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The gauche conformation of the 1,2-difluoroethane motif is known to involve stabilising hyperconjugative interactions between donor (bonding, σC-H) and acceptor (antibonding, σ*C-F) orbitals. This model rationalises the generic conformational preference of F-Cβ-Cα-X systems (φFCCX ≈ 60°), where X is an electron deficient substituent containing a Period 2 atom. Little is known about the corresponding Period 3 systems, such as sulfur and phosphorus, where multiple oxidation states are possible. Conformational analyses of β-fluorosulfides, -sulfoxides and -sulfones are disclosed here, thus extending the scope of the fluorine gauche effect to the 3rd Period (F-C-C-S(O) n ; φFCCS ≈ 60°). Synergy between experiment and computation has revealed that the gauche effect is only pronounced in structures bearing an electropositive vicinal sulfur atom (S+-O-, SO2).

The bicyclic silicon(I) ring compound Si4{N(SiMe3)Mes}4 (2) was used as starting material in reactions with chalcogens and chalcogen transfer agents at low temperatures. This resulted in the selective formation of new cage compounds. With Me3NO, a silicon oxide with adamantane‐type cage 3 was isolated that represents the first isolated T4 silsesquioxane. Reactions with propylenesulfide and red selenium gave direct access to defect heterocubane‐type cages 4 and 5 with three Si−Si bonds wherein the silicon atoms adopt different low oxidation states of +I and +III. A reaction with elemental tellurium even occurs below room temperature to provide ditelluro−tetrasila−tricyclohexane 6. [ABSTRACT FROM AUTHOR]

The bicyclic silicon(I) ring compound Si4{N(SiMe3)Mes}4 (2) was used as starting material in reactions with chalcogens and chalcogen transfer agents at low temperatures. This resulted in the selective formation of new cage compounds. With Me3NO, a silicon oxide with adamantane‐type cage 3 was isolated that represents the first isolated T4 silsesquioxane. Reactions with propylenesulfide and red selenium gave direct access to defect heterocubane‐type cages 4 and 5 with three Si−Si bonds wherein the silicon atoms adopt different low oxidation states of +I and +III. A reaction with elemental tellurium even occurs below room temperature to provide ditelluro−tetrasila−tricyclohexane 6. [ABSTRACT FROM AUTHOR]

α-D-2'-Deoxyribonucleosides are products of the γ-irradiation of DNA under oxygen-free conditions and are constituents of anomeric DNA. They are not found as natural building blocks of canonical DNA. Reports on their conformational properties are limited. Herein, the single-crystal X-ray structure of α-D-2'-deoxyadenosine (α-dA), C 10 H 13 N 5 O 3 , and its conformational parameters were determined. In the crystalline state, α-dA forms two conformers in the asymmetric unit which are connected by hydrogen bonds. The sugar moiety of each conformer is arranged in a `clamp'-like fashion with respect to the other conformer, forming hydrogen bonds to its nucleobase and sugar residue. For both conformers, a syn conformation of the nucleobase with respect to the sugar moiety was found. This is contrary to the anti conformation usually preferred by α-nucleosides. The sugar conformation of both conformers is C2'-endo, and the 5'-hydroxyl groups are in a +sc orientation, probably due to the hydrogen bonds formed by the conformers. The formation of the supramolecular assembly of α-dA is controlled by hydrogen bonding and stacking interactions, which was verified by a Hirshfeld and curvedness surface analysis. Chains of hydrogen-bonded nucleobases extend parallel to the b direction and are linked to equivalent chains by hydrogen bonds involving the sugar moieties to form a sheet. A comparison of the solid-state structures of the anomeric 2'-deoxyadenosines revealed significant differences of their conformational parameters., (open access.)

The bicyclic silicon(I) ring compound Si 4 {N(SiMe 3 )Mes} 4 (2) was used as starting material in reactions with chalcogens and chalcogen transfer agents at low temperatures. This resulted in the selective formation of new cage compounds. With Me 3 NO, a silicon oxide with adamantane-type cage 3 was isolated that represents the first isolated T 4 silsesquioxane. Reactions with propylenesulfide and red selenium gave direct access to defect heterocubane-type cages 4 and 5 with three Si-Si bonds wherein the silicon atoms adopt different low oxidation states of +I and +III. A reaction with elemental tellurium even occurs below room temperature to provide ditelluro-tetrasila-tricyclohexane 6., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Azoheteroarenes are emerging as powerful alternatives to azobenzene molecular photoswitches. In this study, water-soluble arylazoisoxazole photoswitches are introduced. UV/vis and NMR spectroscopy revealed moderate to very good photostationary states and reversible photoisomerization between the E- and Z-isomers over multiple cycles with minimal photobleaching. Several arylazoisoxazoles form host-guest complexes with β- and γ-cyclodextrin with significant differences in binding constants for each photoisomer as shown by isothermal titration calorimetry and NMR experiments, indicating their potential for photoresponsive host-guest chemistry in water. One carboxylic acid functionalized arylazoisoxazole can act as a hydrogelator, allowing gel properties to be manipulated reversibly with light. The hydrogel was characterized by rheological experiments, atom force microscopy and transmission electron microscopy. These results demonstrate that arylazoisoxazoles can find applications as molecular photoswitches in aqueous media., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Spirocyclic scaffolds play an increasing role in drug discovery as they define a rigid three-dimensional space to increase specific interactions with protein binding sites. Herein, a spirocyclic center was introduced into the lead compound 1 to rigidify its flexible benzylaminoethyl side chain. The key step of the synthesis was the reaction of different α,β-unsaturated amides 6 and 13-16 with methyl acrylate in the presence of TBDMSOTf. DFT calculations explain the mechanism of this transformation as concerted Diels-Alder reaction (functionals B3LYP and TPSS) or double (aza)-Michael addition (functionals PBE and wB97X-D). After separation of the diastereomeric spirocyclic products 8 and 17-20, LiAlH 4 reduction provided the spirocyclic hydroxymethyl piperidines 21a,b-25a,b showing low nanomolar σ 1 affinity ( K i < 100 nM). trans -Configured ligands (a-series) showed higher or equal σ 1 affinity and higher selectivity over σ 2 receptors and GluN2B-NMDA receptors than their cis C-atoms possess favorable pharmacological ( D 7.4 value in a promising range. The high σ 1 affinity ( K i = 3.6 nM) and the low lipophilicity result in the highest lipophilic ligand efficiency for the dispiro compound 23a (LLE = 6.0). The spirocyclic compounds reported herein and in particular the dispiro compound 23a demonstrate that ligands containing a large number of sp 3 C-atoms possess favorable pharmacological ( σ 1 receptor affinity, receptor selectivity) and physicochemical properties (log  D 7.4 value) resulting in promising LLE.

An isostructural series of boron/phosphorus Lewis pairs was systematically investigated. The association constants of the Lewis pairs were determined at variable temperatures, enabling the extraction of thermodynamic parameters. The stabilization of the Lewis adduct increased with increasing size of the dispersion energy donor groups, although the donor and acceptor properties of the Lewis pairs remained largely unchanged. This data was utilized to challenge state-of-the-art quantum chemical methods, which finally led to an enhanced workflow for the determination of thermochemical properties of weakly bound Lewis pairs within an accuracy of 0.6 to 1.0 kcal mol -1 for computed association free energies., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Skeletal ring enlargement is gaining renewed interest in synthetic chemistry and has recently focused on insertion of one or two atoms. Strategies for heterocyclic expansion through small-ring insertion remain elusive, although they would lead to the efficient formation of bicyclic products. Here, we report a photoinduced dearomative ring enlargement of thiophenes by insertion of bicyclo[1.1.0]butanes to produce eight-membered bicyclic rings under mild conditions. The synthetic value, broad functional-group compatibility, and excellent chemo- and regioselectivity were demonstrated by scope evaluation and product derivatization. Experimental and computational studies point toward a photoredox-induced radical pathway.

Intermolecular carboamination of olefins offers a powerful platform for the rapid construction of structurally complex amines from abundant feedstocks. However, these reactions often require transition-metal catalysis, and are mainly limited to 1,2-carboamination. Herein, we report a novel radical relay 1,4-carboimination across two distinct olefins with alkyl carboxylic acid-derived bifunctional oxime esters via energy transfer catalysis. The reaction is highly chemo- and regioselective, and multiple C-C and C-N bonds were formed in a single orchestrated operation. This mild and metal-free method features a remarkably broad substrate scope with excellent tolerance of sensitive functional groups, therefore providing easy access to structurally diverse 1,4-carboiminated products. Moreover, the obtained imines could be easily converted into valuable biologically relevant free γ-amino acids., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Negative allosteric modulators of N-methyl- d-aspartate receptors containing the GluN2B subunit represent promising drug candidates for the treatment of various neurological disorders including stroke, epilepsy, and Parkinson's disease. To increase the bioavailability and GluN2B affinity, the phenol of the potent benzazepine-based inhibitor, WMS-1410 (3), was replaced bioisosterically by a benzoxazolone moiety and the phenylbutyl side chain was conformationally restricted in a phenylcyclohexyl substituent. A four-step, one-pot procedure transformed the oxazolo-benzazepine 7 into the phenylcyclohexyl derivative 11. The same protocol was applied to the methylated analog 12, which unexpectedly led to ring-contracted oxazolo-isoquinolines 18. This rearrangement was explained by the additional methyl moiety in the 8-position inhibiting the formation of the planar intermediate iminium ion with phenylcyclohexanone. The allyl protective group of 11 and 18 was removed with RhCl 3 and HCl to obtain the tricyclic compounds 5 and 19 without substituent at the oxazolone ring. The structures of the rearranged products 18 and 19 were elucidated by X-ray crystal structure analysis. The oxazolo-isoquinoline trans-18 with allyl moiety (K i  = 89 nM) and the oxazolo-benzazepine 5 without substituent at the oxazolone ring (K i  = 114 nM) showed GluN2B affinity in the same range as the lead compound 3. In two-electrode voltage clamp measurements, 5 displayed only weak inhibitory activity., (© 2022 The Authors. Archiv der Pharmazie published by Wiley-VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

β-Amino acids are frequently found as important components in numerous biologically active molecules, drugs and natural products. In particular, they are broadly utilized in the construction of bioactive peptides and peptidomimetics, thanks to their increased metabolic stability. Despite the number of methodologies established for the preparation of β-amino acid derivatives, the majority of these methods require metal-mediated multistep manipulations of prefunctionalized substrates. Here we disclose a metal-free, energy-transfer enabled highly regioselective intermolecular aminocarboxylation reaction for the single-step installation of both amine and ester functionalities into alkenes or (hetero)arenes. A bifunctional oxime oxalate ester was developed to simultaneously generate C-centred ester and N-centred iminyl radicals. This mild method features a remarkably broad substrate scope (up to 140 examples) and excellent tolerance of sensitive functional groups, and substrates that range from the simplest ethylene to complex (hetero)arenes can participate in the reaction, thus offering a general and practical access to β-amino acid derivatives., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

N-Methyl-d-aspartate (NMDA) receptors containing one or two GluN2B subunits play a crucial role in a variety of neurodegenerative diseases, such as Alzheimer's and Huntington's disease. In order to increase selectivity for GluN2B NMDA receptors, the piperidine ring of eliprodil (2) was conformationally restricted by introduction of an ethano bridge across C-2 and C-6 resulting in a tropane scaffold. Benzylidenetropanes 15 and 16 and benzyltropanes 17 and 18 were prepared by nucleophilic opening of enantiomerically pure phenyloxiranes 13 and 14 with racemic secondary amines (Z/E)-11 and diastereomeric mixtures (r/s)-12. The diastereomers were separated by preparative HPLC to obtain enantiomerically pure test compounds 15-18. The absolute and relative configuration of the products were determined by X-ray crystal structure analysis. Benzylidenetropanes 15 and 16 as well as benzyltropanes 17 and 18 display very high GluN2B affinity in receptor binding studies. Benzylidinetropanes with the phenyl moiety oriented towards C-5 of the tropane system showed higher GluN2B affinity than their analogs with the phenyl moiety oriented towards C-1. In benzyltropanes endo-configured stereoisomers exhibit higher GluN2B affinity than exo-configured diastereomers. Unfortunately, tropanes 15-18 show also high σ 1 and σ 2 affinity with the same trends for the stereoisomers as for GluN2B affinity. The high-affinity GluN2B ligand (R,r)-17b was able to inhibit the ion flux in two-electrode voltage clamp experiments using GluN1a/GluN2B expressing oocytes., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

8-Furylimidazolo-2'-deoxycytidine ( fur ImidC), C 14 H 14 N 4 O 5 , is a fluorescent analogue of 2'-deoxycytidine, also displaying the same recognition face. As a constituent of DNA, fur ImidC forms extraordinarily strong silver-mediated self-pairs. Crystal structure determination revealed that fur ImidC adopts two types of disordered residues: the sugar unit and the furyl moiety. The disorder of the sugar residue amounts to an 87:13 split. The disorder of the furyl ring results from axial chirality at the C8-C2'' bond connecting the nucleobase to the heterocycle. The two atropisomers are present in unequal proportions [occupancies of 0.69 (2) and 0.31 (2)], and the nucleobase and the furyl moiety are coplanar. Considering the atomic sites with predominant occupancy, an anti conformation with χ = - 147.2 (7)° was found at the glycosylic bond and the 2'-deoxyribosyl moiety shows a C2'-endo (S, 2 T 1 ) conformation, with P = 160.0°. A 1 H NMR-based conformational analysis of the furanose puckering revealed that the S conformation predominates also in solution. In the solid state, two neighbouring fur ImidC molecules are arranged in a head-to-tail fashion, but with a notable tilt of the molecules with respect to each other. Consequently, one N-H...N hydrogen bond is found for neighbouring molecules within one layer, while a second N-H...N hydrogen bond is formed to a molecule of an adjacent layer. In addition, hydrogen bonding is observed between the nucleobase and the sugar residue. A Hirshfeld surface analysis was performed to visualize the intermolecular interactions observed in the X-ray study. In addition, the fluorescence spectra of fur ImidC were measured in solvents of different polarity and viscosity. fur ImidC responds to microenvironmental changes (polarity and viscosity), which is explained by a hindered rotation of the furyl residue in solvents of high viscosity., (open access.)

Following the concept of conformational restriction to obtain high affinity σ 1 ligands, the piperidine ring of eliprodil was replaced by the bicyclic tropane system and an exocyclic double bond was introduced. The envisaged benzylidenetropanes 9 were prepared by conversion of tropanone 10 into the racemic mixture of (Z)-14 and (E)-14. Reaction of racemate (Z)-14/(E)-14 with enantiomerically pure (R)- or (S)-configured 2-phenyloxirane provided mixtures of diastereomeric β-aminoalcohols (R,Z)-9 and (R,E)-9 as well as (S,Z)-9 and (S,E)-9, which were separated by chiral HPLC, respectively. X-ray crystal structure analysis of (S,Z)-9 allowed the unequivocal assignment of the configuration of all four stereoisomers. In receptor binding studies with radioligands, (R,E)-9 and (S,Z)-9 showed subnanomolar σ 1 affinity with eudismic ratios of 8.3 and 40. In both compounds the 4-fluorophenyl moiety is oriented towards (S)-configured C-5 of the tropane system. Both compounds display high selectivity for the σ 1 receptor over the σ 2 subtype but moderate selectivity over GluN2B NMDA receptors. In vivo, (R,E)-9 (K i (σ 1 ) = 0.80 nM) showed high antiallodynic activity in the capsaicin assay. The effect of (R,E)-9 could be reversed by pre-administration of the σ 1 agonist PRE-084 confirming the σ 1 antagonistic activity of (R,E)-9., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Novel complexes of type [Cu(N-N)(dmtp) 2 (OH 2 )](ClO 4 ) 2 ·dmtp (( 1 ) N-N: 2,2'-bipyridine; ( 2 ) L: 1,10-phenantroline and dmtp: 5,7-dimethyl-1,2,4-triazolo[1,5- a ]pyrimidine) were designed in order to obtain biologically active compounds. Complexes were characterized as mononuclear species that crystallized in the space group P-1 of the triclinic system with a square pyramidal geometry around the copper (II). In addition to the antiproliferative effect on murine melanoma B16 cells, complex ( 1 ) exhibited low toxicity on normal BJ cells and did not affect membrane integrity. Complex ( 2 ) proved to be a more potent antimicrobial in comparison with ( 1 ), but both compounds were more active in comparison with dmtp-both against planktonic cells and biofilms. A stronger antimicrobial and antibiofilm effect was noticed against the Gram-positive strains, including methicillin-resistant Staphylococcus aureus (MRSA). Both electron paramagnetic resonance (EPR) and Saccharomyces cerevisiae studies indicated that the complexes were scavengers rather than reactive oxygen species promoters. Their DNA intercalating capacity was evidenced by modifications in both absorption and fluorescence spectra. Furthermore, both complexes exhibited nuclease-like activity, which increased in the presence of hydrogen peroxide.

Direct enantioselective hydrogenation of unsaturated compounds to generate chiral three-dimensional motifs is one of the most straightforward and important approaches in synthetic chemistry. We realized the Ru(II)-NHC-catalyzed asymmetric hydrogenation of 2-quinolones under mild reaction conditions. Alkyl-, aryl- and halogen-substituted optically active dihydro-2-quinolones were obtained in high yields with moderate to excellent enantioselectivities. The reaction provides an efficient and atom-economic pathway to construct simple chiral 3,4-dihydro-2-quinolones. The desired products could be further reduced to tetrahydroquinolines and octahydroquinolones., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The development of organic materials with high solid-state luminescence efficiency is highly desirable because of their fundamental importance and applicability in optoelectronics. Herein, a rapid construction of novel BF 2 complexes with N,O-bidentate ligands by using Cu(BF 4 ) 2 •6H 2 O as a catalyst and BF 2 source is disclosed, which avoids the need for pre-composing the N,O-bidentate ligands and features a broad substrate scope and a high tolerance level for sensitive functional groups. Moreover, molecular oxygen is employed as the terminal oxidant in this transformation. A library of 36 compounds as a new class of BF 2 complexes with remarkable photophysical properties is delivered in good to excellent yields, showing a substituent-dependency on the photophysical properties, derived from the π-π* character of the photoexcited state. In addition, aggregation-induced emission (AIE) is observed and quantified for the brightest exemplars. The excited state properties are fully investigated in solids and in THF/H 2 O mixtures. Hence, a new series of photofunctional materials with variable photophysical properties is reported, with potential applications for sensing, bioimaging, and optoelectronics., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

β-2'-Deoxyribonucleosides are the constituents of nucleic acids, whereas their anomeric α-analogues are rarely found in nature. Moreover, not much information is available on the structural and conformational parameters of α-2'-deoxyribonucleosides. This study reports on the single-crystal X-ray structure of α-2'-deoxycytidine, C 9 H 13 N 3 O 4 (1), and the conformational parameters characterizing 1 were determined. The conformation at the glycosylic bond is anti, with χ = 173.4 (2)°, and the sugar residue adopts an almost symmetrical C2'-endo-C3'-exo twist ( 2 3 H NMR spectrum, indicating a hindered rotation around the C4-N4 bond and a relatively short C-N bond in the solid state. Crystal packing is controlled by N-H...O and O-H...O contacts between the nucleobase and sugar moieties. Moreover, two weak C-H...N contacts (C1'-H1' and C3'-H3'A) are observed. A Hirshfeld surface analysis was carried out and the results support the intermolecular interactions observed by the X-ray analysis.1 H NMR spectrum, indicating a hindered rotation around the C4-N4 bond and a relatively short C-N bond in the solid state. Crystal packing is controlled by N-H...O and O-H...O contacts between the nucleobase and sugar moieties. Moreover, two weak C-H...N contacts (C1'-H1' and C3'-H3'A) are observed. A Hirshfeld surface analysis was carried out and the results support the intermolecular interactions observed by the X-ray analysis., (open access.)

Dearomative cycloaddition reactions represent an ideal means of converting flat arenes into three-dimensional architectures of increasing interest in medicinal chemistry. Quinolines, isoquinolines, and quinazolines, despite containing latent diene and alkene subunits, are scarcely applied in cycloaddition reactions because of the inherent low reactivity of aromatic systems and selectivity challenges. Here, we disclose an energy transfer-mediated, highly regio- and diastereoselective intermolecular [4 + 2] dearomative cycloaddition reaction of these bicyclic azaarenes with a plethora of electronically diverse alkenes. This approach bypasses the general reactivity and selectivity issues, thereby providing various bridged polycycles that previously have been inaccessible or required elaborate synthetic efforts. Computational studies with density functional theory elucidate the mechanism and origins of the observed regio- and diastereoselectivities., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)