Angewandte Chemie International Edition

The powerful antitumor agents, the epothilones, bind to tubulin and interfere with microtubule dynamics. Until now, no high-resolution structure for the tubulin–epothilone complex was available. NMR spectroscopy studies provide a high-resolution structure of epothilone bound to tubulin and show two major conformational changes of epothilone relative to the free conformation. These results correlate well with chemical-modification data. These findings and NMR techniques are discussed in the Communications by Carlomagno and co-workers on pp. 2511–2517.

Helical structures can be formed in different ways: In rigid molecules through steric interactions and in flexible molecules through intramolecular noncovalent interactions or through supramolecular associations.

Checking the traps: The transport of excess electrons in DNA has great potential for DNA chip technology. Radiolysis studies, for example, with mitoxanton as the electron acceptor and new photochemical assays (see scheme) have given new insights into the mechanisms of these processes.

Does size matter? Can a drug-like molecule efficiently modulate the interaction between proteins in which the protein–protein interface (as indicated in the scheme) is many times larger than the small molecule itself? If so, how do you identify such organic molecules? Answers to these questions can be found in this review on the current research aimed at producing the next generation of drugs.

They do indeed exist, but not as expected: binary peroxide compounds of phosphorus. Whereas the peroxide P₂O₆ described by Schenk in 1937 still remains a presumption, the reaction of phosphorus(III) oxide with ozone at low temperature has led to the tetraozonide P₄O₁₈ (see picture), the first defined binary peroxo compound of phosphorus. This is the oxygen-richest phosphorus compound known to date, and possibly could be used as a source for the generation of singlet oxygen under very mild conditions.

In only twelve steps the total synthesis of (−)-epipodophyllotoxin (2) has been completed starting from commercially available piperonal (1). The first stereocenter was formed under auxilary control, while the following epoxidation and radical cyclization proceeded with outstanding diastereoselectivity, which enabled the target molecule to be isolated in an overall yield of 30 % and with 97 % ee.

Methyl-substituted arenes can be synthesized with high regioselectivity in only two steps through formal exchange of an aromatic carboxylic acid function with an alkyl substituent. The results obtained with toluic acid illustrate that good to very good yields can be obtained from inexpensive reagents (see scheme).

Smoothly linked: Polymer-supported phosphorane 1 is a C-nucleophile that can be acylated under mild reaction conditions. Diversely substituted α-ketocarbonyl and α-hydroxycarbonyl compounds 2 are furnished following to a reaction sequence including oxidative cleavage of the supported phosphoranes.

Stranded solvents: The aminocarbene chromium complex shown forms fiberlike aggregates of several μm length by self-assembly through noncovalent interactions. These strands allow an efficient immobilization of organic solvents in the form of a gel. The carbohydrate head group may induce supramolecular chirality in the aggregates.

Unprecedented coordination polymers of hexagonal tungsten bronze topology represent a new type of metal–organic zeolites: the compounds have a microporous structure, they are thermally stable and are capable of the reversible adsorption of dichloromethane (see picture).

More than just a light switch: A phototriggered molecule-releasing system controlled through intramolecular triplet quenching by using a molecular beacon strategy with photoactive probe oligodeoxynucleotides (ODNs) has been developed (see picture).

Positive discrimination: Confocal microscopy analysis has shown that TentaGel beads functionalized with unnatural carbohydrate-based ligands (2) can discriminate extremely well between carbohydrate-binding proteins labeled separately with fluorescein and tetramethylrhodamine (blue ellipsoids and red triangles, respectively) that recognize the same natural carbohydrate ligands (1, see schematic representation).

A highly fluorophilic environment comprising the HC_αCO unit of Asn 98 in the active site of thrombin was identified by X-ray crystallography of a complex formed between the enzyme and a synthetic inhibitor (see partial X-ray structure, distances are in Angstroms). Short CF⋅⋅⋅HC_α and CF⋅⋅⋅CO contacts involving HC_αCO fragments were also frequently observed in small-molecule X-ray crystal structures.

The tubulin-bound structure of epothilone A (shown in green) differs substantially from its free conformation (determined by X-ray crystallography, shown in gray). The new structural data correlate well with results from chemical modification experiments, giving a consistent picture of the functionally important regions of epothilone.

C–C torsion angles in HC-CCH₃ moieties can be measured by a new NMR experiment based on the measurement of CH–CH dipolar–dipolar cross-correlated relaxation rates and is demonstrated on a mixture of ¹³C-labeled epothilone (1) and tubulin. The new pulse sequence is broadly applicable to any HC-CCH₃ moiety and therefore to a number of amino acid side chains in proteins.

The most potent epothilone analogue reported to date was obtained by incorporation of an E double bond at C9C10 in the epothilone B series (see picture). Molecular modeling, NMR spectroscopic analysis, and chemical observations were used to rationalize the remarkable potency-enhancing effect of the double bond.

A total synthesis of epothilone C (1) with concomitant formal synthesis of epothilone A is described, using immobilized reagents and scavengers to effect multistep synthetic transformations and purifications.

Stereogenic quaternary carbons present the primary challenge in the syntheses of trispyrrolidinoindoline alkaloids such as idiospermuline. In its synthesis the two contiguous quaternary centers are expediently addressed by combining the lithium dienolate of a differentially protected dihydroisoindigo with a tartrate-derived electrophile. The third quaternary stereocenter is introduced by a catalytic asymmetric Heck reaction.

A late-stage resolution of the meso-3a,3a′-bispyrrolidinoindoline unit of rac-7 in a catalytic asymmetric transformation earmarks the remarkably short, ten-step, total syntheses of hodgkinsine and hodgkinsine B. The enantioselective total synthesis of hodgkinsine B establishes the relative and absolute configuration of this trispyrrolidinoindoline alkaloid.

Chiral dyads of (S)-ketoprofen and (S)- or (R)-tetrahydrofurfurylamine show diastereomeric differentiation in photoinduced hydrogen abstractions, which could be directly followed by time-resolved observation of the ketone triplet state. A unimolecular rate constant of k_H=3.0×10⁵ s⁻¹ was found for the S,S diastereomer, while the S,R diastereomer reacts four times slower (k_H=7.5×10⁴ s⁻¹).

Side-stepping thermodynamics. In contrast to the traditional benzoin reaction, which can yield a mixture of homo and mixed adducts, only one regioisomer was obtained from the new cyanide-catalyzed silyl benzoin reaction between acylsilanes and aldehydes (see scheme).

Egg yolk provided the starting disialylundecasaccharide for a highly efficient chemoenzymatic synthesis of a biantennary complex-type glycopeptide (see picture). Repetitive protection and deprotection steps required in oligosaccharide synthesis were thus avoided, and the desired glycopeptide was rapidly assembled on a solid phase (R=peptide).

Only nine steps away: PPh₃/CCl₄-mediated stereospecific rearrangement of α,α-disubstituted indoline-2-methanol to 2,2,3-trisubstituted optically active tetrahydroquinoline (see scheme) has been developed. The reaction was applied to the first total synthesis of natural virantmycin, in only nine steps from commercially available starting material.

Two forms of a cyclic molecule, namely a rhomb and a square, are observed for an oligosaccharide, which has four repeating units that consist only of amino sugars (see picture). A relatively high water content (ca. 34 %) can be discerned from the crystals, which were formed from a water/polyethylene glycol solution by utilizing a hanging-drop crystallization technique.

Pyrene reduction revisited: A reductive dimerization process is observed for strained pyrene derivatives, which occurs through single-electron reduction with lithium metal (see scheme). This process has implications for the reduction of pyrene itself. Various NMR methods can be utilized to characterize the products that result from such reactions.

Terminal alkenes act as dual nucleophiles in a zirconocene-mediated, highly 1,4-diastereoselective, tandem reduction–allylation reaction of 1,4-diketones. A zirconocene–alkene complex (in equilibrium with an allyl–zirconocene–hydride species) can deliver both hydride and an allyl group to a diketone, with control of the relative configuration of up to three new stereogenic centers (see scheme).