Enantioselective Chemical Probe for Chikungunya nsP2 Helicase with Antialphaviral Activity.

Chikungunya virus (CHIKV) replication relies on the multifunctional nsP2 protein, making it an attractive target for antiviral drug discovery. Here, we report the resolution of oxaspiropiperidine , a first-in-class inhibitor of the CHIKV nsP2 RNA helicase (nsP2hel), into its constitutive enantiomers and characterization of their antiviral activity. The enantiomer ()- exhibited potent inhibition of viral replication, nsP2hel ATPase activity, and dsRNA unwinding, while the ()- enantiomer was >100-fold less active.

Correction: Pronounced electronic modulation of geometrically-regulated metalloenediyne cyclization.

[This corrects the article DOI: 10.1039/D4SC05396F.].

Metallo-azapeptides: Controlled Metal Chelation to Peptide Backbone Nitrogen.

We present the first approach to controlled metal chelation of peptide backbones, where the anchoring site is an aza-amino acid nitrogen and the directionality of chelation events is dictated by the acidity of neighboring NHs. Selective backbone chelation precludes the need for metal-binding side chains and/or free - or -termini in peptides. We show that the presence and location of an aza-amino acid impact complex formation and report the first X-ray crystal structures of azapeptides bound to palladium and nickel.

Regulating Access to Active Sites via Hydrogen Bonding and Cation-Dipole Interactions: A Dual Cofactor Approach to Switchable Catalysis.

Hydrogen bonding networks are ubiquitous in biological systems and play a key role in controlling the conformational dynamics and allosteric interactions of enzymes. Yet in small organometallic catalysts, hydrogen bonding rarely controls ligand binding to the metal center. In this work, a hydrogen bonding network within a well-defined organometallic catalyst works in concert with cation-dipole interactions to gate substrate access to the active site.

Mechanism-Guided Kinetic Analysis of Electrocatalytic Proton Reduction Mediated by a Cobalt Catalyst Bearing a Pendant Basic Site.

Cobalt polypyridyl complexes stand out as efficient catalysts for electrochemical proton reduction, but investigations into their operating mechanisms, with broad-reaching implications in catalyst design, have been limited. Herein, we investigate the catalytic activity of a cobalt(II) polypyridyl complex bearing a pendant pyridyl base with a series of organic acids spanning 20 p units in acetonitrile. Structural analysis, as well as electrochemical studies, reveals that the Co(III) hydride intermediate is formed through reduction of the Co(II) catalyst followed by direct metal protonation in the initial EC step despite the presence of the pendant base, which is commonly thought of as a more kinetically accessible protonation site.

Synthesis and bonding analysis of pentagonal bipyramidal rhenium carboxamide oxo complexes.

Seven-coordinate rhenium oxo complexes supported by a tetradentate bipyridine carboxamide/carboxamidate ligand are reported. The neutral dicarboxamide Hbpy-da ligand initially coordinates in an L (ONNO) fashion to an octahedral rhenium oxo precursor, yielding a seven-coordinate rhenium oxo complex. Subsequent deprotonation generates a new oxo complex featuring the dianionic (LX) carboxamidate (NNNN) form of the ligand.

Visible light induced formation of a tungsten hydride complex.

When irradiated with blue light in the presence of a Lewis base (L), [CpW(CO)] undergoes metal-metal bond cleavage followed by a disproportionation reaction to form [CpW(CO)L] and [CpW(CO)]. Here, we show that in the presence of pyridinium tetrafluoroborate, [CpW(CO)] reacts further to form a metal hydride complex CpW(CO)H. The rection was monitored through photo H NMR spectroscopy experiments and the mechanism of light-driven hydride formation was investigated by determining quantum yields of formation.

Oxidative Addition of a Phosphinite P-O Bond at Nickel.

Oxidative addition is an essential elementary reaction in organometallic chemistry and catalysis. While a diverse array of oxidative addition reactions has been reported to date, examples of P-O bond activation are surprisingly rare. Herein, we report the ligand-templated oxidative addition of a phosphinite P-O bond in the diphosphinito aniline compound HN(2-OPPr-3,5-Bu-CH) [H(PONO)] at Ni to form (PONO)Ni(HPPr) after proton rearrangement.

Isocyanide Ligands Promote Ligand-to-Metal Charge Transfer Excited States in a Rhenium(II) Complex.

A metal-to-ligand charge transfer with mixed intraligand character is observed for the rhenium hexakisarylisocyanide complex [Re(CNAr)]PF (CNAr = 2,6-dimethylphenylisocyanide, λ = 300 nm). Upon oxidation to [Re(CNAr)](PF), the dominant low energy optical transition is a ligand-to-metal charge transfer (LMCT) mixed with intraligand transitions (λ = 650 nm). TD-DFT was used to identify the participating ligand-based orbitals in the LMCT transition, revealing that the majority of the donor orbital is based on the aryl ring (85%) as opposed to the CN bond (14%).

Doubly stereoconvergent crystallization enabled by asymmetric catalysis.

Synthetic methods that enable simultaneous control over multiple stereogenic centers are desirable for the efficient preparation of pharmaceutical compounds. Herein, we report the discovery and development of a catalyst-mediated asymmetric Michael addition/crystallization-induced diastereomer transformation of broad scope. The sequence controls three stereogenic centers, two of which are stereochemically labile.

A Redox-Active Tetrazine-Based Pincer Ligand for the Reduction of N-Oxyanions Using a Redox-Inert Metal.

The reaction chemistry of the bis-tetrazinyl pyridine ligand (btzp) towards nitrogen oxyanions coordinated to zinc is studied in order to explore the reduction of the NO substrates with a redox-active ligand in the absence of redox activity at the metal. Following syntheses and characterization of (btzp)ZnX for X=Cl, NO and NO , featuring O-Zn linkage of both nitrogen oxyanions, it is shown that a silylating agent selectively delivers silyl substituents to tetrazine nitrogens, without reductive deoxygenation of NO . A new synthesis of the highly hydrogenated H btzp, containing two dihydrotetrazine reductants is described as is the synthesis and characterization of (H btzp)ZnX for X=Cl and NO , both of which show considerable hydrogen bonding potential of the dihydrotetrazine ring NH groups.

Redox-Induced Structural Reorganization Dictates Kinetics of Cobalt(III) Hydride Formation via Proton-Coupled Electron Transfer.

Two-electron, one-proton reactions of a family of [CoCp(dxpe)(NCCH)] complexes (Cp = cyclopentadienyl, dxpe = 1,2-bis(di(aryl/alkyl)phosphino)ethane) form the corresponding hydride species [HCoCp(dxpe)] (dxpe = dppe (1,2-bis(diphenylphosphino)ethane), depe (1,2-bis(diethylphosphino)ethane), and dcpe (1,2-bis(dicyclohexylphosphino)ethane)) through a stepwise proton-coupled electron transfer process. For three [CoCp(dxpe)(NCCH)] complexes, peak shift analysis was employed to quantify apparent proton transfer rate constants from cyclic voltammograms recorded with acids ranging 22 p units. The apparent proton transfer rate constants correlate with the strength of the proton source for weak acids, but these apparent proton transfer rate constants curiously plateau () as the reaction becomes increasingly exergonic.

Polarity-Tolerant Chloride Binding in Foldamer Capsules by Programmed Solvent-Exclusion.

Persistent anion binding in a wide range of solution environments is a key challenge that continues to motivate and demand new strategies in synthetic receptor design. Though strong binding in low-polarity solvents has become routine, our ability to maintain high affinities in high-polarity solvents has not yet reached the standard set by nature. Anions are bound and transported regularly in aqueous environments by proteins that use secondary and tertiary structure to isolate anion binding sites from water.

Selecting Double Bond Positions with a Single Cation-Responsive Iridium Olefin Isomerization Catalyst.

The catalytic transposition of double bonds holds promise as an ideal route to alkenes of value as fragrances, commodity chemicals, and pharmaceuticals; yet, selective access to specific isomers is a challenge, normally requiring independent development of different catalysts for different products. In this work, a single cation-responsive iridium catalyst selectively produces either of two different internal alkene isomers. In the absence of salts, a single positional isomerization of 1-butene derivatives furnishes 2-alkenes with exceptional regioselectivity and stereoselectivity.

Stabilization of the Dinitrogen Analogue, Phosphorus Nitride.

The N analogue phosphorus nitride (PN) was the first phosphorus-containing compound to be detected in the interstellar medium; however, this thermodynamically unstable compound has a fleeting existence on Earth. Here, we show that reductive coupling of iron(IV) nitride and molybdenum(VI) phosphide complexes assembles PN as a bridging ligand in a structurally characterized bimetallic complex. Reaction with C≡N Bu releases the mononuclear complex [(NN)Mo-PN], NN = [(MeSiNCHCH)N]), which undergoes light-induced linkage isomerization to provide [(NN)Mo-NP], as revealed by photocrystallography.

Two-State Reactivity in Iron-Catalyzed Alkene Isomerization Confers σ-Base Resistance.

A low-coordinate, high spin ( = 3/2) organometallic iron(I) complex is a catalyst for the isomerization of alkenes. A combination of experimental and computational mechanistic studies supports a mechanism in which alkene isomerization occurs by the allyl mechanism. Importantly, while substrate binding occurs on the = 3/2 surface, oxidative addition to an η-allyl intermediate only occurs on the = 1/2 surface.

Nitrogen oxyanion reduction by Co(ii) augmented by a proton responsive ligand: recruiting multiple metals.

Deoxygenation of nitrite oxygen with divalent cobalt was achieved using (PNNH)CoCl2, carrying a pyridyl pincer ligand with one P(t-Bu)2 arm and one pyrazole arm. Reaction of (PNNH)CoCl2 with NaNO2 at a 2 : 5 mole ratio promptly forms equimolar (PNNH)Co(NO2)3 and (PNN)Co(NO2)(NO), {CoNO}8 with the lost ligand proton combined with removed oxo as hydroxide. These two CoIII products are characterized, showing a bent CoNO unit as the fate of the reduced nitrogen.

Unusual Dinitrogen Binding and Electron Storage in Dinuclear Iron Complexes.

A rare example of a dinuclear iron core with a non-linearly bridged dinitrogen ligand is reported in this work. One-electron reduction of [(pyrrpy)Fe(OEt)] () (pyrrpy = 2,6-bis((3,5-di--butyl)pyrrol-2-yl)pyridine) with KC yields the complex [K][(pyrrpy)Fe](μ-η:η-N) (), where the unusual -divacant octahedral coordination geometry about each iron and the η-cation-π coordination of two potassium ions with four pyrrolyl units of the ligand cause distortion of the bridging end-on μ-N about the FeNFe core. Attempts to generate a EtO-free version of resulted instead in a dinuclear helical dimer, [(pyrrpy)Fe] (), via bridging of the pyridine moieties of the ligand.

Electrochemical C-H bond activation cationic iridium hydride pincer complexes.

A C-H bond activation strategy based on electrochemical activation of a metal hydride is introduced. Electrochemical oxidation of ( PCP)IrH ( PCP is [1,3-( BuPCH)-CH]) in the presence of pyridine derivatives generates cationic Ir hydride complexes of the type [( PCP)IrH(L)] (where L = pyridine, 2,6-lutidine, or 2-phenylpyridine). Facile deprotonation of [( PCP)IrH(2,6-lutidine)] with the phosphazene base -butylimino-tris(pyrrolidino)phosphorane, BuP(pyrr), results in selective C-H activation of 1,2-difluorobenzene (1,2-DFB) solvent to generate ( PCP)Ir(H)(2,3-CFH).

Hydrosilylation of an Iron(IV) Nitride Complex.

The nitride ligand in iron(IV) complex PhB(MesIm)Fe≡N reacts with excess HSiPh to afford PhB(MesIm)Fe(μ-H)(SiHPh) as the major product, which has been structurally and spectroscopically characterized. Bulkier silane HSiPh provides iron(II) amido complex PhB(MesIm)FeN(H)(SiHPh) as the initial product of the reaction, with excess HSiPh affording diamagnetic PhB(MesIm)Fe(μ-H)(SiPh) as the major product. Unobserved iron(II) hydride PhB(MesIm)Fe-H is implicated as an intermediate in this reaction, as suggested by the results of the reaction between iron(II) amido PhB(MesIm)FeN(H)Bu and HSiPh, which provides PhB(MesIm)Fe(H)(μ-H)(Si(NHBu)Ph) as the sole product.

Dinitrogen Reduction to Ammonium at Rhenium Utilizing Light and Proton-Coupled Electron Transfer.

The direct scission of the triple bond of dinitrogen (N) by a metal complex is an alluring entry point into the transformation of N to ammonia (NH) in molecular catalysis. Reported herein is a pincer-ligated rhenium system that reduces N to NH via a well-defined reaction sequence involving reductive formation of a bridging N complex, photolytic N splitting, and proton-coupled electron transfer (PCET) reduction of the metal-nitride bond. The new complex (PONOP)ReCl (PONOP = 2,6-bis(diisopropylphosphinito)pyridine) is reduced under N to afford the -isomer of the bimetallic complex [(PONOP)ReCl](μ-N) as an isolable kinetic product that isomerizes sequentially upon heating into the and isomers.

Strong π-Backbonding Enables Record Magnetic Exchange Coupling Through Cyanide.

The paramagnetic cyano-bridged complex PhB(BuIm)Fe-NC-Mo(NBuAr) (Ar = 3,5-MeCH) is readily assembled from a new four-coordinate, high-spin ( = 2) iron(II) monocyanide complex and the three-coordinate molybdenum(III) complex Mo(NBuAr). X-ray diffraction and IR spectroscopy reveal that delocalization of unpaired electron density into the cyanide π* orbitals leads to a reduction of the C-N bond order. Direct current (dc) magnetic susceptibility measurements, supported by electronic structure calculations, demonstrate the presence of strong antiferromagnetic exchange between spin centers, with a coupling constant of = -122(2) cm.

Intramolecular Hydrogen Bonding Facilitates Electrocatalytic Reduction of Nitrite in Aqueous Solutions.

This work reports a combined experimental and computational mechanistic investigation into the electrocatalytic reduction of nitrite to ammonia by a cobalt macrocycle in an aqueous solution. In the presence of a nitrite substrate, the Co(III) precatalyst, [Co(DIM)(NO)] (DIM = 2,3-dimethyl-1,4,8,11-tetraazacyclotetradeca-1,3-diene), is formed . Cyclic voltammetry and density functional theory (DFT) calculations show that this complex is reduced by two electrons, the first of which is coupled with nitrite ligand loss, to provide the active catalyst.