and 3 bonds utilizing C−H bond functionalisation as a key step along with variety catalysts, exemplifies their biological relevance.

Язык: Английский

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Palladium-Catalyzed Enantioselective β-C(sp³)–H Activation Reactions of Aliphatic Acids: A Retrosynthetic Surrogate for Enolate Alkylation and Conjugate Addition

Accounts of Chemical Research, Год журнала: 2022, Номер 55(4), С. 537 - 550

Опубликована: Янв. 25, 2022

Enolate alkylation and conjugate addition into an α,β-unsaturated system have served as long-standing strategic disconnections for the installation of α- or β-substituents on carbonyl-containing compounds. At onset our efforts to develop C-H activation reactions organic synthesis, we set eye toward developing asymmetric β-C-H aliphatic acids with perspective that this bond-forming event could serve a more flexible retrosynthetic surrogate both canonical carbonyl-related transformations.In Account, describe early using strongly coordinating chiral oxazolines probe reaction mechanism stereochemical nature cleavage transition state. The characterization key reactive intermediates through X-ray crystallography computational studies suggested state Pd-OAc bonds being approximately coplanar optimum interaction. We then moved forward practical, weakly monodentate amide directing groups, necessary advance achieving native carboxylic acids. Throughout journey, gradual deconvolution between substrate's effect its intimate interplay ligand properties has culminated in design new classes ultimately allowed competency activation. These established importance acceleration Pd-catalyzed activation, where weak coordination is responsible positioning catalyst cleavage, while direct participation from bifunctional enthalpically stabilizing state.Building upon these principles, developed five ligands (MPAA, MPAQ, MPAO, MPAThio, MPAAM) enable enantioselective reactions, including carbon-carbon carbon-heteroatom bond formation. accumulated data indicate possessing point chirality are most effective imparting stereoinduction step, application which enabled desymmetrization subsequent functionalization enantiotopic carbon protons across range arylamides and, recently, free Progress design, conjunction enabling alkali metal countercations, led realization suite β-methyl now methylene C(sp

Язык: Английский

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Catalyst-controlled site-selective methylene C–H lactonization of dicarboxylic acids

Science, Год журнала: 2022, Номер 376(6600), С. 1481 - 1487

Опубликована: Май 26, 2022

Catalyst-controlled site-selective activation of β- and γ-methylene carbon-hydrogen (C-H) bonds free carboxylic acids is a long-standing challenge. Here we show that, with pair palladium catalysts assembled quinoline-pyridone ligands different chelate ring sizes, it possible to perform highly monolactonization reactions wide range dicarboxylic acids, generating structurally diverse synthetically useful γ- δ-lactones via or C-H activation. The remaining carboxyl group serves as versatile linchpin for further synthetic applications, demonstrated by the total synthesis two natural products, myrotheciumone A pedicellosine, from abundant acids.

Язык: Английский

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Ligand-controlled divergent dehydrogenative reactions of carboxylic acids via C–H activation

Science, Год журнала: 2021, Номер 374(6572), С. 1281 - 1285

Опубликована: Дек. 2, 2021

Desaturating acids Molecular motifs with neighboring C=C and C=O double bonds are central to the synthesis of fine chemicals, pharmaceuticals, polymers. Wang et al . report a versatile palladium-catalyzed reaction produce this motif from carboxylic by oxidation adjacent carbons, molecular oxygen as viable terminal oxidant (see Perspective Iwabuchi). The method relies on fine-tuned ligand geometry complements approaches constrained their reliance enolate chemistry. Swapping in an alternate promotes extension desaturation coupling alkynes. —JSY

Язык: Английский

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Palladium-Catalyzed Nondirected Late-Stage C–H Deuteration of Arenes

Journal of the American Chemical Society, Год журнала: 2021, Номер 143(40), С. 16370 - 16376

Опубликована: Сен. 28, 2021

We describe a palladium-catalyzed nondirected late-stage deuteration of arenes. Key aspects include the use D2O as convenient and easily available deuterium source discovery highly active N,N-bidentate ligands containing an N-acylsulfonamide group. The reported protocol enables high degrees incorporation via reversible C–H activation step features extraordinary functional group tolerance, allowing for complex substrates. This is exemplified by isotopic labeling various pharmaceutically relevant motifs related scaffolds. expect that this method, among other applications, will prove useful tool in drug development processes mechanistic studies.

Язык: Английский

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Pd-catalysed C–H functionalisation of free carboxylic acids

Chemical Science, Год журнала: 2022, Номер 13(9), С. 2551 - 2573

Опубликована: Янв. 1, 2022

Pd-catalysed C–H functionalisation of free carboxylic acids has drawn significant attention over the last few years due to predominance acid moieties in pharmaceuticals and agrochemicals.

Язык: Английский

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One-Step Synthesis of β-Alkylidene-γ-lactones via Ligand-Enabled β,γ-Dehydrogenation of Aliphatic Acids

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(28), С. 12924 - 12933

Опубликована: Июль 8, 2022

Ligand-enabled Pd-catalyzed regioselective α,β-dehydrogenation of carbonyl compounds via β-methylene C–H activation has recently emerged as a promising transformation. Herein, we report the realization β,γ-dehydrogenation and subsequent vinyl olefination reactions free carboxylic acids, thus providing unique method for structural diversification aliphatic acids containing α-quaternary centers through sequential functionalizations two β-C–H bonds one γ-C–H bond. This tandem dehydrogenation–olefination–lactonization reaction offers one-step preparation β-alkylidene-γ-lactones, which are often difficult to prepare conventional methods, from inexpensive abundant acids. A variety such isosteviol grandiflorolic acid natural products, olefins compatible with reported protocol. The newly designed bidentate oxime ether-pyridone morpholine-pyridone ligands crucial this proceed. Notably, these also enable preferential methylene over previously reported, competing process methyl bond olefination.

Язык: Английский

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Rhodium‐Catalyzed Stereoselective Deuteration of Benzylic C–H Bonds via Reversible η⁶‐Coordination

Angewandte Chemie International Edition, Год журнала: 2022, Номер 61(11)

Опубликована: Янв. 10, 2022

We report a convenient method for benzylic H/D exchange of wide variety substrates bearing primary, secondary, or tertiary C-H bonds via reversible η6 -coordination strategy. A doubly cationic [CpCF3 RhIII ]2+ catalyst that serves as an arenophile facilitates deprotonation inert hydrogen atoms (pKa >40 in DMSO) without affecting other atoms, such those on aromatic rings α-positions carboxylate groups. Notably, the reactions feature high stereoretention. demonstrated potential utility this by using it deuterium labeling ten pharmaceuticals and their analogues.

Язык: Английский

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Hydrogenative alkene perdeuteration aided by a transient cooperative ligand

Nature Chemistry, Год журнала: 2023, Номер 15(10), С. 1384 - 1390

Опубликована: Сен. 4, 2023

Язык: Английский

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