Structural diversity in the host–guest complexes of the antifolate pemetrexed with native cyclodextrins: gas phase, solution and solid state studies

• Magdalena Ceborska,
• Magdalena Zimnicka,
• Aneta Aniela Kowalska,
• Kajetan Dąbrowa and
• Barbara Repeć

Beilstein J. Org. Chem. 2017, 13, 2252–2263, doi:10.3762/bjoc.13.222

• signals of acidic protons are not visible in D2O due to the fast substitution by deuterium atoms we performed 1D NMR measurements in DMSO-d6 (see Figures S15–S17, S18, S23 and Tables S5 and S6 in Supporting Information File 1). From these experiments it can be clearly seen that pyrrolic proton PTX#H4

Remarkable functions of sn-3 hydroxy and phosphocholine groups in 1,2-diacyl-sn-glycerolipids to induce clockwise (+)-helicity around the 1,2-diacyl moiety: Evidence from conformation analysis by ¹H NMR spectroscopy

• Yoshihiro Nishida,
• Mengfei Yuan,
• Kazuo Fukuda,
• Kaito Fujisawa,
• Hirofumi Dohi and
• Hirotaka Uzawa

Beilstein J. Org. Chem. 2017, 13, 1999–2009, doi:10.3762/bjoc.13.196

• ; deuterium labeling; sn-glycerol; glycerolipids; glycerophospholipids; helicity; Karplus equation; proton NMR spectroscopy; staggered conformers; Introduction Glycerophospholipids, constituting the basic elements of cytoplasm bilayer membranes, are responsible for several cell functions [1][2][3]. These

• storage in CDCl3 solution. Acquisition of the 1H NMR spectral data of H1proR and H1proS signals Each of the four glycerolipids 1–4 is dissolved in either CDCl3 or the mixed solvents containing methanol-d4 in CDCl3 (deuterium content > 99.5%) at ca. 10 mM concentrations. 1H NMR spectroscopy is measured on

18-Hydroxydolabella-3,7-diene synthase – a diterpene synthase from Chitinophaga pinensis

• Jeroen S. Dickschat,
• Jan Rinkel,
• Patrick Rabe,
• Arman Beyraghdar Kashkooli and
• Harro J. Bouwmeester

Beilstein J. Org. Chem. 2017, 13, 1770–1780, doi:10.3762/bjoc.13.171

• analysis of the obtained terpene products. Incubation of (R)-(1-13C,1-2H)GGPP with HdS resulted in the specific incorporation of the deuterium labelling into the 2α position as indicated by a deminished crosspeak in the HSQC spectrum, while the crosspeak for H2β was strongly enhanced because of the 13C

• labelling of C2 (Figure 2). Consistently, the substrate (S)-(1-13C,1-2H)GGPP gave a product with specific incorporation of the deuterium label into the 2β position. Assuming inversion of configuration at C1 for the cyclisation of GGPP to 3 as reported for several other terpene synthases [13][20][21][22

• gave a stereospecific incorporation of the deuterium labelling into H10α from (R)-(1-13C,1-2H)GPP and into H10β from (S)-(1-13C,1-2H)GPP (Figure 3), which pointed to the same absolute configuration for 3 as deduced from the experiments with the two enantiomers of (1-13C,1-2H)GGPP. Similar incubation

Theoretical simulation of the infrared signature of mechanically stressed polymer solids

• Matthew S. Sammon,
• Milan Ončák and
• Martin K. Beyer

Beilstein J. Org. Chem. 2017, 13, 1710–1716, doi:10.3762/bjoc.13.165

• modes specific to the polymer ends would be very weak. Therefore, hydrogen atoms from the terminal methyl groups were substituted with deuterium. The spectral lines originating from these CD3 groups were removed from the simulated spectra. To simulate the intensities of infrared bands in the fingerprint

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

• Leadlay and co-workers applying LC−sequential and high-resolution mass spectrometry in combination with deuterium exchange experiments [54]. Instead of the additional hydroxy group proposed by the Small group, these studies provided strong evidence for mycolactone D (3) to feature an extra methyl group at

• spectrometry in conjunction with oxidative degradation and deuterium exchange experiments [56]. In spite of the challenge posed by the severely limited availability of natural material for structural analysis, Kishi and co-workers later demonstrated by total synthesis (vide infra) that the Leadlay structure

Molecular recognition of N-acetyltryptophan enantiomers by β-cyclodextrin

• Spyros D. Chatziefthimiou,
• Mario Inclán,
• Petros Giastas,
• Athanasios Papakyriakou,
• Konstantina Yannakopoulou and
• Irene M. Mavridis

Beilstein J. Org. Chem. 2017, 13, 1572–1582, doi:10.3762/bjoc.13.157

• chromatography [24], or in capillary electrophoresis [25]. Results and Discussion NMR studies In deuterium oxide (D2O), each of the NAcTrp enantiomers induced significant chemical shift displacements (shielding) in the 1H NMR signals of the β-CD cavity protons, namely H3 (near the wider, secondary side) and H5

• orientation of the guest inside the host and the formation of the crystals per se. Experimental Materials and methods N-Acetyl-L-tryptophan (L-NAcTrp), N-acetyl-D-tryptophan (D-NAcTrp) and β-CD were obtained from Sigma-Aldrich. Deuterium oxide was a product of Deutero GmbH. NMR spectroscopy The spectra were

A novel approach to oxoisoaporphine alkaloids via regioselective metalation of alkoxy isoquinolines

• Benedikt C. Melzer and
• Franz Bracher

Beilstein J. Org. Chem. 2017, 13, 1564–1571, doi:10.3762/bjoc.13.156

• , 1 h, 25 °C) was performed in order to identify the position(s) of ring metalation of 12. In recovered (about 80%) educt, deuterium incorporation (about 40%; calculated from integrals of the 1H NMR spectrum) was observed exclusively at C-6 of the benzamide moiety (Scheme 6). It is known for decades

• of 1 h, followed by D2O quenching resulted in complete decomposition. In contrast, metalation of amide 16 under the same conditions and quenching with D2O led to the formation of the benzo[c]fluoren-7-one 17 in 38% yield. In recovered (about 20%) educt 16, deuterium incorporation (about 20

Glycoscience@Synchrotron: Synchrotron radiation applied to structural glycoscience

• Serge Pérez and
• Daniele de Sanctis

Beilstein J. Org. Chem. 2017, 13, 1145–1167, doi:10.3762/bjoc.13.114

New approach toward the synthesis of deuterated pyrazolo[1,5-a]pyridines and 1,2,4-triazolo[1,5-a]pyridines

• Aleksey Yu. Vorob’ev,
• Vyacheslav I. Supranovich,
• Gennady I. Borodkin and
• Vyacheslav G. Shubin

Beilstein J. Org. Chem. 2017, 13, 800–805, doi:10.3762/bjoc.13.80

• and a high degree of deuterium incorporation were achieved. The procedure was applied for several 4-R-1-aminopyridinium cations (R = H, Me, OMe). Keywords: deuteration; 1,3-dipolar cycloaddition; pyrazolo[1,5-a]pyridine; 1,2,4-triazolo[1,5-a]pyridine; Introduction Isotopically labeled compounds find

• broad applications in studies of chemical and biochemical reaction mechanisms and metabolism pathways. Deuterium is the most common used isotopic label in mechanistic studies. Deuterated organic compounds are widely used in biological [1] and pharmacological [2][3][4][5] investigations. In the last

• intramolecular ring closure [21][22][23][24]. The importance of these cores for medical chemistry studies suggests that isotopically labeled pyrazolo[1,5-a]pyridines and triazolo[1,5-a]pyridines could be of interest. Recently, deuterium-labeled pyridinium-N-imines were applied to mechanistic studies of the

Membrane properties of hydroxycholesterols related to the brain cholesterol metabolism

• Malte Hilsch,
• Ivan Haralampiev,
• Peter Müller,
• Daniel Huster and
• Holger A. Scheidt

Beilstein J. Org. Chem. 2017, 13, 720–727, doi:10.3762/bjoc.13.71

• wt % deuterium-depleted water. The samples were equilibrated by ten freeze-thaw cycles and transferred into 5 mm glass vials and sealed. 2H NMR measurements The 2H NMR experiments were performed on a Bruker DRX300 NMR spectrometer (Bruker BioSpin, Rheinstetten, Germany) at a resonance frequency of

Synthesis of 1-indanones with a broad range of biological activity

• Marika Turek,
• Dorota Szczęsna,
• Marek Koprowski and
• Piotr Bałczewski

Beilstein J. Org. Chem. 2017, 13, 451–494, doi:10.3762/bjoc.13.48

• -indanones 159a–g by a rhodium-catalyzed isomerization of racemic α-arylpropargyl alcohols 158 has been developed by Shintani, Okamoto and Hayashi (Scheme 46) [76]. By the mechanistic investigations using deuterium-labeled substrates, the authors have disclosed that the methine proton of the alcohol goes to

Biosynthetic origin of butyrolactol A, an antifungal polyketide produced by a marine-derived Streptomyces

• Enjuro Harunari,
• Hisayuki Komaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2017, 13, 441–450, doi:10.3762/bjoc.13.47

• addition, the 2H (deuterium) NMR spectrum showed deuterium signals for the methyl group (H-25, H-26, H-27) of L-valine-d8-labeled 1 (Figure 7a). The mass spectrum of the L-valine-d8-labeled 1 displayed the molecular ion with a mass increment of 6 Da (Figure 7b), corresponding to the incorporation of six

• deuterium atoms into the terminal methyl groups. Based on these results from precursor-feeding experiments, we concluded that the tert-butyl group and the adjacent methylene carbon (C-23) are derived from valine and the S-methyl carbon of methionine. It is controversial whether pivaloyl CoA is loaded onto

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

Beilstein J. Org. Chem. 2017, 13, 348–371, doi:10.3762/bjoc.13.39

• deuterium label was retained at the C-2 position bearing the D-configured methyl group (generated by module 2), while no labeling was observed at C-4 bearing the L-configured methyl group (generated by module 1). The opposite labeling pattern was obtained when biosynthesis was carried out with unlabeled

• additional epimerization step must occur in module 1 to yield the L-methyl stereochemistry present at C-4 (thus explaining the loss of deuterium from the 2-position when (2RS)-[2-2H]methylmalonyl-CoA was used, and its incorporation from solvent in the presence of unlabeled extender) (mechanism III, Figure 9

• the KR prior to ketoreduction (the alternative possibility that epimerization occurs in all modules but that the KRs select the correct isomer is excluded by the in vitro studies with DEBS 1-TE (Figure 9) [46], as no deuterium from the deuterated extender unit would have been retained in the triketide

The reductive decyanation reaction: an overview and recent developments

• Jean-Marc R. Mattalia

Beilstein J. Org. Chem. 2017, 13, 267–284, doi:10.3762/bjoc.13.30

• intermediates were trapped using the radical probe 4 (Scheme 4). Replacing t-BuOH with t-BuOD in Scheme 3 (R = CH3 case), yielded the decyanation product 3 with 92% deuterium incorporation. With respect to the mechanism described in Scheme 1, the authors suggest that t-BuOH (or Ph3CH) could act as H-atom donor

• treatment with NaBH4 in 2-propanol by using both basic and nucleophilic properties of the hydride ion. The proposed mechanism involves a double-bond isomerization to the α-aminonitrile intermediate which is then reduced by the hydride ion in a classical way (Scheme 7). Interestingly, deuterium-labelling

• reduction of radical probes (no rearranged products formed from 25d,l,m) and deuterium-labelling experiments (no deuterium incorporation using THF-d8 and quenching with D2O) discard the possibility of a single-electron transfer pathway. Other reductions suggest a hydride addition with formation of an iminyl

Silyl-protective groups influencing the reactivity and selectivity in glycosylations

• Mikael Bols and
• Christian Marcus Pedersen

Beilstein J. Org. Chem. 2017, 13, 93–105, doi:10.3762/bjoc.13.12

• stereoselectivity has been demonstrated in radical reactions, however, with the twist that stereoselectivity here is opposite. The reduction of the selenoglycosides (analogues to 20) with tributyltin deuteride gave predominantly deuterium in the β-position for silylated derivatives in the 1C4 conformation, because

• the reaction intermediate is a radical that prefers to be axial. On the other hand, with acetate protective groups, the addition of deuterium occurred predominantly from the β-side [45][46]. The principle of conformational stereocontrol was also used for the stereoselective addition of carbon radicals

Phosphated cyclodextrins as water-soluble chiral NMR solvating agents for cationic compounds

• Cira Mollings Puentes and
• Thomas J. Wenzel

Beilstein J. Org. Chem. 2017, 13, 43–53, doi:10.3762/bjoc.13.6

• either as hydrochloride salts or neutral compounds. Neutral substrates were converted to their hydrochloride salts in deuterium oxide (D2O) by adding a slight excess of deuterium chloride (DCl). II. Apparatus Proton (1H) NMR spectra were obtained using a Bruker Avance 400 MHz NMR spectrometer. Samples

Effects of solvent additive on “s-shaped” curves in solution-processed small molecule solar cells

• John A. Love,
• Shu-Hua Chou,
• Ye Huang,
• Guilllermo C. Bazan and
• Thuc-Quyen Nguyen

Beilstein J. Org. Chem. 2016, 12, 2543–2555, doi:10.3762/bjoc.12.249

• , resulting in a depth profile. To improve contrast between the two materials, deuterated fullerene PC61BM-d5 was used as a surrogate for PC71BM to establish a unique mass signal for the fullerene component [12][66][67]. Thus detection of deuterium in the mass spectrum implicitly signifies PC61BM-d5 in the

• rate. Thus the x-axis has been scaled for film thickness, where the turn-on of the nitrogen and deuterium signals at x = 0 nm corresponds to the top surface of the films, what would be the cathode interface in a complete device architecture. The turn-off of the signals thus corresponds to the BHJ/PEDOT

• cast from pure chlorobenzene (yellow) and with 1.5% DIO (blue) with (solid) and without (dashed) methanol treatment. Dynamic secondary ion mass spectrometry (DSIMS) profile showing scaled nitrogen (solid) and deuterium (dashed) signals for films cast a) with no DIO and b) with 1.5% DIO. a) A schematic

Protonated paramagnetic redox forms of di-o-quinone bridged with p-phenylene-extended TTF: A EPR spectroscopy study

• Nikolay O. Chalkov,
• Vladimir K. Cherkasov,
• Gleb A. Abakumov,
• Andrey G. Starikov and
• Viacheslav A. Kuropatov

Beilstein J. Org. Chem. 2016, 12, 2450–2456, doi:10.3762/bjoc.12.238

• under such conditions is the proton attached to the semiquinone. Due to deuterium exchange the spectrum transforms into a broadened triplet of triplets (Figure 2b), since the higher spin (S = 3/2) and the small gyromagnetic ratio of the deuterium nucleus (γN = 4.1065 × 103 rad G−1 s−1) renders the

A detailed view on 1,8-cineol biosynthesis by Streptomyces clavuligerus

• Jan Rinkel,
• Patrick Rabe,
• Laura zur Horst and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 2317–2324, doi:10.3762/bjoc.12.225

• in both cases a syn addition, as could be shown by incubation of (2-13C)geranyl diphosphate in deuterium oxide. Keywords: biosynthesis; enzyme mechanisms; isotopic labelling; stereochemistry; terpenes; Introduction Among all classes of natural products the climax of structural diversity and

• or an anti addition to the olefinic double bond, requiring a protonation of the original C-2 of GPP. To distinguish between these alternatives (2-13C)GPP was synthesised from sulcatone (Scheme S2, Supporting Information File 1) and converted by the 1,8-cineol synthase in deuterium oxide. The obtained

• product was analysed by HSQC spectroscopy (Figure 3A), showing that deuterium is taken up into the exo position at the 13C-labelled C-2 of 1 (indicated by H’), while the endo position (H’’) is occupied by the proton from the substrate, resulting in a strong crosspeak [22]. Furthermore, deuterium

Enantioconvergent catalysis

• Justin T. Mohr,
• Jared T. Moore and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2016, 12, 2038–2045, doi:10.3762/bjoc.12.192

• . Deuterium labeling experiments have shown that the hydrogenation reaction occurs only on the chiral keto tautomer, and therefore the catalyst selects one enantiomer of the substrate when the reduction takes place. Enantioconvergent methods are not limited to carbon stereocenters. An exceptional example of

Mechanistic investigations on six bacterial terpene cyclases

• Patrick Rabe,
• Thomas Schmitz and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 1839–1850, doi:10.3762/bjoc.12.173

• containing water or deuterium oxide allowed for detailed insights into the cyclisation mechanisms of the bacterial terpene cyclases. Keywords: absolute configuration; biosynthesis; enzyme mechanisms; structure elucidation; terpenes; Introduction Terpenes are structurally fascinating natural products with

• to 4 (Scheme 1). This biosynthetic model was tested by incubation of (6-13C)FPP with the 7-epi-α-eudesmol synthase in deuterium oxide to follow the reprotonation of the neutral intermediate 4a [54][55]. A simple extraction of the reaction mixture with (2H6)benzene and direct 13C NMR analysis resulted

• in a highfield shifted triplet at 38.7 ppm (Δδ = −0.5 ppm, 1JC,D = 19.4 Hz), demonstrating the introduction of deuterium at C-6 of 4 (Figure 4). The singlet at 39.2 ppm is observed due to residual water in the enzyme reaction. Germacranes have been suggested as general precursors for eudesmanes [56

Cp₂TiCl/D₂O/Mn, a formidable reagent for the deuteration of organic compounds

• Antonio Rosales and
• Ignacio Rodríguez-García

Beilstein J. Org. Chem. 2016, 12, 1585–1589, doi:10.3762/bjoc.12.154

• experimental conditions and with great economic advantages. Keywords: deuteration; deuterium atom transfer; radical and/or organometallic chemistry; titanocene; Introduction Deuterium is a stable isotope of hydrogen with 0.015% natural abundance broadly used in organic chemistry, pharmacology, organometallic

• chemistry, spectroscopy and many other fields [1][2][3][4]. Exchange of hydrogen for deuterium produces primary and secondary kinetic isotope effects (KIE) causing isotopically substituted molecules to react at different rates (kH ≠ kD). This behaviour is due to the differences in bond dissociation energies

• for both species, which in turn, is dependent upon the zero point for the vibrational energy of both isotopic molecules. As the mass of deuterium is about twice the mass of hydrogen there is a larger activation energy for the C–D bond dissociation than for the C–H bond [4]. The KIE observed allows

The EIMS fragmentation mechanisms of the sesquiterpenes corvol ethers A and B, epi-cubebol and isodauc-8-en-11-ol

• Patrick Rabe and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 1380–1394, doi:10.3762/bjoc.12.132

• , introduction of labelling into the various positions of the compound of interest may require a different synthetic strategy for each individual target isotopomer. Most of these studies made use of deuterium labellings that can frequently be introduced into reactive positions of a (functionalised) terpene

• isolated from the producing organism. Deuterium labellings also allow to follow hydrogen rearrangements, but non-specific hydrogen migrations during the fragmentation process and kinetic isotope effects can make data interpretation difficult. In contrast, the introduction of 13C-labelling into a terpene

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• mechanism of their reaction through a combination of DFT calculations, deuterium labeling studies, and control experiments (Scheme 13) [34]. The authors proposed that after migratory insertion of the rhodium–aryl bond across the acrylate, 58 undergoes β-hydride elimination of the enamide proton to generate

• rhodium catalyst binding to the benzoxazole nitrogen 68. Deuterium labeling studies were performed on the system and based on their results a mechanism was proposed in which the stereodetermining step is a rhodium-hydride transfer instead of protonation of an oxo-π-allylrhodium species (Scheme 17

Synthesis of a deuterated probe for the confocal Raman microscopy imaging of squalenoyl nanomedicines

• Eric Buchy,
• Branko Vukosavljevic,
• Maike Windbergs,
• Dunja Sobot,
• Camille Dejean,
• Simona Mura,
• Patrick Couvreur and
• Didier Desmaële

Beilstein J. Org. Chem. 2016, 12, 1127–1135, doi:10.3762/bjoc.12.109

• squalenoyl gemcitabine nanoparticles displayed significant Raman scattering signals. They revealed no differences except from the deuterium peak patterns in the silent spectral region of cells. This paves the way for label-free intracellular trafficking studies of squalenoyl nanomedicines. Keywords

• : deuterium labelling; nanomedicine; Raman spectroscopy; Shapiro reaction; squalene; Introduction Application of nanotechnology to medicine holds promises to profoundly impact healthcare especially to treat severe diseases such as cancer, intracellular infections, neurodegenerative diseases, etc. Indeed, the

• when dealing with low drug concentrations or biological-like structures such as peptide drugs or nucleoside analogues. To overcome this issue, deuterium can be introduced to a sample molecule, as it exhibits a significant Raman signal at around 2200 cm−1, which is in a so called “silent region” (1800