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^III(O)]⁺ ( 1 ) and [(N4Py)Co^IV(O)]²⁺ ( 2 ). Infrared photodissociation spectroscopy revealed that the Co?O bond in 1 is rather strong, in accordance with its lack of chemical reactivity. On the contrary, 2 has a very weak Co?O bond characterized by a stretching frequency of ≤659 cm^?1. Accordingly, 2 can abstract hydrogen atoms from non‐activated secondary alkanes. Previously, this reactivity has only been observed in the gas phase for small, coordinatively unsaturated metal complexes. Multireference ab‐initio calculations suggest that 2 , formally a cobalt(IV)‐oxo complex, is best described as cobalt(III)‐oxyl. Our results provide important data on changes to metal‐oxo bonding behind the oxo wall and show that cobalt‐oxo complexes are promising targets for developing highly active C?H oxidation catalysts.     

A diastereoselective C–C bond formation at C-5 of d-gulose. A convenient approach to (5S)-5-C-alkyl-β-l-lyxo-hexofuranoses

A flexible approach to the stereoselective synthesis of (5S)-5-C-methyl- and (5S)-5-C-ethyl-β-l-lyxo-hexofuranoses 15a, 22 starting from 1,2:5,6-di-O-isopropylidene-α-d-gulofuranose 3 as the source of chirality is described. The corresponding C-5 alkyl groups were introduced via a Wittig olefination followed by Pd/C-mediated hydrogenation of the conformationally restricted alkenes in a highly diastereoselective manner.     

The fluorine-NHC gauche effect: a structural and computational study

Herein, we report the synthesis and X-ray structural analysis of a collection of fluorinated metal N-heterocyclic carbenes (Ag, Au, Pd, Rh, Ir) and their precursor salts. The common structural feature of these species is a flanking fluoroethyl group, which is either freely rotating or embedded within a bicyclic framework. Solid state analysis confirmed a gauche conformational preference in all cases with the fluorine adopting a syn clinal arrangement (?_[NCCF]～60°) with respect to the triazolium nitrogen at the vicinal position of the NHC. A density functional theory analysis was employed to quantify these effects and evaluate the influence of electronic modulation of the carbenic carbon [(CN⁺); neutral carbene (C:); metal-bound carbene (CM)], on the relative gauche/anti preference, thus highlighting the potential of this conformational phenomenon as a useful molecular design strategy for controlling the topology of organometallic complexes.     

The cyclobutane dimers of 2'-deoxyuridine, 2'-deoxycytidine, 5-methyl-2'-deoxycytidine and 5-bromo-2'-deoxyuridine

Irradiation of DNA and RNA pyrimidine nucleosides with UV light in frozen aqueous solution or in solution with acetone often results in the formation of cyclobutane dimers (CBDs). Many of these photodimers have not been characterized. We present here the results of work designed to achieve the isolation, spectroscopic characterization and determination of the stereochemical nature of a number of little studied or previously unstudied CBDs of four 2'-deoxyribonuclesides. These nucleosides are 2'-deoxyuridine (dUrd), 2'-deoxycytidine (dCyd), 5-methyl-2'-deoxycytidine (5-MedCyd) and 5-bromo-2'-deoxyuridine (5-BrdUrd). In particular, we have isolated and characterized six dUrd CBDs, five dCyd CBDs, five 5-MedCyd CBDs and four 5-BrdUrd CBDs. Photoproducts were studied by UV spectroscopy, mass spectrometry, proton NMR spectroscopy and via chemical approaches. Also presented are results from less definitive studies of a number of (6-4) (or 5-4) photoadducts of these nucleosides. In addition, results from exploratory photochemical studies of other 2'-deoxyribonucleosides in frozen solution, as well as some mixtures of two nucleosides, are given. The latter results indicate that 5-iodo-2'-deoxyuridine (5-IdUrd), 5-bromo-2'-deoxycytidine and 5-iodo-2'-deoxycytidine each form putative CBDs and that 5-BrdUrd is capable of forming putative mixed CBDs and (6-4) and/or (5-4) adducts with thymidine (Thd); 5-IdUrd similarly forms a (6-4) (or (5-4)) adduct with Thd.     

Synthesis and antisense properties of fluoro cyclohexenyl nucleic acid (F-CeNA), a nuclease stable mimic of 2'-fluoro RNA

We report the design and synthesis of 2'-fluoro cyclohexenyl nucleic acid (F-CeNA) pyrimidine phosphoramidites and the synthesis and biophysical, structural, and biological evaluation of modified oligonucleotides. The synthesis of the nucleoside phosphoramidites was accomplished in multigram quantities starting from commercially available methyl-D-mannose pyranoside. Installation of the fluorine atom was accomplished using nonafluorobutanesulfonyl fluoride, and the cyclohexenyl ring system was assembled by means of a palladium-catalyzed Ferrier rearrangement. Installation of the nucleobase was carried out under Mitsunobu conditions followed by standard protecting group manipulations to provide the desired pyrimidine phosphoramidites. Biophysical evaluation indicated that F-CeNA shows behavior similar to that of a 2'-modified nucleotide, and duplexes with RNA showed slightly lower duplex thermostability as compared to that of the more rigid 3'-fluoro hexitol nucleic acid (FHNA). However, F-CeNA modified oligonucleotides were significantly more stable against digestion by snake venom phosphodiesterases (SVPD) as compared to unmodified DNA, 2'-fluoro RNA (FRNA), 2'-methoxyethyl RNA (MOE), and FHNA modified oligonucleotides. Examination of crystal structures of a modified DNA heptamer duplex d(GCG)-T*-d(GCG):d(CGCACGC) by X-ray crystallography indicated that the cyclohexenyl ring system exhibits both the (3)H(2) and (2)H(3) conformations, similar to the C3'-endo/C2'-endo conformation equilibrium seen in natural furanose nucleosides. In the (2)H(3) conformation, the equatorial fluorine engages in a relatively close contact with C8 (2.94 ?) of the 3'-adjacent dG nucleotide that may represent a pseudo hydrogen bond. In contrast, the cyclohexenyl ring of F-CeNA was found to exist exclusively in the (3)H(2) (C3'-endo like) conformation in the crystal structure of the modified A-form DNA decamer duplex [d(GCGTA)-T*-d(ACGC)](2.) In an animal experiment, a 16-mer F-CeNA gapmer ASO showed similar RNA affinity but significantly improved activity compared to that of a sequence matched MOE ASO, thus establishing F-CeNA as a useful modification for antisense applications.     

Triphenylene silanes for direct surface anchoring in binary mixed self-assembled monolayers

New triphenylene-based silanes 2-(ω-(chlorodimethylsilyl)-n-alkyl)-3,6,7,10,11-penta-m-alkoxytriphenylene 4 (Tm-Cn) with n = 8 or 9 and m = 7, 8, 9, 10, or 11 were synthesized, and their self-assembly behavior in the liquid state and at glass and silicon oxide surfaces was investigated. The mesomorphic properties of triphenylene silanes 4 (Tm-Cn) and their precursors 3 (Tm-Cn) were determined by differential scanning calorimetry (DSC), polarizing optical microscopy (POM), and X-ray diffraction. From the small-angle X-ray scattering (SAXS) regime, a preferential discotic lamellar mesophase can be deduced, and wide-angle X-ray scattering (WAXS) highlights the liquid-like characteristics of the alkyl side chains. To transfer these bulk structural properties to thin films, self-assembled monolayers (SAMs) were obtained by adsorption from solution and characterized by water contact angle measurements, null ellipsometry, and atomic force microscopy (AFM). Employing the concentration as an additional degree of freedom, binary SAMs of 2-(ω-(chlorodimethylsilyl)-undecyl)-3,6,7,10,11-penta-decyloxytriphenylene 4 (T10-C11) were coassembled with chlorodecyldimethylsilane or chlorodimethyloctadecylsilane, and their capability as model systems for organic templating was evaluated. The structure of the resulting binary mixed SAMs was analyzed by water contact angle measurements, null ellipsometry, and X-ray reflectivity (XRR) in combination with theoretical modeling by a multidimensional Parratt algorithm and AFM. The composition dependence of film thickness and roughness can be explained by a microscopic model including the steric hindrance of the respective molecular constituents.     

Extremely slow Li ion dynamics in monoclinic Li(2)TiO(3)-probing macroscopic jump diffusion via(7)Li NMR stimulated echoes

A thorough understanding of ion dynamics in solids, which is a vital topic in modern materials and energy research, requires the investigation of diffusion properties on a preferably large dynamic range by complementary techniques. Here, a polycrystalline sample of Li(2)TiO(3) was used as a model substance to study Li motion by both (7)Li spin-alignment echo (SAE) nuclear magnetic resonance (NMR) and ac-conductivity measurements. Although the two methods do probe Li dynamics in quite different ways, good agreement was found so that the Li diffusion parameters, such as jump rates and the activation energy, could be precisely determined over a dynamic range of approximately eleven decades. For example, Li solid-state diffusion coefficients D(σ) deduced from impedance spectroscopy range from 10(-23) m(2) s(-1) to 10(-12) m(2) s(-1) (240-835 K). These values are in perfect agreement with the coefficients D(SAE) deduced from SAE NMR spectroscopy. As an example, D(SAE) = 2 × 10(-17) m(2) s(-1) at 433 K and the corresponding activation energy determined by NMR amounts to 0.77(2) eV (400-600 K). At room temperature D(σ) takes a value of 3 × 10(-21) m(2) s(-1).     

Deamidation accelerates amyloid formation and alters amylin fiber structure

Deamidation of asparagine and glutamine is the most common nonenzymatic, post-translational modification. Deamidation can influence the structure, stability, folding, and aggregation of proteins and has been proposed to play a role in amyloid formation. However there are no structural studies of the consequences of deamidation on amyloid fibers, in large part because of the difficulty of studying these materials using conventional methods. Here we examine the effects of deamidation on the kinetics of amyloid formation by amylin, the causative agent of type 2 diabetes. We find that deamidation accelerates amyloid formation and the deamidated material is able to seed amyloid formation by unmodified amylin. Using site-specific isotope labeling and two-dimensional infrared (2D IR) spectroscopy, we show that fibers formed by samples that contain deamidated polypeptide contain reduced amounts of β-sheet. Deamidation leads to disruption of the N-terminal β-sheet between Ala-8 and Ala-13, but β-sheet is still retained near Leu-16. The C-terminal sheet is disrupted near Leu-27. Analysis of potential sites of deamidation together with structural models of amylin fibers reveals that deamidation in the N-terminal β-sheet region may be the cause for the disruption of the fiber structure at both the N- and C-terminal β-sheet. Thus, deamidation is a post-translational modification that creates fibers that have an altered structure but can still act as a template for amylin aggregation. Deamidation is very difficult to detect with standard methods used to follow amyloid formation, but isotope-labeled IR spectroscopy provides a means for monitoring sample degradation and investigating the structural consequences of deamidation.     

DCAP: a broad-spectrum antibiotic that targets the cytoplasmic membrane of bacteria

Persistent infections are frequently caused by dormant and biofilm-associated bacteria, which often display characteristically slow growth. Antibiotics that require rapid cell growth may be ineffective against these organisms and thus fail to prevent reoccurring infections. In contrast to growth-based antimicrobial agents, membrane-targeting drugs effectively kill slow-growing bacteria. Herein we introduce 2-((3-(3,6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl)amino)-2-(hydroxymethyl)propane-1,3-diol (DCAP), a potent broad-spectrum antibiotic that reduces the transmembrane potential of Gram-positive and Gram-negative bacteria and causes mislocalization of essential membrane-associated proteins, including MinD and FtsA. Importantly, DCAP kills nutrient-deprived microbes and sterilizes bacterial biofilms. DCAP is lethal against bacterial cells, has no effect on red blood cell membranes, and only decreases the viability of mammalian cells after ≥6 h. We conclude that membrane-active compounds are a promising solution for treating persistent infections. DCAP expands the limited number of compounds in this class of therapeutic small molecules and provides new opportunities for the development of potent broad-spectrum antimicrobial agents.