Regioselective Deuteration Research Articles

Controlled Reactivity of Viologens in Alkaline Solutions Via Cucurbit[7]uril Complexation

AbstractA series of N‐alkyl‐ and N‐aryl‐viologens has been studied in alkaline solutions. In this work, we evaluated the deuteration rate of the viologens in D2O solutions of pH values ranging from 7.3 to 12.7. Kinetic experiments and computational calculations showed the high reactivity of H−C(2) bonds toward deprotonation of N‐aryl‐pyridinium moieties compared to N‐alkyl‐pyridinium moieties, even in hybrid N‐aryl/N‐alkyl dissymmetric viologens. However this high H−C(2) reactivity in liquid phase contrasted with the proton fragmentation mechanism observed in the gas phase by mass spectrometry. The H/D exchange rate of viologens in very strong alkaline conditions could be significantly reduced using cucurbit[7]uril (CB[7]) as supramolecular protecting group. Ultimately, CB[7] inclusion led to a selective protection of H−C(2) group of N‐aryl‐pyridinium of dissymmetric viologens, and induced a supramolecular regioselective deuteration.

Palladium-Catalyzed Deuteration of Arylketone Oxime Ethers.

We report herein the development of palladium-catalyzed deacylative deuteration of arylketone oxime ethers. This protocol features excellent functional group tolerance, heterocyclic compatibility, and high deuterium incorporation levels. Regioselective deuteration of some biologically important drugs and natural products are showcased via Friedel-Crafts acylation and subsequent deacylative deuteration. Vicinal meta-C-H bond functionalization (including fluorination, arylation, and alkylation) and para-C-H bond deuteration of electro-rich arenes are realized by using the ketone as both directing group and leaving group, which is distinct from aryl halide in conventional dehalogenative deuteration.

Palladium‐Catalyzed Deuteration of Arylketone Oxime Ethers

AbstractWe report herein the development of palladium‐catalyzed deacylative deuteration of arylketone oxime ethers. This protocol features excellent functional group tolerance, heterocyclic compatibility, and high deuterium incorporation levels. Regioselective deuteration of some biologically important drugs and natural products are showcased via Friedel–Crafts acylation and subsequent deacylative deuteration. Vicinal meta‐C−H bond functionalization (including fluorination, arylation, and alkylation) and para‐C−H bond deuteration of electro‐rich arenes are realized by using the ketone as both directing group and leaving group, which is distinct from aryl halide in conventional dehalogenative deuteration.

Pd-Catalyzed Regioselective Deuteration of Indole's C4-Position with Transient Directing Groups.

As a representative scaffold of alkaloids, indoles have been extensively subjected to deuteration, but the regioselective C4 labeling has not been achieved due to its low reactivity. In this work, a Pd-catalyzed deuterium labeling at the indole's C4 position has been developed under the strategy of transient directing, using D2O as a deuterium source. The substituent effect is found to be crucial in facilitating this H/D exchange process, where the reversing C-D bond formation favors an electron-enriched ligation contrary to its C-H halogenation counterpart.

Regioselective Deuteration of Arenes Enabled by Simple Heterogeneous Palladium Catalysis.

A heterogeneous redox-neutral palladium-catalytic platform was reported for the preparation of deuterated (hetero) arenes from (hetero) arenes mediated by regioselective C(sp2)-H thianthrenation utilizing commercially available and recyclable Pd/C catalyst. A wide range of deuterated compounds could be obtained in high yields with excellent levels of deuterium incorporation under these simple heterogeneous catalytic conditions with the requirement of stable and easily handled DCOONa as a deuterium source. The late-stage deuteration of pharmaceuticals and bioactive molecules was also achieved by this approach.

Modified Chemoselective Reduction and Consecutive Regioselective Deuteration Reaction Catalyzed by B(C6F5)3.

An efficient chemoselective reduction of isatin derivatives using catalyst B(C6F5)3, benzyldimethylsilane, and H2O is described. Notably, a small amount of water is shown to be a highly effective reaction promoter that decreases the reaction time and temperature for the synthesis of indolin-3-ones. Moreover, using method, excellent deuterium incorporation is achieved via the catalytic α-deuteration of indolin-3-ones using B(C6F5)3 and D2O.

Deuterated polyunsaturated fatty acids provided protection against oxidative stress in ocular fibroblasts derived from glaucoma patients

Glaucoma is a complex neurodegenerative disease of the optic nerve that leads to irreversible sight loss. Lowering intraocular pressure (IOP) medically or surgically represents the mainstay of treatment but despite adequate treatment optic nerve function can continue to deteriorate leading to blindness. There is significant clinical and experimental evidence that oxidative stress is involved in the pathogenesis of glaucoma. Decreasing the formation of lipid peroxidation products or scavenging them chemically could be beneficial in limiting the deleterious effects of oxidative stress in glaucoma. A solution to control the susceptibility of PUFAs to noxious lipid peroxidation reactions is by regioselective deuteration. Deuterium incorporated into PUFAs at bis-allylic positions (D-PUFAs) inhibits the rate-limiting step of lipid peroxidation. In this study, we have shown that Tenon’s ocular fibroblasts from glaucoma patients have significantly increased basal oxidative stress compared to non-glaucomatous control patients. Furthermore, we have shown that deuterated polyunsaturated fatty acids (D-PUFAs) provide an enhanced rescue of menadione induced lipid peroxidation in both non-glaucomatous and glaucomatous Tenon’s ocular fibroblasts using malondialdehyde (MDA) levels as a marker. Our study suggests that D-PUFAs may provide a potentially safe and effective method to reduce cytotoxic oxidative stress in glaucoma.

The Metal-Free Regioselective Deuteration of 2-Methylquinolin-8-ol and 2,5-Dimethylquinolin-8-ol, Spectroscopic and Computational Studies

Aim and background: Introducing deuterium to a molecule is of interest to a wide variety of research, including investigation of reaction mechanisms or kinetics, analysis of drug metabolism, structural elucidation of molecules, and syntheses of isotopically labeled materials used for NMR spectroscopy and medicinal research. Objective: The transition-metal-free regioselective deuteration of 2-methylquinolin-8-ol (1a) and 2,5- dimethylquinolin-8-ol (2a) with ambient reaction conditions and low-cost reagents is described in the paper. Methods: Regioselective H/D isotope exchange has been presented by combining the following techniques 1H NMR, 13C NMR, GC-MS, and X-ray crystallography. The molecular orbitals of the deuterated molecule 1a have been calculated by density functional theory (DFT) to provide an elucidation of the isotope exchange. Result: The metal-free regioselective green deuteration based on modified Skraup-Doebner-Von Miller synthesis and water-d2 KOD solution or water-d2 D2SO4 solution of hydroxyquinolines was elaborated. Conclusion: The metal-free regioselective green deuteration of hydroxyquinoline-type compounds with ambient reaction conditions and low-cost reagents provided valuable tools for isotopic labeling. The modified Skraup-Doebner-Von Miller synthesis of deuterated hydroxyquinolines has the potential to allow higher deuteration capacity. The presented isotopic exchange reactions also possess synthetic values as the source of deuterated compounds for the studies of NMR spectroscopy, medicinal research, and drug discovery processes.

Recent Advances in the Synthesis of Deuterium‐Labeled Compounds

AbstractDeuterium‐labeled compounds are of importance in chemical, environmental, and biological fields. Preparation methods for deuterium‐labeled compounds have been studied extensively in response to increasing demand for these chemicals. In this review, we summarize recent advances in synthetic methods and present a comprehensive overview of diverse routes, including conventional deuteration and hydrogen‐deuterium exchange. Deuteration by the classical process, which starts from appropriate available labeled precursors, is introduced for different reaction types. Key features of hydrogen‐deuterium exchange are elaborated in detail from the perspective of the catalyst and the chemical structure of the substrate. Regioselective deuteration at the target position is discussed because of the role of stereospecific deuterium labeling in medicine. Finally, challenges and future prospects of these processes are discussed to provide a general guideline for the synthesis of deuterium‐labeled compounds.

Enhancement of a Heroin Vaccine through Hapten Deuteration

The United States is in the midst of an unprecedented epidemic of opioid substance use disorder, and while pharmacotherapies including opioid agonists and antagonists have shown success, they can be inadequate and frequently result in high recidivism. With these challenges facing opioid use disorder treatments immunopharmacotherapy is being explored as an alternative therapy option and is based upon antibody-opioid sequestering to block brain entry. Development of a heroin vaccine has become a major research focal point; however, producing an efficient vaccine against heroin has been particularly challenging because of the need to generate not only a potent immune response but one against heroin and its multiple psychoactive molecules. In this study, we explored the consequence of regioselective deuteration of a heroin hapten and its impact upon the immune response against heroin and its psychoactive metabolites. Deuterium (HdAc) and cognate protium heroin (HAc) haptens were compared head to head in an inclusive vaccine study. Strikingly the HdAc vaccine granted greater efficacy in blunting heroin analgesia in murine behavioral models compared to the HAc vaccine. Binding studies confirmed that the HdAc vaccine elicited both greater quantities and equivalent or higher affinity antibodies toward heroin and 6-AM. Blood-brain biodistribution experiments corroborated these affinity tests. These findings suggest that regioselective hapten deuteration could be useful for the resurrection of previous drug of abuse vaccines that have met limited success in the past.

Silver-catalyzed regioselective deuteration of (hetero)arenes and α-deuteration of 2-alkyl azaarenes.

A simple silver-catalyzed regioselective deuteration of (hetero)arenes and α-deuteration of 2-alkyl azaarenes has been described. This strategy provides an efficient and practical avenue to access various deuterated electron-rich arenes, azaarenes and α-deuterated 2-alkyl azaarenes with good to excellent deuterium incorporation utilizing D2O as the source of deuterium atoms.

Room Temperature Iron-Catalyzed Transfer Hydrogenation and Regioselective Deuteration of Carbon-Carbon Double Bonds.

An iron catalyst has been developed for the transfer hydrogenation of carbon-carbon multiplebonds. Using a well-defined β-diketiminate iron(II) precatalyst, a sacrificial amine and a borane, even simple, unactivated alkenes such as 1-hexene undergo hydrogenation within 1 h at room temperature. Tuning the reagent stoichiometry allows for semi- and complete hydrogenation of terminal alkynes. It is also possible to hydrogenate aminoalkenes and aminoalkynes without poisoning the catalyst through competitive amine ligation. Furthermore, by exploiting the separate protic and hydridic nature of the reagents, it is possible to regioselectively prepare monoisotopically labeled products. DFT calculations define a mechanism for the transfer hydrogenation of propene with nBuNH2 and HBpin that involves the initial formation of an iron(II)-hydride active species, 1,2-insertion of propene, and rate-limiting protonolysis of the resultant alkyl by the amine N-H bond. This mechanism is fully consistent with the selective deuteration studies, although the calculations also highlight alkene hydroboration and amine-borane dehydrocoupling as competitive processes. This was resolved by reassessing the nature of the active transfer hydrogenation agent: experimentally, a gel is observed in catalysis, and calculations suggest this can be formulated as an oligomeric species comprising H-bonded amine-borane adducts. Gel formation serves to reduce the effective concentrations of free HBpin and nBuNH2 and so disfavors both hydroboration and dehydrocoupling while allowing alkene migratory insertion (and hence transfer hydrogenation) to dominate.

Palladium-catalyzed site-selective hydrogen isotope exchange (HIE) reaction of arylsulfonamides using amino acid auxiliary

Hydrogen isotope exchange (HIE) is a versatile method for the introduction of deuterium to organic compounds. Herein, regioselective deuteration of sulfonamides is achieved by palladium-Catalyzed HIE reaction. By using amino acid as weakly coordination-directing auxiliary, a variety of sulfonamides are efficiently deuterated at the ortho-position. Placing competing directing groups on the aromatic ring does not affect the site-selectivity.

Regioselective deuteration of alcohols in D2O catalysed by homogeneous manganese and iron pincer complexes

Regioselective, base-metal catalyzed deuteration of alcohols in D2O.

Ruthenium-Catalyzed Deuteration of Alcohols with Deuterium Oxide

The catalytic properties of a series of ruthenium complexes for H/D exchange between D2O and alcohols were studied. The catalytic activity of the ruthenium complexes and the regioselectivity of the H/D exchange reactions were found to be dependent on the auxiliary ligands. While ruthenium η6-cymene complexes such as [(η6-cymene)RuCl(NH2CH2CH2NTs)]Cl, (η6-cymene)RuCl2/NH2CH2CH2OH, and (η6-cymene)Ru{(S,S)-NHCHPhCHPhNTs} catalyzed regioselective deuteration of alcohols with D2O at the β-carbon positions only, octahedral ruthenium complexes such as RuCl2(2-NH2CH2Py)(PPh3)2 (2-NH2CH2Py = 2-aminomethylpyridine) and RuCl2(NH2CH2CH2NH2)(PPh3)2 catalyzed regioselective H/D exchange reactions of D2O with alcohols at both the α- and β-carbon positions of alcohols. The H/D exchange reactions proceed through reversible dehydrogenation of alcohols and hydrogenation of carbonyl compounds involving hydride species and H/D exchange among D2O and carbonyl and hydride species. The different regioselectivities of the H/D exc...

A Simple and Cost‐Effective Method for the Regioselective Deuteration of Phenols

AbstractA highly effective and operationally simple method for the deuteration of phenols using NaOH as a catalyst and D2O as the deuterium source is presented. A high regioselectivity for the ortho and/or para hydrogens relative to the oxygen atom was achieved, as well as a high degree of deuterium incorporation. The method also has a high functional‐group tolerance, and allowed the deuteration of complex pharmaceutically interesting substrates.

Rapid, regioselective deuteration of dimethyl-2,2′-bipyridines via microwave-assistance

Isotopically pure [D6]-dimethyl-2,2′-bipyridine derivatives were selectively and rapidly formed using microwave-assisted regioselective deuteration of the methyl moieties of the parent bipyridine in a deuterium oxide solution.

A convenient method for the Ru(0)-catalyzed regioselective deuteration of N-alkyl-substituted anilines

A highly effective and operationally practical method for the regioselective deuteration of N-alkyl-substituted anilines employing Ru3(CO)12 (⩽1mol%) as catalyst and D2O as deuterium source was described. A variety of N-alkyl-substituted anilines were efficiently deuterated (up to 98%) at the ortho and/or para position with respect to the nitrogen at neutral conditions. Under the present conditions, deuterated anilines can be easily obtained with simple extraction and evaporation. Substituents with aromatic methoxy groups would not influence the selectivity compared to previous method.

Use of 1,5‐diaminonaphthalene to combine matrix‐assisted laser desorption/ionization in‐source decay fragmentation with hydrogen/deuterium exchange

In-Source Decay (ISD) in Matrix-Assisted Laser Desorption/Ionization (MALDI) mass spectrometry is a fast and easy top-down activation method. Our objective is to find a suitable matrix to locate the deuterons following in-solution hydrogen/deuterium exchange (HDX). This matrix must circumvent the commonly encountered undesired back-exchange reactions, in order to preserve the regioselective deuteration pattern. The 1,5-diaminonaphthalene (1,5-DAN) matrix is known to be suitable for MALDI-ISD fragmentation. MALDI Mass Spectrometry Imaging (MSI) was employed to compare 1,5-DAN and other commonly used MALDI matrices with respect to the extent of back-exchange and the uniformity of the H/D exchange profiles within the MALDI spots. We tested the back-exchange on the highly sensitive amyloid-beta peptide (1-40), and proved the regioselectivity on ubiquitin and β-endorphin. MALDI-MSI results show that 1,5-DAN leads to the least back-exchange over all the spot. MALDI-ISD fragmentation combined with H/D exchange using 1,5-DAN matrix was validated by localizing deuterons in native ubiquitin. Results agree with previous data obtained by Nuclear Magnetic Resonance (NMR) and Electron Transfer Dissociation (ETD). Moreover, 1,5-DAN matrix was used to study the H/D exchange profile of the methanol-induced helical structure of β-endorphin, and the relative protection can be explained by the polarity of residues involved in hydrogen bond formation. We found that controlling crystallization is the most important parameter when combining H/D exchange with MALDI. The 1,5-DAN matrix is characterized by a fast crystallization kinetics, and therefore gives robust and reliable H/D exchange profiles using MALDI-ISD.

Ruthenium‐Catalyzed Regioselective Deuteration of Alcohols at the β‐Carbon Position with Deuterium Oxide

A convenient method for regioselective H/D exchange between D(2)O and alcohols at the β-carbon position using the catalytic system [(p-cymene)RuCl(2)]/ethanolamine/KOH is described. This method is applicable for deuteration of both primary and secondary alcohols. The H/D exchange reactions proceed through an oxidation/modification/reduction reaction sequence. Alcohols are first temporarily oxidized to carbonyl compounds by the hydrogen transfer catalyst. The carbonyl compounds then undergo deuteration at the carbon adjacent to the carbonyl group by keto-enol tautomerization in the presence of D(2)O and a catalytic amount of base. The deuterated carbonyl compounds are then reduced to produce deuterated alcohols. In support of the reaction mechanism, a well-defined bimetallic ruthenium complex was isolated from the reaction of [{(p-cymene)RuCl(2)}(2)] with ethanolamine. The activity of this complex is similar to that of [{(p-cymene)RuCl(2)}(2)]/ethanolamine.