Deuterium in drug discovery: progress, opportunities and challenges

Nature Reviews Drug Discovery, Год журнала: 2023, Номер 22(7), С. 562 - 584

Опубликована: Июнь 5, 2023

Язык: Английский

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Electrochemical Late-Stage Functionalization

Chemical Reviews, Год журнала: 2023, Номер 123(19), С. 11269 - 11335

Опубликована: Сен. 26, 2023

Late-stage functionalization (LSF) constitutes a powerful strategy for the assembly or diversification of novel molecular entities with improved physicochemical biological activities. LSF can thus greatly accelerate development medicinally relevant compounds, crop protecting agents, and functional materials. Electrochemical synthesis has emerged as an environmentally friendly platform transformation organic compounds. Over past decade, electrochemical late-stage (eLSF) gained major momentum, which is summarized herein up to February 2023.

Язык: Английский

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Radical deuteration

Chemical Society Reviews, Год журнала: 2022, Номер 51(15), С. 6291 - 6306

Опубликована: Янв. 1, 2022

This review is a systematic summary of radical deuteration with four reaction types: reductive deuteration, defunctionalization–deuteration, hydrogen–deuterium (H/D) exchange and deuteroalkylation.

Язык: Английский

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Site-Selective and Late-Stage Deuteration of (Hetero)arenes with Supported Iridium Nanoparticles

ACS Catalysis, Год журнала: 2025, Номер unknown, С. 2822 - 2826

Опубликована: Янв. 31, 2025

Deuterated compounds have emerged as critical tools across diverse research areas, including pharmaceuticals, where deuterium incorporation can modulate the absorption, distribution, metabolism, and excretion (ADME) properties of drugs. In this study, we report development a new hydrogen/deuterium (H/D) exchange catalyst based on supported iridium nanoparticles that enables selective deuteration arenes heteroarenes under mild conditions. Using C6D6 source, our catalytic system achieves high chemo- regioselectivity, avoiding common side reactions such hydrogenation dehalogenation observed with traditional heterogeneous catalysts. Notably, occurs selectively at para- meta-C(sp2)–H bonds, leaving ortho-C(sp2)–H C(sp3)–H bonds intact, exhibits broad functional group tolerance, ketones, amides, alkenes, aryl ethers, acidic protons. The nature was confirmed via filtration mercury drop tests. This work presents for regioselective complex molecules, offering complementary site selectivity to existing homogeneous methods possibility being used in late-stage pharmaceuticals.

Язык: Английский

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Site-Specific and Degree-Controlled Alkyl Deuteration via Cu-Catalyzed Redox-Neutral Deacylation

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(22), С. 9570 - 9575

Опубликована: Май 25, 2022

Deuterated organic compounds have become increasingly important in many areas; however, it remains challenging to install deuterium site-selectively unactivated aliphatic positions with control of the degree deuteration. Here, we report a Cu-catalyzed degree-controlled deacylative deuteration diverse alkyl groups methylketone (acetyl) moiety as traceless activating group. The use N-methylpicolino-hydrazonamide (MPHA) promotes efficient aromatization-driven C–C cleavage. Mono-, di-, and trideuteration at specific sites can be selectively achieved. reaction is redox-neutral broad functional group tolerance. utility this method has been demonstrated forming complete set deuterated ethyl groups, merging Diels–Alder reaction, net devinylative deuteration, synthesis d2-analogue Austedo.

Язык: Английский

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Chemoselective Decarboxylative Protonation Enabled by Cooperative Earth‐Abundant Element Catalysis

Angewandte Chemie International Edition, Год журнала: 2022, Номер 62(3)

Опубликована: Ноя. 9, 2022

Decarboxylative protonation is a general deletion tactic to replace polar carboxylic acid groups with hydrogen or its isotope. Current methods rely on the pre-activation of acids, non-sustainable sources, and/or expensive/highly oxidizing photocatalysts, presenting challenges their wide adoption. Here we show that cooperative iron/thiol catalyst system can readily achieve this transformation, hydrodecarboxylating range activated and unactivated acids overcoming scope limitations in previous direct methods. The reaction scaled batch configuration be directly performed deuterated solvent afford high yields d-incorporated products excellent isotope incorporation efficiency; characteristics not attainable photocatalyzed approaches. Preliminary mechanistic studies indicate radical mechanism kinetic results (KIE=1) are consistent light-limited reaction.

Язык: Английский

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Photocatalytic Deuterium Atom Transfer Deuteration of Electron‐Deficient Alkenes with High Functional Group Tolerance

Angewandte Chemie International Edition, Год журнала: 2022, Номер 62(3)

Опубликована: Ноя. 17, 2022

Abstract Due to its mild reaction conditions and unique chemoselectivity, hydrogen atom transfer (HAT) hydrogenation represents an indispensable method for the synthesis of complex molecules. Its analog using deuterium, deuterium (DAT) deuteration, is expected enable access deuterium‐labeled compounds. However, DAT deuteration has been scarcely studied synthetic purposes, a that possesses favorable characteristics HAT hydrogenations remained elusive. Herein, we report protocol photocatalytic electron‐deficient alkenes. In contrast previous this tolerates variety synthetically useful functional groups including haloarenes. The late‐stage also allows deuterated amino acids as well donepezil‐ d 2 . Thus, work demonstrates potential chemistry become alternative choice preparing deuterium‐containing

Язык: Английский

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Recent Advances in Deuteration Reactions^†

Chinese Journal of Chemistry, Год журнала: 2023, Номер 42(10), С. 1145 - 1156

Опубликована: Дек. 26, 2023

Comprehensive Summary The deuteration of organic compounds has attracted more attentions in recent years for the potential applications new drug discovery and synthetic chemistry. For this purpose, many efficient deuterium labeling methodologies have been developed, including hydrogen isotope exchange (HIE), reductive deuteration, dehalogenative that allow synthesis selectively deuterated compounds. In last few years, great breakthroughs selective achieved interest molecules is rising. review, we summarized developments since 2021. Several types key processes incorporation reactions, H/D exchange, are introduced discussed. Key Scientists 2000s, Derdau Atzrodt's group made contributions to directing assisted noble‐metal catalyzed arenes labeled During same period, Sajiki co‐workers completed a series reactions by heterogeneous platinum‐group metal catalysts. Since 2015, Gregory Pieters developed ruthenium catalysts exchange. 2016, Chirik's presence homogeneous iron complex. David MacMillan coworkers photocatalyzed HIE α‐amino C(sp 3 )–H bonds. From 2020, nanoelectrodes were designed deuterations unactivated unsaturated bonds Zhang's group. Recently, Beller's several strategies isotopic using earth‐abundant Our review latest important

Язык: Английский

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Ligand‐Enabled Palladium(II)‐Catalyzed Enantioselective β‐C(sp³)−H Arylation of Aliphatic Tertiary Amides**

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(17)

Опубликована: Март 5, 2023

Amide is one of the most widespread functional groups in organic and bioorganic chemistry, it would be valuable to achieve stereoselective C(sp3 )-H functionalization amide molecules. Palladium(II) catalysis has been prevalently used C-H activation chemistry past decades, however, due weakly-coordinating feature simple amides, challenging their direct with enantiocontrol by PdII catalysis. Our group developed sulfoxide-2-hydroxypridine (SOHP) ligands, which exhibited remarkable activity Pd-catalyzed C(sp2 activation. In this work, we demonstrate that chiral SOHP ligands served as an ideal solution enantioselective amides. Herein, report efficient asymmetric /SOHP-catalyzed β-C(sp3 arylation aliphatic tertiary ligand plays a key role deprotonation-metalation step.

Язык: Английский

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Metal-free photoinduced hydrogen atom transfer assisted C(sp³)–H thioarylation

Green Chemistry, Год журнала: 2023, Номер 25(9), С. 3431 - 3436

Опубликована: Янв. 1, 2023

A mild metal-free approach for C(sp 3 )–H thioarylation of organic building blocks.

Язык: Английский

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