Vicinal Bis(methylene) Heterocyclic Diene in Natural Product Synthesis: A Convergent Biomimetic Total Synthesis of Prunolactone A.

The first total syntheses of the natural isocoumarin prunolactone A with a 6/6/6/6/6 spiropentacyclic skeleton and its unnatural (3')-epimer in 10 and 8 steps, respectively, are reported. The syntheses feature generation of a reactive 3,4-bis(methylene)isocoumarin intermediate, its biomimetic Diels-Alder reactions with the shikimic-acid-derived scytolide and (8)-scytolide, and a Mitsunobu reaction allowing access to scytolide in a stereochemically pure form. Computational support for the selectivity of the Diels-Alder reaction is provided.

Acidity constants and protonation sites of cyclic dinucleotides determined by capillary electrophoresis, quantum chemical calculations, and NMR spectroscopy.

Cyclic dinucleotides (CDNs) are important second messengers in bacteria and eukaryotes. Detailed characterization of their physicochemical properties is a prerequisite for understanding their biological functions. Herein, we examine acid-base and electromigration properties of selected CDNs employing capillary electrophoresis (CE), density functional theory (DFT), and nuclear magnetic resonance (NMR) spectroscopy to provide benchmark pK values, as well as to unambiguously determine the protonation sites.

Discovery of a Druggable, Cryptic Pocket in SARS-CoV-2 nsp16 Using Allosteric Inhibitors.

A collaborative, open-science team undertook discovery of novel small molecule inhibitors of the SARS-CoV-2 nsp16-nsp10 2'--methyltransferase using a high throughput screening approach with the potential to reveal new inhibition strategies. This screen yielded compound , a ligand possessing an electron-deficient double bond, as an inhibitor of SARS-CoV-2 nsp16 activity. Surprisingly, X-ray crystal structures revealed that covalently binds within a previously unrecognized cryptic pocket near the -adenosylmethionine binding cleft in a manner that prevents occupation by -adenosylmethionine.

Comprehensive Mechanistic View of the Hydrolysis of Oxadiazole-Based Inhibitors by Histone Deacetylase 6 (HDAC6).

Histone deacetylase (HDAC) inhibitors used in the clinic typically contain a hydroxamate zinc-binding group (ZBG). However, more recent work has shown that the use of alternative ZBGs, and, in particular, the heterocyclic oxadiazoles, can confer higher isoenzyme selectivity and more favorable ADMET profiles. Herein, we report on the synthesis and biochemical, crystallographic, and computational characterization of a series of oxadiazole-based inhibitors selectively targeting the HDAC6 isoform.

Can Copper(I) and Silver(I) be Hydrogen Bond Acceptors?

Gold(I) centers can form moderately strong (Au⋅⋅⋅H) hydrogen bonds with tertiary ammonium groups, as has been demonstrated in the 3AuCl (3 =1-(tert-butyl)-3-phenyl-4-(2-((dimethylammonio)methyl)phenyl)-1,2,4-triazol-5-ylidene) complex. However, similar hydrogen bonding interactions with isoelectronic silver(I) or copper(I) centers are unknown. Herein, we first explored whether the Au⋅⋅⋅H bond originally observed in 3AuCl can be strengthened by replacing Cl with Br or I.

Exhaustive Mapping of the Conformational Space of Natural Dipeptides by the DFT-D3//COSMO-RS Method.

We extensively mapped energy landscapes and conformations of 22 (including three His protonation states) proteinogenic α-amino acids in configuration and the corresponding 484 (22) dipeptides. To mimic the environment in a protein chain, the and termini of the studied systems were capped with acetyl and -methylamide groups, respectively. We systematically varied the main chain dihedral angles (ϕ, ψ) by 40° steps and all side chain angles by 90° or 120° steps.

Acid-Responsive Nanoporphyrin Evolution for Near-Infrared Fluorescence-Guided Photo-Ablation of Biofilm.

Combating biofilm infections remains a challenge due to the shield and acidic conditions. Herein, an acid-responsive nanoporphyrin (PN3-NP) based on the self-assembly of a water-soluble porphyrin derivative (PN3) is constructed. Additional kinetic control sites formed by the conjugation of the spermine molecules to a porphyrin macrocycle make PN3 self-assemble into stable nanoparticles (PN3-NP) in the physiological environment.

Evidence for H-bonding interactions to the μ-η:η-peroxide of oxy-tyrosinase that activate its coupled binuclear copper site.

The factors that control the diverse reactivity of the μ-η:η-peroxo dicopper(II) oxy-intermediates in the coupled binuclear copper proteins remain elusive. Here, spectroscopic and computational methods reveal H-bonding interactions between active-site waters and the μ-η:η-peroxide of oxy-tyrosinase, and define their effects on the Cu(II)O electronic structure and O activation.

Spectroscopic Characterization of a Reactive [Cu (μ-OH) ] Intermediate in Cu/TEMPO Catalyzed Aerobic Alcohol Oxidation Reaction.

Cu /TEMPO (TEMPO=2,2,6,6-tetramethylpiperidinyloxyl) catalyst systems are versatile catalysts for aerobic alcohol oxidation reactions to selectively yield aldehydes. However, several aspects of the mechanism are yet unresolved, mainly because of the lack of identification of any reactive intermediates. Herein, we report the synthesis and characterization of a dinuclear [L1 Cu ] complex 1, which in presence of TEMPO can couple the catalytic 4 H /4 e reduction of O to water to the oxidation of benzylic and aliphatic alcohols.

Plasmon-assisted click chemistry at low temperature: an inverse temperature effect on the reaction rate.

Plasmon assistance promotes a range of chemical transformations by decreasing their activation energies. In a common case, thermal and plasmon assistance work synergistically: higher temperature results in higher plasmon-enhanced catalysis efficiency. Herein, we report an unexpected tenfold increase in the reaction efficiency of surface plasmon-assisted Huisgen dipolar azide-alkyne cycloaddition (AAC) when the reaction mixture is cooled from room temperature to -35 °C.

Closed Shell Iron(IV) Oxo Complex with an Fe-O Triple Bond: Computational Design, Synthesis, and Reactivity.

Iron(IV)-oxo intermediates in nature contain two unpaired electrons in the Fe-O antibonding orbitals, which are thought to contribute to their high reactivity. To challenge this hypothesis, we designed and synthesized closed-shell singlet iron(IV) oxo complex [(quinisox)Fe(O)] (1 ; quinisox-H=(N-(2-(2-isoxazoline-3-yl)phenyl)quinoline-8-carboxamide). We identified the quinisox ligand by DFT computational screening out of over 450 candidates.

Chemoselectivity in the Oxidation of Cycloalkenes with a Non-Heme Iron(IV)-Oxo-Chloride Complex: Epoxidation vs. Hydroxylation Selectivity.

We report and analyze chemoselectivity in the gas phase reactions of cycloalkenes (cyclohexene, cycloheptene, cis-cyclooctene, 1,4-cyclohexadiene) with a non-heme iron(IV)-oxo complex [(PyTACN)Fe(O)(Cl)], which models the active species in iron-dependent halogenases. Unlike in the halogenases, we did not observe any chlorination of the substrate. However, we observed two other reaction pathways: allylic hydrogen atom transfer (HAT) and alkene epoxidation.

M-O Bonding Beyond the Oxo Wall: Spectroscopy and Reactivity of Cobalt(III)-Oxyl and Cobalt(III)-Oxo Complexes.

Terminal oxo complexes of late transition metals are frequently proposed reactive intermediates. However, they are scarcely known beyond Group 8. Using mass spectrometry, we prepared and characterized two such complexes: [(N4Py)Co (O)] (1) and [(N4Py)Co (O)] (2).

Characterized cis-Fe(O)(OH) intermediate mimics enzymatic oxidations in the gas phase.

Fe(O)(OH) species have long been proposed to play a key role in a wide range of biomimetic and enzymatic oxidations, including as intermediates in arene dihydroxylation catalyzed by Rieske oxygenases. However, the inability to accumulate these intermediates in solution has thus far prevented their spectroscopic and chemical characterization. Thus, we use gas-phase ion spectroscopy and reactivity analysis to characterize the highly reactive [Fe(O)(OH)(tpa)] (3) complex.

Spectroscopic and Computational Evidence of Intramolecular Au ⋅⋅⋅H -N Hydrogen Bonding.

Despite substantial evidence of short Au⋅⋅⋅H-X contacts derived from a number of X-ray structures of Au compounds, the nature of Au ⋅⋅⋅H bonding in these systems has not been clearly understood. Herein, we present the first spectroscopic evidence for an intramolecular Au ⋅⋅⋅H -N hydrogen bond in a [Cl-Au-L] complex, where L is a protonated N-heterocyclic carbene. The complex was isolated in the gas phase and characterized with helium-tagging infrared photodissociation (IRPD) spectra, in which H -N-mode-derived bands evidence the intramolecular Au ⋅⋅⋅H -N bond.

Experimentally Calibrated Analysis of the Electronic Structure of CuO : Implications for Reactivity.

The CuO core is a central motif of reactive intermediates in copper-catalysed oxidations occurring in nature. The high reactivity of CuO stems from a weak bonding between the atoms, which cannot be described by a simple classical model. To obtain the correct picture, we have investigated the acetonitrile-ligated CuO ion using neon-tagging photodissociation spectroscopy at 5 K.

Trapping Iron(III)-Oxo Species at the Boundary of the "Oxo Wall": Insights into the Nature of the Fe(III)-O Bond.

Terminal non-heme iron(IV)-oxo compounds are among the most powerful and best studied oxidants of strong C-H bonds. In contrast to the increasing number of such complexes (>80 thus far), corresponding one-electron-reduced derivatives are much rarer and presumably less stable, and only two iron(III)-oxo complexes have been characterized to date, both of which are stabilized by hydrogen-bonding interactions. Herein we have employed gas-phase techniques to generate and identify a series of terminal iron(III)-oxo complexes, all without built-in hydrogen bonding.

Nucleophilic versus Electrophilic Reactivity of Bioinspired Superoxido Nickel(II) Complexes.

The formation and detailed spectroscopic characterization of the first biuret-containing monoanionic superoxido-Ni intermediate [LNiO ] as the Li salt [2; L=MeN[C(=O)NAr) ; Ar=2,6-iPr C H )] is reported. It results from oxidation of the corresponding [Li(thf) ] [LNi Br ] complex M with excess H O in the presence of Et N. The [LNiO ] core of 2 shows an unprecedented nucleophilic reactivity in the oxidative deformylation of aldehydes, in stark contrast to the electrophilic character of the previously reported neutral Nacnac-containing superoxido-Ni complex 1, [L'NiO ] (L'=CH(CMeNAr) ).

Aurophilic Interactions in [(L)AuCl]...[(L')AuCl] Dimers: Calibration by Experiment and Theory.

Attractive metallophilic (aurophilic, argentophilic, cuprophilic, etc.) interactions play an important role in arrangement and stabilization of oligonuclear metal ion complexes. We report a combined experimental and theoretical assessment of aurophilic interactions in closed-shell gold(I) dimers.

Detection of Indistinct Fe-N Stretching Bands in Iron(V) Nitrides by Photodissociation Spectroscopy.

We report for the first time infrared spectra of three non-heme pseudo-octahedral iron(V) nitride complexes with assigned Fe-N stretching vibrations. The intensities of the Fe-N bands in two of the complexes are extremely weak. Their detection was enabled by the high resolution and sensitivity of the experiments performed at 3 K for isolated complexes in the gas phase.

Spin-State-Controlled Photodissociation of Iron(III) Azide to an Iron(V) Nitride Complex.

The generation of iron(V) nitride complexes, which are targets of biomimetic chemistry, is reported. Temperature-dependent ion spectroscopy shows that this reaction is governed by the spin-state population of their iron(III) azide precursors and can be tuned by temperature. The complex [(MePy TACN)Fe(N )] (MePy TACN=N-methyl-N,N-bis(2-picolyl)-1,4,7-triazacyclononane) exists as a mixture of sextet and doublet spin states at 300 K, whereas only the doublet state is populated at 3 K.

A Cu/Cu prototypical organometallic mechanism for the deactivation of an active pincer-like Cu catalyst in Ullmann-type couplings.

Unraveling the mechanistic details of copper-catalyzed arylation of nucleophiles (Ullmann-type couplings) is a very challenging task. It is a matter of intense debate whether it is a radical-based process or an organometallic redox-based process. The ancillary ligand choice in Ullmann-type couplings plays a key role in such transformations and can strongly influence the catalytic efficiency as well as the mechanism.

Generation, Spectroscopic, and Chemical Characterization of an Octahedral Iron(V)-Nitrido Species with a Neutral Ligand Platform.

Iron complex [Fe(N)(MePytacn)](PF) (1), containing a neutral triazacyclononane-based pentadentate ligand, and a terminally bound azide ligand has been prepared and spectroscopically and structurally characterized. Structural details, magnetic susceptibility data, and Mössbauer spectra demonstrate that 1 has a low-spin (S = 1/2) ferric center. X-ray diffraction analysis of 1 reveals remarkably short Fe-N (1.

Reactivity of Copper(III)-Oxo Complexes in the Gas Phase.

An efficient way to generate [(L)CuO] complexes with a number of monodentate and bidentate ligands (L) from their [(L)Cu(ClO )] precursors by electrospray ionization was herein explored. Further, we studied [(L)CuO] with L=9,10-phenanthraquinone, 1,10-phenanthroline, and acetonitrile in detail. The signature of these terminal copper-oxo complexes was found to be elimination of the oxygen atom upon collisional activation.

Chasing the Evasive Fe═O Stretch and the Spin State of the Iron(IV)-Oxo Complexes by Photodissociation Spectroscopy.

We demonstrate the application of infrared photodissocation spectroscopy for determination of the Fe═O stretching frequencies of high-valent iron(IV)-oxo complexes [(L)Fe(O)(X)] (L = TMC, N4Py, PyTACN, and X = CHCN, CFSO, ClO, CFCOO, NO, N). We show that the values determined by resonance Raman spectroscopy in acetonitrile solutions are on average 9 cm red-shifted with respect to unbiased gas-phase values. Furthermore, we show the assignment of the spin state of the complexes based on the vibrational modes of a coordinated anion and compare reactivities of various iron(IV)-oxo complexes generated as dications or monocations (bearing an anionic ligand).