Angewandte Chemie International Edition

The exotic natural product palau'amine contains a number of rare structural features, just like the extraordinary biodiversity found in the island nation of Palau. As such, palau'amine has been the most actively pursued alkaloid among synthetic chemists in the 21st century, and its first total synthesis is now described by P. S. Baran and co-workers in their Communication on page 1095 ff. The successful route features transformations on unprotected intermediates, cascade reactions, and a remarkable finale involving a transannular cyclization to forge the critical bond. Cover designed by Paul Krawczuk; photograph courtesy of iStockphoto.com/clumpner.

The molecular-force sensor titin kinase (TK) is embedded in the M-band structure of the sarcomere at an ideal position to sense force imbalances. H. E. Gaub and E. M. Puchner demonstrate in their Communication on page 1147 ff. a new AFM-based single-molecule pump-and-probe protocol to mechanically prepare different conformations of TK and to read out their function. The results show that the binding pocket for the co-substrate ATP is shielded by two sequential barriers in the force-induced activation pathway.

“The best advice I have ever been given is “Hard work never killed anyone!” The worst advice I have ever been given was “Don't go to Oxford—you'll flounder.” …” This and more about Simon Aldridge can be found on page 1008.

Oxford University Press, New York 2009. 432 pp., hardcover € 59.95.—ISBN 978-0195369632

All that glitters: Binary catalytic systems of gold(I) complexes and chiral Brønsted acids, which were recently reported by the research groups of Dixon and Gong, represent a significant leap forwards in the area of sequential one-pot reactions. The special feature of these reactions is the isolobal analogy of the proton and [LAu^I] cations, which requires a delicate balance between the reactivities of the acids and the gold complexes.

Simple and practical: The asymmetric alkynylation of imines has been revolutionized with two nice examples of a novel model of H-bonding asymmetric metal catalysis with Brønsted acids. The catalytic model comprises two well-differentiated and parallel catalytic cycles: one involving metallic alkynylydes (metal catalysis) and the other one using a chiral Brønsted acid (organocatalysis; see scheme; PG=protecting group).

No laughing matter: In view of its significance as an atmospheric pollutant and greenhouse gas, an important research goal has been to understand the reactivity of N₂O with metal centers in the gas phase, on solid supports, in enzymes, and as soluble complexes in solution. Recent studies provide provocative mechanistic insights into how N₂O might bind to metal ions and be activated for NN or NO bond scission or insertion into MC or MH bonds.

From the drawing of blood to diagnosis: Clinical chemistry makes an important contribution to medical diagnostics and the prevention of disease. New insights from the natural sciences and information technologies can reach into medicine by way of clinical chemistry. This Review presents the historic roots of the subject as well as current methods for measurement and analysis. Research projects and future developments are also discussed.

Cocaine cracked: The gel–sol transition of an enzyme-caged hydrogel has been efficiently controlled by target binding events, which trigger release of the enzyme to take part in its catalytic role for signal amplification (see picture). As low as 20 ng of cocaine can be visually detected within 10 min without any aid of sophisticated instrumentation.

Cleaning up: A cubic thorium borate possesses a porous supertetrahedral cationic framework with extraframework borate anions. These anions are readily exchanged with a variety of environmental contaminants (see picture), especially those from the nuclear industry, including chromate and pertechnetate.

Gold service: The asperities on a polished gold surface are quickly dissolved by the OH^. radicals of Fenton's reagent. The dissolution of Au is rapid at the beginning of the reaction and is negligible when the asperities have been dissolved. Although the OH^. radicals also oxidize the smooth parts of the Au surface, they do not dissolve them, but form a stable oxide monolayer.

Reactive aldehyde-modified DNA was prepared in two steps by Suzuki cross-coupling of halogenated nucleoside triphosphates (dNTPs) with 4-formylthiophene-2-boronic acid and subsequent polymerase incorporation of the modified nucleotides into DNA (see scheme; PEX=primer extension, PCR=polymerase chain reaction). Formation of hydrazones with arylhydrazines under aqueous conditions was used for DNA staining.

Helical by nature: Urea-based peptidomimetics with proteinogenic side chains are fully helical in the crystalline state (see picture). Four acyclic residues are sufficient to drive complete helix formation with all complementary H-bonding sites being satisfied (up to 14 for a 8-mer). Helices pack head-to-tail to create infinite H-bonded networks with different topologies.

Cell mates: Various ligand–receptor interactions in different human cancer cell lines were probed directly by two-dimensional transferred-NOE spectroscopy (see picture) to prove recognition specificity and determine an affinity ranking of several ligands.

Into the void: A large, cavity-containing trinuclear triangle with accessible binding sites has been synthesized, structurally characterized, and incorporated into a chiral metal–organic framework (see picture). The resulting 3D framework, with a trifunctional amine bridging group, has a void volume of 56 % that is accessible to solvent and adsorbs a variety of gases to various degrees.

Bright bubbles! Ultrabright sonoluminescence is observed from concentrated phosphoric acid (see picture). Two independent molecular emission species (excited OH^. and PO^.) can be observed from multibubble sonoluminescence; both of them can be used as spectroscopic thermometers to probe the extreme conditions generated during bubble collapse.

Missing in action: Relativistic density-functional methods provide a reliable framework to predict the features of ¹⁹⁵Pt, ¹⁸³W, and ¹⁷O NMR spectra of terminal oxo Pt and Au complexes (see picture for [P₂W₂₀O₇₀Au(O)(OH₂)₃]⁹⁻; Au yellow, W blue, P orange, O red, H white). The complexes have an extremely small HOMO–LUMO gap, and both orbitals are localized on an MO fragment.

Thoroughly absorbing: The simple combination of lithium ions and isonicotinate anions (1) leads to the formation of a lightweight salt (see picture; C black, O red, N blue, Li purple) that is able to reversibly sorb H₂ , N₂ , CO₂ , and CH₄ . The salt exists as a 3D network of microchannels that are occupied by solvent molecules.

The dynamic duo: Different topologies of dynamic supramolecular polymers, such as linear (see picture, left) and cross-linked species (right), can be reversibly interconverted by external stimuli that utilize host–guest and metal–ligand non-covalent recognition motifs.

Worth the wait: The long anticipated total synthesis of palau'amine has been accomplished by a route featuring highly chemoselective transformations, cascade reactions, and a remarkable transannular cyclization to secure the unprecedented trans-5,5 ring junction (shown in red).

Ring around the rosy: A novel multifunctional disulfide-containing hyperbranched poly(amido amine) that is stimuli-responsive, biocompatible, biodegradable, and photoluminescent can assemble DNA into a well-defined nanoring with strong photoluminescence. The nanoring is stimuli-responsive and the ring wall is biocompatible and controllably bioreducible; it has potential applications in gene and drug delivery, and molecular imaging.

Key to success: The first catalytic asymmetric total synthesis of ent-hyperforin (see picture) was accomplished by using a Diels–Alder reaction promoted by a chiral cationic iron catalyst (A; 96 % ee, d.r.>33:1), a diastereoselective Claisen rearrangement (B; 12:1 selectivity), an intramolecular aldol reaction (C), and a vinylogous Pummerer rearrangement (D) as key steps.

The key to motion: A second-generation molecular rotary motor, which contains a DB24C8 macrocycle ring incorporated into the lower stator half and a dialkyl ammonium ion attached to the upper rotor half, forms a [1]pseudorotaxane in less polar solvents such as CH₂Cl₂. In this self-complexing system, acid–base-controlled threading–dethreading movements can be utilized to unlock or lock the molecular motor (see picture).

A bimetallic copper/palladium catalyst system is disclosed that enables the use of tosylates as carbon electrophiles in decarboxylative coupling reactions. A variety of aromatic carboxylate salts, regardless of their substitution pattern, have been coupled with these inexpensive and readily available electrophiles to give the corresponding biaryl compounds in good yields (see scheme).

A versatile Cu-catalyzed direct CH alkenylation of N-iminopyridinium ylides, compatible with several different copper sources (including a penny), provides a powerful and inexpensive method for the synthesis of functionalized pyridine derivatives. Chemoselective functionalization of halide-containing compounds allows the synthesis of alkenyl pyridines containing reactive tethers for further functionalization.

Practical catalyst: A magnetic nanoparticle-supported palladium catalyst was developed for the highly efficient heterogeneous Suzuki, Sonogashira, and Stille couplings of a wide variety of aryl chlorides. Furthermore, the catalyst could be recycled by facile magnetic separation without any loss of activity.

Lose one, keep one! A wide range of cyclic and acyclic β-aminofluoroalkenes are prepared by the title reaction. The key fluorinated palladium π-allyl intermediate is generated using a catalytic allylic CF bond activation.

Pore-ing acid: Mesoporous Nb–W oxides (Nb:W=3:7) are found to be a recyclable, highly active solid acid. They surpass ion-exchange resins (Nafion NR50 and Amberlyst-15) and zeolites (H-ZSM5 and H-Beta) in Friedel–Crafts alkylation and hydrolysis reactions (see picture). The high activity is due to strong acid sites and a mesoporous structure with a high surface area and easy reactant accessibility.

Isatis indigotica has long been used as a source of therapeutic compounds in traditional Chinese medicine (the roots are the source of Ben Lan Gen herbal tea). In 2007 the leaves of I. indigotica yielded isatisine A, an unusual oxidized bis-indole. A concise, enantiospecific total synthesis of isatisine A is reported using a homochiral cyclopropane diester to construct the key tetrahydrofuran ring.

Chain gang: Lipophilic pyridinium bisphosphonates containing long alkyl chains (see picture, P red, N blue, C orange, H gray) stimulate human γδ T cells expressing the Vγ2Vδ2 T cell receptor. Stimulation with such compounds is more potent than with zoledronate, which is active against breast and prostate cancer. The lipophilic bisphosphonates bind poorly to bone and are thus less likely to cause side effects associated with bisphosphonates in clinical use.

On the move: A palladium-catalyzed reaction of aryl iodides, diazo compounds or N-tosylhydrazones, and carbon monoxide affords β-oxo esters or ketones/enones (see scheme; DCE=1,2-dichloroethane). The products are delivered with high efficiency through the title sequence.

Foxy ligands: An efficient three-step synthesis allows the new highly modular family of olefin–oxazoline ligands (OlefOx; see picture) to be exploited in asymmetric catalysis. The ease of electronic and steric variation and the successful application in the highly enantioselective rhodium-catalyzed conjugate addition of aryl boronic acids to cylic enones demonstrate the importance of this new ligand class.

Feel the force: A new AFM-based single-molecule pump-and-probe protocol has been used to investigate the function of different force-induced conformations of proteins (see picture). It was found that the autoinhibited enzyme titin kinase reaches its ability to bind ATP after the first two barriers of the complex mechanical activation pathway.

A-maze-ing peptides: The structure of the novel lantibiotic labyrinthopeptin A2 (see picture) contains labionin—an unprecedented carbacyclic, posttranslationally modified amino acid. The identification of the biosynthetic gene cluster of labyrinthopeptins was also successful. Labyrinthopeptin A2 revealed a pronounced in vivo efficacy (attenuation of tactile allodynia) in a mouse model of neuropathic pain.

Selective, sensitive, and specific breast cancer diagnosis: Neuropeptide Y (NPY) and the Y₁R-selective [Phe⁷, Pro³⁴]NPY peptide were labeled with Re/^99mTc and pre-clinically characterized using competition receptor binding and signal transduction assays, and also microscopic, metabolic-stability, rabbit body-uptake, and protein-binding studies. Selective uptake of the ^99mTc(core)³⁺-(N^αHis-ac)-labeled [Phe⁷, Pro³⁴]NPY analogue in human breast-cancer patients was obtained by whole body scintimammography.

Strung out: Fe^II complexes containing pairs of planar terdentate N ligands form regular one-dimensional aggregates on highly oriented pyrolytic graphite, on a length scale of hundreds of nanometers. STM spectroscopy was used to probe the molecular conductance and thus the spin state. The distribution of spin states is random in the single-molecule chain, but local cooperativity sets in when the chain is made up of oligonuclear “beads” (see picture).