Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(6), P. 6634 - 6718

Published: Feb. 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.

Language: Английский

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Access to N-α-deuterated amino acids and DNA conjugates via Ca(II)-HFIP-mediated reductive deutero-amination of α-oxo-carbonyl compounds

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 20, 2025

The development of practical and selective strategies for deuterium incorporation to construct deuterated molecules, particularly deuterium-labeled amino acids, has become as a growing focus basic research, yet it remains formidable challenge. Herein, we present bioinspired calcium-HFIP-mediated site-selective reductive deutero-amination α-oxo-carbonyl compounds with amines. Utilizing d2-Hantzsch ester the source, this reaction attains remarkable deuteration efficiency (> 99% deuteration). It enables synthesis N-α-deuterated acid motifs wide range functionality, evidenced by over 130 examples. method exhibits compatibility diverse substrates, such peptides, drug natural products bearing different substituents. Moreover, application strategy in DNA-tagged acids/peptides been demonstrated. This work offers an efficient innovative solution chemistry holds substantial potential organic synthesis, medicinal chemistry, chemical biology.

Language: Английский

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Copper-Catalyzed Transfer Hydrodeuteration of Aryl Alkenes with Quantitative Isotopomer Purity Analysis by Molecular Rotational Resonance Spectroscopy

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(20), P. 7707 - 7718

Published: May 17, 2021

A copper-catalyzed alkene transfer hydrodeuteration reaction that selectively incorporates one hydrogen and deuterium atom across an aryl is described. The protocol selective a variety of internal terminal alkenes also demonstrated on alkene-containing complex natural product analog. Beyond using 1H, 2H, 13C NMR analysis to measure selectivity, six products were analyzed by molecular rotational resonance (MRR) spectroscopy. application MRR spectroscopy the isotopic impurities in deuteration chemistry further explored through measurement methodology compatible with high-throughput sample analysis. In first step, signatures all variants accessible are broadband chirped-pulse Fourier transform microwave spectrometer. With hand, scripts created quantitatively analyze composition commercial cavity enhanced consumption below 10 mg times order min this instrument-both representing order-of-magnitude reduction compared To date, these measurements represent most precise spectroscopic determination selectivity confirm regioselectivity ratios >140:1 achievable under mild protocol.

Language: Английский

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Catalytic Transfer Deuteration and Hydrodeuteration: Emerging Techniques to Selectively Transform Alkenes and Alkynes to Deuterated Alkanes

Chemistry - A European Journal, Journal Year: 2021, Volume and Issue: 27(39), P. 9988 - 10000

Published: May 12, 2021

Increasing demand for deuterium-labeled organic molecules has spurred a renewed interest in selective methods deuterium installation. Catalytic transfer deuteration and hydrodeuteration are emerging as powerful techniques the incorporation of into small molecules. These reactions not only obviate use D2 gas pressurized reaction setups but provide new opportunities selectively installing Commercial or readily synthesized donors typically employed easy-to-handle reagents reactions. In this minireview, recent advances catalytic alkenes alkynes synthesis deuterated alkanes will be discussed.

Language: Английский

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Enantioselective Synthesis of Enantioisotopomers with Quantitative Chiral Analysis by Chiral Tag Rotational Spectroscopy

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(33)

Published: June 14, 2022

Abstract Fundamental to the synthesis of enantioenriched chiral molecules is ability assign absolute configuration at each stereogenic center, and determine enantiomeric excess for compound. While determination often considered routine in many facets asymmetric synthesis, same determinations enantioisotopomers remains a formidable challenge. Here, we report first highly enantioselective metal‐catalyzed that are by virtue deuterium substitution along with general spectroscopic technique assignment quantitative isotopically molecules. Chiral tag rotational spectroscopy uses noncovalent derivatization, which eliminates possibility racemization during perform analysis without need reference samples enantioisotopomer.

Language: Английский

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Copper-Catalyzed Formal Transfer Hydrogenation/Deuteration of Aryl Alkynes

Organic Letters, Journal Year: 2020, Volume and Issue: 22(22), P. 9139 - 9144

Published: Nov. 10, 2020

A copper-catalyzed reduction of alkynes to alkanes and deuterated is described under transfer hydrogenation deuteration conditions. Commercially available alcohols silanes are used interchangeably with their analogues as the hydrogen or deuterium sources. Transfer terminal internal aryl occurs high levels incorporation. Alkyne-containing complex natural product undergo selectively, in yield. Mechanistic experiments support reaction occurring through a cis-alkene intermediate demonstrate possibility for regioselective alkyne hydrodeuteration reaction.

Language: Английский

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Remote Site-Selective C(sp³)–H Monodeuteration of Unactivated Alkenes via Chain-Walking Strategy

ACS Catalysis, Journal Year: 2023, Volume and Issue: 13(6), P. 3644 - 3654

Published: Feb. 28, 2023

The installation of deuterium atoms at distal C(sp3)–H bonds is a longstanding synthetic challenge. Through the synergistic combination chain-walking strategy and transfer hydrodeuteration, we present remote hydrodeuteration unactivated alkenes sites, aided by native directing groups, using readily available pinacolborane (HBpin) D2O as H– D+ sources, respectively. Significantly, this tactic offers complementary pattern to conventional methods that adduct H–D, or its surrogate, unsaturated bonds. Both experimental data density functional theory (DFT) studies demonstrated critical role group in guiding olefin isomerization process. DFT calculations suggest it was situ-generated Ni(II)–hydride rather than Ni(I)–hydride performed active intermediates insertion steps.

Language: Английский

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Precision Deuteration Using Cu-Catalyzed Transfer Hydrodeuteration to Access Small Molecules Deuterated at the Benzylic Position

JACS Au, Journal Year: 2023, Volume and Issue: 3(6), P. 1583 - 1589

Published: May 17, 2023

A highly regio- and chemoselective Cu-catalyzed aryl alkyne transfer hydrodeuteration to access a diverse scope of alkanes precisely deuterated at the benzylic position is described. The reaction benefits from high degree regiocontrol in hydrocupration step, leading highest selectivities reported date for an reaction. Only trace isotopic impurities are formed under this protocol, analysis isolated product by molecular rotational resonance spectroscopy confirms that purity products can be generated readily accessible substrates.

Language: Английский

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A Torquoselective Thermal 6π‐Electrocyclization Approach to 1,4‐Cyclohexadienes via Solvent‐Aided Proton Transfer: Experimental and Theoretical Studies

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: 30(16)

Published: Jan. 5, 2024

Abstract The thermal 6π‐electrocyclization of hexatriene typically delivers 1,3‐cyclohexadiene (1,3‐CHD). However, there is only limited success in directly synthesizing 1,4‐cyclohexadiene (1,4‐CHD) using such an approach, probably due to the difficulty realizing thermally‐forbidden 1,3‐hydride shift after electrocyclic ring closure. present study shows that by heating (2 E ,4 ,6 )‐hexatrienes bearing ester or ketone substituents at C1‐position a mixture toluene/MeOH EtOH : 1) solvents 90–100 °C, 1,4‐CHDs can be selectively synthesized. This achieved through torquoselective disrotatory 6π‐electrocyclic closure followed proton‐transfer process. this method depends on polar protic solvent‐assisted intramolecular proton transfer from 1,3‐CHD 1,4‐CHD, which has been confirmed deuterium‐labeling experiments. There are no reports date for isomerization. Density functional theory (DFT) studies have suggested forming and subsequent isomerization thermodynamically feasible process, regardless groups involved. Two possible successive pathways identified

Language: Английский

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Indium‐Catalysed Transfer Hydrogenation for the Reductive Cyclisation of 2‐Alkynyl Enones towards Trisubstituted Furans

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 60(44), P. 23661 - 23666

Published: Sept. 3, 2021

Indium tribromide catalysed the transfer hydrogenation from dihydroaromatic compounds, such as commercially available γ-terpinene, to enones, which resulted in cyclisation trisubstituted furan derivatives. The reaction was initiated by a Michael addition of hydride nucleophile enone subunit followed Lewis-acid-assisted and formation furan-indium intermediate Wheland derived starting material. product formed protonation complex replaced indium substituent. In addition, site-specific deuterium labelling HD surrogates site specific products gave useful insights into mechanism H-D scrambling.

Language: Английский

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