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Gangliosides are intimately involved in a plenum of (neuro)inflammatory processes, yet progress in establishing structure-function interplay is frequently hindered by the availability of well-defined glycostructures. Motivated by the ubiquity of the ganglioside GM 3 in chemical neurology, and in particular by its conspicuous presence in myelin, the GM 3 epitope was examined with a view to preclinical validation as a tracer. The suitability of this scaffold for the noninvasive imaging of oligodendrocyte differentiation in Multiple sclerosis is disclosed. The stereocontrolled synthesis of a site-selectively fluorinated analogue (F-GM 3 ) is also disclosed to enable a comparative analysis in oligodendrocyte (OL) differentiation. Whereas the native epitope caused a decrease in the viability in a dose-dependent manner, the addition of distinct F-GM 3 concentrations over 48 h had no impact on the OL viability. This is likely a consequence of the enhanced hydrolytic stability imparted by the fluorination and highlights the potential of fluorinated glycostructures in the field of molecular imaging. Given the predominant expression of GM 3 in oligodendrocytes and the capacity of GM 3 to interact with myelin-associated proteins, this preclinical evaluation has revealed F-GM 3 to be an intriguing candidate for neurological imaging.

The oxidative activation of the perfluorinated analogue of dimethyl sulfoxide, DMSO-F 6 , by hydroxyl radicals efficiently produces trifluoromethyl radicals based on pulse radiolysis, laboratory scale experiments, and comparison of rates of reaction for analogous radical systems. In comparison to commercially available precursors, DMSO-F 6 proved to be more stable, easier to handle and overall more convenient than leading F 3 C-reagents and may therefore be an ideal surrogate to study F 3 C radicals for time-resolved kinetics studies. In addition, we present an improved protocol for the preparation of this largely unexplored reagent.

The TeF 5 group is significantly underexplored as a highly fluorinated substituent on an organic framework, despite it being a larger congener of the acclaimed SF 5 group. In fact, only one aryl-TeF 5 compound (phenyl-TeF 5 ) has been reported to date, synthesized using XeF 2 . Our recently developed mild TCICA/KF approach to oxidative fluorination provides an affordable and scalable alternative to XeF 2 . Using this method, we report a scope of extensively characterized aryl-TeF 5 compounds, along with the first SC-XRD data on this compound class. The methodology was also extended to the synthesis and structural study of heretofore unknown aryl-TeF 4 CF 3 compounds. Additionally, preliminary reactivity studies unveiled some inconsistencies with previous literature regarding phenyl-TeF 5 . Although our studies conclude that the arene-based TeF 5 (and TeF 4 CF 3 ) group is not quite as robust as the SF 5 group, we find that the TeF 5 group is more stable than previously thought, thus opening a door to explore new applications of this motif., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report a mild approach to the synthesis of difluoro(aryl)-λ 3 -iodanes (aryl-IF 2 compounds) and tetrafluoro(aryl)-λ 5 -iodanes (aryl-IF 4 compounds) using trichloroisocyanuric acid (TCICA) and potassium fluoride (KF). Under these reaction conditions, selective access to either the I(iii)- or I(v)-derivatives is predictable based solely on the substitution pattern of the iodoarene starting material. Moreover, the discovery of this TCICA/KF approach prompted detailed dynamic NMR, kinetic, computational, and crystallographic studies on the relationship between the IF 2 group and the ortho -substituents on carefully designed probe molecules. It was during these experiments that the role of the ortho -substituent in inhibiting further oxidative fluorination of I(iii)-compounds to I(v)-compounds during the reaction with TCICA and KF was revealed. Additionally, a notable exception to this empirical trend is discussed herein., (This journal is © The Royal Society of Chemistry 2019.)

Modern pentafluorosulfanyl (SF 5 ) chemistry has an Achilles heel: synthetic accessibility. Herein, we present the first approach to aryl-SF 4 Cl compounds (key intermediates in state-of-the-art aryl-SF 5 synthesis) that overcomes the reliance on hazardous fluorinating reagents and/or gas reagents (e.g. Cl 2 ) by employing easy-to-handle trichloroisocyanuric acid, potassium fluoride, and catalytic amounts of acid. These simple, mild conditions allow direct access to aryl-SF 4 Cl intermediates that either have not been or cannot be demonstrated using previous methods. Furthermore, the same approach provides access to aryl-SF 3 and aryl-SeF 3 compounds, which extend the applications of this chemistry beyond arene SF 5 -functionalization, and demonstrate its ability to address a more general oxidative fluorination problem., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cyclic benziodoxole systems have become a premier scaffold for the design of electrophilic transfer reagents. A particularly intriguing aspect is the fundamental I I -I III tautomerism about the hypervalent bond, which has led in certain cases to a surprising re-evaluation of the classic hypervalent structure. Thus, through a combination of 17 O NMR spectroscopy at natural abundance with DFT calculations, we establish a convenient method to provide solution-phase structural insights for this class of ubiquitous reagents. In particular, we confirm that Shen's revised, electrophilic SCF 3 -transfer reagent also adopts an "acyclic" thioperoxide tautomeric form in solution. After calibration, the approach described herein likely provides a more general and direct method to distinguish between cyclic and acyclic structural features based on a single experimental 17 O NMR spectrum and a computationally-derived isotropic shift value. Furthermore, we apply this structural elucidation technique to predict the constitution of an electrophilic iodine-based cyano-transfer reagent as an NC-I-O motif and study the acid-mediated activation of Togni's trifluoromethylation reagent.

Relapsing multiple sclerosis is synonymous with demyelination, and thus, suppressing and or reversing this process is of paramount clinical significance. While insulating myelin sheath has a large lipid composition (ca. 70-80%), it also has a characteristically large composition of the sialosylgalactosylceramide gangliosde GM 4 present. In this study, the effect of the carbohydrate epitope on oligodendrocyte differentiation is determined. While the native epitope had no impact on oligodendroglial cell viability, a single site OH → F substitution is the structural basis of a significant increase in ATP production that is optimal at 50 μg/mL. From a translational perspective, this subtle change increases the amount of MBP+ oligodendrocytes compared to the control studies and may open up novel therapeutic remyelination strategies.

We present the thermolysis of cyclic hypervalent iodine(III) perfluoroalkyl transfer reagents carried out in standard GC-MS instrumentation. Through heating, these structures undergo fragmentation to afford perfluoroalkyl radicals F 2n+1 C n . (n). This parameter T IP (n) not only reflects the stability of the F IP (n) not only reflects the stability of the F 2n+1 C n -I bond, but potentially also carries information regarding fundamental properties of the linear perfluoroalkyl chains., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We present an experimental electrophilicity index (ϻ) for the classification of radicals. The ϻ-scale is based on the equilibrium constant determined for the reversible addition of a radical R . to an aromatic radicophile (HisNH 2 ). This experimental approach is in excellent agreement with the computed global electrophilicity index ω and serves to validate the latter., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Herein we investigate the propensity of hypervalent iodine based electrophilic trifluoromethylating agents to undergo thermally induced fragmentation of the F 3 C-I-O motif. For the first time we are able to observe a dissociative electron transfer mechanism using mass spectroscopy techniques to generate and trap CF 3 radicals. Consistent with this mechanism, alkyl radical elimination from these reagents is in full support of an intermediate cyclic iodanyl radical and a reagent-specific temperature of maximum radical production was found to correlate with reported solution phase reactivity.

Pervasive in Nature, the propane unit is an essential component of numerous bioactive molecules. These range from acyclic systems, such as the neurotransmitter γ-aminobutyric acid, through to the bicyclic nuclei of various chromanes and dihydrobenzofurans. In the latter case, cyclisation via cyclic ether formation ensures a highly pre-organised structure, whilst linear scaffolds display more dynamic conformational behaviour resulting from rotation about the two internal C(sp 3 )-C(sp 3 ) bonds. In this study, the replacement of -[CH 2 ]- units by -[CHF]- centres is evaluated as a strategy to achieve acyclic conformational control by hindering these internal rotations. Reinforcing, non-covalent fluorine interactions are validated as powerful design features that result in programmable conformational behaviours: These are encoded by the relative configuration of each centre. By exploiting cooperative neighbouring stereoelectronic effects in a multi-vicinal fluoroalkane it is possible to emulate the overall conformation of the dihydrobenzofuran scaffold found in a variety of natural products with an acyclic mimic. This is described as a function of two bond vectors at the chain termini and validated by combined theoretical, crystallographic and spectroscopic analyses. In view of the favourable physicochemical properties associated with fluorine introduction, this approach to bioactive scaffold design may prove to be expansive., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The radical trifluoromethylation of thiophenol in condensed phase applying reagent 1 (3,3-dimethyl-1-(trifluoromethyl)-1λ(3),2-benziodoxol) has been examined by both theoretical and experimental methodologies. On the basis of ab initio molecular dynamics and metadynamics we show that radical reaction mechanisms favourably compete with polar ones involving the S-centred nucleophile thiophenol, their free energies of activation, ΔF(≠), lying between 9 and 15 kcal mol(-1). We further show that the origin of the proton activating the reagent is important. Hammett plot analysis reveals intramolecular protonation of 1, thus generating negative charge on the sulfur atom in the rate-determining step. The formation of a CF3 radical can be thermally induced by internal dissociative electron transfer, its activation energy, ΔF(≠), amounting to as little as 10.8 and 2.8 kcal mol(-1) for reagent 1 and its protonated form 2, respectively. The reduction of the iodine atom by thiophenol occurs either subsequently or in a concerted fashion., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Further development of the chemistry and applications of chiral compounds that possess configurationally stable stereogenic nitrogen atoms is hampered by the lack of efficient strategies to access such compounds in an enantiomerically pure form. Esters of propiolic acid and chiral alcohols were evaluated as cheap and readily available Michael acceptors in a diastereoselective synthesis of N-stereogenic compounds by means of a double aza-Michael conjugate addition. Diastereomeric ratios of up to 74:26 and high yields were achieved with (-)-menthyl propiolate as a substrate. Furthermore, a detailed mechanistic investigation was undertaken to shed some light on the course of this domino transformation. Kinetic studies revealed that the protic-solvent additive acts as a Brønsted acid and activates the ester toward the initial attack of the tetrahydrodiazocine partner. Conversely, acidic conditions proved unfavorable during the final cyclization step that provides the product., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Herein we disclose the synthesis of 2-fluoro-2-deoxyisosorbide 5-mononitrate (2F-IS-5MN), a fluorinated analogue of the commonly prescribed vasodilator isosorbide 5-mononitrate (IS-5MN). X-ray structural data for IS-5MN and its C2-epimeric congener IM-5MN are presented together with structural data for 2F-IS-5MN. Radioisotope labeling of 2F-IS-5MN has, for the first time, allowed observation of the in vivo biodistribution of this organic nitrate by means of dynamic positron emission tomography (PET) in wild-type mice., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The synthesis of 5-nitro-1-(trifluoromethyl)-3H-1λ(3),2-benziodaoxol-3-one (3), a hypervalent-iodine-based electrophilic trifluoromethylating reagent, is described. Whereas considerations based on cyclic voltammetry and X-ray structural properties would predict an inferior reactivity when compared to the non-nitrated derivative 2, (19)F NMR kinetic studies showed that this new derivative is almost one order of magnitude more reactive. Furthermore, differential scanning calorimetry measurements indicated that, in addition, it is also safer to handle.

This account aims at providing a general overview over studies carried out in our group on 3,3-dimethyl-1-(trifluoromethyl)-3H-1λ³,2-benziodaoxole (1) and 1-(trifluoromethyl)-3H-1λ³,2-benziodaoxol-3-one (2). While the first part deals with the syntheses of these increasingly popular reagents, the second part provides in-depth analyses of solid state structures of different derivatives. By means of bond-length derived parameters p changes in the hypervalent bond resulting from backbone modifications could be classified. Furthermore, it is showcased that the parameter p also correlates to solution phase reactivities. Lastly, diverse strategies directed towards the activation of the reagents are exemplified based on selected applications of 1 and 2.

Novel C2-symmetric doubly bidentate Se,N and S,N-ligands based on a readily available Tröger's base backbone were synthesized and fully characterized. Their coordination properties were studied in dinuclear Ag(I)-complexes employing (1)H, (77)Se and (1)H-(15)N HETCOR NMR spectroscopy as well as X-ray diffraction crystallography. In solution, a single ligand can accommodate two silver atoms by coordination to nitrogen and sulfur or selenium. The investigations in the solid state revealed the presence of a pentacoordinated silver atom (NSO(3) and N(3)Se(2) donor sets are influenced by the solvent employed during the crystallization). In the solid state, the Ag(I)-complex with the S,N-ligand 2b forms dimeric structures bridged by the two perchlorate counterions. The analogous Se,N-ligand 2c coordinates to Ag(I) and forms polymeric enantiomerically pure helices, although the crystal is racemic.

A series of S-hydrogen phosphorothioates have been converted to the corresponding S-trifluoromethyl derivatives upon reaction with the electrophilic trifluoromethylation reagent 1 (trifluoromethyl 1,3-dihydro-3,3-dimethyl-1,2-benziodoxole). Relative rate data were obtained by (19)F NMR monitoring of competition experiments and were evaluated by means of the Taft equation. A high positive polar sensitivity factor of 2.55 was found for electron-rich substrates and a negative one of -0.37 for electron-poor ones, implying the involvement of two different rate-determining steps. Furthermore, the reaction was found to be unaffected by steric factors.