Angewandte Chemie International Edition

Pharmaceutically active compounds… … and their intermediates require selective, efficient, and robust syntheses that utilize green chemistry principles. In their Communication on page 8395 ff., O. R. Thiel, M. Achmatowicz, and co-workers describe a two-step procedure involving selective palladium-catalyzed carbon–nitrogen bond formation followed by a clean oxidative cyclization that affords access to a variety of bicyclic and tricyclic heteroaromatic scaffolds.

Large biomolecular systems have been probed for the first time by solid-state ¹⁷O NMR spectroscopy. In their Communication on page 8399 ff., G. Wu and co-workers show that high-quality solid-state ¹⁷O NMR spectra can be obtained for large protein–ligand complexes at an ultrahigh magnetic field of 21 T. The sensitivity of solid-state ¹⁷O NMR experiments at this field should allow biomolecular systems of up to 300 kDa in size to be tackled.

“The part of my job which I enjoy the most is working with motivated and talented students. I am waiting for the day when someone will discover a cure for major diseases such as Alzheimer's disease and cancer …” This and more about Milko E. van der Boom can be found on page 8301.

Gotcha! Unstable dithio- and diselenobenzoquinones can be trapped by coordination to an [(η⁵-C₅Me₅)Ir] moiety (see structure; gray C, white H, pink Ir, yellow Se). In vitro investigations on the anticancer activity of the resulting complexes showed them to be comparable to cis-platin. These organometallic species could form the basis for new anticancer agents.

Ground-breaking progress has been made in the synthesis of chiral cyclic compounds from nonchiral unsaturated substrates with a nucleophilic functionality. A number of highly enantioselective electrophilic halocyclizations based on either the interaction of a chiral Lewis acid with an unsaturated substrate or the generation of a chiral electrophilic intermediate in situ from an electrophile and a chiral reagent (see scheme) were developed.

Humble beginnings: It is 50 years since the foundation of Bruker Physik AG in Karlsruhe. In this Essay, Prof. Richard R. Ernst looks at the early years of the company, and how researchers in Zurich contributed to its success in the field of NMR instrumentation.

A “Prins” among reactions: The first report of a Prins macrocyclization appeared in 1979, but only since late 2008 has this strategy gained momentum in natural product synthesis. Convergent, selective, and high yielding, the Prins macrocyclization forms tetrahydropyran-containing macrocycles in a merged CO and CC bond-forming event (see scheme).

Pores for thought: This Review describes porous functional materials in which the organic groups act as a part of the pore wall. The focus is on functional mesoporous organosilicas as well as meso- and microporous polymers. The large number of functional groups in such porous materials allows, for example, a new approach to bridging the gap between homogeneous and heterogeneous catalysis.

The bigger they are, the harder they fall: Recent advancements in NMR spectroscopy, biophysics, and related research areas have resulted in solid-state NMR (ssNMR) spectroscopy having the potential to study complex biomolecular systems at atomic resolution in situ. Methodological challenges of ssNMR spectroscopy for studying complex biomolecules are described as well as recent and possible applications.

Parahydrogen-induced polarization is used for the continuous generation of hyperpolarized molecules. Constant ¹H and ¹³C NMR signal enhancement is demonstrated using a continuous delivery of parahydrogen by hollow fiber membranes (see picture, left), which allows the acquisition of two-dimensional NMR signals requiring multiple acquisitions with constant initial polarization.

Sensitivity enhancement of several orders of magnitude provided by combining parahydrogen-induced polarization (PHIP) and remote-detection (RD) NMR techniques enables gas-flow visualization in microfluidic devices (see scheme). A 7700-fold reduction in the imaging time compared to the current state-of-the-art is achieved, and it can also be used to significantly improve the spatial resolution in such experiments.

Picking sides: Asymmetric protonation of the titled compounds poses a most significant challenge and has been addressed by taking advantage of internal protonation and subsequent hemiacetal formation to avoid epimerization (see scheme). The substrates employed in these transformations can be easily accessed through a sequence of vinylogous aldol reactions with subsequent conjugate reductions.

The case of the notorious aryls is solved: The first efficient catalytic and enantioselective method for allylic substitutions that furnish quaternary carbon stereogenic centers by additions of aryl- or heteroarylmetals is reported (see scheme). Highly site- and enantioselective processes begin with readily available organolithium reagents.

Micro construction sites: Engineered peptides and ligand-functionalized gold nanoparticles have been assembled into micrometer-scale 3D cube-shaped crystals (see picture), creating a physical framework for a biomimetic assembly strategy. The NPs join the peptide nanowires through streptavidin–biotin interactions to create cubic unit cells.

Simply complex: Diverse and structurally complex chroman derivatives with a quaternary stereocenter have been obtained through the titled reaction of thiols with nitroolefin enoates using the bifunctional catalyst 1. The reaction features simple experimental procedures, high yield, enantiomeric excess, and excellent diastereoselectivity.

The largest tungstogermanate and third-largest polytungstate (see picture) was obtained by K⁺-directed self-assembly of three unprecedented types of [GeW₁₀O₃₈]¹²⁻ fragments stabilized by coordination of Ce ions on the vacancies. In its Ce₆O₄₂ central ring, which displays antiferromagnetic interactions, a K⁺ cation is captured by internal water molecules. Gray octahedra WO₆, green tetrahedra GeO₄; Ce orange, K purple, O red.

Boranes were getting borin': Owing to the Lewis acidic character of the central carbon atom, a bisfluorenyl-substituted allene 1 could be used instead of B(C₆F₅)₃ for the generation of frustrated Lewis pairs. Mixtures of the allene and the bulky N-heterocyclic carbene shown in red (Dipp=diisopropylphenyl) caused heterolytic cleavage of the SS bond in disulfides.

Chemoselectivity in DNA: The thymidine lesion 5-formyl-2′-deoxyuridine (1) induces the mutation of DNA. Its derivatization with the specific fluorogenic reagent 2-amino-4,5-dimethoxythiophenol (2) gives 3, which shows strong fluorescence. This fast method for the detection of 1 requires no enzymatic digestion, HPLC separation, or MS analysis. ROS=reactive oxygen species.

The palladium-catalyzed intermolecular coupling of aldehyde-derived hydrazones with chloroazines, followed by oxidative cyclization under mild conditions afforded access to a broad variety of bicyclic heterocyclic scaffolds (see scheme) that have potential for use in drug discovery.

Oxygen, oxygen, everywhere! Poor sensitivity has hindered the development of solid-state ¹⁷O NMR spectroscopy as a practical technique for the structural elucidation of protein complexes. However, this has now changed and it has been demonstrated that multinuclear ¹⁷O, ²⁷Al, ¹³C NMR parameters can be used to aid structural refinement for a protein-bound ligand molecule (see picture).

Nanojewels as catalysts: Degradation of phenol with a small excess of H₂O₂ can be achieved by using gold nanoparticles supported on Fenton-treated diamond nanoparticles as a highly selective (at least 79 %) and efficient (turnover number: 321 000) catalyst for the Fenton reaction at room temperature. The proposed mechanism is shown schematically in the picture.

Storage shells: The assembly of negatively charged graphene oxide and positively charged oxide nanoparticles by electrostatic interactions, and subsequent chemical reduction, leads to metal oxides encapsulated in flexible and ultrathin graphene shells (see picture). These electrochemically active nanoparticles show a remarkable lithium storage capacity, with an excellent cycle performance.

Choose the right cat.: A highly enantioselective synthesis of oxazolin-4-ones by the formal [3+2] cycloaddition of ketenes and a racemic oxaziridines has been developed (see scheme; cat.=N-heterocyclic carbenes for disubstituted ketenes or cinchona alkaloids for monosubstituted ketenes, Ts=4-toluenesulfonyl).

A surprising turn of events: Mechanistic studies, including trapping, control, and isotope-labeling experiments, led to the proposal of a rearrangement mechanism involving oxidation of aliphatic CH bonds (see scheme; TMEDA=tetramethylethylenediamine).

One bond makes all the difference: Three suitably positioned amino acid side chains (see picture) and a hydrophobic environment are all that is required for an amidation reaction with remarkable consequences. An emerging central building block of bacterial surface proteins owes its stability to a spontaneously formed isopeptide bond. The impact of this bond on protein structure and dynamics and the mechanism of its formation are scrutinized in detail.

Quick release: Polymer-coated gold nanoparticles (AuNPs) are used as nanocarriers and nanoscale acceptors are used to represent proteins and lipid membranes in a model drug-delivery system. The fluorescence of a drug is quenched in the vicinity of the AuNPs but reemerges upon its release (see picture). The critical role of nanoacceptors in facilitating drug release is demonstrated.

Forced into line: External pressure was used to engineer nanoparticle assembly. Reversible manipulation of the unit-cell dimensions of a 3D ordered nanoparticle array under a hydrostatic pressure field enabled the fine-tuning of the interparticle distance. Under a uniaxial pressure field, nanoparticles were forced to contact and coalesce into nanorods or nanowires and ordered ultrahigh-density arrays (see picture; small arrows denote pressure).

Change of heart: A solution-phase enantiomeric excess that has the handedness of the minor population of the solid phase is observed during grinding of a slurry of racemic conglomerate crystals. This excess is the driving force for a net flux of molecules from crystals of the minor handedness to crystals of the major handedness, thus explaining the complete deracemization of the solid phase (see picture: blue: S form, red: R form).

Along came poly: A novel macroporous polymer-supported chiral Ru^II/pheox catalyst (1, see SEM image) afforded excellent reactivity and enantioselectivity in inter- and intramolecular cyclopropanation reactions with a broad range of substrates. The catalyst showed no leaching and could be reused up to 11 times, even after storage.

Plastic batteries: Polyimides are proposed as cathode materials for rechargeable lithium batteries. Although they are regarded as insulators, five polyimides with different structures all show good electrochemical activity and some of them show promising performance, which could allow their use in a new generation of “green battery” applications.

Spin doesn't matter: A ruthenium(II)–aqua complex bearing a pentadentate pyridylamine with a carboxylate group as a ligand affords a seven-coordinate low-spin (S=0) ruthenium(IV)–oxo complex (see structure) by oxidation through proton-coupled electron transfer. Comparison of the reactivity of the low-spin and an intermediate-spin (S=1) Ru^IV–oxo complexes revealed that the spin state does not affect the reactivity of catalytic oxidation of organic compounds.

Turn up the volume: In a simple and highly sensitive aptamer-based assay that relies on the ability of nanomaterials to protect DNA from nuclease cleavage, the aptamer is released from the nanomaterial when challenged with a target. The nuclease then cleaves the free aptamer and releases the target, which can initiate a new cycle. Recycling of the target in this way leads to significant signal amplification (see diagram).

Rapamycin to the rescue: Native protein concentration was precisely controlled in living cells by using the small molecule rapamycin. The addition of rapamycin “shielded” a destabilization domain from degradation and induced complementation of split ubiquitin (UbN and UbC); as a result, proteins (Pro) of interest were released. This technology enables the investigation of native protein biology over a broad concentration range.

When structural flexibility is a plus: A link between structural flexibility of biomimetic antimicrobials and their ability to penetrate into the hydrophobic core and disrupt the integrity of bacterial lipid model membranes has been established using liquid surface X-ray scattering techniques. Results indicate that the modes of interaction of flexible and conformationally restrained antimicrobials with the bacterial membranes are different (see picture).

Disturbing neighbors: Alkenylgold species with a heteroatom substituent are thought to be key intermediates in gold-catalyzed trans additions of protic nucleophiles to alkynes. One reason for the scarcity of such compounds lies in the non-innocence of the neighboring heteroatom, which may enforce the uptake of a second gold fragment with formation of surprisingly robust species with a gem-digold unit adjacent to a largely cationic center (see scheme).

Donuts anyone? Molecules based on a meta-linked aromatic segment self-assemble into hexameric macrocycles that, in turn, stack on top of each other to from elongated tubular helical suprastructures. The formed tubules dissociate into discrete stacks of toroids in response to the addition of silver salt (see picture).

Neptune's necklace: Fe₃O₄ colloidal nanocrystal clusters (ca. 200 nm in diameter) were organized into one-dimensional nanochains and coated with a highly cross-linked polymer in a facile one-pot synthesis (see picture). The nanochains have enhanced hydrogen T₂ relaxation rates, facile magnetic manipulation, good water dispersivity, and excellent biocompatibility.

Rising from the ashes: Fine chars produced from biomass can be used as a feedstock for the production of CaC₂ in an autothermal process that operates at a temperature 500 °C lower than the traditional electric arc process and with greatly reduced reaction time (see scheme for the reaction of CaO and C forming CaC₂).

Switching the motor off: Privileged chemical scaffolds were used as a starting point for the development of a specific chemical inhibitor 1 of myosin V, a key motor protein required for intracellular transport (see picture; ADP=adenosine diphosphate, ATP=adenosine triphosphate). The potency of 1, which does not compete directly with nucleotide binding, is comparable to that of other known motor-protein inhibitors used as probes in chemical biology.

A healthy appetite: A new metal–organic framework (DUT-9; see picture) has an unprecedented topology that contains {Ni₅(μ₃-O)₂(CO₂)₆} clusters (green polyhedra; C gray, O red). DUT-9 has very high storage capacities for methane, hydrogen, and carbon dioxide because of the presence of open metal sites (marked by stars).

Buttered side up: A one nanometer thick membrane with different functional groups on each side was fabricated from self-assembled monolayers of aromatic molecules. The amino side of this Janus membrane was modified with tetramethylrhodamine (TMR) fluorescent dye, and the thiol side with ATTO647N (see picture). The functionalization and functionality of the nanomembrane were demonstrated by X-ray photoelectron spectroscopy and fluorescence microscopy.

A “shot in the arm” for cancer therapy: Coupling of synthetic glycopeptide tandem-repeat sequences of the epithelial mucin MUC1 with the Thomsen–Friedenreich (T) antigen (A) or a difluoro analogue (B) to tetanus toxoid (TTox) affords synthetic vaccines, which induce very strong immune responses in mice overriding the natural tolerance of the immune system. The induced antibodies are selectively directed against the tumor-associated MUC1 structures and strongly bind to breast cancer cells of the MCF-7 cell line.

Completeanalysis! Combinatorial mutation interference analysis (CoMA) is a highly efficient method to identify catalytically essential nucleotides in deoxyribozymes by the simultaneous assessment of all possible mutations in the active site of the catalyst. The application of CoMA for two different deoxyribozymes revealed indispensable guanosine nucleotides for DNA-catalyzed RNA ligation.

Relax! In the dilute mixed-crystal system [Zn_1−xFe_x(bbtr)₃](ClO₄)₂, x=2 % (bbtr=1,4-di(1,2,3-triazol-1-yl)butane), the iron(II) centers are predominantly in the high-spin state. The low-spin state can be populated as a metastable state by irradiation with near-IR light; the rate constant of the low-spin→high-spin relaxation spans 14 orders of magnitude between 40 and 220 K (see picture).

The harder they come, the better they leave! Chloride is superior to all common leaving groups in the γ-selective allylic substitution of linear precursors. This approach involves a novel copper-catalyzed SiB bond activation (see scheme; γ/α≥98:2, 7 examples; Si=SiMe₂Ph and B=Bpin with pin=pinacolato).

Al be there for you: Sensitive functional groups, including ester and cyano groups, can be present in allylic aluminum reagents prepared by aluminum insertion in the presence of InCl₃. These aluminum organometallic compounds undergo addition reactions to various functionalized aldehydes or ketones with remarkable diastereoselectivities allowing the construction of two adjacent quaternary and tertiary centers (see scheme).

Zirconium bases reach lots of places: Only 25 % of zirconium metal is required for the metalation of various functionalized aromatic compounds and heterocycles. All four 2,2,6,6-tetramethylpiperidyl (tmp) groups of the new base tmp₄Zr⋅4 MgCl₂⋅6 LiCl (1) are used up in the metalation process. The resulting zirconium species smoothly undergo palladium-catalyzed cross-couplings and addition to CO₂ and epoxides (see scheme).

A reaction cascade combining sulfur dioxide with a 1-oxy-1,3-diene and (E)-silyl enol ether formed the basis of a short total synthesis of (−)-dolabriferol (see scheme; TMS=trimethylsilyl). The absolute configuration of this natural product, which was first extracted from a gastropod mollusc in 1996, was established unequivocally.