Accessing unusual heterocycles: ring expansion of benzoborirenes by formal cycloaddition reactions.

Benzoborirenes are a very rare class of strained boron heterobicyclic systems. In this study a kinetically stabilized benzoborirene 1 is shown to react with multiple bonds of trimethylphosphine oxide, acetaldehyde, and tert-butyl isonitrile. The (2 + 2) cycloaddition product with trimethylphosphine oxide, benzo[c][1,2,5]oxaphosphaborole, has a long apical PO bond (194.0 pm) that must be considered on the border line between ionic and covalent according to the natural bond orbital, quantum theory of atoms in molecules, and compliance matrix approaches to the description of chemical bonding. The coordination compound between the benzoborirene and phosphine oxide was observed by NMR spectroscopy at 213 K. The Lewis acidity of 1 is similar to that of B(OCH2CF3)3 and B(C6F5)3 based on the 31P{1H} NMR chemical shift of the Lewis acid base complexes with trimethylphosphine oxide at 213 K. Benzoboriene 1 does not react with acetone, but forms a (2 + 2) cycloaddition product, an oxaborole, with acetaldehyde. In contrast, it undergoes a double (2 + 1) reaction with tert-butyl isonitrile to yield a boro-indane derivative under mild conditions. The observed reactivity of 1 is in agreement with computational analyses of the respective potential energy surfaces.

Synthesis, Reactivity and Coordination Chemistry of Group 9 PBP Boryl Pincer Complexes: [(PBP)M(PMe3)n] (M = Co, Rh, Ir; n = 1, 2).

The unsymmetrical diborane(4) derivative [(d(CH2P(iPr)2)abB)-Bpin] (1) proved to be a versatile PBP boryl pincer ligand precursor for Co(I) (2a, 4a), Rh(I) (2-3b) and Ir(I/III) (2-3c, 5-6c) complexes, in particular of the types [(d(CH2P(iPr)2)abB)M(PMe3)2] (2a-c) and [(d(CH2P(iPr)2)abB)M-PMe3] (2b-c). Whilst similar complexes have been obtained before, for the first time, the coordination chemistry of a homologous series of PBP pincer complexes, in particular the interconversion of the five- and four-coordinate complexes 2a-c/3a-c, was studied in detail. For Co, instead of the mono phosphine complex 2a, the dinitrogen complex [(d(CH2P(iPr)2)abB)Co(N2)(PMe3)] (4a) is formed spontaneously upon PMe3 abstraction from 2a in the presence of N2. All complexes were comprehensively characterised spectroscopically in solution via multinuclear (VT-)NMR spectroscopy and structurally in the solid state through single-crystal X-ray diffraction. The unique properties of the PBP ligand with respect to its coordination chemical properties are addressed.

Cyclopropylmethyldiphosphates are substrates for sesquiterpene synthases: experimental and theoretical results.

New homo-sesquiterpenes are accessible after conversion of presilphiperfolan-8ß-ol synthase (BcBOT2) with cyclopropylmethyl analogs of farnesyl diphosphate, and this biotransformation is dependent on subtle structural refinements. Two of the three cyclisation products are homo variants of germacrene D and germacrene D-4-ol while the third product reported contains a new bicyclic backbone for which no analogue in nature has been described so far. The findings on diphosphate activation are discussed and rationalised by relaxed force constants and dissociation energies computed at the DFT level of theory.

Cis- and trans-binding influences in [NUO·(N2)n].

Uranium nitride-oxide cations [NUO]+ and their complexes with equatorial N2 ligands, [NUO·(N2)n]+ (n = 1-7), were synthesized in the gas phase. Mass-selected infrared photodissociation spectroscopy and quantum chemical calculations confirm [NUO·(N2)5]+ to be a sterically fully coordinated cation, with electronic singlet ground state of 1A1, linear [NUO]+ core, and C5v structure. The presence of short N-U bond distances and high stretching modes, with slightly elongated U-O bond distances and lowered stretching modes, is rationalized by attributing them to cooperative covalent and dative [ǀN≡U≡Oǀ]+ triple bonds. The mutual trans-interaction through flexible electronic U-5f6d7sp valence shell and the linearly increasing perturbation with increase in the number of equatorial dative N2 ligands has also been explained, highlighting the bonding characteristics and distinct features of uranium chemistry.

Masked Amino Trimethyl Lock (H2 N-TML) Systems: New Molecular Entities for the Development of Turn-On Fluorophores and Their Application in Hydrogen Sulfide (H2 S) Imaging in Human Cells.

Masked trimethyl lock (TML) systems as molecular moieties enabling the bioresponsive release of compounds or dyes in a controlled temporal and spatial manner have been widely applied for the development of drug conjugates, prodrugs or molecular imaging tools. Herein, we report the development of a novel amino trimethyl lock (H2 N-TML) system as an auto-immolative molecular entity for the release of fluorophores. We designed Cou-TML-N3 and MURh-TML-N3 , two azide-masked turn-on fluorophores. The latter was demonstrated to selectively release fluorescent MURh in the presence of physiological concentrations of the redox-signaling molecule H2 S in vitro and was successfully applied to image H2 S in human cells.

How Strong is a Reverse Dative Bond? Compliance Constants as Unique Bond Strength Descriptors.

The concepts of bond strength and bond order are at the very heart of chemistry. Nevertheless, the study of local mechanical bond strengths in large polyatomic molecules is a nontrivial task. In a recent publication, Peters and Lehnert et al. [Inorg. Chem. 2020, 59 (20), 14967-14982] found a quite strong (reverse) dative Fe···B bond for a synthesized low-spin {FeNO}10 complex supported by an ambiphilic trisphosphineborane ligand. Their conclusion was, among other criteria, based on a surprisingly high Fe-B force constant of 1.56 mdyn/Å. Nevertheless, this high value might be based on numerical ambiguities of (rigid) real-space force constants, a flaw, that may affect many other combined spectroscopic and electronic structure studies.

Antibiotic Conjugates with an Artificial MECAM-Based Siderophore Are Potent Agents against Gram-Positive and Gram-Negative Bacterial Pathogens.

The development of novel drugs against Gram-negative bacteria represents an urgent medical need. To overcome their outer cell membrane, we synthesized conjugates of antibiotics and artificial siderophores based on the MECAM core, which are imported by bacterial iron uptake systems. Structures, spin states, and iron binding properties were predicted in silico using density functional theory. The capability of MECAM to function as an effective artificial siderophore in Escherichia coli was proven in microbiological growth recovery and bioanalytical assays. Following a linker optimization focused on transport efficiency, five ß-lactam and one daptomycin conjugates were prepared. The most potent conjugate 27 showed growth inhibition of Gram-positive and Gram-negative multidrug-resistant pathogens at nanomolar concentrations. The uptake pathway of MECAMs was deciphered by knockout mutants and highlighted the relevance of FepA, CirA, and Fiu. Resistance against 27 was mediated by a mutation in the gene encoding ExbB, which is involved in siderophore transport.

Biomimetic enterobactin analogue mediates iron-uptake and cargo transport into E. coli and P. aeruginosa.

The design, synthesis and biological evaluation of the artificial enterobactin analogue EntKL and several fluorophore-conjugates thereof are described. EntKL provides an attachment point for cargos such as fluorophores or antimicrobial payloads. Corresponding conjugates are recognized by outer membrane siderophore receptors of Gram-negative pathogens and retain the natural hydrolyzability of the tris-lactone backbone. Initial density-functional theory (DFT) calculations of the free energies of solvation (ΔG(sol)) and relaxed Fe-O force constants of the corresponding [Fe-EntKL]3- complexes indicated a similar iron binding constant compared to natural enterobactin (Ent). The synthesis of EntKL was achieved via an iterative assembly based on a 3-hydroxylysine building block over 14 steps with an overall yield of 3%. A series of growth recovery assays under iron-limiting conditions with Escherichia coli and Pseudomonas aeruginosa mutant strains that are defective in natural siderophore synthesis revealed a potent concentration-dependent growth promoting effect of EntKL similar to natural Ent. Additionally, four cargo-conjugates differing in molecular size were able to restore growth of E. coli indicating an uptake into the cytosol. P. aeruginosa displayed a stronger uptake promiscuity as six different cargo-conjugates were found to restore growth under iron-limiting conditions. Imaging studies utilizing BODIPYFL-conjugates, demonstrated the ability of EntKL to overcome the Gram-negative outer membrane permeability barrier and thus deliver molecular cargos via the bacterial iron transport machinery of E. coli and P. aeruginosa.

Experimental and theoretical characterization of the strong effects on DNA stability caused by half-sandwich Ru(II) and Ir(III) bearing thiabendazole complexes.

The synthesis and characterization of two half-sandwich complexes of Ru(II) and Ir(III) with thiabendazole as ancillary ligand and their DNA binding ability were investigated using experimental and computational methods. 1H NMR and acid-base studies have shown that aquo-complexes are the reactive species. Kinetic studies show that both complexes bind covalently to DNA through the metal site and non covalently through the ancillary ligand. Thermal stability studies, viscosity, circular dichroism measurements and quantum chemical calculations have shown that the covalent binding causes breaking of the H-bonding between base pairs, bringing about DNA denaturation and compaction. Additionally, molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations shed light into the binding features of the Ru(II) and Ir(III) complexes and their respective enantiomers toward double-helical DNA, highlighting the important role played by the NˆN ancillary ligand once the complexes are covalently linked to DNA. Moreover, metal quantification in the nucleus of SW480 colon adenocarcinoma cells were carried out by inductively coupled plasma-mass spectrometry (ICP-MS), both complexes are more internalized than cisplatin after 4 h of exposition. However, in spite of the dramatic changes in the helicity of the DNA secondary structure induced by these complexes and their nuclear localization, antiproliferative studies have revealed that both, Ru(II) and Ir(III) complexes, cannot be considered cytotoxic. This unexpected behavior can be justified by the fast formation of aquo-complexes, which may react with components of the cell culture medium or the cytoplasm compartment in such a way that they may become deactivated before reaching DNA.

Novel atrazine-binding biomimetics inspired to the D1 protein from the photosystem II of Chlamydomonas reinhardtii.

Biomimetic design represents an emerging field for improving knowledge of natural molecules, as well as to project novel artificial tools with specific functions for biosensing. Effective strategies have been exploited to design artificial bioreceptors, taking inspiration from complex supramolecular assemblies. Among them, size-minimization strategy sounds promising to provide bioreceptors with tuned sensitivity, stability, and selectivity, through the ad hoc manipulation of chemical species at the molecular scale. Herein, a novel biomimetic peptide enabling herbicide binding was designed bioinspired to the D1 protein of the Photosystem II of the green alga Chlamydomonas reinhardtii. The D1 protein portion corresponding to the QB plastoquinone binding niche is capable of interacting with photosynthetic herbicides. A 50-mer peptide in the region of D1 protein from the residue 211 to 280 was designed in silico, and molecular dynamic simulations were performed alone and in complex with atrazine. An equilibrated structure was obtained with a stable pocked for atrazine binding by three H-bonds with SER222, ASN247, and HIS272 residues. Computational data were confirmed by fluorescence spectroscopy and circular dichroism on the peptide obtained by automated synthesis. Atrazine binding at nanomolar concentrations was followed by fluorescence spectroscopy, highlighting peptide suitability for optical sensing of herbicides at safety limits.

Kinetic Studies of Donor-Acceptor Cyclopropanes: The Influence of Structural and Electronic Properties on the Reactivity.

The kinetics of (3+2) cycloaddition reactions of 18 different donor-acceptor cyclopropanes with the same aldehyde were studied by in situ NMR spectroscopy. Increasing the electron density of the donor residue accelerates the reaction by a factor of up to 50 compared to the standard system (donor group=phenyl), whereas electron-withdrawing substituents slow down the reaction by a factor up to 660. This behavior is in agreement with the Hammett substituent parameter σ. The obtained rate constants from the (3+2) cycloadditions correlate well with data from additionally studied (3+n) cycloadditions with a nitrone (n=3) and an isobenzofuran (n=4). A comparison of the kinetic data with the bond lengths in the cyclopropane (obtained by X-ray diffraction and computation), or the 1 H and 13 C NMR shifts, revealed no correlation. However, the computed relaxed force constants of donor-acceptor cyclopropanes proved to be a good indicator for the reactivity of the three-membered ring.

Structural Elucidation of Trace Components Combining GC/MS, GC/IR, DFT-Calculation and Synthesis-Salinilactones, Unprecedented Bicyclic Lactones from Salinispora Bacteria.

The analysis of volatiles released by marine Salinispora bacteria uncovered a new class of natural compounds displaying an unusual bicyclic [3.1.0]-lactone skeleton. Although only sub-µg quantities of the compounds were available, the combination of analytical methods, computational spectroscopy, and synthesis allowed unambiguous structural identification of the compounds, called salinilactones, without the need for isolation. Orthogonal hyphenated methods, GC/MS and solid-phase GC/IR allowed to propose a small set of structures consistent with the data. A candidate structure was selected by comparison of DFT-calculated IR spectra and the experimental IR-spectrum. Synthesis confirmed the structure and absolute configuration of three bicyclic lactones, salinilactones A-C. The salinilactones are structurally closely related to the A-factor class of compounds, autoregulators from streptomycete bacteria. They exhibited inhibitory activity against Salinispora and Streptomyces strains.

The Interstitial Carbon of the Nitrogenase FeMo Cofactor is Far Better Stabilized than Previously Assumed.

The first quantum-mechanical calculations of all relevant potential constants in both the iron-molybdenum cofactor and the iron-vanadium cofactor of nitrogenase suggest that the carbide is bound to the center of the enzyme much more strongly than hitherto assumed. Previous studies seemed to indicate a dummy function of the interstitial carbon, with a weak force constant (ca. 0.32 N cm-1 ). Our new investigations confirm a different picture: the central carbon atom binds the iron-sulfur cluster through six covalent C-Fe bonds. With a potential constant of more than 1.3 N cm-1 , the interstitial carbon also appears to be dynamically persistent. According to our investigations, the values for the elasticity within the iron-sulfur cluster have to be corrected too. These new details on the mechano-chemical properties of the FeMo cofactor will be important for elucidating the catalytic cycle of nitrogen fixation. By implementing our new algorithm in the freely available COMPLIANCE program, the dependence on the coordinates during the calculation of Hesse matrices is eliminated completely.

The Weakness of B-H⋠⋠⋠π Interactions: Much Softer than a Hydrogen Bond.

Recently, a new type of non-covalent interaction, the B-H⋅⋅⋅π interaction, was introduced. Nevertheless, the unique determination of individual, non-covalent bond strengths in complex molecular systems is a non-trivial task with often controversial results. The utilization of generalized compliance constants (relaxed force constants) is proposed as unique bond-strength descriptors for classical and non-classical hydrogen bonds. The strength of recently proposed B-H⋅⋅⋅π bonds is discussed.

Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic-ribosome complex supervised by experiment and electronic structure methods.

We propose several new and promising antibacterial agents for the treatment of serious Gram-positive infections. Our predictions rely on force field simulations, supervised by first principle calculations and available experimental data. Different force fields were tested in order to reproduce linezolid's conformational space in terms of a) the isolated and b) the ribosomal bound state. In a first step, an all-atom model of the bacterial ribosome consisting of nearly 1600 atoms was constructed and evaluated. The conformational space of 30 different ribosomal/oxazolidinone complexes was scanned by stochastic methods, followed by an evaluation of their enthalpic penalties or rewards and the mechanical strengths of the relevant hydrogen bonds (relaxed force constants; compliance constants). The protocol was able to reproduce the experimentally known enantioselectivity favoring the S-enantiomer. In a second step, the experimentally known MIC values of eight linezolid analogues were used in order to crosscheck the robustness of our model. In a final step, this benchmarking led to the prediction of several new and promising lead compounds. Synthesis and biological evaluation of the new compounds are on the way.

Correction: Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic-ribosome complex supervised by experiment and electronic structure methods.

[This corrects the article DOI: 10.3762/bjoc.12.45.].

Comment on "The Nature of the Fourth Bond in the Ground State of C2: The Quadruple Bond Conundrum".

Is it time to reconsider the whole concept of quadruple bonding? Contrary to the conclusion of Shaik and co-workers in Chem. Eur. J.­ 2014, 20, 6220­6232, there is no "deviation of C2 from the Badger Rule".

Oligoene-Based π-Helicenes or Dispiranes? Winding up Oligoyne Chains by a Multiple Carbopalladation/Stille/(Electrocyclization) Cascade.

A domino approach consisting of up to five consecutive steps to access either highly substituted dispiranes or π-helicenes from oligoyne chains is reported. The domino sequence consists of several carbopalladation reactions, a Stille cross-coupling to obtain the helicenes, and, depending on the steric demands of the helicene, a final 6π-electrocyclization to afford the dispiranes. Formally, the latter transformation contravenes the Woodward-Hoffmann rules, as revealed by X-ray crystallography of the dispirane. Additionally, the racemization barrier of the (Z,Z,Z)-triene-based helicene has been determined by a kinetic analysis and compared with results from density functional theory calculations. Characteristic points on the reaction coordinate were further analyzed according to their relaxed force constants (compliance constants).

Sigillin†A, a unique polychlorinated arthropod deterrent from the snow flea Ceratophysella sigillata.

The snow flea Ceratophysella sigillata, a winter-active species of springtail, produces unique polychlorinated octahydroisocoumarins to repel predators. The structure of the major compound, sigillin A, was elucidated through isolation, spectroscopic analysis, and X-ray crystallography. Sigillin A showed high repellent activity in a bioassay with predatory ants. A promising approach for the total synthesis of members of this new class of natural compounds was also developed.