Synthesis of deuterated 5‐n‐alkylresorcinols

Four alternative strategies for the preparation of deuterium poly‐labelled 5‐n‐alkylresorcinols are explored. Ring‐labelled ²H₃‐alkylresorcinols synthesized by acidic H/D exchange are stable under electrospray ionization MS conditions but scrambling occurs in electron bombardment ionization MS. Side chain‐labelled ²H₄‐derivatives prepared by two different total synthesis approaches are contaminated by isotopologues with varying number of deuterium labels due to H/D redistribution and exchange during D₂ gas deuterogenation. The derivative carrying an ω‐²H₃ label is isotopically pure and completely stable under all relevant analytical conditions encountered in quantitation work. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of the perdeuterated cellulose solvents 1‐ethyl‐3‐methylimidazolium acetate (EMIM‐OAc‐d14) and 1‐butyl‐3‐methylimidazolium acetate (BMIM‐OAc‐d18) and of 2‐13C‐butyl‐3‐methylimidazolium acetate

The syntheses of two perdeuterated ionic liquids (ILs), which have found use as solvents for cellulose derivatization and processing in addition, are described: 1‐ethyl‐3‐methylimidazolium acetate (EMIM‐OAc‐d₁₄) and 1‐butyl–3‐methylimidazolium acetate (BMIM‐OAc‐d₁₈). The targets were obtained from imidazole in three‐step sequences starting with butylation and ethylation, respectively. The resulting 1‐alkyl imidazoles were purified, and subsequently methylated according to a novel protocol using dimethylcarbonate‐d₆. To obtain the 1‐alkyl‐3‐methylimidazolium moiety, methylation of 1‐alkylimidazoles proved to be superior to the conventional approach of alkylating 1‐methylimidazole. Addition of acetic acid‐d₄ caused traceless degradation of the methylcarbonate counter anions, which were neatly exchanged for acetate. The IL 2‐¹³C‐butyl‐3‐methylimidazolium acetate, in which the isotopically enriched C‐2 is a good NMR‐indicator of side reactions and solvent–solute interactions, was synthesized according to the same reaction sequence, starting from 2‐¹³C‐1‐alkylimidazole which, in turn, was obtained by reaction of glyoxale, alkylamine, ammonia and paraformaldehyde‐¹³C. Copyright © 2009 John Wiley & Sons, Ltd.     

A simple method for α‐position deuterated carbonyl compounds with pyrrolidine as catalyst

A simple, cost‐effective method for deuteration of carbonyl compounds employing pyrrolidine as catalyst and D₂O as deuterium source was described. High degree of deuterium incorporation (up to 99%) and extensive functional group tolerance were achieved. It is the first time that secondary amines are used as catalysts for H/D exchange of carbonyl compounds, which also allow the deuteration of complex pharmaceutically interesting substrates. A possible catalytic mechanism, based on the hydrolysis of 1‐pyrrolidino‐1‐cyclohexene, for this pyrrolidine‐catalyzed H/D exchange reaction has been proposed.     

Cytotoxicity,genotoxicity, oxidative stress,and apoptosis in HepG2 cells induced by the imidazole ionic liquid 1‐dodecyl‐3‐methylimidazolium chloride

This study purposes to assess the cytotoxicity of 1‐dodecyl‐3‐methylimidazolium chloride ([C₁₂min]Cl) in human hepatocellular carcinoma (HepG2) cells. To this end, HepG2 cells were exposed to a range concentration of [C₁₂min]Cl and evaluated cell viability, genotoxicity, oxidative stress, apoptosis, cell cycle, and apoptosis‐related gene expression to determine cytotoxicity. The outcomes showed that [C₁₂min]Cl curbed HepG2 cell growth and reduced cell viability in a concentration‐ and time‐dependent manner. Moreover, our assay results also revealed that exposure to [C₁₂min]Cl prompted DNA damage and apoptosis, reduced SOD and GSH content, enhanced MDA level, and changed the cell cycle of HepG2 cells. In addition, [C₁₂min] Cl caused alters in the expression levels of p53, Bax, and Bcl‐2, indicating that p53 and Bcl‐2 family may be involved in the cytotoxicity and apoptosis of HepG2 cells induced by [C₁₂min]C1. In summary, these results indicate that [C₁₂min]Cl exerts genotoxicity, physiological toxicity and prompts apoptosis in HepG2 cells, and is not an alleged green solvent.     

An improvement to the synthesis of deuterated meso‐tetraphenylporphyrins

An improved method for the synthesis of deuterated tetraphenylporphyrins (TPPs) is reported. In this method, deuterium labelling at the pyrrole–β‐position is increased to more than 95 at%. TPP is the most widely used synthetic porphyrin and high deuterium incorporation is essential for spectroscopic studies and kinetic studies involving relaxation processes. Copyright © 2006 John Wiley & Sons, Ltd.     

5‐Trideuteromethyl‐α‐tocotrienol and 5‐14CH3‐α‐tocotrienol as biological tracers of tocotrienols

The tocotrienols have attracted increased attention recently as evidence has accrued that their biological activities are significantly different from tocopherols. The biokinetics and metabolic fate of tocopherols have long been studied using deuteromethylated forms of α‐tocopherol prepared by a stannous chloride catalysed paraformaldehyde methylation of γ‐ and δ‐tocopherols. We show here that his methodology is not an efficient route to deuterated α‐tocotrienol because of low yields and extensive exchange of allylic hydrogens under the prolonged acidic conditions of the deuteromethylation. Instead, we have prepared deuteromethylated and ¹⁴C‐radiolabelled α‐tocotrienol by aminomethylation at C‐5 of γ‐tocotrienol (available from palm oil), followed by reduction with NaCNBD₃ in refluxing iso‐butanol. The deuteromethylation procedure is amenable to multi‐gram scale reactions. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of deuterium‐labeled d3‐androstenone and d3‐skatole for boar taint analysis

The steroidal pig pheromone androstenone (5α‐androst‐16‐en‐3‐one) as well as the indole derivate skatole are known to be the major compounds contributing to boar taint. The preparation of ²H‐labeled internal standards of androstenone and skatole for stable isotope dilution assay–gas chromatography–mass spectrometry analysis of pig back fat samples is presented. The synthesis of d₃‐androstenone is highlighted by a palladium catalyzed deuteration of a Δ5,6‐double bond of a hydrophobic steroid in a polar, D₂O‐containing solvent mixture. Moreover, the utilization of D₂O as a deuterium source with in situ formation of D₂ by means of Mg⁰ was found to be a very feasible and convenient alternative with respect to costs and technical effort.     

Application of 1‐butyl‐3‐methylimidazolium hexafluorophosphate to Ir(I)‐catalyzed hydrogen isotope exchange labelling of substrates poorly soluble in dichloromethane

Substrate solubility remains a major limitation in Ir(I)‐catalyzed isotopic hydrogen exchange labelling. In the search for an alternative to the solvent dichloromethane, which is critical to the success of the reaction, we examined a series of ionic liquids for their suitability. Commercially available 1‐butyl‐3‐methylimidazolium hexafluorophosphate (abbreviated to [BMI][PF₆]) was found to support efficient deuterium and tritium exchange labelling of N‐(4‐methoxyphenyl)‐N‐methyl benzamide 1 under standard conditions. The solvent dissolves both polar hydroxyl and carboxylic acid substituted acetanilides, providing isotopomers in unprecedentedly high deuterium incorporation as compared to dichloromethane. We report the application of [BMI][PF₆] and its potential for extending the scope of Ir(I)‐catalyzed H/T exchange to more polar compounds. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of uniformly deuterated n‐dodecyl‐β‐d‐maltoside (d39‐DDM) for solubilization of membrane proteins in TROSY NMR experiments

This work reports the first synthesis of uniformly deuterated n‐dodecyl‐β‐d ‐maltoside (d₃₉‐DDM). DDM is a mild non‐ionic detergent often used in the extraction and purification of membrane proteins and for solubilizing them in experimental studies of their structure, dynamics and binding of ligands. We required d₃₉‐DDM for solubilizing large α‐helical membrane proteins in samples for [¹⁵N–¹H]TROSY (transverse relaxation‐optimized spectroscopy) NMR experiments to achieve the highest sensitivity and best resolved spectra possible. Our synthesis of d₃₉‐DDM used d₇‐d ‐glucose and d₂₅‐n‐dodecanol to introduce deuterium labelling into both the maltoside and dodecyl moieties, respectively. Two glucose molecules, one converted to a glycosyl acceptor with a free C4 hydroxyl group and one converted to a glycosyl donor substituted at C1 with a bromine in the α‐configuration, were coupled together with an α(1 → 4) glycosidic bond to give maltose, which was then coupled with n‐dodecanol by its substitution of a C1 bromine in the α‐configuration to give DDM. ¹H NMR spectra were used to confirm a high level of deuteration in the synthesized d₃₉‐DDM and to demonstrate its use in eliminating interfering signals from TROSY NMR spectra of a 52‐kDa sugar transport protein solubilized in DDM.     

Iridium‐mediated β‐deuteration of enones

Exposure of captodative enone systems to deuterium in the presence of Crabtree's catalyst ( 1 ) results in deuteration at the vinylic site β‐ to the ketone carbonyl, as well as at any accessible ortho‐position. β‐exchange is also observed during the reduction of ethyl cinnamate ( 3 ) catalyzed by 1 . Copyright © 2003 John Wiley & Sons, Ltd.     

Stereoselective synthesis of L‐[2,3,4,5‐D4] ornithine

Synthesis of L ‐[2,3,4,5‐D₄]ornithine in which all of the diastereotopic hydrogens were stereoselectively labeled with deuterium was investigated. The chirally deuterated 3‐aminopropanal derivative, a key intermediate in this synthesis, was prepared by a catalytic deuteration of an unsaturated γ‐lactone derived for L ‐glutamic acid followed by several functional group interconversions. Condensation of the obtained deuterium‐labeled 3‐aminopropanal derivative with a chiral glycine template afforded unsaturated ornithine. The dehydroornithine was then subjected to a catalytic deuteration followed by deprotection to give the L ‐[2,3,4,5‐D₄]ornithine. Copyright © 2002 John Wiley & Sons, Ltd.     

Preparation of labelled 2‐methoxy‐3‐alkylpyrazines: synthesis and characterization of deuterated 2‐methoxy‐3‐isopropylyrazine and 2‐methoxy‐3‐isobutylpyrazine

Efficient synthetic routes for a number of deuterated analogues of 2‐methoxy‐3‐isopropylpyrazines and 2‐methoxy‐3‐isobutylpyrazines have been developed involving the condensation of glyoxal with an α‐amino acid amide followed by methylation with iodomethane. In this way [²H₃]2‐methoxy‐3‐isopropylpyrazine, 2‐methoxy‐3‐isopropyl‐[²H₂]pyrazine, [²H₃]2‐methoxy‐3‐isopropyl‐[²H₂]pyrazine, [²H₃]2‐methoxy‐3‐isobutylpyrazine; 2‐methoxy‐3‐isobutyl‐[²H₂]pyrazine and [²H₃]2‐methoxy‐3‐isobutyl‐[²H₂]pyrazine were prepared and characterized by NMR and MS. Copyright © 2002 John Wiley & Sons, Ltd.     

Green profiling of aprotic versus protic ionic liquids: Synthesis and microbial toxicity of analogous structures

How does the variation in the ionic nature of ionic liquids (ILs) affect their antimicrobial properties? To answer this question with a direct connection to the molecular structure of ILs is integral for the design of new task specific ILs. The effect of ionic nature can be investigated through a comparison between analogous aprotic and protic ILs. However, while there have been extensive studies on the toxicology of both aprotic and protic ILs, the number of different structures and procedures employed makes quantitative comparison impossible. To address this, a series of analogous N,N,N-trimethylethanolammonium (cholinium) derived aprotic ILs (AILs) and N,N-dimethylethanolammonium derived protic ILs (PILs) with acetate, hexanoate, d,l-mandelate and 3-ethoxypropionate anions were prepared and characterised. All ILs were subsequently screened for antimicrobial activity against eight bacterial and twelve fungi strains. From the antimicrobial activity screening, little difference was found between the toxicities of AILs and PILs with shorter chains terminating in hydroxyl functional groups (e.g cholinium hexanoate and N,N-dimethylethanolammonium hexanoate). Variations between anion structure demonstrated slightly higher toxicities for more lipophilic anions. Antimicrobial activities were found to significantly increase for ILs with a long ether chain functional groups in the cation, due to the enhanced surfactant properties of these long chain cations. The importance of toxicity screening of analogous series of AILs and PILs as part of a future comprehensive biodegradation analysis has also been proposed based on postulated IL breakdown pathways.     

Synthesis of 2H‐ and 3H‐labeled N‐cyclopropylmethyl‐7α‐[(R)‐1‐hydroxy‐1‐methyl‐3‐(2thienyl)‐propyl]‐6,14‐endoethano‐6,7,8,14‐tetrahydro nororipavine

A procedure for deuterium and tritium labeling of the titled compound, an analgesic agent, was developed. A secondary amine intermediate was acylated to an acylamide, then the carbonyl function was reduced by LiAlD₄ to yield the tertiary amine. In the tritium‐labeled synthesis, the process utilized a bromo‐substituted precursor, which was subsequently reduced with ³H₂ in the presence of a Pd/C catalyst. The labeled compounds were successfully applied in pharmacokinetic and pharmacological studies. Copyright © 2005 John Wiley & Sons, Ltd.     

Current-stimulated release of solutes solubilized in water-immiscible room temperature ionic liquids (RTILs)

Room temperature ionic liquids (RTILs), salts which are liquid at room temperature, may be water-soluble or water immiscible, depending on the combination of cation and anion. They are efficient solvents for a wide range of solutes including drugs. The water-immiscible RTILs studied in this paper (the 1-butyl, hexyl and octyl 3-methyl imidazolium (BMIM, HMIM, and OMIM) hexafluorophosphate (PF₆^?) salts) can act as drug reservoirs. Passage of an electric current through these immiscible liquids can enhance the release of some solutes into an aqueous medium. Current flow (over the range 1–5?mA) increased the release rate of a solubilized hydrophilic solute, ³H-sucrose, and of a model hydrophobic drug, ³H-dexametasone. A threefold increase in the release rate of both sucrose and dexamethasone into water was observed under some conditions although the effect of application of current was not always linear. OMIM[PF₆] was the most responsive liquid. Some measurable physical properties of the ionic liquids change on the application of current. For example, the surface tension of the three RTILs studied decreased significantly on application of current for 15?min (from 47.8 mNm^?1 to 36.2 mNm^?1 for BMIM) but the effect on the surface tension of the OMIM salt was small. Only a small decrease in the viscosity of RTILs was observed. Although the mechanisms of the enhanced release are not yet elucidated, RTILs are potentially interesting depots for electrically controlled drug delivery.     

A convenient method for palladium‐catalyzed reductive deuteration of organic substrates using deuterated hypophosphite in D2O

A convenient method for the deuteration of organic substrates using deuterated hypophosphite as the deuterium source was investigated. Transfer deuteration of organic substrates, such as aromatic halides, alkenes, alkynes, epoxides, and O‐benzyl derivatives, in the presence of palladium on carbon in deuterium oxide proceeded efficiently to give the corresponding deuterated products in excellent yields with high deuterium contents.     

Synthesis of 1, 1′, 2, 2′, 3, 3′, 4, 4′ ‐ octadeutero‐sulforaphane

Sulforaphane (SFN), a naturally occurring isothiocyanate present in broccoli, shows strong evidence of anti‐carcinogenic activity. The mechanism of action, absorption, distribution, metabolism and excretion of the compound is however still poorly understood and requires a stable isotope labelled version of the compound for further studies. The paper describes an optimized synthesis of octadeutero‐SFN. Copyright © 2004 John Wiley & Sons, Ltd.     

In vitro cytotoxicities of ionic liquids: effect of cation rings, functional groups, and anions

In vitro cytotoxicities were measured for ionic liquids (ILs) containing various cations and anions using the MCF7 human breast cancer cell line. We measured the cytotoxicities of ionic liquids containing the cations pyridinium, pyrrolidinium, piperidinium, or imidazolium with various alkyl chain lengths, and the anions bromide, bis(trifluoromethanesulfone)imide (Tf(2)N), trifluoromethylsulfonate (TfO), or nonafluoromethylsulfonate (NfO). Three new hydrophobic, task-specific ionic liquids (TSILs), namely, [MBCNPip](+)[Tf(2)N](-), [MPS(2)Pip](+)[Tf(2)N](-), and [MPS(2)Pyrro](+)[Tf(2)N](-) designed for metal-ion extraction were also evaluated. IC(50) values of the ionic liquids toward the MCF7 cells ranged from 8 microM to 44 mM. The toxicity depended significantly on the nature of the cations and anions, especially when the cations contained a long side chain. TSILs studied in this work were less toxic than the classical ILs.     

The embryonic and postembryonic developmental toxicity of imidazolium‐based ionic liquids on Physa acuta

The embryonic and postembryonic developmental toxicity of imidazolium‐based ionic liquids (ILs) to the snail Physa acuta was evaluated in this study. The results of embryonic toxicity tests showed that lower concentrations of 1‐octyl‐3‐methylimidazolium bromide ([C₈mim]Br) (1.5 and 2.1 mg/L) inhibited the hatching rate of snail embryos, and partial snails hatched normally and died, while all of the treated embryos died when the exposure concentration was higher than 4.16 mg/L, at which IL caused the deformation, death, and decay of snail embryos. Statistical analyses revealed obvious differences in the hatching rates between three developmental stages in the 2.1 and 2.94 mg/L groups, indicating that the veliger stage is more sensitive to [C₈mim]Br exposure than the blastula and gastrula stages. Furthermore, the 96 h LC₅₀ values of [C₈mim]Br on the tested snails at three developmental stages (juvenile, subadult, and adult) were 70.83 ± 2.99, 97.59 ± 4.05, and 109.3 ± 2.22 mg/L, respectively, indicating that young snails were more sensitive to [C₈mim]Br toxicity than adults. In addition, the 96 h LC₅₀ values of ILs with different alkyl chain lengths, that is, [C₁₂mim], [C₁₀mim], [C₈mim], and [C₆mim], in adult snails were 1.35 ± 0.24, 8.96 ± 5.66, 109.3 ± 4, and 359.6 ± 11.6 mg/L, respectively, suggesting that longer alkyl chains can increase the toxicity of imidazolium ILs on snails. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 697–704, 2014.     

Synthesis of [2H3]‐dextromethorphan and its major urinary metabolites [2H3]‐dextrorphan and [2H3]‐dextrorphan‐β‐glucuronide

Starting from dextromethorphan, [²H₃]‐dextrorphan‐β‐glucuronide was synthesized in four steps with [²H₃]‐dextromethorphan and [²H₃]‐dextrorphan as intermediates with an overall yield of 11%. Copyright © 2002 John Wiley & Sons, Ltd.