Hetero-Diels-Alder Reactions of In Situ-Generated Azoalkenes with Thioketones; Experimental and Theoretical Studies.

The hetero-Diels-Alder reactions of in situ-generated azoalkenes with thioketones were shown to offer a straightforward method for an efficient and regioselective synthesis of scarcely known N-substituted 1,3,4-thiadiazine derivatives. The scope of the method was fairly broad, allowing the use of a series of aryl-, ferrocenyl-, and alkyl-substituted thioketones. However, in the case of N-tosyl-substituted cycloadducts derived from 1-thioxo-2,2,4,4-tetramethylcyclobutan-3-one and the structurally analogous 1,3-dithione, a more complicated pathway was observed. By elimination of toluene sulfinic acid, the initially formed cycloadducts afforded 2H-1,3,4-thiadiazines as final products. Advanced DFT calculations revealed that the observed high regioselectivity was due to kinetic reaction control and that the (4 + 2)-cycloadditions of sterically less unhindered thiones occurred via highly unsymmetric transition states with shorter C..S-distances (2.27-2.58 Å) and longer N..C-distances (3.02-3.57 Å). In the extreme case of the sterically very hindered 2,2,4,4-tetramethylcyclobutan-1,3-dione-derived thioketones, a zwitterionic intermediate with a fully formed C‒S bond was detected, which underwent ring closure to the 1,3,4-thiadiazine derivative in a second step. For the hypothetical formation of the regioisomeric 1,2,3-thiadiazine derivatives, the DFT calculations proposed more symmetric transition states with considerably higher energies.

Thyrotropin Receptor: Allosteric Modulators Illuminate Intramolecular Signaling Mechanisms at the Interface of Ecto- and Transmembrane Domain.

The large TSH-bound ectodomain of the thyrotropin receptor (TSHR) activates the transmembrane domain (TMD) indirectly via an internal agonist (IA). The ectodomain/TMD interface consists of a converging helix, a Cys-Cys-bridge-linked IA, and extracellular loops (ECL). To investigate the intramolecular course of molecular activation, especially details of the indirect activation, we narrowed down allosteric inhibition sites of negative allosteric modulator (NAM) by mutagenesis, homology modeling, and competition studies with positive allosteric modulator (PAM). From the inhibitory effects of NAM S37a on: 1) chimeras with swapped ectodomain, 2) stepwise N-terminal truncations, 3) distinct constitutively active mutations distributed across the hinge region and ECL, but not across the TMD, we conclude that S37a binds at the ectodomain/TMD interface, between the converging helix, ECL1, and the IA. This is also supported by the noncompetitive inhibition of PAM-C2-activation by S37a in the TSHR-TMD construct lacking the ectodomain. Mutagenesis studies on the IA and ECL were guided by our refined model of the ectodomain/TMD interface and indicate an interaction with the TSHR-specific residues E404 (preceding IA) and H478 (ECL1). At this new allosteric interaction site, NAM S37a blocks both TSH- and PAM-induced activation of the TSHR. Our refined models, mutations, and new allosteric binding pocket helped us to gain more detailed insights into the intramolecular course of TSHR activation at the ectodomain/TMD interface, including the delocalization of the converging helix and rearrangement of the conformation of IA. These changes are embedded between the ECL and cooperatively trigger active conformations of TMD. SIGNIFICANCE STATEMENT: The intramolecular activation mechanisms of the TSHR appear to be distinct from those of other G protein-coupled receptors, as the TSHR has a uniquely large N-terminal ectodomain that includes the hormone binding site and an internal agonist sequence. We present new molecular and structural insights into the interface between ectodomain and transmembrane domain in the TSHR, as well as the transfer of activation to the transmembrane domain. This knowledge is critical for understanding activation or inhibition of the receptor by allosteric ligands. We have identified a new allosteric antagonist binding pocket that is located exactly at this interface and possesses specific features that may allow the generation of potent highly TSHR-selective drugs, of potential value for the treatment of Graves' orbitopathy.

Naphthocage: A Flexible yet Extremely Strong Binder for Singly Charged Organic Cations.

We report a quite flexible naphthol-based cage (so-called "naphthocage") which adopts a self-inclusion conformation in its free state and is able to bind singly charged organic cations extremely strongly ( Ka > 107 M-1). Ion-selective electrodes prepared with this naphthocage show a super-Nernstian response to acetylcholine. In addition, the highly stable complex (1010 M-1) between ferrocenium and the naphthocage can be switched electrochemically, which lays a basis for its application in stimuli-responsive materials.

Corannulenes with Electron-Withdrawing Substituents: Synthetic Approaches and Resulting Structural and Electronic Properties.

Corannulene is a multifaceted polyaromatic compound. It has many interesting properties; for example, it has a bowl-shaped molecular structure that, in addition, undergoes a dynamic inversion process. It has attracted much attention within the last decades. This is not only due to its structural properties but also its electronic properties and its various potential applications to materials chemistry. Here, synthetic approaches towards corannulene derivatives with electron-withdrawing substituents are summarized. This includes both selective and unselective methods. Further, the electrochemical properties, that is, the reduction potentials, are analyzed and compared. As a main conclusion, one can state that the electron affinity depends roughly linearly on the number of substituents. Finally, the structural behavior of the substituted buckybowls in the solid state is highlighted. This also allows a general statement about the influence of the electronic and steric nature of substituents on the molecular structures and the solid-state packing of the corannulene derivatives.

Pyridyl-Functionalized 1-Phosphabarrelene: Synthesis, Coordination Chemistry and Photochemical di-π-Methane Rearrangement.

The [4+2] cycloaddition of 2-(2'-pyridyl)-4,6-diphenyl-λ3 -phosphinine with the highly reactive dienophile hexafluoro-2-butyne has been studied and the first pyridyl-functionalized 1-phosphabarrelene was obtained and structurally characterized. Although monodentate CF3 -1-phosphabarrelenes show only a poor coordination ability, the chelating nature of the novel P,N-hybrid ligand gives access to various transition-metal complexes. Upon irradiation with UV light, the pyridyl-functionalized 1-phosphabarrelene undergoes a rather selective di-π-methane rearrangement in the coordination sphere of the metal center, leading to the formation of a complex based on a hitherto unknown pyridyl-functionalized 5-phosphasemibullvalene derivative. DFT calculations provide first insights into the mechanism of this reaction.

Microwave-Assisted Synthesis of Mono- and Disubstituted 4-Hydroxyacetophenone Derivatives via Mannich Reaction: Synthesis, XRD and HS-Analysis.

An efficient microwave-assisted one-step synthetic route toward Mannich bases is developed from 4-hydroxyacetophenone and different secondary amines in quantitative yields, via a regioselective substitution reaction. The reaction takes a short time and is non-catalyzed and reproducible on a gram scale. The environmentally benign methodology provides a novel alternative, to the conventional methodologies, for the synthesis of mono- and disubstituted Mannich bases of 4-hydroxyacetophenone. All compounds were well-characterized by FT-IR, ¹H NMR, 13C NMR, and mass spectrometry. The structures of 1-{4-hydroxy-3-[(morpholin-4-yl)methyl]phenyl}ethan-1-one (2a) and 1-{4-hydroxy-3-[(pyrrolidin-1-yl)methyl]phenyl}ethan-1-one (3a) were determined by single crystal X-ray crystallography. Compound 2a and 3a crystallize in monoclinic, P21/n, and orthorhombic, Pbca, respectively. The most characteristic features of the molecular structure of 2a is that the morpholine fragment adopts a chair conformation with strong intramolecular hydrogen bonding. Compound 3a exhibits intermolecular hydrogen bonding, too. Furthermore, the computed Hirshfeld surface analysis confirms H-bonds and π⁻π stack interactions obtained by XRD packing analyses.

Dienamine-Induced Divinylcyclopropane-Cycloheptadiene Rearrangements.

Sigmatropic rearrangements constitute an important group of pericyclic reactions. In contrast to cycloaddition reactions, examples of catalytic variants of electrocyclic reactions and sigmatropic rearrangements are still scarce in the chemical literature. Herein, we report the first organocatalytic Cope rearrangement of in situ-generated divinylcyclopropanes. The reactive motif was generated by condensation of 4-(2-vinylcyclopropyl)but-2-enal derivatives with a secondary amine catalyst to form a transient dienamine. The cycloheptadiene products could be obtained in high yield and excellent diastereoselectivity. Importantly, the reaction was demonstrated to be stereospecific, proceeding under mild conditions, while exhibiting broad functional group tolerance.

Synthesis of Enantioenriched Bromohydrins via Divergent Reactions of Racemic Intermediates from Anchimeric Oxygen Borrowing.

We report a chiral phosphoric acid catalyzed bromocyclization/regiodivergent reaction of racemic intermediates sequence, which is enabled by anchimeric oxygen borrowing. Different types of alkenes are applicable, and both enantiomers of the bromohydrin products were obtained in generally excellent yields and enantioselectivities. In addition, an example of enantioconvergent synthesis from the two isomeric products is presented.

Organocatalytic C-F Bond Activation with Alanes.

Hydrodefluorination reactions (HDF) of per- and polyfluorinated olefins and arenes by cheap aluminum alkyl hydrides in non-coordinating solvents can be catalyzed by O and N donors. TONs with respect to the organocatalysts of up to 87 have been observed. Depending on substrate and concentration, high selectivities can be achieved. For the prototypical hexafluoropropene, however, low selectivities are observed (E/Z≈2). DFT studies show that the preferred HDF mechanism for this substrate in the presence of donor solvents proceeds from the dimer Me4 Al2 (µ-H)2 ⋅THF by nucleophilic vinylic substitution (SN V)-like transition states with low selectivity and without formation of an intermediate, not via hydrometallation or σ-bond metathesis. In the absence of donor solvents, hydrometallation is preferred but this is associated with inaccessibly high activation barriers at low temperatures. Donor solvents activate the aluminum hydride bond, lower the barrier for HDF significantly, and switch the product preference from Z to E. The exact nature of the donor has only a minimal influence on the selectivity at low concentrations, as the donor is located far away from the active center in the transition states. The mechanism changes at higher donor concentrations and proceeds from Me2 AlH⋅THF via SN V and formation of a stable intermediate, from which elimination is unselective, which results in a loss of selectivity.

Selective Synthesis of Perfluoroalkylated Corannulenes and Investigation of their Structural, Dynamic and Electrochemical Behavior.

Herein we report general methods allowing the synthesis of various perfluoroalkylated corannulenes with a specific substitution pattern. Variable temperature NMR spectroscopic investigations revealed dynamic behavior which was analyzed by line shape analysis. The activation parameters of these dynamic processes were determined. For a tetrasubstituted compound it was possible to observe through space scalar coupling. The packing motifs were elucidated by X-ray crystallography, showing that the substitution pattern as well as the size of substituents strongly influence intermolecular π-stacking. The reduction potentials of the perfluoroalkylated compounds were determined by cyclic voltammetry.

Closing the Gap: Structural Evidence for the Missing Hexabromide Dianion [Br6 ]2.

The formation and experimental characterization of the first hexabromide dianion is presented. This dianion fills the last remaining gap in the series of polybromides from the tribromide [Br3 ]- to the undecabromide [Br11 ]- . The experimental results are compared to quantum-chemical calculations. These calculations predict-based on electrostatic interactions-a T-structure for the hexabromide dianion, while halogen-halogen bonding favors the hockey-stick-like structure experimentally found in the crystal structure. The hexabromide is built of two tribromide moieties, one of which is highly asymmetric. The classification of this unique anion as hexabromide dianion is discussed. The counter ion [C5 H10 N2 Br]+ stabilizes the hexabromide dianion by additional σ-hole interactions. The compound is fully characterized by mass spectrometry, NMR-, IR and single crystal Raman spectroscopies as well as single-crystal X-ray diffraction.

To Anion-π or not to Anion-π: The Case of Anion-Binding to Divalent Fluorinated Pyridines in the Gas Phase.

A series of mono- and divalent fluorinated pyridine derivatives is investigated by electrospray ionization (tandem) mass spectrometry and quantum chemical calculations with respect to their capability to bind anions in the gas phase. The pyridine derivatives differ not only in valency, but also with regard to the degree of fluorination of the pyridine rings, the positions of the fluorine atoms, the rigidity of the spacers connecting the two pyridines in the divalent compounds, and the relative configuration. While the monovalent compounds did not form anion complexes, the divalent analogues exhibit anion binding even to weakly coordinating anions such as tetrafluoroborate. Three different tandem mass spectrometric experiments were applied to rank the gas-phase binding energies: (i) collision-induced dissociation (CID) experiments in a Fourier transform ion-cyclotron-resonance (FTICR) mass spectrometer on two different, simultaneously mass-selected complexes with different receptors, (ii) determination of the collision energy required to fragment 50 % of the mass-selected complexes in an ESI-QToF mass spectrometer, and (iii) CID of heterodimers formed from two different, competing pyridine receptors and indigo carmine, a dianion with two identical binding sites. All three experiments result in consistent binding energy ranking. This ranking reveals surprising features, which are not in agreement with binding through anion-π interactions. Density functional theory (DFT) calculations comparing different potential binding modes provide evidence that the ranking can instead nicely be explained, when C-H⋅⋅⋅anion interactions with the spacers are invoked. These results are supported by gas-phase IR spectroscopy and ion mobility-mass spectrometry (IM-MS) on a selected set of chloride pyridine complexes.

Synthesis of (+)-Vitepyrroloid A and (+)-Vitepyrroloid B by Late-Stage Ni-Catalyzed C(sp2)-C(sp3) Cross-Electrophile Coupling.

A concise and scalable five-step synthesis of vitepyrroloids A and B, two cytotoxic labdane diterpenoid alkaloids from Vitex trifolia, is reported. The presented approach features a Ni-catalyzed cross-electrophile coupling between a (+)-sclareolide-derived alkyl iodide and 3-bromo-2-cyanopyrrole.

Mechanistic Studies on the Organocatalytic α-Chlorination of Aldehydes: The Role and Nature of Off-Cycle Intermediates.

Herein we report the isolation and characterization of aminal intermediates in the organocatalytic α-chlorination of aldehydes. These species are stable covalent ternary adducts of the substrate, the catalyst and the chlorinating reagent. NMR-assisted kinetic studies and isotopic labeling experiments with the isolated intermediate did not support its involvement in downstream stereoselective processes as proposed by Blackmond. By tuning the reactivity of the chlorinating reagent, we were able to suppress the accumulation of rate-limiting off-cycle intermediates. As a result, an efficient and highly enantioselective catalytic system with a broad functional group tolerance was developed.

Synthesis and Structure Revision of Dichrocephones†A and B.

Herein, we report the first enantioselective synthesis of dichrocephones A and B, which are cytotoxic triquinane sesquiterpenes with a dense array of stereogenic centers within a strained polycyclic environment. Key features include the application of a catalytic asymmetric Wittig reaction, followed by stereoselective functionalization of the propellane core into a pentacyclic intermediate. Double reductive ring cleavage yielded the proposed structure of dichrocephone A. Mismatched spectroscopic data for our synthetic material compared to the natural isolate led us to revise the previously proposed configuration based on biosynthetic considerations and NMR calculations. Implementation of these findings culminated in the synthesis of dichrocephones A and B.

Palladium-Catalyzed Directed Halogenation of Bipyridine N-Oxides.

The palladium-catalyzed directed C-H halogenation of bipyridine N-oxides was investigated. Using NCS or NBS (N-chloro- or N-bromosuccinimide) and 5 mol % Pd(OAc)2 in chlorobenzene (0.10 molar) at 110 °C, pyridine-directed functionalization took place and 3-chloro- or 3-bromobipyridine N-oxides were obtained in high yields. The reaction is sensitive to steric hindrance by 4- and 6'-substituents. Only in the latter case, where coordination of palladium by the pyridine is hindered, 3'-halogenation directed by the N-oxide function was observed. The halogenated products were deoxygenated by PCl3 or PBr3.

Direct Experimental Evidence for Halogen-Aryl π†Interactions in Solution from Molecular Torsion Balances.

We dissected halogen-aryl π interactions experimentally using a bicyclic N-arylimide based molecular torsion balances system, which is based on the influence of the non-bonded interaction on the equilibria between folded and unfolded states. Through comparison of balances modulated by higher halogens with fluorine balances, we determined the magnitude of the halogen-aryl π interactions in our unimolecular systems to be larger than -5.0 kJ mol-1 , which is comparable with the magnitude estimated in the biomolecular systems. Our study provides direct experimental evidence of halogen-aryl π interactions in solution, which until now have only been revealed in the solid state and evaluated theoretically by quantum-mechanical calculations.

How a Thermally Unstable Metal Hydrido Complex Can Yield High Catalytic Activity Even at Elevated Temperatures.

Despite their instability in ethereal solvents, organotitanium hydride catalysts are successfully employed in catalysis at moderate to high temperatures (110 °C), even in the presence of alcohols. It is shown computationally (bond dissociation energy (BDE) analysis and energetic profile for regeneration) and experimentally (EPR studies and kinetic studies), with the specific example of hydrodefluorination (HDF), that despite the long standing belief, regeneration of Ti-H bonds from Ti-F bonds using silanes is endergonic. The resulting low concentration of Ti-H species is crucial for the catalytic stability of those systems. The resting state in the catalysis is a Ti-F species. The most promising silanes for regeneration are not the ones that have the strongest Si-F bond, but the ones that show the largest difference in Si-F and Si-H BDEs.