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 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.     

Proton exchange reactions in isotope chemistry (I)

Direct H–D exchange reactions were applied to the preparations of stable isotope‐labeled TKI258 and two TKI258 metabolites. Each compound was made in one single H–D exchange reaction with excellent isotope incorporation. The number of deuterium incorporation and deuterium distribution in the molecules was similar in all three compounds. Stable isotope‐labeled TKI258 was also prepared from d₈‐methylpiperazine in a multistep synthesis.     

A two‐step synthesis of deuterium labeled 8, 8, 9, 9‐d4‐hexadecane from nonanoic acid

Labeled compounds are essential in elucidating metabolic mechanisms and reaction pathways. A two‐step synthesis of deuterium‐labeled 8, 8, 9, 9‐d₄‐hexadecane from nonanoic acid is described here. The synthesis procedures involved hydrogen–deuterium exchange of nonanoic acid with 3.00 m DCl‐D₂O and then Kolbe electrolysis of the deuterated nonanoic acid to achieve the desired n‐alkane that was confirmed by gas chromatography‐mass spectrometry and ¹H nuclear magnetic resonance. This method might provide an alternative route for the preparation of specifically deuterated alkanes of different chain lengths (C > 4) in which deuterium atoms are located at two adjacent carbons of the alkane's carbon chain. Copyright © 2012 John Wiley & Sons, Ltd.     

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.     

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.     

Synthesis of 3H‐ and 2H4‐labelled versions of the hypoxia‐activated pre‐prodrug 2‐[(2‐bromoethyl)‐2,4‐dinitro‐6‐ [[[2‐(phosphonooxy)ethyl]amino]carbonyl]anilino]ethyl methanesulfonate (PR‐104)

³H‐ and ²H₄‐versions of the hypoxia‐activated pre‐prodrug PR‐104 [2‐[(2‐bromoethyl)‐2,4‐dinitro‐6‐[[[2‐(phosphonooxy)ethyl]amino]carbonyl]anilino]ethyl methanesulfonate], labelled in the ethylcarboxamide side chain, have been prepared, respectively, by [³H]NaBH₄ reduction of a precursor late stage aldehyde, and by late stage incorporation of deuterium with 2‐amino[1,1,2,2‐²H₄]ethanol. Copyright © 2007 John Wiley & Sons, Ltd.     

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 [2H5]‐ebastine fumarate and [2H5]‐hydroxyebastine

This study describes the synthesis of deuterium‐labelled ebastine fumarate and its deuterium‐labelled metabolite hydroxyebastine. The synthesis of the two desired compounds both used [²H₅]‐bromodiphenylmethane as deuterium‐labelled reagent, which was synthesized beforehand in three steps. [²H₅]‐ebastine was synthesized in further three steps with a 27% overall yield and [²H₅]‐hydroxyebastine was synthesized in further seven steps with a 13% overall yield. Copyright © 2011 John Wiley & Sons, Ltd.     

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 [2H]‐labelled phase‐I‐metabolites using 1‐[2H]‐pyridinium hydrochloride

Simultaneous O‐demethylation and hydrogen/deuterium exchange of aryl‐methyl‐ethers can be obtained using 1‐[²H]‐pyridinium hydrochloride as reagent at 220°C for 6 h. This reaction was applied to dextromethorphan and various non‐steroidal anti‐inflammatory drugs. Copyright © 2005 John Wiley & Sons, Ltd.     

Frustrated Lewis pairs: A real alternative to deuteride/tritide reductions

Deuterium‐ and tritium‐labeled compounds play a principal role in tracing of biologically active molecules in complicated biochemical systems. The state‐of‐the‐art techniques using noble metal catalysts or strong reducing agents often suffers from low functional group tolerances, poor selectivity, tricky or multistep synthesis of reagents, and low specific activity of the labeled product. Herein, we demonstrate a mild and nonmetallic technique of deuteration and tritiation of polarized double bonds, such as carbonyl compounds, yielding labeled alcohols of high specific activities. This one‐pot synthesis uses carrier‐free hydrogen gas in situ activated by a freshly prepared frustrated Lewis pair, generating reducing reagents. This labeling strategy shows better selectivity and functional group tolerances compared with current reductive methods. Reported is an example of the selective reduction of the aldehyde moiety of 3‐acetylbenzaldehyde. What makes this technology groundbreaking is its mildness, selectivity, and generation of limited amount of radioactive waste as almost no byproducts were generated after use of (B(C₆F₅)₃³H)(³HTMP) reducing reagent. Radiochemical purity of desired ³H‐labeled product in a crude reaction mixture was determined of over 94%. This work provides, to the community of radiochemists, a practical protocol for frustrated Lewis pairs (FLP)‐assisted deuterium/tritium labeling technology.     

Proton exchange reactions in isotope chemistry (II) synthesis of stable isotope‐labeled LCQ908

The proton exchange reaction was applied to the preparation of stable isotope‐labeled LCQ908. For this synthesis, a suitable intermediate with protons alpha to a carbonyl group was first subjected to the H–D exchange reaction; subsequent coupling of a carbonyl group with [¹³C₂]triethyl phosphonoacetate, followed by hydrogenation and hydrolysis, led to the stable labeled compound. Incorporation of two carbon‐13 atoms in the molecule eliminated the presence of undesired M+0.     

Synthesis of new deuterium‐labelled lignanolactones

Deuteration of several lignanolactones, using ²H₃PO₄·BF₃/²H₂O as the deuteration reagent, is described, affording new stable isotopically pure polydeuterated lignans. All aromatic hydrogens are exchanged, including the less active ones. The order of ¹H/²H exchange is studied by comparing calculated electrostatic potential values and experimental observations. Labile deuteriums are exchanged back to hydrogens with methanolic HCl to achieve stable isotopically pure compounds. Copyright © 2008 John Wiley & Sons, Ltd.     

Evaluation of the efficiency of Pd/H2‐catalyzed benzylic H/D exchange of dehydroabietinal with D2O and synthesis of a tritium‐labeled analogue

Dehydroabietinal (DA) has been identified as an important signaling molecule in systemic acquired resistance in plants. Deuterium and tritium‐labeled DA were synthesized to confirm its role in signaling and to further elucidate the mechanism by which DA induces systemic acquired resistance. Pd/H₂‐catalyzed exchange of benzylic hydrogen atoms of DA with ²H‐H₂O or ³H‐H₂O was conducted with >97% label incorporation for ²H‐DA and a specific activity of 12.6 mCi/mmol for ³H‐DA synthesized from 90 mCi/mmol ³H‐H₂O. The extent of deuterium labeling at each benzylic position was determined via an inverse‐gated ¹³C NMR experiment. C7 and C15 were 87% and 81% labeled, respectively. Isotope‐induced chemical shift changes at C6 were used to approximate the amount of singly (66%) and doubly (17%) labeled ²H‐DA at C7. Results also indicated that two of the three benzylic protons in DA underwent facile exchange. Exchange at the remaining position was likely hampered by steric interactions of nearby methyl groups at the surface of the Pd catalyst.     

A facile synthesis of 5,5‐dideutero‐4‐dimethyl(phenyl)silyl‐6‐undecyl‐tetrahydropyran‐2‐one as a deuterium labeled synthon for (−)‐tetrahydrolipstatin and (+)‐δ‐hexadecanolide

Deuterium‐labeled biologically active compounds are gaining importance because they can be utilized as tracers or surrogate compounds to understand the mechanism of action, absorption, distribution, metabolism, and excretion. Deuterated drug molecules (heavy drugs) become novel as well as popular because of better stability and bioavailability compared with their hydrogen analogs. Labeling of organic molecules with deuterium at specific positions is thus gaining popularity. In this work, we have exploited a highly regioselective and enantioselective direct Michael addition of methyl‐d₃ alkyl ketones to dimethyl(phenyl)silylmethylene malonate that was catalyzed by (S)‐N‐(2‐pyrrolidinylmethyl)pyrrolidine/trifluoroacetic acid/ D₂O combination with high yield and isotopic purity. The 5,5‐dideutero‐4‐dimethyl(phenyl)silyl‐6‐undecyl‐tetrahydropyran‐2‐one was obtained from the adduct of methyl‐d₃ undecanyl ketone and dimethyl(phenyl)silylmethylene malonate by a silicon controlled diastereoselective ketone reduction, lactonization, and deethoxycarbonylation. The dideuterated silylated tetrahydropyran‐2‐one is the precursor for geminal ²H₂‐labeled (+)‐4‐hydroxy‐6‐undecyl‐tetrahydropyran‐2‐one, an advanced intermediate for gem‐dideutero (–)‐tetrahydrolipstatin and (+)‐δ‐hexadecanolide syntheses.     

Deuterated batracylin: deuterium–hydrogen exchange during synthesis and mass spectral analysis

Deuterium‐labeled analogs of the topoisomerase inhibitor batracylin were prepared for metabolism studies to further its evaluation as an antitumor agent. Established syntheses of unlabeled batracylin were adapted for the preparation of deuterated batracylin that was trideuterated in the quinazoline ring (d₃‐batracylin 5), tetradeuterated in the isoindolo ring (d₄‐batracylin 11), and heptadeuterated in both rings (d₇‐batracylin 12). Extensive exchange of deuterium or hydrogen in the quinazoline ring was observed from an intermediate in the final concentrated sulfuric acid promoted deblocking/cyclodehydration step of the synthesis. Introduction of deuterated concentrated sulfuric acid in the final step both retained the label in the quinazoline‐labeled product and enabled extended labeling of a more exhaustively deuterated analog. Batracylin itself did not readily exchange aromatic protons under the reaction conditions but did loose and scramble deuterium atoms during mass spectral analysis leading to an under calculation of the deuterium content in the quinazoline ring. These results identify a chemical exchange process that can either undo, maintain, or facilitate the labeling process and also mass spectral analyses issues that must be taken into account to characterize and utilize these analogs and, more broadly, that can be recognized as potentially applicable to other classes of compounds. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of [2H8]‐enterolactone and [2H10]‐enterodiol

Enterolactone and enterodiol are the main mammalian metabolites of dietary butyrolactone type lignans. The study of biological properties and potential health effects of these compounds requires isotopically labelled compounds as standards for quantitative measurements. An expedient deutero‐labelling method for enterolactone is to use the D₃PO₄·BF₃/D₂O complex at room temperature which will exchange all eight aromatic hydrogens, even from inactivated meta positions, to form [2,4,5,6,2′,4′,5′,6′‐²H₈]‐enterolactone in 74% yield and 99% isotopic purity. [2,4,5,6,9,9,2′,4′,5′,6′‐²H₁₀]‐Enterodiol was prepared from [2,4,5,6,2′,4′,5′,6′‐²H₈]‐enterolactone by reduction with LiAlD₄ which introduces two more deuterium atoms into the molecule. Copyright © 2003 John Wiley & Sons, Ltd.     

The synthesis of deuterium‐labeled spermine,N1‐acetyl‐spermine and N1‐acetylspermidine

The synthesis of deuterium‐labeled spermine, N¹‐acetylspermine and N¹‐acetylspermidine is reported. 1,1,3,3‐²H₄‐N¹‐Acetylspermine hydrochloride, 1,1,3,3‐²H₄‐N¹‐acetylspermidine hydrochloride and 1,1,3,3,10,10,12,12‐²H₈‐spermine dihydrochloride were obtained in seven, four and three steps, respectively. All the syntheses were carried out by simple protection and deprotection steps from commonly used selective protecting reagents. These deuterium‐labeled compounds can be used as mechanistic probes of polyamine oxidizing enzymes. Copyright © 2007 John Wiley & Sons, Ltd.