Deuterium Labeling Research Articles

Ruthenium-Catalyzed Intramolecular Allene-alkyne Cascade Cyclization: Access to the Sulfone-cyclopenta[a]naphthalene Core.

A ruthenium-catalyzed intramolecular cascade cyclization of allene-alkyne has been achieved. This method offers a streamlined and atom-economical approach for the construction of sulfone bearing 1H-cyclopenta[a]naphthalenes, an important structural scaffold that exists in biologically active compounds. Our approach, backed by mechanistic insights from deuterium labeling, DFT calculations, and potential for reaction scale-up, presents synthetic chemists with an invaluable tool for efficiently producing a distinct carbon framework in a one-pot manner. This protocol is operationally simple, exhibiting a broad substrate scope with consistently high yields.

C‐C Coupling of Ketones with Ethanol and Methanol Enabled by Nickel Catalysis

Herein, we have reported the application of C1 and C2 alcohols for the C‐C coupling with ketones enabled by nickel. De‐hydrogenation of ethanol took place under relatively milder conditions (100 oC) and resulted the functionalized 1,5‐diketones with acetophenone derivatives in one pot operation. Further, multi‐component strategy using ketones, and methanol in combination with various nitrogen‐based nucleophiles resulted the α‐aminomethylation under nickel‐catalysis. For a synthetic application, a series of tetra‐substituted pyridines have been demonstrated. Preliminary mechanistic investigations, control experiments and deuterium labelling studies were established the interrupted borrowing hydrogen (I‐BH) strategy. The catalytic transformations are highly sustainable and released water and dihydrogen as by products.

Measuring HSD17β13 protein turnover in mouse liver with D2O metabolic labeling and hybrid LC-MS.

Metabolic labeling with heavy water (D2O) followed by LC-MS has become a powerful tool for studying protein turnover in vivo. Developing a quantitative method to measure partially labeled low-abundance proteins poses many challenges because heavy isotopomers of peptides, especially their changes through deuterium labeling, are difficult to detect. A workflow that coupled immunocapture and LC-high-resolution MS to determine the synthesis rate of HSD17β13 protein in mouse liver was presented. Deuterium labeling of tryptic peptides was analyzed, and data were fitted into an exponential rise equation. HSD17β13 protein t1/2 were calculated to be 31.8, 36.1, and 28.9 hr from 3 different peptides with an average of 32.3 hr. The established workflow can be adapted from hybrid LC-MS protein quantitation assays to assess protein turnover in vivo using D2O metabolic labeling.

Rapid and Controlled Assembly of Polysubstituted Furans and Their Oligoaryls from Alkynes and Aldehydes Facilitated by Sequential Deprotonation.

A new sequential deprotonation strategy of dimethyl sulfoxide (DMSO) and propargyl alcohol in the presence of a base was developed for the generation of the α-hydroxyl carbanion, which enables rapid and controllable access to a wide range of valuable highly functionalized furans in one pot from alkynes and aldehydes under transition-metal- and additive-free conditions. Preliminary mechanistic studies revealed the crucial role of the base and DMSO. More importantly, deuterium labeling experiments confirmed the formation of the α-hydroxyl carbanion.

Drought in a warmer, CO2-rich climate restricts grassland water use and soil water mixing.

Soil water sustains terrestrial life, yet its fate is uncertain under a changing climate. We conducted a deuterium labeling experiment to determine whether elevated atmospheric carbon dioxide (CO2), warming, and drought impact soil water storage and transport in a temperate grassland. Elevated CO2 created a wetter rootzone compared with ambient conditions, whereas warming decreased soil moisture. Soil water remained well mixed in all global change treatments except for summer drought combined with warming and elevated CO2. These combined treatments caused the grassland to conserve water and restricted soil water flow to large, rapidly draining pores without mixing with small, slowly draining pores. Our results suggest that drought in a warmer, more CO2-rich climate can severely alter grassland ecohydrology by constraining postdrought soil water flow and grassland water use.

Visible-light-driven net-1,2-hydrogen atom transfer of amidyl radicals to access β-amido ketone derivatives.

Hydrogen atom transfer (HAT) processes provide an important strategy for selective C-H functionalization. Compared with the popularity of 1,5-HAT processes, however, net-1,2-HAT reactions have been reported less frequently. Herein, we report a unique visible-light-mediated net-1,2-HAT of amidyl radicals for the synthesis of β-amido ketone derivatives. Single-electron transfer (SET) to N-aryloxy amides generates nitrogen-centered radicals (N˙), which undergo a rare net-1,2-HAT to form carbon-centered radicals (C˙). The C-centered radicals are then captured by silyl enol ethers on the way to β-amido ketones. A series of β-amido ketone derivatives (33 examples, up to 97% yield) were prepared with good functional group tolerance demonstrating the synthetic utility of this method. Mechanistic studies, including EPR, radical trapping experiments, deuterium labeling and KIE measurements, suggest an intramolecular radical net-1,2-HAT pathway.

Strain-release enables access to carbonyl conjugated allylic diborons and alkenyl boronates having multiple contiguous stereocenters in a one-pot process.

Allylic diboronates are highly valuable reagents in organic synthesis. Existing methods predominantly yield alkyl-substituted allylic diboronates, while the incorporation of electrophilic carbonyl groups conjugated to these allylic systems remains unknown. We present a strain-release promoted cycloaddition-based strategy that enabled access to unprecedented carbonyl conjugated secondary allylic diborons. This mild base-free method also facilitated a one-pot multicomponent cycloaddition-allylboration sequence for a highly diastereoselective installation of contiguous quaternary, tertiary and secondary carbon centers on a scaffold featuring valuable β-hydroxy ester, β-vinyl ester and vinyl boronate motifs. The synthetic utility of these densely functionalized products was demonstrated through their transformation into other rare and sterically congested alkenylborons such as borylated spiro-fused β-lactones and bicyclic γ-butyrolactones. Detailed 11B NMR, deuterium labeling and mass spectrometry studies provided insights on an unexpected base-free deboronative allylic shift reaction of conjugated allylic diboronates.

Mechanistic Insights Into Post‐translational α‐Keto‐β‐Amino Acid Formation by a Radical S‐Adenosyl Methionine Peptide Splicease

Radical S‐adenosyl methionine enzymes catalyze a diverse repertoire of post‐translational modifications in protein and peptide substrates. Among these, an exceptional and mechanistically obscure example is the installation of α‐keto‐β‐amino acid residues by formal excision of a tyrosine‐derived tyramine unit. The responsible spliceases are key maturases in a widespread family of natural products termed spliceotides that comprise potent protease inhibitors, with the installed β‐residues being crucial for bioactivity. Here, we established the in vitro activity of the model splicease PcpXY to interrogate the mechanism of non‐canonical protein splicing. Identification of shunt and coproducts, deuterium labeling studies, and density functional theory energy calculations of hypothesized intermediates support a mechanism involving hydrogen abstraction at tyrosine Cα as the initial site of peptide radical formation and release of 4‐hydroxybenzaldehyde as the tyrosine‐derived coproduct. The data illuminate key features of this unprecedented radical‐mediated biotransformation yielding ketoamide pharmacophores that are also present in peptidomimetic therapeutics.

Mechanistic Insights Into Post-Translational α-Keto-β-Amino Acid Formation by a Radical S-Adenosyl Methionine Peptide Splicease.

Radical S-adenosyl methionine enzymes catalyze a diverse repertoire of post-translational modifications in protein and peptide substrates. Among these, an exceptional and mechanistically obscure example is the installation of α-keto-β-amino acid residues by formal excision of a tyrosine-derived tyramine unit. The responsible spliceases are key maturases in a widespread family of natural products termed spliceotides that comprise potent protease inhibitors, with the installed β-residues being crucial for bioactivity. Here, we established the in vitro activity of the model splicease PcpXY to interrogate the mechanism of non-canonical protein splicing. Identification of shunt and coproducts, deuterium labeling studies, and density functional theory energy calculations of hypothesized intermediates support a mechanism involving hydrogen abstraction at tyrosine Cα as the initial site of peptide radical formation and release of 4-hydroxybenzaldehyde as the tyrosine-derived coproduct. The data illuminate key features of this unprecedented radical-mediated biotransformation yielding ketoamide pharmacophores that are also present in peptidomimetic therapeutics.

Iridium-Catalyzed Highly Selective 1,4-Reduction of α,β-Unsaturated Carbonyl Compounds.

In this study, an iridium-catalyzed selective 1,4-reduction of α,β-unsaturated carbonyl compounds is realized, with water as a solvent and formic acid as a hydride donor. The new efficient iridium catalyst features a 2-(4,5-dihydroimidazol-2-yl)quinoline ligand. The chemoselectivity and catalyst efficiency are highly dependent on the electronic and steric properties of the substrates. For α,β-unsaturated amides, acids, and esters, only the electron-deficient C=C bonds are reduced (1,4-reduction), and the other functional groups are left intact. The S/C ratio and initial TOF reach 7000 and 18,480 h-1, respectively. A gram-scale 1,4-reduction is also performed. Deuterium labeling shows that the β-hydrogens of the products originate from the formyl hydrogen in the formic acid. The application of the 1,4-reduction for the modification the structures of some medications is demonstrated.

Metabolomic characterization of a new strain of microalgae by GC-MS method with the introduction of a deuterium label.

Microalgae are active producers of various compounds, including toxic substances. However, their metabolism is very diverse and insufficiently known. We demonstrate an approach that includes growing a new strain of cyanobacterium Leptolyngbya sp. (IPPAS B-1204) on an isotopically labeled medium (D2O) and evaluating the metabolomic composition of these microorganisms after deuterium uptake. Despite the low resolution of the GC-MS method, the interpretation of the obtained spectra allowed us to find out not only the amount of the embedded isotope label but also to assume the position in the structure where the label is embedded. We present the results of reliably detecting more than 30 compounds with isotope labels belonging to various classes of biological compounds produced by this cyanobacterium, revealing the metabolic pathways of entry of this label. We also demonstrate that the synthesis of unsaturated fatty acids is suppressed under the growth on D2O medium. In addition, we found an isotopic effect in the chromatographic separation of isotopically labeled compounds in gas chromatography. These data can be used in the future both for the identification of compounds and the analysis of the biosynthesis pathways of secondary biologically active compounds and in the analysis of the production of isotopically labeled standards of compounds.

Transition-Metal-Catalyzed Deuteration via Hydrogen Isotope Exchange

AbstractDirect hydrogen isotope exchange represents a distinctive strategy for deuterium labelling, where the protium is directly replaced by deuterium. In this graphical review, we summarize the progress in deuteration via transition-metal-catalyzed hydrogen isotope exchange. The review is organized according to the mechanism of C–H bond activation relating to the homogeneous catalysis, and heterogeneous catalysis is also discussed according to the catalyst type. Representative mechanistic processes are depicted, and proven cases for tritiation are also highlighted.

On the Functionalization of C60 with Vinylallenes Generated in situ by Rhodium Catalysis

AbstractThe functionalization of fullerenes is important for several reasons, primarily related to enhancing their chemical reactivity, solubility, and potential of applications in optoelectronics and biomedicine. In this study, we present a novel approach to functionalize C60 through a cascade process encompassing an unprecedented Rh‐catalyzed cycloisomerization of 1,6‐allenynes to in situ generate a vinylallene that is followed by a Diels‐Alder reaction with pristine fullerene, resulting in the formation of 6,6‐fused bicyclic fullerene derivatives. The mechanism governing this process was elucidated by DFT calculations and confirmed by deuterium labelling and control experiments, demonstrating the critical role of traces of water in the reaction medium to mediate the observed reactivity.

Iron-Mediated Segment Coupling of Alkenols with Acceptors via C-C Radical Translocation and Remote Oxidative 1,5/6-Hydrogen Atom Transfer.

Iron-mediated segment coupling followed by oxidative 1,5/6-hydrogen atom transfer (HAT) for synthesis of ε-oxo alkene derivatives is developed. This transformation involved translocation of the radical from H-to-C-to-C-to-C followed by the oxidation under MHAT conditions providing rapid access to 1,6/1,7-keto functionalized esters/ketone/sulfones/phosphonates/arenes. The different outcomes of coupling with acceptors could be explained by bond dissociation energies (BDEs), and mechanistic insights were gained through control experiments, including deuterium labeling studies.

C−X (X=C, O, S, N, B, P) Bond Deuteration and Late‐Stage Applications

AbstractPrecise deuterium labeling has gained significant attentions owing to the wide applications in organic synthesis, medicinal chemistry, and organic materials. C−C and C‐heteroatom bonds constitute the skeleton of organic molecules. This review summarizes the advancements on C−C and C‐heteroatom bond deuterations as well as their applications in late‐stage deuterations of natural products and pharmaceutically relevant molecules.

Radical‐Based Enantioconvergent Reductive Couplings of Racemic Allenes and Aldehydes

AbstractTransition metal‐catalyzed radical‐based enantioconvergent reactions have become a powerful strategy to synthesize enantiopure compounds from racemic starting materials. However, existing methods primarily address precursors with central chirality, neglecting those with axial chirality. Herein, we describe the enantioconvergent reductive coupling of racemic allenes with aldehydes, facilitated by a photoredox, chromium, and cobalt triple catalysis system. This method selectively affords one product from sixteen possible regio‐ and stereoisomers. The protocol leverages CoIII−H mediated hydrogen atom transfer (MHAT) and Cr‐catalyzed radical‐polar crossover for efficient stereoablation of axial chirality and asymmetric addition, respectively. Supported by mechanistic insights from control experiments, deuterium labeling, and DFT calculations, our approach offers synthetic chemists a valuable tool for creating enantioenriched chiral homoallylic alcohols, promising to advance radical‐based strategies for synthesizing complex chiral molecules.

Redox-Neutral, Iron-Mediated Directed C-H Activation: General Principles and Mechanistic Insights.

Experimental and computational studies have been conducted and established the general principles for enabling redox-neutral C-H activation by iron(II) complexes. The idealized octahedral iron(II) dimethyl complex, (depe)2Fe(CH3)2 (depe = 1,2-bis(diethylphosphino)ethane) promoted the directed, regioselective ortho C(sp2)-H methylation of pivalophenone. The rate of the iron(II)-mediated C(sp2)-H functionalization depended on the lability of L-type phosphine ligands, the spin state of the iron center, and the size of the X-type ligands (halide, hydrocarbyl) in P4FeIIX2 complexes. The C(sp2)-H alkylation reaction proved general among multiple substrates with directing groups including carbonyl, imines and pyridines. Among these, ketones and aldehydes were identified as optimal and were compatible with various steric environments and presence of acidic α-hydrogens. With stronger nitrogen donors, higher barriers for product-forming reductive elimination were observed. The effect of orbital hybridization on the chemoselectivity of C-H activation through a σ-CAM pathway by dn>0 transition metals was also established by studying the stoichiometric reactivity of the differentially substituted (depe)2Fe(Me)R complexes (R = alkyl, aryl), where the Fe-R bond with greater s-character preferentially promoted selective C-H activation. Deuterium labeling and kinetic studies, coupled with computational analysis, supported a pathway involving phosphine dissociation and rate-determining C-H bond activation, leading to the observed products.

Radical-Based Enantioconvergent Reductive Couplings of Racemic Allenes and Aldehydes.

Transition metal-catalyzed radical-based enantioconvergent reactions have become a powerful strategy to synthesize enantiopure compounds from racemic starting materials. However, existing methods primarily address precursors with central chirality, neglecting those with axial chirality. Herein, we describe the enantioconvergent reductive coupling of racemic allenes with aldehydes, facilitated by a photoredox, chromium, and cobalt triple catalysis system. This method selectively affords one product from sixteen possible regio- and stereoisomers. The protocol leverages CoIII-H mediated hydrogen atom transfer (MHAT) and Cr-catalyzed radical-polar crossover for efficient stereoablation of axial chirality and asymmetric addition, respectively. Supported by mechanistic insights from control experiments, deuterium labeling, and DFT calculations, our approach offers synthetic chemists a valuable tool for creating enantioenriched chiral homoallylic alcohols, promising to advance radical-based strategies for synthesizing complex chiral molecules.

Moderation of the Electronic Structure of Phosphamides to Execute the Catalytic Appel Reaction Bypassing Phosphine.

A set of structurally analogous, albeit electronically distinct, phosphamides (1aa-10aa) is prepared, and the effect of the electronic amendment due to p-substitution has been tested for the conversion of alcohols to halides via the Appel reaction. The -OMe-substituted diphosphamide (8aa) remains the most active, providing ∼96% conversion of alcohols to halides with a TON of 11 in moderate reaction conditions with a large substrate scope. Halide formation follows a pseudo-first-order rate with a constant rate (kobs) of 7.13 × 10-5 s-1. Temp-dependent kinetics and Eyring analyses reveal the activation parameters ΔH‡ of 28.95 (±1.6) kcal mol-1, ΔS‡ of -70.02 (±0.4) cal K-1 mol-1, and ΔG‡298 of 49.81 (±1.2) kcal mol-1. The deuterium labeling study highlights the O-H dissociation of the alcohol as the rate-determining step, while the Hammett analysis with p-substituted benzyl alcohols indicates a positive charge accumulation at the phosphorus center during the Appel reaction. The HOMO-LUMO energy and NPA analyses show that p-OMe substitutions in 8aa make the "P═O" bond more ionic and corresponding aminophosphine is nucleophilic, which are favorable for the Appel reaction. In situ detection of the Appel salt, [R3PX]CX3 and alkoxy phosphonium cation [R3POR]X, validates the reaction pathway mediated by the phosphamides.

Ru(II)-Catalyzed C7 Trifluoromethylthiolation and Thioarylation of Indolines Using Bench-Stable Reagents.

A Ru(II)-catalyzed C(sp2)-H trifluoromethylthiolation and thioarylation of indolines using bench-stable reagents have been explored. Diversely substituted indolines were functionalized at C7 position in good to excellent yields. Radical quenching, deuterium labeling, KIE, and reaction order determination experiments were performed to support the proposed reaction pathway. Gram-scale synthesis and post-transformation of the synthesized products have also been carried out to demonstrate the applicability of the developed catalytic protocol.