Angewandte Chemie International Edition

The teamwork between carbohydrate chemistry and total synthesis is surely one of the most exciting aspects of organic chemistry. In this review the contributions made by the principal author's research group in the areas of chemical synthesis and biological chemistry of carbohydrates are presented. Specifically, the use of carbohydrates as starting materials for total synthesis, the development of new technologies for carbohydrate synthesis, the construction of complex oligosaccharides in solution or on solid support, and the use of carbohydrate templates as scaffolds for peptide mimetics and other interesting compounds are discussed.

As many materials cannot be prepared in the form of single crystals appropriate for single-crystal X-ray diffraction, structure determination of such materials requires the use of powder X-ray diffraction data. However, the determination of crystal structures directly from powder X-ray diffraction data is associated with a number of intrinsic challenges. In recent years there has been substantial progress in the development of techniques to tackle these challenges. In addition to surveying these advances in methodology, the opportunities that now exist for exploiting powder diffraction in structure determination are highlighted with examples taken from diverse areas across the chemical and materials sciences. The picture shows the β phase from 1,4-diketo-2,5-di-tert-butoxycarbonyl-3,6-diphenylpyrrolo[3,4]pyrrole.

Enantioselective fluorinations made easier! Chiral N-fluoroammonium salts such as A, or chiral catalysts generated from complexes B (L=ligand) broaden the substrate scope for electrophilic fluorination. Starting from prochiral substrates they offer an efficient approach to chiral fluoro derivatives such as C. Additionally, fluorinated stereogenic centers can be generated from nucleophilic, catalytic epoxide opening.

Much more versatile than previously anticipated are the coordination modes of tris(pyrazolyl)borate ligands (scorpionates). Recent contributions in this area not only lead to a new understanding of the electronic effects, but for the first time report unusually high and low hapticities as well as novel coordination modes such as the π coordination of a pyrazolyl ring to potassium (see structure). Potentially useful new ligands have been made available through innovative synthetic routes.

Esterified B₁₂icosahedra with totally organoderivatized surfaces are obtained from the reaction of [closo-B₁₂(OH)₁₂]²⁻ with acetic anhydride or benzoyl chloride. The resulting “closomers”, in which each cluster vertex is substituted with an organic ester moiety, can provide camouflaged modules of variable size, shape, charge, hydrophobicity, etc. and represent the first examples of this structural motif known in chemistry. The figure displays, in a space-filling representation, the result of an X-ray analysis performed with the dodecabenzoate ester derivative.

Per-O-benzylation of [closo-B₁₂(OH)₁₂]²⁻ (1²⁻) using benzyl chloride followed by oxidation with two equivalents of Fe^III gave compound 2, the per(benzyloxy) derivative of hypercloso-B₁₂H₁₂ (see scheme). Species 2 is characterized by ¹¹B NMR and electronic spectroscopy, mass spectrometry, cyclic voltammetry, and X-ray crystallography.

In contrast to what has been accepted, electroweak quantum chemistry predicts the heats of formation, the structures, the microwave and infrared spectra of enantiomers of chiral molecules to be different. The R enantiomer of fluoroxirane is calculated to be more stable than the S enantiomer by the minute amount of 2×10⁻¹² J mol⁻¹, and the relative IR frequency shifts are ≤10⁻¹⁸ (see scheme). Nevertheless, this recently synthesized compound may prove useful for fundamental experimental tests and calculations of parity violation in chiral molecules because of its particularly simple rovibrational spectrum and its rigid cyclic structure composed of light atoms.

Conformational flexibility of L-iduronic acid is a key feature of this typical component of heparin. Three pentasaccharides have now been synthesized, which are analogues of the active site of heparin and in which the single L-iduronic acid is conformationally locked in either the ¹C₄, ⁴C₁, or ²S₀ form. Only the ²S₀ variant 1 was able to fully activate antithrombin inhibition of the blood coagulation factor Xa.

A route to unsubstituted tetrahedrane? One option is offered by the tetrakis(trimethylsilyl) derivative, which is generated upon irradiation of the corresponding cyclobutadiene (see scheme). Tetrahedrane itself could also possibly be accessed from the tetralithiotetrahedrane by this route.

In less than one minute dianion 1 can be oxidized with 1,2-dibromoethane to give pure tetrakis(trimethylsilyl)cyclobutadiene (2, see scheme). The bridged cyclobutadiene derivative 6 was also similarly synthesized and characterized by X-ray crystallography; it exhibits a planar rectangular structure with localized C=C bonds.

The water-exchange reactions of three modified iron(III) porphyrins were studied in acidic medium as a function of temperature and pressure using ¹⁷O NMR spectroscopic techniques. The positive activation entropies and activation volumes support a dissociative mechanism (see scheme showing the transition state; L=nucleophile, H₂O, NO). A comparison with available literature data reveals that the rate and mechanism of complex-formation reactions of such metal porphyrins are controlled by the water-exchange process.

By a factor of 10⁴–10⁵ that is how much the reactivity of Pt^II(terpyridine) complexes exceeds the reactivity of the corresponding Pt^II(diene) complexes in nucleophilic substitution reactions. A systematic π-acceptor study was performed on a series of aqua complexes (see scheme) to elucidate that the source of this unusual acceleration is π conjugation!

Diffusion or perfusion—this is no longer the question for electroosmotic flow (EOF) through capillaries with fixed beds. The intraparticle EOF in capillary electrochromatography has been shown by using special NMR techniques and forms the basis for a further improvement in separation efficiency, mass sensitivity, and analysis speed. Electroosmotic perfusion phenomena in porous materials also play an important role in other areas, such as in the dewatering of waste sludge and the removal of contaminants from soil.

The first stereoselective access to an axially chiral arylanthraquinone, the antimalarial natural product knipholone (3), was achieved by application of the “lactone concept”. Key steps were the intramolecular coupling of the bromoester 1, to give the configurationally unstable biaryl lactone 2, and the enantioselective ring cleavage to form 3.

8-Ring and 16-ring channels with 5.3×5.3 Å and 4.9×17.2 Å windows, respectively, are contained in the new CU-4 phase. The larger channel exhibits an elliptical pore structure templated by an alkali metal chloride salt. CU-4 is structurally related to CU-2 (see picture), and can be chemically modified to CU-2 by an ion-exchange reaction at 600°C.

A new oxyA gene replacement mutant of Amycolatopsis mediterranei enabled us to isolate two peptides, SP-1132 (1) and SP-1294 (2), which only have one diaryl ether bridge. These vancomycin-type structures provide further insight into the oxidative ring-bridging steps in their biosynthesis.

Going up!n-Selectivity and activity can be increased simultaneously in hydroformylation by the use of novel hybrid ligands such as 1 containing O-acylphosphite groups. For the first time these ligands deliver impressively n-selective rhodium-catalyzed hydroformylation of internal octenes, and this with an industrial relevant catalytic activity.

B-trichloroborazene reacts with bis(trimethylsilyl)carbodiimide to form non-oxide gels (see scheme). The xerogels consist of a polymeric network of borazine rings linked by carbodiimide groups. Pyrolysis at 1200°C provides amorphous ceramics with the composition BC_0.23N_1.1Si_0.05H_0.09 ≈ B₄CN₄. At 2000°C pure B₄C is formed.

Template effect versus hydogen bonding in self-assembly: As predicted, the scaffold of molecular gyroscope [(NaBr)₂∩Cu₆{(2,5-Me₂C₆H₃CH₂)N(CH₂CH₂O)₂}₆] (1) is generated from N-substituted diethanolamine together with a copper(II) salt and sodium bromide. However, we did not predict the one-dimensional coordination polymer [Cu₄{H[HN(CH₂CH₂O)₂]}₄(OAc)₄] (2) generated with an unsubstituted diethanolamine. The formation of 2 is a further impressive example of nature's virtuosity in using hydrogen bonds.

More like an industrial fungicide than a natural product is the title compound, which occurs as the potassium salt in the carrot truffle, Stephanospora caroticolor, and is responsible for its orange color (see picture). On injury of the fruit body, 1 is transformed into the toxic 2-chloro-4-nitrophenolate (2) by loss of the side chain.

Microspheres formed from a new poly(β-amino ester) degrade slowly at pH 7.4 (left fluorescence microscopy image) but dissolve quickly at pH values below 6.5 (right), to release encapsulated material rapidly and quantitatively. As the pH/solubility transition occurs within the intracellular pH range, these tiny spheres hold promise as intracellular drug delivery vehicles.

Micrometer-level billiards or rod-formation: The careful design of poly(propyleneimine) dendrimers enables the physical properties of self-assembled vesicular structures to be tuned so that they behave as hard spheres that either undergo collision in a billiardlike manner or merge (see picture).

Greater than 400-fold selectivity for glucose over galactose, mannose, and fructose has been achieved with a receptor designed by the computer program CAVEAT. The receptor has precisely positioned boronic acid groups for cyclic boronate formation with the 1,2- and 4,6-hydroxy groups of α-D-glucopyranose (see picture) and exhibits a 50 % decrease in fluorescence upon glucose binding.

A prismlike hollow structure was assembled when three pyridyl-substituted porphyrin panels were linked by six Pd^II ions. A dramatic D_3h→C₂ structural change of the prism (see scheme) was triggered by complexation of pyrene.

Intimate electrical contact occurs between a substituted poly(metaphenylenevinylene) (PmPV) and bundles of single-walled nanotubes (SWNT) as evidenced by atomic force microscopy, optical, and electronic measurements carried out on single, isolated SWNT/PmPV structures (see picture). PmPV may provide a useful route toward “functionalizing” the SWNT without destroying their electrical character.

A hexanuclear flying saucer, [Cu₆(Acntb)₆]⁶⁺ (see structure), is obtained by the reaction of Cu(ClO₄)₂⋅6 H₂O with the sodium salt of the tripodal ligand Acntb⁻. Intermolecular hydrogen bonding generates an open three-dimensional nanoporous network containing intra- and intermolecular cavities of different polarity for guest inclusion. HAcntb=N-[N′-(carboxymethyl)benzimidazol-2-ylmethyl]-N,N-bis(benzimidazol-2-ylmethyl)amine.

Blood typing with the ABO classification is based on cell-surface glycoproteins. In a significant step toward the synthesis of these compounds, the laboratory synthesis of a fully functional N-linked glycopeptide featuring H-type blood group determinants 1 is described.

A low temperature mobility up to 10 000 cm² V⁻¹ s⁻¹ at 1.7 K was observed for a new polymorphic form of pentacene (C₂₂H₁₄, see picture). Optical measurements show a band gap of the order of 2 eV, and transport measurements revealed a mobility above 3 cm² V⁻¹ s⁻¹ at room temperature.

A most elusive of synthetic targets, azinomycin A 1 has now been synthesized for the first time. Using a modular synthetic approach, and after considerable developmental effort, this antitumor agent has been synthesized in a stereocontrolled manner using a convergent series of fragment couplings and a final cyclization to form the structurally unique aziridino[1,2-a]pyrrolidine ring system.

Specific binding of an antibody to its antigen at subnanomolar concentrations has been detected electrically by impedance spectroscopy through changes in the ion-conductance of a synthetic ligand-gated ion channel (SLIC) in a supported lipid bilayer on a gold electrode (see picture).

Fluoroalkylsilane treatment of super-hydrophobic, aligned carbon nanotube films (see electron micrograph) prepared by pyrolysis of metal phthalocyanines results in the films having both super-hydrophobic and super-lipophobic properties, namely they are super-“amphiphobic” surfaces.

The multipoint hydrogen-bonded complex 1 (R=alkanoyl) is readily formed between a ferrocene-modified artificial receptor and a dinucleotide. This principle can be used effectively in highly selective, large-scale separations of dinucleotides from mixtures of mono- and oligonucleotides. The process is economically viable and environmentally friendly.

45 000 electrons per molecule per second: such currents and a rectification ratio of 5.38 at 2.2 V were detected between oxide-free Au electrodes for a Langmuir–Blodgett monolayer of the D⁺–π–A⁻ molecule 1.

Diastereoselectivities as high as 98 % were the result of the photochemical ring-closure of stereochemically pure copper(I) helicates of a chiral oxazoline-substituted 1,2-dithienylethene photochrome (see scheme). The variations in optical rotation that accompany the photochromic event provide a means to read stored information in a nondestructive manner.

The antitumor and antimalarial activity of fish oils may involve the action of phospholipid hydroperoxides. Two such phosphatidylcholines, 1 and 2, bearing the hydroperoxides of docosahexaenoic and eicosapentaenoic acids—the two major fatty acids in fish oils—have been synthesized. In spite of its high degree of unsaturation, 1 is sufficiently stable to permit its use in biological studies.

A tricyclic polyamide receptor threads onto the polyethylene glycol chain of a carbohydrate-attached resin, as shown by gel-phase MAS NMR spectroscopy. This observation led to syntheses of a polymer-supported pseudorotaxane and a porphyrin-stoppered rotaxane (see picture).

Slow magnetic relaxation and hysteresis effects of dynamic origin have been observed above liquid helium temperature in a chain compound (see picture), comprising Co^II centers and organic radicals, without any evidence of phase transition to three-dimensional magnetic order. These results are the first evidence of the slow dynamics predicted for one-dimensional magnetic systems with Ising anisotropy, and they open the possibility of storing information in a single magnetic nanowire.

A 1.87-eV energy gap between the lowest energy excitation maximum and the emission maximum in solution was found for the novel hexanuclear gold(I) sulfido complex 1 (Ar=p-CH₃C₆H₄), which has a heterocubane-type structure. Besides this abnormally large Stokes shift of around 15 000 cm⁻¹, 1 exhibits intense orange luminescence in the solid state.

Sheetlike and helical coordination polymers, {Λ_L-[Ag{Co(L-cys-N,S)(en)₂}](NO₃)₂}_∞ (1) and {Δ_L-[Ag{Co(L-cys-N,S)(en)₂}](NO₃)₂}_∞ (2), were obtained by treating Λ_L- and Δ_L-[Co(L-cys-N,S)(en)₂]⁺ (L-cys=L-cysteinate, en=H₂NCH₂CH₂NH₂) with AgNO₃ in water, respectively. Their structures are comparable to those of the β-sheet and α-helix forms of proteins. Compound 2 undergoes reversible conversion into a third compound on changing the pH of the solution.

Most hydrogenase enzymes have organometallic active sites with CO and CN⁻ as ligands and metal–metal bonds. Recent evidence points to a novel 2-aza-1,3-propanedithiolate cofactor that directly participates in the heterolytic processing of dihydrogen. A close analogue of this cofactor and its organometallic subunit has been synthesized (see picture); spectroscopic, structural, and theoretical analysis of this model provides detailed insights into the properties of the proposed enzyme active site.

A high-throughput fluorescence assay for amidases is demonstrated. It illustrates a new principle in enzyme assays, whereby changes in the pM value during the reaction are recorded (pM=−lg[M], M=free metal ions). An orange fluorescent quinacridone-based ligand 1 is the pM sensor (shown chelated to a reporter metal ion, M²⁺=Cu²⁺ or Ni²⁺) that is used to monitor the release of metal-chelating amino acids by the enzymes acylase I and aminopeptidase.

The irreversible formation of carbonic anhydrase inhibitors from competing building block precursors is templated by the active site of the enzyme itself. The reagents are brought into close proximity of each other in a ternary complex with the enzyme (see scheme).

Nonhazardous and highly selective H₂O₂production! An H₂-permselective membrane (2) has been developed which consists of thin films of Pd–Ag alloy (2b) and oxidized Pd (2c), and a hydrophobic polymer membrane (2d) supported on a tubular membrane (2a) within a reactor wall (1). Hydrogen atoms permeate through the membrane and react with molecular O₂ in a liquid medium (LM; 2 M H₂SO₄).

Stacks of croconate dianions separated by K⁺ ions and H₂O molecules: the crystal structure of potassium croconate dihydrate, K₂(C₅O₅)⋅2 H₂O, isolated and described by Leopold Gmelin more than 170 years ago, has now been established by X-ray analysis (see picture). Since the anions have a formal charge of −2 and an interplanar separation of only 3.30 Å, the structure is not easily explained in terms of a simple ionic model.