Nico Santschi

Electrophilic Trifluoromethylation of S-Hydrogen Phosphorothioates

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.

Synthesis and characterization of novel S,N and Se,N homodimetallic Ag(I)-complexes

Novel C2-symmetric doubly bidentate Se,N and S,N-ligands based on a readily available Trögers 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.

S-Trifluoromethylation of Thiols by Hypervalent Iodine Reagents: A Joint Experimental and Computational Study

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.

Hypervalent iodine-based Trifluoromethylating agents made in Switzerland.

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.

Organofluorine chemistry: A Janus cyclohexane ring

The first synthesis of the all-cis isomer of 1,2,3,4,5,6-hexafluorocyclohexane, a molecule with one hydrocarbon face and one fluorocarbon face, is a tour de force of organofluorine chemistry and opens up new possibilities for molecular design.

Emulating Natural Product Conformation by Cooperative, Non‐Covalent Fluorine Interactions

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(sp3 )-C(sp3 ) bonds. In this study, the replacement of -[CH2 ]- 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.

Single Site Fluorination of the GM4 Ganglioside Epitope Upregulates Oligodendrocyte Differentiation

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 GM4 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.

Mapping Perfluoroalkyl Effects in Togni-Type Reagents by Thermolysis

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 F2n+1 Cn. and each reagent can be characterized by means of a threshold temperature, TIP (n). This parameter TIP (n) not only reflects the stability of the F2n+1 Cn -I bond, but potentially also carries information regarding fundamental properties of the linear perfluoroalkyl chains.

Synthesis of 2-[18F]Fluoro-2-deoxyisosorbide 5-mononitrate and Assessment of Its in vivo Biodistribution as Determined by Dynamic Positron Emission Tomography (PET)

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.