Diastereoselective Synthesis of Sulfoxide-Functionalized N-Heterocyclic Carbene Ruthenium Complexes: An Experimental and Computational Study.

The synthesis of sulfoxide-functionalized NHC ligand precursors were carried out by direct and mild oxidation from corresponding thioether precursors with high selectivity. Using these salts, a series of cationic [Ru(II)(η6-p-cymene)(NHC-SO)Cl]+ complexes were obtained in excellent yields by the classical Ag2O transmetallation route. NMR analyses suggested a chelate structure for the metal complexes, and X-ray diffractometry studies of complexes 4 b, 4 c, 4dBArF and 4 e unambiguously confirmed the preference for the bidentate (κ2-C,S) coordination mode of the NHC-SO ligands. Interestingly, only one diastereomer, in the form of an enantiomeric pair, was observed both in 1H NMR and in the solid state for the complexes. DFT calculations showed a possible intrinsic energy difference between the two pairs of diastereomer. The calculated energy barriers suggested that inversion of the sulfoxide is only plausible from the higher energy diastereomer together with bulky substituents. Inverting the configuration at the Ru center instead shows a lower and accessible activation barrier to provide the most stable diastereomer through thermodynamic control, consistent with the observation of a single species by 1H NMR as a pair of enantiomers. All these complexes catalyse the ß-alkylation of secondary alcohols. Complex 4dPF6 bearing an NHC-functionalised S-Ad group has been further studied with different primary and secondary alcohols as substrates, showing high reactivity and high to moderate ß-ol-selectivities.

2,4,5,7-Tetranitrofluorenone Oximate for the Naked-Eye Detection of H-Bond Donors and the Chiroptical Sensing of Enantiopure Reagents.

Hydrogen bonding greatly influences rates and equilibrium positions of chemical reactions, conformations, and sometimes even stereochemistry. This study reports on tetranitrofluorenone oximate, a novel dye capable of naked-eye detection of hydrogen-bond donating species (HBDs) and of rapid determination of H-bond donation strength by hypsochromic shift monitoring. In addition, the molecule possesses atropisomeric conformations, of M and P configuration, as evidenced in solid and solution state studies by X-ray diffraction and electronic circular dichroism (ECD), respectively. In the latter case, enantiopure bis-thioureas were the most effective HBDs to promote a chiral induction (diastereoselective recognition, Pfeiffer effect); the ECD results being rationalized by time-dependent density functional theory (TDDFT) calculations. Based on these experiments, bis-thioureas were used as chiral reagents in asymmetric 1,3-dipolar cycloadditions of structurally-related nitrones; the ECD sensing of the stereoinduction between bis-thioureas and the oximate serving as an indirect method of selection of the most effective HBD for asymmetric synthesis.

Acetylene Derivatives of Cationic Diazaoxatriangulenes and Diaza [4]Helicenes - Access to Red Emitters and Planar Chiral Stereochemical Traits.

Cationic triangulenes, and related helicenes, constitute a rich class of dyes and fluorophores, usually absorbing and emitting light at low energy, in the orange to red domains. Recently, to broaden the scope of applications, regioselective late-stage functionalizations on these core moieties have been developed. For instance, with the introduction of electron-donating groups (EDGs), important bathochromic shifts are observed pushing absorptions towards or in the near-infrared (NIR) spectral domain while emissive properties disappear essentially completely. Herein, to upset this drawback, acetylene derivatives of cationic diazaoxa triangulenes (DAOTA) and [4]helicenes are prepared (16 examples). Contrary to other EDG-functionalized derivatives, C≡C- functionalized products remain broadly fluorescent, with red-shifted absorptions (Δλabs up to 25 nm) and emissions (Δλem up to 73 nm, ΦPL up to 51 %). Quite interestingly, a general dynamic stereoisomerism phenomenon is evidenced for the compounds derived from achiral DAOTA cores. At low temperature in 1 H NMR spectroscopy (218 K), N-CH2 protons become diastereotopic with chemical shifts differences (Δδ) as high as +1.64 ppm. The signal coalescence occurs around 273 K with a barrier of ∼12 kcal mol-1 . This phenomenon is due to planar chiral conformations (Sp and Rp configurations), induced by the geometry of the alkyl (n-propyl) side-chains next to the acetylenic substituents. Ion pairing studies with Δ-TRISPHAT anion not only confirm the occurrence of the chiral conformations but evidence a moderate but definite asymmetric induction from the chiral anion onto the cations. Finally, DFT calculations offer a valuable insight on the geometries, the corresponding stereodynamics and also on the very large difference in NMR for some of the diastereotopic protons.

Chemo- and Regioselective Multiple C(sp2 )-H Insertions of Malonate Metal Carbenes for Late-Stage Functionalizations of Azahelicenes.

Chiral quinacridines react up to four times, step-by-step, with α-diazomalonates under RuII and RhII catalysis. By selecting the catalyst, [CpRu(CH3 CN)3 ][PF6 ] (Cp=cyclopentadienyl) or Rh2 (oct)4 , chemo and regioselective insertions of derived metal carbenes are achieved in favor of mono- or bis-functionalized malonate derivatives, respectively, (r.r.>49 : 1, up to 77 % yield, 12 examples). This multi-introduction of malonate groups is particularly useful to tune optical and chemical properties such as absorption, emission or Brønsted acidity but also cellular bioimaging. Density-functional theory further elucidates the origin of the carbene insertion selectivity and also showcases the importance of conformations in the optical response.

Anion Transport with Pnictogen Bonds in Direct Comparison with Chalcogen and Halogen Bonds.

In this Communication, we introduce transmembrane anion transport with pnictogen-bonding compounds and compare their characteristics with chalcogen- and halogen-bonding analogues. Tellurium-centered chalcogen bonds are at least as active as antimony-centered pnictogen bonds, whereas iodine-centered halogen bonds are 3 orders of magnitude less active. Irregular voltage-dependent single-channel currents, high gating charges, and efficient dye leakage support for the formation of bulky, membrane-disruptive supramolecular amphiphiles due to "too strong" binding of anions to tris(perfluorophenyl)stibanes. In contrast, the chalcogen-bonding bis(perfluorophenyl)tellanes do not cause leakage and excel as carriers with nanomolar activity, with P(Cl/Na) = 10.4 for anion/cation selectivity and P(Cl/NO3) = 4.5 for anion selectivity. The selectivities are lower with pnictogen-bonding carriers because their membrane-disturbing 3D structure also affects weaker binders ( P(Cl/Na) = 2.1, P(Cl/NO3) = 2.5). Their 2D structure, directionality, hydrophobicity, and support from proximal anion-π interactions are suggested to contribute to the unique power of chalcogen bonds to transport anions across lipid bilayer membranes.

Fluorescent Flipper Probes: Comprehensive Twist Coverage.

To image the membrane tension in living cells, planarizable push-pull probes have been introduced. The first operational probe is built around two dithieno[3,2-b:2',3'-d]thiophenes (DTTs) that are twisted out of co-planarity and polarized with donors and acceptors at either end. In this report, the chemical space available for the twisting of "flipper probes" is assessed comprehensively. The result is, not surprisingly, that every atom matters: Removal of one methyl group in the twist region yields probes that planarize already in solution and are thus less sensitive to membrane tension. Addition of one or more carbons in the same region hinders non-interfering probe alignment along lipid tails and thus partitioning into lipid bilayer membranes as well as mechanosensitivity. However, substitution of one methyl by an isosteric trifluoromethyl group in the twist region, achieved by quite substantial multistep organic synthesis, yields excitation maxima that shift over +100 nm to the red in response to increasing order of the surrounding membrane. This record redshift comes with record changes in fluorescence intensity and lifetime, high push-pull transition dipoles and higher rotational barriers. Supported by distinct dependence on viscosity and twist of the push-pull probes, kinetic competition between dark, fully twisted and bright, fully planarized relaxed excited states emerges as unifying origin of fluorescence quantum yields.

Catalysis with Pnictogen, Chalcogen, and Halogen Bonds.

Halogen- and chalcogen-based σ-hole interactions have recently received increased interest in non-covalent organocatalysis. However, the closely related pnictogen bonds have been neglected. In this study, we introduce conceptually simple, neutral, and monodentate pnictogen-bonding catalysts. Solution and in silico binding studies, together with high catalytic activity in chloride abstraction reactions, yield compelling evidence for operational pnictogen bonds. The depth of the σ holes is easily varied with different substituents. Comparison with homologous halogen- and chalcogen-bonding catalysts shows an increase in activity from main group VII to V and from row 3 to 5 in the periodic table. Pnictogen bonds from antimony thus emerged as by far the best among the elements covered, a finding that provides most intriguing perspectives for future applications in catalysis and beyond.

Palladium-Catalyzed Hydrohalogenation of 1,6-Enynes: Hydrogen Halide Salts and Alkyl Halides as Convenient HX Surrogates.

Difficulties associated with handling H2 and CO in metal-catalyzed processes have led to the development of chemical surrogates to these species. Despite many successful examples using this strategy, the application of convenient hydrogen halide (HX) surrogates in catalysis has lagged behind considerably. We now report the use of ammonium halides as HX surrogates to accomplish a Pd-catalyzed hydrohalogenation of enynes. These safe and practical salts avoid many drawbacks associated with traditional HX sources including toxicity and corrosiveness. Experimental and computational studies support a reaction mechanism involving a crucial E-to-Z vinyl-Pd isomerization and a carbon-halogen bond-forming reductive elimination. Furthermore, rare examples of C(sp3)-Br and -Cl reductive elimination from Pd(II) as well as transfer hydroiodination using 1-iodobutane as an alternate HI surrogate are also presented.

Stereoselective and Enantiospecific Mono- and Bis-C-H Azidation of Tröger Bases: Insight on Bridgehead Iminium Intermediates and Application to Anion-Binding Catalysis.

In the context of Tröger base chemistry, regio- and stereoselective Csp3 -H azidation reactions are reported. Azide functional groups are introduced at either one or the two benzylic positions selectively. Mild conditions and good yields are afforded by the combination of TMSN3 and iodosobenzene PhIO. The process occurs with high enantiospecificity (es 96-99 %) and-interestingly and importantly-via bridgehead iminium intermediates as shown by mechanistic and in-silico studies. Finally, mono- and bistriazole derivatives were prepared in high yields and enantiospecificity by using copper-catalyzed alkyne azide cycloaddition (CuAAC) reactions; some of the products were used as anion-binding organocatalysts for the tritylation of amines and alcohols.

Rhodium-Catalyzed Enantioselective Isomerization of meso-Oxabenzonorbornadienes to 1,2-Naphthalene Oxides.

Herein we describe a rhodium-catalyzed enantioselective isomerization of meso-oxabicyclic alkenes to 1,2-naphthalene oxides. These potentially useful building blocks can be accessed in moderate to excellent yields with impressive enantioselectivities. Additionally, experimental findings supported by preliminary computations suggest that ring-opening reactions of bridgehead disubstituted oxabicyclic alkenes proceed through the intermediacy of these epoxides and may point to a kinetically and thermodynamically favored reductive elimination as the origin for the observed enantioselectivities.

A Highly Effective Ruthenium System for the Catalyzed Dehydrogenative Cyclization of Amine-Boranes to Cyclic Boranes under Mild Conditions.

We recently disclosed a new ruthenium-catalyzed dehydrogenative cyclization process (CDC) of diamine-monoboranes leading to cyclic diaminoboranes. In the present study, the CDC reaction has been successfully extended to a larger number of diamine-monoboranes (4-7) and to one amine-borane alcohol precursor (8). The corresponding NB(H)N- and NB(H)O-containing cyclic diaminoboranes (12-15) and oxazaborolidine (16) were obtained in good to high yields. Multiple substitution patterns on the starting amine-borane substrates were evaluated and the reaction was also performed with chiral substrates. Efforts have been spent to understand the mechanism of the ruthenium CDC process. In addition to a computational approach, a strategy enabling the kinetic discrimination on successive events of the catalytic process leading to the formation of the NB(H)N linkage was performed on the six-carbon chain diamine-monoborane 21 and completed with a (15) N NMR study. The long-life bis-σ-borane ruthenium intermediate 23 possessing a reactive NHMe ending was characterized in situ and proved to catalyze the dehydrogenative cyclization of 1, ascertaining that bis σ-borane ruthenium complexes are key intermediates in the CDC process.

[CpRu]-catalyzed carbene insertions into epoxides: 1,4-dioxene synthesis through S(N)1-like chemistry with retention of configuration.

Rather than lead to the usual deoxygenation pathway, metal carbenes derived from α-diazo-ß-ketoesters undergo three-atom insertions into epoxides using a combination of 1,10-phenanthroline and [CpRu(CH3CN)3][BAr(F)] as the catalyst. Original 1,4-dioxene motifs are obtained as single regio- and stereoisomers. A perfect syn stereochemistry (retention, e.r. up to 97:3) is observed for the ring opening, which behaves as an S(N)1-like transformation.

Assisted Tandem Pd Catalysis Enables Regiodivergent Heck Arylation of Transiently Generated Substituted Enol Ethers.

Two complementary regiodivergent Pd-catalyzed assisted tandem [isomerization/Heck arylation] reactions are reported. They provide access to a broad array of acyclic trisubstituted vinyl ethers starting from readily available alkenyl ethers. In both cases, the isomerization is conducted with a [Pd-H] precatalyst supported by tris-tert-butyl phosphine ligands. When the catalyst is modified by the addition of a chelating bisphosphine ligand (dppp), an organic base (Cy2NMe), sodium acetate, and aryl triflates are used as electrophiles, the α-arylation pathway is promoted preferentially. The ß-arylation pathway is favored for electron-deficient and electron-neutral aryl halides when the catalyst is simply modified by the addition of an excess of an organic base (Et3N) after completion of the isomerization reaction. Electron-rich aryl halides lead to reduced levels of regiocontrol. The moderate stereoselectivity obtained are proposed to reflect the absence of stereocontrol in the isomerization step. Computational analyses suggest that migratory insertion is selectivity-determining for both the arylations. For the ß-selective arylation, an energy decomposition analysis underscored that electronic factors favor α-regioselectivity and steric effects favor ß-regioselectivity. Preliminary investigations show that high levels of stereoselectivity can be achieved for the α-selective arylation by ligand control. Complementarily, reaction conditions for postcatalytic stereo-correction have also been identified for each catalytic system.

Structures of d4 MH3X: a computational study of the influence of the metal and the ligands.

Density functional theory (DFT, PBE0, and range separated DFT, RSH + MP2) and coupled-cluster with single and double and perturbative triple excitations (CCSD(T)) calculations have been used to probe the structural preference of d(4) MH(3)X(q) (M = Ru, Os, Rh(+), Ir(+), and Re(-); X = H, F, CH(3), CF(3), SiH(3), and SiF(3)) and of MX(4) (M = Ru; X = H, F, CH(3), CF(3), SiH(3), and SiF(3)). Landis et al. have shown that complexes in which the metal is sd(3) hybridized have tetrahedral and non-tetrahedral structures with shapes of an umbrella or a 4-legged piano stool. In this article, the influence of the metal and ligands on the energies of the three isomeric structures of d(4) MH(3)X and MX(4) is established and rationalized. Fluoride and alkyl ligands stabilize the tetrahedral relative to non-tetrahedral structures while hydride and silyl ligands stabilize the non-tetrahedral structures. For given ligands and charge, 4d metal favors more the non-tetrahedral structures than 5d metals. A positive charge increases the preference for the non-tetrahedral structures while a negative charge increases the preference for the tetrahedral structure. The factors that determine these energy patterns are discussed by means of a molecular orbital analysis, based on Extended Hückel (EHT) calculations, and by means of Natural Bond Orbital (NBO) analyses of charges and resonance structures (NRT analysis). These analyses show the presence of through-space interactions in the non-tetrahedral structures that can be sufficiently stabilizing, for specific metals and ligands, to stabilize the non-tetrahedral structures relative to the tetrahedral isomer.

Cyclic Thiosulfonates for Thiol-Mediated Uptake: Cascade Exchangers, Transporters, Inhibitors.

Thiol-mediated uptake is emerging as a powerful method to penetrate cells. Cyclic oligochalcogenides (COCs) have been identified as privileged scaffolds to enable and inhibit thiol-mediated uptake because they can act as dynamic covalent cascade exchangers, i.e., every exchange produces a new, covalently tethered exchanger. In this study, our focus is on the essentially unexplored COCs of higher oxidation levels. Quantitative characterization of the underlying dynamic covalent exchange cascades reveals that the initial ring opening of cyclic thiosulfonates (CTOs) proceeds at a high speed even at a low pH. The released sulfinates exchange with disulfides in aprotic but much less in protic environments. Hydrophobic domains were thus introduced to direct CTOs into hydrophobic pockets to enhance their reactivity. Equipped with such directing groups, fluorescently labeled CTOs entered the cytosol of living cells more efficiently than the popular asparagusic acid. Added as competitive agents, CTOs inhibit the uptake of various COC transporters and SARS-CoV-2 lentivectors. Orthogonal trends found with different transporters support the existence of multiple cellular partners to account for the diverse expressions of thiol-mediated uptake. Dominant self-inhibition and high activity of dimers imply selective and synergistic exchange in hydrophobic pockets as distinguishing characteristics of thiol-mediated uptake with CTOs. The best CTO dimers with hydrophobic directing groups inhibit the cellular entry of SARS-CoV-2 lentivectors with an IC50 significantly lower than the previous best CTO, below the 10 µM threshold and better than ebselen. Taken together, these results identify CTOs as an intriguing motif for use in cytosolic delivery, as inhibitors of lentivector entry, and for the evolution of dynamic covalent networks in the broadest sense, with reactivity-based selectivity of cascade exchange emerging as a distinguishing characteristic that deserves further attention.

Pnictogen-Centered Cascade Exchangers for Thiol-Mediated Uptake: As(III)-, Sb(III)-, and Bi(III)-Expanded Cyclic Disulfides as Inhibitors of Cytosolic Delivery and Viral Entry.

Dynamic covalent exchange cascades with cellular thiols are of interest to deliver substrates to the cytosol and to inhibit the entry of viruses. The best transporters and inhibitors known today are cyclic cascade exchangers (CAXs), producing a new exchanger with every exchange, mostly cyclic oligochalcogenides, particularly disulfides. The objective of this study was to expand the dynamic covalent chalcogen exchange cascades in thiol-mediated uptake by inserting pnictogen relays. A family of pnictogen-expanded cyclic disulfides covering As(III), Sb(III), and Bi(III) is introduced. Their ability to inhibit thiol-mediated cytosolic delivery is explored with fluorescently labeled CAXs as transporters. The promise of inhibiting viral entry is assessed with SARS-CoV-2 lentiviral vectors. Oxygen-bridged seven-membered 1,3,2-dithiabismepane rings are identified as privileged scaffolds. The same holds for six-membered 1,3,2-dithiarsinane rings made from asparagusic acid and para-aminophenylarsine oxide, which are inactive or toxic when used alone. These chemically complementary Bi(III) and As(III) cascade exchangers inhibit both thiol-mediated cytosolic delivery and SARS-CoV-2 lentivector uptake at concentrations of 10 µM or lower. Crystal structures, computational models, and exchange kinetics support that lentivector entry inhibition of the contracted dithiarsinane and the expanded dithiabismepane rings coincides with exchange cascades that occur without the release of the pnictogen relay and benefit from noncovalent pnictogen bonds. The identified leads open perspectives regarding drug delivery as well as unorthodox approaches toward dynamic covalent inhibition of cellular entry.

Enabling Cyclization Strategies through Carbonyl-Ylide-Mediated Synthesis of Malonate Enol Ethers.

Malonate enol ethers are afforded in one step by condensation of cyclic ketones with α-diazomalonates under [CpRu(CH3CN)3][BArF] catalysis. The dual reactivity of these 2-vinyloxymalonates can be used to expand the classical range of cyclizations derived from carbonyl ylide intermediates.

Regiodivergent synthesis of pyrazino-indolines vs. triazocines via α-imino carbenes addition to imidazolidines.

Hexahydropyrazinoindoles were prepared in a single step from N-sulfonyl triazoles and imidazolidines. Under dirhodium catalysis, α-imino carbenes were generated and formed nitrogen ylide intermediates that, after subsequent aminal opening, afforded the pyrazinoindoles predominantly via formal [1,2]-Stevens and tandem Friedel-Crafts cyclizations. Of mechanistic importance, a regiodivergent reactivity was engineered through the use of a specific unsymmetrically substituted imidazolidine that promoted the exclusive formation of 8-membered ring 1,3,6-triazocines. Based on DFT calculations, an original Curtin-Hammett-like situation was demonstrated for the mechanism. Further derivatizations led to functionalized tetrahydropyrazinoindoles in high yields.

Synthesis, characterization, catalytic and biological application of half-sandwich ruthenium complexes bearing hemilabile (κ2-C,S)-thioether-functionalised NHC ligands.

A series of cationic Ru(ii)(η6-p-cymene) complexes with thioether-functionalised N-heterocyclic carbene ligands have been prepared and fully characterized. Steric and electronic influence of the R thioether substituent on the coordination of the sulfur atom was investigated. The molecular structure of three of them has been determined by means of X-ray diffractrometry and confirmed the bidentate (κ2-C,S) coordination mode of the ligand. Interestingly, only a single diastereomer, as an enantiomeric couple, was observed in the solid state for complexes 1c, 1i and 1j. DFT calculations established a low energy inversion barrier between the two diastereomers through a sulfur pyramidal inversion pathway with R donating group while a dissociative/associative mechanism is more likely with R substituents that contain electron withdrawing group, thus suggesting that the only species observed by the 1H-NMR correspond to an average resonance position of a fluxional mixtures of isomers. All these complexes were found to catalyse the oxydant-free double dehydrogenation of primary amine into nitrile. Ru complex bearing NHC-functionalised S-tBu group was further investigated in a wide range of amines and was found more selective for alkyl amine substrates than for benzylamine derivatives. Finally, preliminary results of the biological effects on various human cancer cells of four selected Ru complexes are reported.

Pnictogen-bonding catalysis: brevetoxin-type polyether cyclizations.

Pnictogen-bond donors are attractive for use in catalysis because of deep σ holes, high multivalency, rich hypervalency, and chiral binding pockets. We here report natural product inspired epoxide-opening polyether cyclizations catalyzed by fluoroarylated Sb(v) > Sb(iii) > Bi > Sn > Ge. The distinctive characteristic found for pnictogen-bonding catalysis is the breaking of the Baldwin rules, that is selective endo cyclization into the trans-fused ladder oligomers known from the brevetoxins. Moreover, tris(3,4,5-trifluorophenyl)stibines and their hypervalent stiborane catecholates afford different anti-Baldwin stereoselectivity. Lewis (SbCl3), Brønsted (AcOH) and π acids fail to provide similar access to these forbidden rings. Like hydrogen-bonding catalysis differs from Brønsted acid catalysis, pnictogen-bonding catalysis thus emerges as the supramolecular counterpart of covalent Lewis acid catalysis.