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Recent achievements in our laboratory toward the “bottom-up” fabrication of addressable multicomponent molecular entities obtained by self-assembly of C₆₀ and porphyrins on Ag(100) and Ag(111) surfaces are described. Scanning tunneling microscopy (STM) studies on ad-layers constituting monomeric and triply linked porphyrin modules showed that the molecules self-organize into ordered supramolecular assemblies, the ordering of which is controlled by the porphyrin chemical structure, the metal substrate, and the surface coverage. Specifically, the successful preparation of unprecedented two-dimensional porphyrin-based assemblies featuring regular pores on Ag(111) surfaces has been achieved. Subsequent co-deposition of C₆₀ molecules on top of the porphyrin monolayers results in selective self-organization into ordered molecular hybrid bilayers, the organization of which is driven by both fullerene coverage and porphyrin structure. In all-ordered fullerene–porphyrin assemblies, the C₆₀ guests organize, unusually, into long chains and/or two-dimensional arrays. Furthermore, sublimation of C₆₀ on top of the porous porphyrin network reveals the selective long-range inclusion of the fullerene guests within the hosting cavities. The observed mode of the C₆₀ self-assembly originates from a delicate equilibrium between substrate–molecule and molecule–molecule interactions involving charge-transfer processes and conformational reorganizations as a consequence of the structural adaptation of the fullerene–porphyrin bilayer.

A novel series of biaryl-type, meso,meso-linked and planar, triply fused diporphyrin derivatives was prepared and fully characterized together with the corresponding monoporphyrin control compounds. They feature peripheral meso-3-cyanophenyl and meso-3,5-cyanophenyl groups, which have previously been shown to undergo transformation into malonates without perturbation of the porphyrin core and subsequent Bingel addition to fullerene C₆₀. The tetrapyrrolic metal binding sites in the diporphyrin arrays are either complexed to two Zn^II or Cu^II ions, or, in a mixed coordination, to one Cu^II and one Zn^II ion; alternatively, one or both sites remain unoccupied. The interaction between the differentially metallated porphyrin rings was systematically investigated by UV/Vis spectroscopy and electrochemistry. Cyclic voltammetry and differential pulse voltammetry reveal that electronic communication in the diporphyrin arrays varies strongly with the mode of connection (meso,meso-linked or triply fused), the nature of the bound metal ion, and the number of peripheral cyano groups. The electrochemical HOMO–LUMO gap in both series of diporphyrins is strongly but differentially affected by the choice of the inserted metal ions. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

A series of differently substituted 1,3-diethynylallenes (DEAs) have been synthesized, confirming that the previously introduced construction protocols tolerate a variety of functional groups. The new DEAs bear at least one polar group to facilitate enantiomer separations on chiral stationary phases and to allow further functionalization. They are thermally and environmentally stable compounds since bulky substituents next to the cumulene moiety suppress the tendency to undergo [2+2] cyclodimerization. A series of length-defined oligomers were obtained as mixtures of stereoisomers by oxidative coupling of a monomeric DEA under Glaser–Hay conditions. The electronic absorption data indicate a lack of extended π-electron conjugation across the oligomeric backbone due to the orthogonality of the allenic π-systems. Remarkably, even complex mixtures of stereoisomers only yield one single set of NMR signals, which underlines the low stereodifferentiation in acyclic allenoacetylenic structures. Optical resolution of DEAs represents an amazing challenge, and preliminary results on the analytical level are reported. Asymmetric synthesis by Pd-mediated S_N2′-type cross-coupling of an alkyne to an optically pure bispropargylic precursor opens another promising route to optically active allenes with stereoselectivities currently reaching up to 78 % ee. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

In this paper, we describe the structure-based design, synthesis, and biological evaluation of cytosine derivatives and analogues that inhibit IspF, an enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. This pathway is responsible for the biosynthesis of the C₅ precursors to isoprenoids, isopentenyl diphosphate (IPP, 1) and dimethylallyl diphosphate (DMAPP, 2; Scheme 1). The non-mevalonate pathway is the sole source for 1 and 2 in the protozoan Plasmodium parasites. Since mammals exclusively utilize the alternative mevalonate pathway, the enzymes of the non-mevalonate pathway have been identified as attractive new drug targets in the fight against malaria. Based on computer modeling (cf. Figs. 2 and 3), new cytosine derivatives and analogues (Fig. 1) were selected as potential drug-like inhibitors of IspF protein, and synthesized (Schemes 2–5). Determination of the enzyme activity by ¹³C-NMR spectroscopy in the presence of the new ligands showed inhibitory activities for some of the prepared cytosine and pyridine-2,5-diamine derivatives in the upper micromolar range (IC₅₀ values; Table). The data suggest that it is possible to inhibit IspF protein without binding to the polar diphosphate binding site and the side chain of Asp56′, which interacts with the ribose moiety of the substrate and substrate analogues. Furthermore, a new spacious sub-pocket was discovered which accommodates aromatic spacers between cytosine derivatives or analogues (binding to ‘Pocket III’) and rings that occupy the flexible hydrophobic region of ‘Pocket II’. The proposed binding mode remains to be further validated by X-ray crystallography.

In this paper, we describe the synthesis and biological evaluation of highly substituted perhydropyrrolizines that inhibit the peptidyl-prolyl cis/trans isomerase (PPIase) Pin1, an oncogenic target. The enzyme selectively catalyzes the cis/trans isomerization of peptide bonds between a phosphorylated serine or threonine, and proline, thereby inducing a conformational change. Such structural modifications play an important role in many cellular events, such as cell-cycle progression, transcriptional regulation, RNA processing, as well as cell proliferation and differentiation. Based on computer modeling (Fig. 2), the new perhydropyrrolizinone derivatives (−)-1a,b, decorated with two substituents, were selected and synthesized (Schemes 1–3). While enzymatic assays showed no biological activity, ¹⁵N,¹H-HSQC-NMR spectroscopy revealed that (−)-1a,b bind to the WW recognition domain of Pin1, apparently in a mode that does not inhibit PPIase activity. To enforce complexation into the larger active site rather than into the tighter WW domain of Pin1 and to enhance the overall binding affinity, we designed a perhydropyrrolizine scaffold substituted with additional aromatic residues (Fig. 5). A novel, straightforward synthesis towards this class of compounds was developed (Schemes 4 and 5), and the racemic compounds (±)-22a–22d were found to inhibit Pin1 with K_i values (K_i = inhibition constant) in the micromolar range (Table 2). To further enhance the potency of these inhibitors, the optically pure ligands (+)-22a and (+)-33b,c were prepared (Schemes 6 and 7) and shown to inhibit Pin1 with K_i values down to the single-digit micromolar range. According to ¹⁵N,¹H-HSQC-NMR spectroscopy and enzymatic activity assays, binding occurs at both the WW domain and the active site of Pin1. Furthermore, the new synthetic protocol towards perhydropyrrolizines was extended to the preparation of highly substituted perhydroindolizine ((±)-43; Scheme 8) and pyrrolidine ((±)-48a,b; Scheme 9) derivatives, illustrating a new, potentially general access to these highly substituted heterocycles.

Moleküle in Rotation: Ein „Bottom-up“-Ansatz führte zu einem supramolekularen Rotor, der an einen mechanischen Drehschalter erinnert. Durch Selbstorganisation bildet ein funktionalisiertes Porphyrin ein poröses Netzwerk mit chiralen Hohlräumen. Gastmoleküle in diesen Hohlräumen können thermisch oder mit der Spitze eines Rastertunnelmikroskops in Rotation versetzt werden (siehe die Bilder).

A series of donor–acceptor chromophores was prepared in which the spacer separating 4-dimethylanilino (DMA) donor and C(CN)₂ acceptor moieties is systematically varied. All of the new push–pull systems, except 4 b, are thermally stable molecules. In series a, the DMA rings are directly attached to the central spacer, whereas in series b additional acetylene moieties are inserted. X-ray crystal structures were obtained for seven of the new, intensely colored target compounds. In series a, the DMA rings are sterically forced out of the mean plane of the residual π system, whereas the entire conjugated π system in series b is nearly planar. Support for strong donor–acceptor interactions was obtained through evaluation of the quinoid character of the DMA ring and by NMR and IR spectroscopy. The UV/Vis spectra feature bathochromically shifted, intense charge-transfer bands, with the lowest energy transitions and the smallest optical gap being measured for the two-dimensionally extended chromophores 6 a and 6 b. The redox behavior of the push–pull molecules was investigated by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). In the series 1 b, 2 b, 4 b, 5 b, in which the spacer between donor and acceptor moieties is systematically enlarged, the electrochemical gap decreases steadily from 1.94 V (1 b) to 1.53 V (5 b). This decrease is shown to be a consequence of a reduction in the D–A conjugation with increasing spacer length. Degenerate four-wave mixing experiments reveal high third-order optical nonlinearities, pointing to potentially interesting applications of some of the new chromophores in optoelectronic devices.

Die medizinisch-chemische Forschung hat sich in den letzten Jahren Proteinen zugewandt, die wie Proteinkinasen und Proteinphosphatasen eine Phosphatbindungsstelle aufweisen. Dieser Aufsatz versucht, mithilfe von Datenbankrecherchen einen Überblick über die wichtigsten Prinzipien der molekularen Erkennung von Phosphatgruppen durch Enzyme zu geben. 3003 Kristallstrukturen von Proteinen mit gebundenem organischem Phosphat aus der RCSB-Proteindatenbank wurden im Hinblick auf H-Brücken zwischen Protein und Ligand untersucht. Die bekannten Bindungsmotive für Phosphate werden behandelt und Ähnlichkeiten bei der Komplexierung von Phosphaten durch synthetische Rezeptoren hervorgehoben. Eine Analyse der Häufigkeit, mit der spezifische Aminosäuren in unterschiedlichen phosphatbindenden Enzymklassen H-Brücken eingehen, führt zu einer für die Enzymklasse charakteristischen Verteilung. Der Aufsatz zeigt, dass bei strukturbasierter Ligandenentwicklung und -optimierung die Umgebung der Phosphatbindungsstelle sorgfältig mitberücksichtigt werden sollte und weist gleichzeitig auf Alternativen hin, wie diese Bindungstaschen zu füllen sind.

Eine „Klick“-Reaktion – die Cycloaddition von Tetracyanethylen (TCNE) an elektronenreiche Alkine – mit anschließender Retro-Elektrocyclisierung liefert multivalente Charge-Transfer-Chromophore, die bis zu 24 Elektronen aufnehmen. Eine Kaskadenaddition von TCNE und Tetrathiafulvalen (TTF) an Polyine führt zu konjugierten Donor-Akzeptor-substituierten [AB]-Oligomeren mit vielversprechenden optoelektronischen Eigenschaften (siehe Schema).

Fein ausbalanciert: Eine molekulare Torsionswaage, deren Gerüst um ein Indolfragment erweitert wurde, hat die erforderliche Geometrie für die Messung der orthogonalen nichtkovalenten Wechselwirkung eines C-F-Bindungsdipols mit der CO-Gruppe eines Amides (siehe Bild; F grün, O rot, N blau). Es wurden negative freie Wechselwirkungsenthalpien gemessen. Orthogonale dipolare Wechselwirkungen bieten eine Möglichkeit, Protein-Ligand-Komplexe zu stabilisieren und supramolekulare Architekturen aufzubauen.

Hemmung durch H-Brücken: Die Inhibition der tRNA-Guanin-Transglycosylase (TGT) wurde als neuartiger Ansatz zur Bekämpfung von Shigellenbakterien erkannt, und mithilfe des strukturbasierten Wirkstoffdesigns konnte eine Serie hochaffiner Inhibitoren entwickelt werden. Anhand der kristallographischen Daten und einer Analyse der pK_S-Werte wird angenommen, dass das 2-Aminoimidazol des zentralen lin-Benzoguaninkerns protoniert vorliegt und dass die Bildung ladungsverstärkter Wasserstoffbrücken die Komplexe deutlich stabilisiert.

Ein molekularer Korb (siehe Bild) und eine molekulare Röhre können reversibel zwischen einer geschlossenen und einer offenen Konformation geschaltet werden. In ihren geschlossenen Formen bilden diese beiden neuartigen Containermoleküle Einschlussverbindungen mit Cycloalkanen. Durch die Zugabe von Säure kann die Komplexierung vollständig abgeschaltet werden, Neutralisieren mit Base führt wieder zu den ursprünglichen Komplexen.

IspE kinase inhibitors. The first inhibitors for the kinase IspE, an enzyme of the non-mevalonate pathway, are presented. The nonphosphate based inhibitors avoid binding to the ATP site but instead occupy the substrate site and a small, newly detected hydrophobic subpocket at the active site of IspE. With appropriate filling of this pocket, competitive inhibition constants K_ic in the upper nanomolar range are measured.

This review describes simple and useful concepts for predicting and tuning the pK_a values of basic amine centers, a crucial step in the optimization of physical and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pK_a values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chemistry. Next, the changes in pK_a of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivatives are systematically analyzed, leading to the derivation of simple rules for pK_a prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pK_a predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.

Subversive substrates. Replacing the 3,4-dichlorophenyl entity of diphenyl sulfide-based trypanothione reductase (TR) inhibitors for a nitrofuran moiety led to a new class of inhibitors with a distinctively changed inhibition mode. These ligands do not only undergo mixed competitive–uncompetitive inhibition but additionally act as subversive substrates for TR.

Abstract

Fluorine substituents have become a widespread and important drug component, their introduction facilitated by the development of safe and selective fluorinating agents. Organofluorine affects nearly all physical and adsorption, distribution, metabolism, and excretion properties of a lead compound. Its inductive effects are relatively well understood, enhancing bioavailability, for example, by reducing the basicity of neighboring amines. In contrast, exploration of the specific influence of carbon-fluorine single bonds on docking interactions, whether through direct contact with the protein or through stereoelectronic effects on molecular conformation of the drug, has only recently begun. Here, we review experimental progress in this vein and add complementary analysis based on comprehensive searches in the Cambridge Structural Database and the Protein Data Bank.

Spinning tops: A supramolecular rotary device, reminiscent of a mechanical rotary switch, was engineered by a bottom-up approach. Self-assembly of a functionalized porphyrin molecule leads to the formation of a porous network that features chiral cavities. These serve as hosts for molecular guests, which can be induced to rotate either thermally or by using the scanning tunneling microscopy tip (see images).

A molecular basket (see picture) and a molecular tube can be reversibly switched between closed and open forms. In their closed forms, these novel container molecules encapsulate cycloalkanes such as cyclohexane. Their binding capabilities can be completely turned off by the addition of acid. Neutralization with base leads to restoration of the original complexes.

Drug-discovery research in the past decade has seen an increased selection of targets with phosphate recognition sites, such as protein kinases and phosphatases, in the past decade. This review attempts, with the help of database-mining tools, to give an overview of the most important principles in molecular recognition of phosphate groups by enzymes. A total of 3003 X-ray crystal structures from the RCSB Protein Data Bank with bound organophosphates has been analyzed individually, in particular for H-bonding interactions between proteins and ligands. The various known binding motifs for phosphate binding are reviewed, and similarities to phosphate complexation by synthetic receptors are highlighted. An analysis of the propensities of amino acids in various classes of phosphate-binding enzymes showed characteristic distributions of amino acids used for phosphate binding. This review demonstrates that structure-based lead development and optimization should carefully address the phosphate-binding-site environment and also proposes new alternatives for filling such sites.

It all clicks into place: The cycloaddition of tetracyanoethylene (TCNE) to electron-rich alkynes (“click” reaction) followed by retro-electrocyclization affords multivalent charge-transfer chromophores that accept up to 24 electrons. The cascade additions of TCNE and tetrathiafulvalene (TTF) to polyynes provides access to conjugated donor–acceptor-substituted [AB] oligomers with promising optoelectronic properties (see scheme).

Improving inhibition: tRNA-Guanine transglycosylase (TGT) is a newly recognized target to reduce the pathogenicity of disease-causing Shigella bacteria. A potent family of inhibitors of this enzyme has been developed by structure-based design. Crystallographic data and pK_a analysis suggest that the aminoimidazole moiety of the central lin-benzoguanine scaffold is protonated and stabilization of the complexes results from charge-assisted hydrogen bonding.

Finding the right balance: An indole-extended molecular torsion balance has the geometry for measuring a truly orthogonal noncovalent interaction between a CF bond dipole and an amide carbonyl group (see picture, green F, red O, blue N). Employing a double-mutant cycle approach, negative interaction free enthalpies were determined. Thus orthogonal dipolar interactions can be a new tool for stabilizing protein–ligand complexes and assembling supramolecular architectures.

Resorcin[4]arene cavitands with four quinoxaline bridges are a family of macrocycles that adopt, at elevated temperature, a contracted, vase-type conformation, capable of guest inclusion, whereas at low temperature they switch to an expanded, kite-type conformation with a large flat surface. The present investigations lay the foundation for the use of such dynamic cavitands as miniaturized mechanical grippers for supramolecular construction at the single-molecule level. New vase–kite switching modes, stimulated by pH changes or stoichiometric metal-ion complexation, have been discovered and monitored by ¹H NMR and optical absorption spectroscopy. The solid-state geometries of the two states have been revealed by X-ray crystallography, and the kinetics and thermodynamics of the switching processes in solution as well as their solvent dependency has been investigated in great detail. Monolayers of the cavitand in the vase form have been studied by scanning tunneling microscopy at molecular resolution; conformational switching is also observed in Langmuir monolayers at the air/water interface. Synthetic protocols have been developed for preparation of partially and asymmetrically bridged resorcin[4]arene cavitands, which are also shown to undergo conformational switching. These synthetic advances pave the way to new, dynamic molecular receptors for steroids, tetrathiofulvalene-bridged grippers with the potential to undergo electrochemically induced conformational switching, and systems with greatly extended, rigid cavity walls functionalized at the termini by dipyrrometheneboron difluoride dyes. The latter cavitands are shown by fluorescence resonance energy transfer to undergo geometrically precisely defined motions between a contracted (≈ 7 Å linear extension) and a strongly expanded (≈ 7 nm linear extension) state.

Miniaturized molecular grippers for supramolecular construction are described by François Diederich and co-workers on p. 147. These grippers are based on resorcin[4]arene cavitands with four quinoxaline bridges; these macrocycles can be switched between a closed (left) and open (right) configuration via temperature changes, pH changes, or stoichiometric metal-ion complexation. The background is a scanning tunneling microscopy image of a self-assembled monolayer of the closed cavitands. Individual gripper “fingers” are seen as lighter spots, four per gripper, which in turn pack into a well-ordered array.

Resorcin[4]arene cavitands with four quinoxaline bridges are a family of macrocycles that adopt, at elevated temperature, a contracted, vase-type conformation, capable of guest inclusion, whereas at low temperature they switch to an expanded, kite-type conformation with a large flat surface. The present investigations lay the foundation for the use of such dynamic cavitands as miniaturized mechanical grippers for supramolecular construction at the single-molecule level. New vase–kite switching modes, stimulated by pH changes or stoichiometric metal-ion complexation, have been discovered and monitored by ¹H NMR and optical absorption spectroscopy. The solid-state geometries of the two states have been revealed by X-ray crystallography, and the kinetics and thermodynamics of the switching processes in solution as well as their solvent dependency has been investigated in great detail. Monolayers of the cavitand in the vase form have been studied by scanning tunneling microscopy at molecular resolution; conformational switching is also observed in Langmuir monolayers at the air/water interface. Synthetic protocols have been developed for preparation of partially and asymmetrically bridged resorcin[4]arene cavitands, which are also shown to undergo conformational switching. These synthetic advances pave the way to new, dynamic molecular receptors for steroids, tetrathiofulvalene-bridged grippers with the potential to undergo electrochemically induced conformational switching, and systems with greatly extended, rigid cavity walls functionalized at the termini by dipyrrometheneboron difluoride dyes. The latter cavitands are shown by fluorescence resonance energy transfer to undergo geometrically precisely defined motions between a contracted (≈ 7 Å linear extension) and a strongly expanded (≈ 7 nm linear extension) state.

A variety of achiral and chiral macrocyclic oligomalonates were synthesised in a one-step procedure through condensation of malonyl dichloride with α,ω-diols. We have investigated the applicability of this method by varying the length and type of the spacers in the diol. Product distribution analysis revealed that the preferential formation of monomeric, dimeric, or trimeric macrocyclic malonates can be controlled by choosing diols with specific spacers connecting the hydroxy groups. Of special interest are the macrocyclic bismalonates, as they show pronounced crystallisability and arrange into columnar motifs in the solid state. They feature distinctive dihedral angles: all ester moieties adopt anti conformations whereas the planes of the carboxy moieties of each malonate residue arrange in an approximately orthogonal fashion. The latter geometry is enforced by the macrocyclic structures, as revealed by a conformational search in the Cambridge Structural Database. The X-ray diffraction data show that C=O···H–C, and C–O···H–C hydrogen bonds stabilise the columnar arrangement of the dimeric rings with formation of tubular assemblies. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Inhibition of the enzyme catechol O-methyltransferase (COMT) represents a viable strategy for regulation of the catabolism of catecholamine neurotransmitters or their precursors, and is of considerable interest in the therapy of Parkinson's disease. Herein, we report the development of a new generation of potent bisubstrate inhibitors of COMT derived from nitro-substituted ligand 1 (K_i = 28 nM, Table 1), which achieve high biological activity despite the lack of a NO₂ substituent on the catechol moiety. Their synthesis takes advantage of a convergent approach, in which a series of functionalized catechol intermediates is prepared (Schemes 2–7) and coupled to a common adenosine-derived allylic amine building block (Scheme 8). Biological activities of the newly synthesized inhibitors, determined by in vitro enzymatic assay and kinetic studies, clearly demonstrate that high inhibitory potency of the bisubstrate inhibitors is not correlated with the pK_a of the catechol OH groups. Aromatic residues, connected to the catechol via a biaryl-type linkage, were found to maximally benefit from additional favorable hydrophobic interactions with the enzyme and thus to be preferred replacements of the NO₂ group in 1. A competitive kinetic inhibition mechanism (Fig. 2) with respect to the cofactor binding site was confirmed in all cases, supporting a bisubstrate inhibition mode for inhibitors 2–19.

We report the synthesis of novel resorcin[4]arene-based cavitands featuring two extended bridges consisting of quinoxaline-fused TTF (tetrathiafulvalene) moieties. In the neutral form, these cavitands were expected to adopt the vase form, whereas, upon oxidation, the open kite geometry should be preferred due to Coulombic repulsion between the two TTF radical cations (Scheme 2). The key step in the preparation of these novel molecular switches was the P(OEt)₃-mediated coupling between a macrocyclic bis(1,3-dithiol-2-thione) and 2 equiv. of a suitable 1,3-dithiol-2-one. Following the successful application of this strategy to the preparation of mono-TTF-cavitand 3 (Scheme 3), the synthesis of the bis-TTF derivatives 2 (Scheme 4) and 19 (Scheme 5) was pursued; however, the target compounds could not be isolated due to their insolubility. Upon decorating both the octol bowl and the TTF cavity rims with long alkyl chains, the soluble bis-TTF cavitand 23 was finally obtained, besides a minor amount of the novel cage compound 25a featuring a highly distorted TTF bridge (Scheme 6). In contrast to 25a, the deep cavitand 23 undergoes reversible vase  kite switching upon lowering the temperature from 293 to 193 K (Fig. 1). Electrochemical studies by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) provided preliminary evidence for successful vase  kite switching of 23 induced by the oxidation of the TTF cavity walls.

This paper describes the rational design, synthesis, and biological evaluation of a new generation of inhibitors of the bacterial enzyme tRNA-guanine transglycosylase (TGT), which has been identified as a new target in the fight against bacillary dysentery (Shigellosis). The enzyme catalyzes the exchange of guanine in the anticodon wobble position of tRNA by the modified base preQ₁, a guanine derivative, according to a ping-pong mechanism involving a covalent TGT-tRNA intermediate (Fig. 2). Based on computer modeling (Fig. 3), lin-benzoguanine (6-aminoimidazol[4,5-g]quinazolin-8(7H)-one (2)) was selected as an extended central scaffold, to form up to seven in-plane intermolecular H-bonds with the protein while sandwiching between Tyr106 and Met260. Versatile synthetic protocols were developed for the synthesis of 2, and derivatives with phenyl, benzyl, and 2-phenylethyl side chains (i.e., 16, 17a, and 12a, 12b, 13, 17, resp.) to reach into the lipophilic pocket lined by Val282, Val45, and Leu68 (Schemes 1–3). To account for the limited solubility of the new ligands and in consequence of a recently developed detailed understanding of the mechanism of TGT catalysis (Fig. 2), the enzyme kinetic assay was completely redesigned, providing competitive (K_ic) and uncompetitive (K_iu) inhibition constants with respect to tRNA binding by TGT. The modifications of the various parameters in the new assay are described in detail. Binding affinities of the new inhibitors were found to be in the single-digit micromolar range (K_ic values, Fig. 8). Decoration of the lin-benzoguanine scaffold with lipophilic residues only gave a modest improvement in biological activity which was explained on structural grounds with the help of four crystal structures (Fig. 10) obtained by soaking the protein with inhibitors 2 and 12a–12c. Both biochemical and biostructural analyses reported in this paper provide a fertile basis for the development of more potent future generations of TGT inhibitors.

In the completion of our fluorine scan of tricyclic inhibitors to map the fluorophilicity/fluorophobicity of the thrombin active site, a series of 11 new ligands featuring alkyl, alkenyl, and fluoroalkyl groups was prepared to explore fluorine effects on binding into the hydrophobic proximal (P) pocket, lined by Tyr 60A and Trp 60D, His 57, and Leu 99. The synthesis of the tricyclic scaffolds was based on the 1,3-dipolar cycloaddition of azomethine ylides, derived from L-proline and 4-bromobenzaldehyde, with N-(4-fluorobenzyl)maleimide. Introduction of alkyl, alkenyl, and partially fluorinated alkyl residues was achieved upon substitution of a sulfonyl group by mixed Mg/Zn organometallics followed by oxidation/deoxyfluorination, as well as oxidation/reduction/deoxyfluorination sequences. In contrast, the incorporation of perfluoroalkyl groups required a stereoselective nucleophilic addition reaction at the “upper” carbonyl group of the tricycles, thereby yielding scaffolds with an additional OH, F, or OMe group, respectively. All newly prepared inhibitors showed potent biological activity, with inhibitory constants (K_i values) in the range of 0.008–0.163 μM. The X-ray crystal structure of a protein–ligand complex revealed the exact positioning of a difluoromethyl substituent in the tight P pocket. Fluorophilic characteristics are attributed to this hydrophobic pocket, although the potency of the inhibitors was found to be modulated by steric rather than electronic factors.

Strukturbasiert entworfene Hemmstoffe (wie 1) von IspF, einem Schlüsselenzym im „Nicht-Mevalonat-Weg“ der Terpenbiosynthese, wurden synthetisiert und auf ihre biologische Aktivität untersucht. Ihre Affinität gegen IspF aus E. coli wurde durch Fluoreszenztitration bestimmt. Der röntgenographisch ermittelte Bindungsmodus von zwei Liganden in Komplexen mit IspF und einem Zn^II-Ion liefert Erkenntnisse für die Entwicklung niedermolekularer, Wirkstoff-ähnlicher Hemmstoffe.

Das passt! Eine neue Klasse von Aspartylprotease-Hemmern wirkt selektiv und hoch potent gegen die Plasmepsine I, II und IV des Malaria-Erregers, während sie die nahe verwandten humanen Aspartylproteasen Cathepsin D und E nur schwach hemmt. Die Inhibitoren binden mithilfe einer neuartigen „Diaminklammer“ an die katalytische Diade (siehe Bild).

A wide variety of monomeric and oligomeric, donor-substituted 1,1,4,4-tetracyanobutadienes (TCBDs) have been synthesized by [2+2] cycloaddition between tetracyanoethylene (TNCE) and donor-substituted alkynes, followed by electrocyclic ring opening of the initially formed cyclobutenes. Reaction yields are often nearly quantitative but can be affected by the electron-donating power and steric demands of the alkyne substituents. The intramolecular charge-transfer (CT) interactions between the donor and TCBD acceptor moieties were comprehensively investigated by X-ray crystallography, electrochemistry, UV-visible spectroscopy, and theoretical calculations. Despite the nonplanarity of the new chromophores, which have a substantial twist between the two dicyanovinyl planes, efficient intramolecular CT interactions are observed, and the crystal structures demonstrate a high quinoid character in strong donor substituents, such as N,N-dimethylanilino (DMA) rings. The maxima of the CT bands shift bathochromically upon reduction of the amount of conjugative coupling between strong donor and acceptor moieties. Each TCBD moiety undergoes two reversible, one-electron reduction steps. Thus, a tri-TCBD derivative with a 1,3,5-trisubstituted benzene core shows six reversible reduction steps within an exceptionally narrow potential range of 1.0 V. The first reduction potential E_red,1 is strongly influenced by the donor substitution: introduction of more donor moieties causes an increasingly twisted TCBD structure, a fact that results in the elevation of the LUMO level and, consequently, a more difficult first reduction. The potentials are also strongly influenced by the nature of the donor residues and the extent of donor–acceptor coupling. A careful comparison of electrochemical data and the correlation with UV-visible spectra made it possible to estimate unknown physical parameters such as the E_red,1 of unsubstituted TCBD (−0.31 V vs Fc⁺/Fc) as well as the maxima of highly broadened CT bands. Donor-substituted TCBDs are stable molecules and can be sublimed without decomposition. With their high third-order optical nonlinearities, as revealed in preliminary measurements, they should become interesting chromophores for ultra-thin film formation by vapor deposition techniques and have applications in opto-electronic devices.

The controllable switching of suitably bridged resorcin[4]arene cavitands between a “vase” conformation, with a cavity capable of guest inclusion, and a “kite” conformation, featuring an extended flattened surface, provides the basis for ongoing developments of dynamic molecular receptors, sensors, and molecular machines. This paper describes the synthesis, X-ray crystallographic characterization, and NMR analysis of the “vase–kite” switching behavior of a fully pyrazine-bridged cavitand and five other mixed-bridged quinoxaline-bridged cavitands with one methylene, phosphonate, or phosphate bridge. The pyrazine-bridged resorcin[4]arene cavitand displayed an unexpectedly high preference for the kite conformation in nonpolar solvents, relative to the quinoxaline-bridged analogue. This observation led to extensive solvent-dependent switching studies that provide a detailed picture of how solvent affects the thermal vase–kite equilibration. As for any thermodynamic process in the liquid phase, the conformational equilibrium is affected by how the solvent stabilizes the two individual states. Suitably sized solvents (benzene and derivatives) solvate the cavity of the vase form and reduce the propensity for the vase-to-kite transition. Correspondingly, the kite geometry becomes preferred in bulky solvents such as mesitylene, incapable of penetrating the vase cavity. As proposed earlier by Cram, the kite form is preferred at low temperatures due to the more favorable enthalpy of solvation of the enlarged surface. Furthermore, the kite conformation is more preferred in solvents with substantial hydrogen-bonding acidity: weak hydrogen-bonding interactions between the mildly basic quinoxaline and pyrazine nitrogen atoms and solvent molecules are more efficient in the open kite than in the closed vase form. Vase-to-kite conversion is entirely absent in dipolar aprotic solvents lacking any H-bonding acidity. Thermal vase–kite switching requires fully quinoxaline- or pyrazine-bridged cavitands, whereas pH-controlled switching is also applicable to systems incorporating only two or three such bridges.

Double Bingel cyclopropanation of C₇₀ with bismalonates featuring Tröger base derivatives as chiral spacers afforded bisadducts with almost perfect regio- and stereoselectivity. The excellent directing property of these rigidly folded spacers in the remote functionalization of the higher fullerene was further highlighted by the selective formation of a product with a novel bisaddition pattern involving the C(7)C(22) and C(33)C(34) bonds of C₇₀. Enantiomerically pure bisadducts of C₇₀ were prepared by highly diastereoselective transformations of bismalonates incorporating optically pure Tröger base tethers. The absolute configuration of these bisadducts was established by comparison of circular dichroism (CD) spectra with data reported in the literature. For the first time, optically active tetrakisadducts of a fullerene were prepared by two sequential chiral-spacer-controlled remote functionalizations.

A new tris(tetrathiafulvaleno)dodecadehydro[18]annulene with six peripheral n-hexyl substituents was prepared by oxidative Glaser–Hay cyclization of a corresponding diethynylated tetrathiafulvalene (TTF) precursor. The electronic properties of the neutral and oxidized species were studied by both UV/Vis absorption spectroscopy and electrochemistry. From these studies, it transpires that the strongly violet-colored macrocycle does not aggregate in solution to any significant degree, which was confirmed by ¹H NMR spectroscopy. This reluctance towards aggregation contrasts that observed for related TTF–annulenes containing other peripheral substitutents. Oxidation of the TTF–annulene occurs in two three-electron steps as inferred from both the peak amplitudes and the spectroelectrochemical study. We find that the tris(TTF)-fused dehydro[18]annulene is more difficult to oxidize (by +0.20 V) than the silyl-protected diethynylated mono-TTF precursor. In contrast, the first vertical ionization energy calculated at the B3 LYP/6–311+G(2d,p) level for the parent tris(TTF)-fused dehydro[18]annulene devoid of peripheral hexyl substituents is in fact lower (by 0.44 eV). Moreover, the surface morphology of 1 d drop-cast on a mica substrate was investigated by atomic force microscopy (AFM). Crystalline domains with slightly different orientations were observed. The thickness of individual layers seen in the crystalline domains and the thickness of a monolayer obtained from a very dilute solution were determined to 1.8–1.9 nm. This thickness corresponds to the diameter of the macrocycle and the layers seen in the film are apparently formed when the molecules stack in the horizontal direction relative to the substrate.

A series of 16 tricyclic thrombin inhibitors was prepared by using the 1,3-dipolar cycloaddition of azomethine ylides derived from 3- or 4-hydroxyproline and 4-bromobenzaldehyde, with N-(4-fluorobenzyl)maleimide as the key step. The terminal pyrrolidine ring of the inhibitors was systematically substituted to explore the potential bioisosteric behavior of CF, COH, and COMe residues pointing into the environment of the catalytic center of a serine protease. X-ray crystal structure analyses revealed a distinct puckering preference of this ring. Substitution by F, HO, and MeO has a strong effect on the basicity of the adjacent pyrrolidine nitrogen center which originates from two σ-inductive pathways between this center and the electronegative O and F atoms. gem-Difluorination decreases the pK_a value of this tertiary amine center to <2, making the conjugated ammonium ion a moderately strong acid. Unexpectedly, F substitution next to the nitrogen center reduced the lipophilicity of the ligands, as revealed by measurements of the logarithmic partition coefficient log D. The biological assays showed that all compounds are thrombin inhibitors with activities between K_i=0.08 and 2.17 μM. Bioisosteric behavior of F, HO, and MeO substituents was observed. Their electronegative F and O atoms undergo energetically similar polar interactions with positively polarized centers, such as the N atom of His 57 which is hydrogen bonded to the catalytic Ser 195. However, for energetically similar polar interactions of CF, COH, and COMe to occur, sufficient space is necessary for the accommodation of the Me group of the COMe residue, and a H-bond acceptor must be present to prevent unfavorable desolvation of the COH residue.

Inhibition of the enzyme catechol O-methyltransferase offers a therapeutic handle to regulate the catabolism of catecholamine neurotransmitters, providing valuable assistance in the treatment of CNS disorders such as Parkinson's disease. A series of ribose-modified bisubstrate inhibitors of COMT featuring 2′-deoxy-, 3′-deoxy-, 2′-aminodeoxy-3′-deoxy-, and 2′-deoxy-3′-aminodeoxyribose-derived central moieties and analogues containing the carbocyclic skeleton of the natural product aristeromycin were synthesized and evaluated to investigate the molecular recognition properties of the ribose binding site in the enzyme. Key synthetic intermediates in the ribose-derived series were obtained by deoxygenative [1,2]-hydride shift rearrangement of adenosine derivatives; highlights in the synthesis of carbocyclic aristeromycin analogues include a diastereoselective cyclopropanation step and nucleobase introduction with a modified Mitsunobu protocol. In vitro biological evaluation and kinetic studies revealed dramatic effects of the ribose modification on binding affinity: 3′-deoxygenation of the ribose gave potent inhibitors (IC₅₀ values in the nanomolar range), which stands in sharp contrast to the remarkable decrease in potency observed for 2′-deoxy derivatives (IC₅₀ values in the micromolar range). Aminodeoxy analogues were only weakly active, whereas the change of the tetrahydrofuran skeleton to a carbocycle unexpectedly led to a complete loss of biological activity. These results confirm that the ribose structural unit of the bisubstrate inhibitors of COMT is a key element of molecular recognition and that modifications thereof are delicate and may lead to surprises.

Starting from (Z)-bis(N,N-diisopropylanilino)-substituted tetraethynylethene (TEE), perethynylated octadehydro[12]- and dodecadehydro[18]annulenes were prepared by oxidative Hay coupling. The dodecadehydro[18]annulene with six peripheral N,N-diisopropylanilino substituents was characterized by X-ray crystallography. Elongation of the Z-bisdeprotected TEE by Cadiot–Chodkiewicz coupling with 1-bromo-2-(triisopropylsilyl)ethyne provided a Z-configured bis(butadiyne), which after alkyne deprotection afforded under Hay coupling conditions N,N-diisopropylanilino-substituted perethynylated hexadecadehydro[20]- and tetracosadehydro[30]an-nulenes. The diisopropylanilino substituents enhance the properties of these unprecedented all-carbon perimeters in several distinct ways. They ensure their solubility, increase their stability, and importantly, engage in strong intramolecular charge-transfer interactions with the electron-accepting all-carbon cores, resulting in intense, bathochromically shifted charge-transfer bands in the UV/Vis spectra. The charge-transfer character of these bands was confirmed by protonation-neutralization experiments. The redox properties of the new carbon-rich chromophores were investigated by cyclic voltammetry and rotating disk voltammetry, which indicated different redox behavior for aromatic (4n+2 π electrons) and antiaromatic (4n π electrons) dehydroannulenes.

The photophysical, electrochemical, and self-assembly properties of a novel triply fused Zn^II–porphyrin trimer were investigated and compared to the properties of a triply fused porphyrin dimer and the analogous monomer. The trimer exhibited significantly red-shifted absorption bands relative to the corresponding monomer and dimer. Electrochemical investigations indicated a clear trend in redox properties amongst the three porphyrin structures, with the lowest oxidation potential and the lowest HOMO–LUMO gap exhibited by the triply fused trimer. This electrochemical behavior is attributed to the extensive π-electron delocalization in the trimeric structure relative to the monomer and dimer. Additionally, it was found that the trimer forms extremely strong and nearly irreversible supramolecular interactions with single-walled carbon nanotubes (SWNTs), resulting in stable solutions of porphyrin–nanotube complexes in THF. Formation of these complexes required the addition of trifluoroacetic acid (TFA) to the solvent. This allowed the oligomers to make close contact with the nanotubes, enabling the formation of stable supramolecular assemblies. Atomic force microscopy (AFM) was used to observe the supramolecular porphyrin–nanotube complexes and revealed that the porphyrin trimer formed a uniform coating on the SWNTs. Height profiles indicated that nanotube bundles could be exfoliated into either individual tubes or very small bundles by exposure to the porphyrin trimer during sonication.

Nanoscale data recording on high- quality crystalline thin films of N,N- dimethylanilino donor-substituted tricyanoethynylethene acceptors has been achieved by scanning tunneling microscopy with a storage density of about 10¹³ bits cm^–2 (see Figure). The recording is based on an electric-field-induced intermolecular charge-transfer mechanism, which is strongly influenced by the ordered, antiparallel packing mode of the dipolar donor–acceptor molecules in the film.

The synthesis of a series (1–5) of fullerene and Zn(II)-porphyrin amphiphiles with polar dibenzo[24]crown-8 headgroups is described. Their ability to form Langmuir monolayers at the air-water interface was investigated in a systematic study. The Langmuir films were characterized by their surface pressure versus molecular area isotherms, compression and expansion cycles, and Brewsterangle microscopy. Complexation of larger alkali metal cations (K⁺ and Cs⁺) by the polar headgroups leads to higher molecular area requirements and a better anchoring to the aqueous subphase. The monolayers of the porphyrin-(dibenzo[24]crown-8) conjugates were transferred as Langmuir—Blodgett films onto glass slides and the films characterized by UV-vis spectroscopy and grazing-incidence X-ray diffraction. Good evidence was obtained that the porphyrin-fullerene-crown ether triad 5 adopts a sandwich geometry in the LB films. In such an arrangement, the electron-attracting carbon sphere benefits from attractive interactions with the sandwiching electron-rich porphyrin and crown ether chromophores. The described films could have potential applications as functional materials in optical and electronic technology.

We report a short synthetic route that provides optically active 2-substituted hexahydro-1H-pyrrolizin-3-ones in four steps from commercially available Boc (tert-but(oxy)carbonyl))-protected proline. Diastereoisomers (−)-11 and (−)-12 were assembled from the proline-derived aldehyde (−)-8 and ylide 9via a Wittig reaction and subsequent catalytic hydrogenation (Scheme 3). Cleavage of the Boc protecting group under acidic conditions, followed by intramolecular cyclization, afforded the desired hexahydro-1H-pyrrolizinones (−)-1 and (+)-13. Applying the same protocol to ylide 19 afforded hexahydro-1H-pyrrolizinones (−)-25 and (−)-26 (Scheme 5). The absolute configuration of the target compounds was determined by a combination of NMR studies (Figs. 1 and 2) and X-ray crystallographic analysis (Fig. 3).

We report the synthesis and physical properties of novel fullerene–oligoporphyrin dyads. In these systems, the C-spheres are singly linked to the terminal tetrapyrrolic macrocycles of rod-like meso,meso-linked or triply-linked oligoporphyrin arrays. Monofullerene–mono(Zn^II porphyrin) conjugate 3 was synthesized to establish a general protocol for the preparation of the target molecules (Scheme 1). The synthesis of the meso,meso-linked oligopophyrin–bisfullerene conjugates 4–6, extending in size up to 4.1 nm (6), was accomplished by functionalization (iodination followed by Suzuki cross-coupling) of the two free meso-positions in oligomers 21–23 (Schemes 2 and 3). The attractive interactions between a fullerene and a Zn^II porphyrin chromophore in these dyads was quantified as ΔG=−3.3 kcal mol⁻¹ by variable-temperature (VT) ¹H-NMR spectroscopy (Table 1). As a result of this interaction, the C-spheres adopt a close tangential orientation relative to the plane of the adjacent porphyrin nucleus, as was unambiguously established by ¹H- and ¹³C-NMR (Figs. 9 and 10), and UV/VIS spectroscopy (Figs. 13–15). The synthesis of triply-linked diporphyrin–bis[60]fullerene conjugate 8 was accomplished by Bingel cyclopropanation of bis-malonate 45 with two C₆₀ molecules (Scheme 5). Contrary to the meso,meso-linked systems 4–6, only a weak chromophoric interaction was observed for 8 by UV/VIS spectroscopy (Fig. 16 and Table 2), and the ¹H-NMR spectra did not provide any evidence for distinct orientational preferences of the C-spheres. Comprehensive steady-state and time-resolved UV/VIS absorption and emission studies demonstrated that the photophysical properties of 8 differ completely from those of 4–6 and the many other known porphyrin–fullerene dyads: photoexcitation of the methano[60]fullerene moieties results in quantitative sensitization of the lowest singlet level of the porphyrin tape, which is low-lying and very short lived. The meso,meso-linked oligoporphyrins exhibit ¹O₂ sensitization capability, whereas the triply-fused systems are unable to sensitize the formation of ¹O₂ because of the low energy content of their lowest excited states (Fig. 18). Electrochemical investigations (Table 3, and Figs. 19 and 20) revealed that all oligoporphyrin arrays, with or without appended methano[60]fullerene moieties, have an exceptional multicharge storage capacity due to the large number of electrons that can be reversibly exchanged. Some of the Zn^II porphyrins prepared in this study form infinite, one-dimensional supramolecular networks in the solid state, in which the macrocycles interact with each other either through H-bonding or metal ion coordination (Figs. 6 and 7).

A new class of nonpeptidic inhibitors of the Zn^II-dependent metalloprotease neprilysin with IC₅₀ values in the nanomolar activity range (0.034–0.30 μM) were developed based on structure-based de novo design (Figs. 1 and 2). The inhibitors feature benzimidazole and imidazo[4,5-c]pyridine moieties as central scaffolds to undergo H-bonding to Asn542 and Arg717 and to engage in favorable π-π stacking interactions with the imidazole ring of His711. The platform is decorated with a thiol vector to coordinate to the Zn^II ion and an aryl residue to occupy the hydrophobic S1′ pocket, but lack a substituent for binding in the S2′ pocket, which remains closed by the side chains of Phe106 and Arg110 when not occupied. The enantioselective syntheses of the active compounds (+)-1, (+)-2, (+)-25, and (+)-26 were accomplished using Evans auxiliaries (Schemes 2, 4, and 5). The inhibitors (+)-2 and (+)-26 with an imidazo[4,5-c]pyridine core are ca. 8 times more active than those with a benzimidazole core ((+)-1 and (+)-25) (Table 1). The predicted binding mode was established by X-ray analysis of the complex of neprilysin with (+)-2 at 2.25-Å resolution (Fig. 4 and Table 2). The ligand coordinates with its sulfanyl residue to the Zn^II ion, and the benzyl residue occupies the S1′ pocket. The 1H-imidazole moiety of the central scaffold forms the required H-bonds to the side chains of Asn542 and Arg717. The heterobicyclic platform additionally undergoes π-π stacking with the side chain of His711 as well as edge-to-face-type interactions with the side chain of Trp693. According to the X-ray analysis, the substantial advantage in biological activity of the imidazo-pyridine inhibitors over the benzimidazole ligands arises from favorable interactions of the pyridine N-atom in the former with the side chain of Arg102. Unexpectedly, replacement of the phenyl group pointing into the deep S1′ pocket by a biphenyl group does not enhance the binding affinity for this class of inhibitors.

Neprilysin (NEP; neutral endopeptidase EC 3.4.24.11) is a Zn^II-dependent, membrane-bound endopeptidase. NEP is widely distributed in the organs, particularly in the kidneys and lungs, and it is involved in the metabolism of a number of smaller regulatory peptides. Inhibition of NEP has been proposed as a potential target for analgesic and antihypertensive therapies. In this study, new nonpeptidic inhibitors of neprilysin ((±)-1, (±)-43, (±)-45, and (±)-46; Table) were designed, based on the X-ray crystal structure of NEP complexed to phosphoramidon (Fig. 1). They feature an imidazole ring as the central scaffold, acting as a peptide bond isoster to undergo H-bonding with the side chains of Asn542 and Arg717 (Fig. 2). The scaffold is decorated with a thiol group to ligate to the Zn^II ion and two aromatic residues to bind into the hydrophobic S1′ and S2′ pockets. The synthesis of the new inhibitors was approached by two routes (Schemes 1–4 and 5–8), with the second one involving a double directed ortho-metallation of the imidazole platform and a Stille cross-coupling, providing the desired target molecules as hydrochloride salts. In a fluorescence assay, inhibitors (±)-1, (±)-43, (±)-45, and (±)-46 all exhibit IC₅₀ values in the single-digit micromolar activity range (2–4 μM, Table), which validates the binding mode postulated by modeling. Useful guidelines for a next lead optimization cycle were obtained in several control runs.

We report the synthesis of the first- (G1) and second-generation (G2) dendritic Fe^II porphyrins 1⋅Fe–4⋅Fe (G1) and 6⋅Fe (G2) bearing distal H-bond donors ideally positioned for stabilization of Fe^IIO₂ adducts by H-bonding (Fig. 1). A first approach towards the construction of these novel biomimetic systems failed unexpectedly: the Suzuki cross-coupling between appropriately functionalized Zn^II porphyrins and ortho-ethynylated aryl derivatives, serving as anchors for the distal H-bond donor moieties, was unsuccessful (Schemes 1, 3, and 5), presumably due to steric hindrance resulting from unfavorable coordination of the ethynyl residue to the Pd species in the catalytic cycle (Scheme 6). The target molecules were finally prepared by a route in which the ortho-ethynylated meso-aryl ring is introduced during porphyrin construction in a mixed condensation involving the two dipyrrylmethanes 33 and 34, and aldehyde 36 (Schemes 7 and 8). Following attachment of the dendrons (Scheme 11), the distal H-bond donors were introduced by Sonogashira cross-coupling (Scheme 12), and subsequent metallation afforded the dendritic Fe^II porphyrins 1⋅Fe–6⋅Fe. ¹H-NMR Spectroscopy proved the location of the H-bond donor moiety atop the porphyrin surface, and X-ray crystal-structure analysis of model system 45 (Fig. 2) revealed that this moiety would not sterically interfere with gas binding. With 1,2-dimethyl-1H-imidazole (DiMeIm) as ligand, the dendritic Fe^II porphyrins formed five-coordinate high-spin complexes (Figs. 3 and 4) and addition of CO led reversibly to the corresponding stable six-coordinate gas complexes (Fig. 6). Oxygenation, however, did not result in defined Fe^IIO₂ complexes as rapid decomposition to Fe^III species took place immediately, even in the case of the G2 dendrimer 6⋅Fe(DiMeIm) (Fig. 7). In contrast, stable gas adducts are formed between dendritic Co^II porphyrins and O₂ in the presence of DiMeIm as axial ligand, as revealed by electron paramagnetic resonance (EPR). The possible stabilization of these complexes through H-bonding involving the distal ligand is currently under investigation in multidimensional and multifrequency pulse EPR experiments.

The double Bingel reaction of fullerene C₆₀ with bismalonates attached to a Tröger base derived tether afforded trans-1, trans-2, trans-3, and trans-4 bisadducts with excellent regioselectivity. In particular, enantiomerically pure bisadducts with inherently chiral trans-2 or trans-3 addition patterns were prepared starting from enantiomerically pure bismalonates. The absolute configuration of the trans-2 and trans-3 bisadducts was established from their CD spectra. The excellent diastereoselectivity in the double additions to give the trans-2 bisadducts is particularly remarkable given the large distance between the two reacting bonds in opposite hemispheres of the fullerene that is spanned by the tether. Now, all inherently chiral double addition patterns are readily available by tether-directed functionalization using appropriate chiral, nonracemic spacers.

An extensive series of silyl-protected cyanoethynylethenes (CEEs) and N,N-dimethylanilino donor-substituted CEEs have been synthesized. More extended chromophores were constructed by selective silyl deprotection and subsequent oxidative acetylenic coupling. The strong electron-accepting nature of the CEEs was revealed by a combination of ¹³C NMR spectroscopic and electrochemistry measurements. Donor-substituted CEEs display strong intramolecular charge-transfer (CT) character, resulting in intense, bathochromically shifted CT bands in the UV/Vis spectrum. Their structural diversity establishes them as suitable models for the study of π-conjugation and band gap tuning in strong charge-transfer chromophores. The extent of π-conjugation in the donor-substituted CEEs was investigated by a combination of ground-state techniques, such as X-ray crystallography, electrochemistry, B3 LYP calculations, and NMR spectroscopy. The comparison of these ground-state results with the features observed in the UV/Vis spectra reveals that—contrary to expectations—more extensive π-conjugation can lead to larger band gaps in molecules with strong donor and acceptor moieties.

Eine Vielzahl von Studien zur molekularen Erkennung hat unser Wissen über apolare und durch H-Brücken vermittelte Wechselwirkungen sowie Wechselwirkungen zwischen Ionen und Dipolen in den letzten Jahrzehnten beträchtlich erweitert. Weit weniger Beachtung wurde hingegen der Rolle multipolarer Wechselwirkungen (insbesondere solcher mit orthogonaler Anordnung) beim Aufbau eines Kristallgitters oder bei der Stabilisierung von Komplexen biologischer Rezeptoren geschenkt. Das Ziel dieses Aufsatzes ist es daher, anhand von Ergebnissen aus Datenbankrecherchen eine Übersicht über die unterschiedlichen Typen dieser bislang oft übersehenen Wechselwirkungen und ihre strukturellen Charakteristiken zu geben. Die vielen Beispiele solcher Wechselwirkungen, die in Kristallstrukturen kleiner Moleküle und Protein-Ligand-Komplexen identifiziert wurden, sind ein Beleg für ihre Bedeutung bei molekularen Erkennungsprozessen in der Chemie und der Biologie.

Der aromatische Kasten in der S4-Tasche von Faktor Xa, der von Phe 174, Tyr 99 und Trp 215 gebildet wird, ist eine effiziente Onium-Bindungsstelle (siehe Bild; rot O, blau N, grün C_Ligand, grau C_Protein). Der Beitrag zur freien Enthalpie von Kation-π-Wechselwirkungen zwischen quartären Ammonium-Ionen und den aromatischen Resten beträgt dabei ΔΔG=2.8 kcal mol⁻¹. Datenbank-Recherchen zeigen, dass ähnliche Motive in biologischen Systemen häufiger auftreten.

Über einen hochkonvergenten Syntheseweg wurde ein molekularer Schalter auf der Basis eines Resorcin[4]aren-Cavitand-Gerüstes hergestellt, der sehr weiträumige, geometrisch präzise definierte molekulare Bewegungen eingeht (siehe Schema). Das Schalten zwischen kontrahiertem und expandiertem Zustand wird durch pH-Wert- oder Temperaturänderung induziert und lässt sich durch ¹H-NMR-Spektroskopie und resonanten Fluoreszenzenergietransfer (FRET) nachweisen.

Ungewöhnliche große Ringe: Ein chiraler alleno-acetylenischer Makrocyclus (1) und ein entsprechendes Cyclophan (2) mit außergewöhnlichen dreidimensionalen Formen wurden synthetisiert und diastereomerenrein isoliert. Symmetrie und Struktur wurden ¹H-NMR-spektroskopisch und röntgenographisch aufgeklärt. Die isolierten stereoisomeren Cyclophane photoisomerisieren, wobei ihre Anthracen-Einheiten wahrscheinlich als intramolekulare Sensibilisatoren wirken.

The past few decades of molecular recognition studies have greatly enhanced our knowledge on apolar, ion–dipole, and hydrogen-bonding interactions. However, much less attention has been given to the role that multipolar interactions, in particular those with orthogonal dipolar alignment, play in organizing a crystal lattice or stabilizing complexes involving biological receptors. By using results from database mining, this review attempts to give an overview of types and structural features of these previously rather overlooked interactions. A number of illustrative examples of these interactions found in X-ray crystal structures of small molecules and protein–ligand complexes demonstrate their propensity and thus potential importance for both, chemical and biological molecular recognition processes.

The electrochemical and photophysical properties of molecular architectures consisting of oligomeric meso,meso-linked oligoporphyrin rods linked at both extremities to methanofullerene moieties are presented in comparison to those of model systems. Cyclic voltammetry data evidence the presence of a strong intramolecular electronic coupling along the porphyrin oligomers that varies slightly with their length. This interaction affects the redox potentials of both fullerene and porphyrin moieties. The electronic coupling between the two chromophores is confirmed by comparing the redox potentials of porphyrin arrays before and after attachment of the carbon sphere. Electronic absorption, fluorescence, and phosphorescence spectra of the porphyrin oligomers in toluene are reported, which provide the energy of the lowest singlet and triplet electronic excited states. In the fullerene–porphyrin conjugates, ground-state charge-transfer (CT) interactions are evidenced by low-energy absorption features above 750 nm. These systems also exhibit near-infrared (NIR) CT luminescence in toluene with lifetimes shorter than 1000 ps. On increasing the solvent polarity (from toluene to Et₂O and THF), CT emissions become progressively weaker, red-shifted, and shorter lived, which reflects the energy-gap law and Marcus inverted region effects. Luminescence is not detected in benzonitrile. Picosecond transient absorption spectroscopy of the porphyrin–fullerene conjugates allows detection of the porphyrin cation as a clear fingerprint for electron transfer. The rate of charge recombination is in agreement with CT luminescence lifetimes, which confirms the occurrence of NIR radiative back-electron transfer.

A molecular switch based on a resorcin[4]arene cavitand undergoes reversibly very large, geometrically precisely defined molecular motion (see picture). Controlled switching between the contracted (linear extension ≈7 Å) and the expanded (linear extension ≈7 nm) states is induced by pH or temperature changes and was observed by ¹H NMR spectroscopy and fluorescence resonance energy transfer (FRET).

Rings on her fingers: The chiral alleno-acetylenic macrocycle 1 and the related cyclophane 2 with intriguing three-dimensional shapes were prepared and isolated in diastereoisomerically pure form. The symmetries and structures of these novel unsaturated hydrocarbons were elucidated by ¹H NMR spectroscopy and X-ray crystallography. The isolated stereoisomeric cyclophanes undergo photoisomerization; presumably the anthracene moieties serve as intramolecular sensitizers.

The aromatic box formed by the side chains Phe 174, Tyr 99, and Trp 215 in the S4-pocket of Factor Xa is a very effective onium binding site (see picture; red O, blue N, green C_ligand, gray C_protein). The free enthalpy increment for cation–π interactions between quaternary ammonium ions and aromatic groups in this box is determined to be ΔΔG=2.8 kcal mol⁻¹. Database searches reveal that similar cation binding sites are not uncommon in biological systems.

A large selection of linear and cyclic acetylenic scaffolds based on functionalized di- and tetraethynylethenes (DEEs, TEEs) have been prepared during the past ten years, such as poly(triacetylene)s (PTAs), expanded dendralenes, or perethynylated expanded radialenes and dehydroannulenes. These carbon-rich oligoenynes are interesting for their electronic and advanced materials properties. In this account, we highlight their redox properties. Moreover, the electrochemistry of cyanoethynylethenes (CEEs), a class of powerful electron acceptors that have recently attracted our attention, since they combine the scaffolding potential of TEEs with the superior acceptor strength of tetracyanoethene (TCNE), will also be discussed. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

In this paper, we report the synthesis and opto-electronic properties of differentially substituted 1,4-diethynyl- and 1,1,4,4-tetraethynylbuta-1,2,3-trienes. These novel chromophores greatly extend the series of building modules for oxidative coupling, which includes 1,2-diethynyl- and 1,1,2,2-tetraethynylethenes and 1,3-diethynylallenes (Fig. 1). A general synthesis of 1,1,4,4-tetraethynylbutatrienes, which tolerates a significant number of peripheral substituents, starts from pentadiynols that are oxidized to the corresponding dialkynyl ketones, followed by Corey–Fuchs dibromo-olefination, and transition metal mediated dimerization (Schemes 2 and 3). A similar protocol, including oxidation of propargyl aldehydes, dibromo-olefination, and dimerization yields the less stable 1,4-diethynylbutatrienes (Scheme 4). Attempts to prepare 1,1,4,4-tetraethynylbutatrienes with four terminal electron-donor-substituted aryl groups failed so far, mainly due to difficulties in the dibromoolefination step (Scheme 6). cis-trans-Isomerization of differentially substituted 1,1,4,4-tetraethynylbutatrienes is remarkably facile, with barriers to rotation in the range of those for peptide bond isomerization (ΔG^≠≈20 kcal mol⁻¹). Barriers to rotation of 1,4-diethynylbutatrienes are higher (ΔG^≠≈25 kcal mol⁻¹), allowing in some cases the isolation of pure isomers. Both UV/VIS spectroscopy (Figs. 2 and 3) and electrochemical studies (Table) demonstrate that the all-C-cores in diethynyl- and tetraethynylbutatrienes have strong electron-acceptor properties that are greatly enhanced with respect to those of diethynyl- and tetraethynylethenes with two C(sp)-atoms less. Substitution with peripheral electron donor groups leads to efficient intramolecular charge-transfer interactions, as evidenced by intense, bathochromically shifted longest-wavelength bands in the UV/VIS spectra.

We report the detailed investigation of temperature- and pH-triggered conformational switching of resorcin[4]arene cavitands 1–10 (Figs. 1, 8, and 9). Depending on the experimental conditions, these macrocycles adopt a vase conformation, featuring a deep cavity for potential guest inclusion, or two kite conformations (kite 1 and kite 2) with flat, extended surfaces (Schemes 1 and 2). The thermodynamic and kinetic parameters for the interconversion between these structures were determined by variable-temperature NMR (VT-NMR) spectroscopy (Figs. 2–7 and 10, and Tables 1 and 2). It was discovered that vasekite switching of cavitands is strongly solvent-dependent: it is controlled not only by solvent polarity but also by solvent size. Conformational interconversions similar to those of the parent structure 1 with four quinoxaline flaps are also observed when the octol base skeleton is differentially or incompletely bridged. Only octanitro derivative 2 was found to exist exclusively in the kite conformation under all experimental conditions. The detailed insight into the vase⇌kite conformational equilibrium gained in this investigation provides the basis for the design and construction of new, dynamic resorcin[4]arene cavitands that are switchable between bistable states featuring strongly different structures and functions.

A new series of dendrimers was assembled through formation of homo- and heteroleptic Ru^II complexes with [2,2′: 6′,2″]terpyridine ligands bearing hydrophilic and hydrophobic dendrons, with the aim to develop amphiphilic vectors for potential use in gene delivery (Scheme 1). The synthesis started with the preparation of the 4′-(3,5-dihalo-4-methoxyphenyl)-[2,2′: 6′,2″]terpyridine ligands 1a,bvia the Kröhnke pyridine synthesis (Scheme 2), followed by attachment of dendrons 10a–10f (Fig. 2) by Sonogashira cross-coupling to give the dendritic ligands 11–16 (Schemes 3 and 4). Ligands were subsequently introduced into the coordination sphere of Ru^III to give the stable intermediates [Ru(11)Cl₃] (24; Scheme 7) and [Ru(14)Cl₃] (27; Scheme 8). These were transformed under reductive conditions into the heteroleptic complexes [Ru(11)(13)](PF₆)₂ (25) and [Ru(13)(14)](PF₆)₂ (29). Removal of the (tert-butoxy)carbonyl (Boc) protecting groups in 25 and 29 then gave the desired amphiphilic dendrimers 26 (Scheme 7) and 30 (Scheme 8) with branchings of generations 0 and 1. Complex formation was analyzed by high-resolution matrix-assisted laser-desorption-ionization Fourier-transform ion-cyclotron-resonance mass spectrometry (HR-MALDI-FT-ICR-MS), which provided spectra featuring unique fragment-ion series and perfectly resolved isotope distribution patterns (Figs. 4 and 5). The preparation of homo- and heteroleptic complexes with terpyridine ligands bearing generation-2 dendrons failed due to steric hindrance by the bulky wedges.

A new route via intermediate pseudoenantiomers was developed to synthesize racemic and enantiomerically pure new non-peptidic inhibitors of thrombin, a key serine protease in the blood-coagulation cascade. These ligands feature a conformationally rigid tricyclic core and are decorated with substituents to fill the major binding pockets (distal (D), proximal (P), selectivity (S1), and oxyanion hole) at the thrombin active site (Fig. 1). The key step in the preparation of the new inhibitors is the 1,3-dipolar cycloaddition between an optically active azomethine ylide, prepared in situ from L-(4R)-hydroxyproline and 4-bromobenzaldehyde, and N-piperonylmaleimide (Scheme 1). According to this protocol, tricyclic imide (compounds (±)-15-(±)-18 and (+)-21) and lactam (compound (+)-2) inhibitors with OH or ether substituents at C(7) in the proline-derived pyrrolidine ring were synthesized to specifically explore the binding features of the oxyanion hole (Schemes 2–4). Biological assays (Table) showed that the polar oxyanion hole in thrombin is not suitable for the accommodation of bulky substituents of low polarity, thereby confirming previous findings. In contrast, tricyclic lactam (+)-2 (K_i=9 nM, K_i(trypsin)/K_i(thrombin)=1055) and tricyclic imide (+)-21 (K_i=36 nM, K_i(trypsin)/K_i(thrombin)=50) with OH-substituents at the (R)-configured C(7)-atom are among the most-potent and most-selective thrombin inhibitors in their respective classes, prepared today. While initial modeling predicted H-bonding between the OH group at C(7) in (+)-2 and (+)-21 with the H₂O molecule bound in the oxyanion hole (Fig. 2), the X-ray crystal structure of the complex of (+)-21 (Fig. 7, b) revealed a different interaction for this group. The propionate side chain of Glu192 undergoes a conformational change, thereby re-orienting towards the OH group at C(7) under formation of a very short ionic H-bond (OH⋅⋅⋅⁻OOC; d(O⋅⋅⋅O)=2.4 Å). The energetic contribution of this H-bond, however, is negligible, due to its location on the surface of the protein and the unfavorable conformation of the H-bonded propionate side chain.

tRNA-Guanine transglycosylase (TGT) plays a key role in the post-transcriptional modification of tRNA. It has been linked with the pathogenicity of shigellae, the causative agents of bacillary dysentery (shigellosis). Here, we report structureactivity relationships (SARs) for a new series of 2-aminoquinazolin-4(3H)-one-based inhibitors of TGT, resulting from structure-based design (Fig. 2). Versatile synthetic protocols allow selective functionalization of the 2-aminoquinazolin-4(3H)-one core (Schemes 1–6) with H-bond-donor groups in position 6 (for H-bonding to the C=O group of Leu231) and lipophilic residues in position 8 for reaching into a shallow, newly discovered lipophilic pocket lined by Val282, Val45, and Leu68. The binding mode of several of these ligands in the active site of TGT was established by crystal structure analyses (Figs. 4 and 6). A dramatic S effect was observed, with the replacement of the S-atom in the (phenylsulfanyl)methyl residue in position 8 of inhibitor 1c (K_i=100 nM) by the O-atom (in 1h, K_i=5.6 μM) or CH₂ (in 1i, K_i=3.6 μM), resulting in a massive loss of activity (Fig. 3). Crystal structure analysis showed that the lipophilic Me group points into a highly polar region of the active site encompassed by the side chains of Asp280 and Asp102 and collides directly (d(C⋅⋅⋅O)=3.1 Å) with one of the O-atoms of the carboxylate of Asp102. Similarly, lipophilic linkers departing from position 8 and orienting residues in the shallow hydrophobic pocket presumably encounter analogous unfavorable contacts, accounting for the modest contribution to the binding free enthalpy upon introduction of these residues. These findings provide a valuable starting point for future structure-based lead optimization cycles leading to TGT inhibitors with increased in vitro potency.

In this article, we report the preparation of unprecedented π-conjugated macrocycles (Fig. 1) by acetylenic scaffolding using modular tetraethynylethene (TEE, 3,4-diethynylhex-3-ene-1,5-diyne) building blocks. A novel photochemical access to (Z)-bisdeprotected TEEs (Scheme 1) enabled the synthesis of the anilino-substituted perethynylated octadehydro[12]- (5) and dodecadehydro[18]annulenes (6) (Scheme 2). Following the serendipitous discovery of perethynylated radiaannulenes (Scheme 3) that can be viewed as hybrids between perethynylated dehydroannulenes and expanded radialenes, two series of monocyclic (7–9; Scheme 6) and bicyclic (10 and 11; Scheme 7) representatives were prepared. Substantial strain in the macrocyclic perimeter of radiaannulene 7 was revealed by X-ray crystal-structure analysis (Fig. 2). Nevertheless, mono- and bicyclic radiaannulenes are stable at room temperature in air for months. The opto-electronic properties of both dehydroannulenes and radiaannulenes are substantially enhanced by the introduction of the peripheral anilino donor groups that undergo strong intramolecular charge-transfer interactions with the electron-accepting all-C cores. As a result, the UV/VIS spectra feature intense, bathochromically shifted charge-transfer bands that disappear upon protonation of the anilino moieties and are fully recovered upon neutralization (Figs. 4–9). A comparison between anilino-substituted perethynylated dehydroannulenes, expanded radialenes, and radiaannulenes revealed that the efficiency of the intramolecular charge-transfer interaction strongly depends on the structure of the electron-accepting all-C perimeter. Electrochemical investigations (Table) demonstrated that the radiaannulenes are particularly powerful electron acceptors. Thus, bicyclic radiaannulene 11, which possesses eight peripheral 3,5-di(tert-butyl)phenyl substituents, is reversibly reduced at −0.83 V in THF (vs. Fc⁺/Fc), making it a better electron acceptor than buckminsterfullerene C₆₀ under comparable conditions.

Zwei prominente Moleküle verknüpft: Ausgehend von Bismalonat-Derivaten der Trögerschen Base wurden C₆₀-Bisaddukte mit trans-1-, trans-2- und trans-4-Additionsmustern (siehe z. B. Struktur) regio- und diastereoselektiv in hohen Ausbeuten hergestellt. Mit enantiomerenreinen Spacern gelang darüber hinaus die selektive Synthese der beiden Enantiomere eines C₆₀-Bisaddukts mit dem inhärent chiralen trans-2-Additionsmuster.

Schicke Muster: Neuartige ein- und zweidimensionale Fullerenmuster wurden durch Aufdampfen von reinem C₆₀ auf vororganisierte Porphyrin-Monoschichten auf Silberoberflächen aufgebaut. Die Anordnung der Fulleren-Moleküle auf der gemusterten Schicht kann durch die Porphyrin-Struktur gesteuert werden (siehe rastertunnelmikroskopische Aufnahmen).

Durch Kombination eines chemischen Doppelmutationszyklus mit einer Linearen-Freien-Energie-Beziehung konnte eine schwache anziehende Wechselwirkung (−0.8 bis −1.5 kJ mol⁻¹) zwischen einem organischen Fluorsubstituenten und der Ebene einer Amidgruppe nachgewiesen werden (siehe Bild). Diese Untersuchung stützt neuere Ergebnisse, nach denen eine solche Anziehung in Enzym-Inhibitor-Wechselwirkungen wirksam sein könnte.

A new generation of bisubstrate inhibitors for the S-adenosylmethionine- and magnesium ion-dependent enzyme catechol O-methyltransferase (COMT), feature binding affinities (IC₅₀ values) in the double-digit nanomolar range despite the lack of a nitro group on the catechol moiety. Inhibitor potency does not directly correlate with the pK_a value of the catechol HO groups and is strongly enhanced by hydrophobic aromatic substituents attached in a biaryl-type fashion to position 5 of the catechol ring.

Bringing two fascinating molecules together: Bismalonate derivatives of the Tröger base were used in the high-yielding regio- and diastereoselective preparation of bisadducts of C₆₀ with trans-1, trans-2, and trans-4 addition patterns (e.g. see structure). Moreover, both enantiomers of the inherently chiral trans-2 adduct were prepared from enantiomerically pure tethers.

A variety of 1,1,4,4-tetraal kynylbutatrienes and 1,4-dialkynylbutatrienes was synthezized by dimerization of the corresponding gem-dibromoolefins. Both ¹H and ¹³C NMR spectroscopy indicated that the di- and tetraalkynylated butatrienes are formed as a mixture of cis and trans isomers. Variable temperature NMR studies evidenced a facile cis–trans isomerization, thus preventing the separation of these isomers by gravity or high-performance liquid chromatography (HPLC). For 1,1,4,4-tetraalkynylbutatrienes, the activation barrier ΔG^≠ was measured by magnetization transfer to be around 20 kcal mol⁻¹, in the range of the barrier for internal rotation about a peptide bond. Unlike the tetraalkynylated [3]cumulenes, 1,4-dialkynylbutatrienes are more difficult to isomerize and could, in one case, be obtained isomerically pure. Based on experimental data, the rotational barrier ΔG^≠ for 1,4-dialkynylbutatrienes is estimated to be around 25 kcal mol⁻¹. The hypothesis of a stabilizing effect of the four alkynyl substituents on the proposed but-2-yne-1,4-diyl singlet diradical transition state of this cis–trans isomerization is further supported by a computational study.

A combination of a chemical double-mutant cycle and a linear free energy relationship has demonstrated that a weak attractive interaction (−0.8 to −1.5 kJ mol⁻¹) exists between an organic fluorine substituent and the face of an amide functional group (see picture). This study supports recent results that have suggested that such an attraction may be operative in enzyme–inhibitor interactions.

Plenty of room on top: Unprecedented one- and two-dimensional fullerene patterns were obtained upon evaporation of pristine C₆₀ onto pre-organized porphyrin monolayers on silver surfaces following a bottom-up approach. The arrangement of the fullerene molecules on the patterned layer can be controlled by the porphyrin structure (see scanning tunneling microscopy images).

In a systematic fluorine scan of a rigid inhibitor to map the fluorophilicity/fluorophobicity of the active site in thrombin, one or more F substituents were introduced into the benzyl ring reaching into the D pocket. The 4-fluorobenzyl inhibitor showed a five to tenfold higher affinity than ligands with other fluorination patterns. X-ray crystal-structure analysis of the protein–ligand complex revealed favorable CF⋅⋅⋅HC_αCO and CF⋅⋅⋅CO interactions of the 4-F substituent of the inhibitor with the backbone HC_αCO unit of Asn98. The importance of these interactions was further corroborated by the analysis of small-molecule X-ray crystal-structure searches in the Protein Data Base (PDB) and the Cambridge Structural Database (CSD). In the CF⋅⋅⋅CO interactions that are observed for both aromatic and aliphatic CF units and a variety of carbonyl and carboxyl derivatives, the F atom approaches the CO C atom preferentially along the pseudotrigonal axis of the carbonyl system. Similar orientational preferences are also seen in the dipolar interactions CF⋅⋅⋅CN, CF⋅⋅⋅CF, and CF⋅⋅⋅NO₂, in which the F atoms interact at sub-van der Waals distances with the electrophilic centers.

Using X-ray structure-based de novo design, a new class of inhibitors of the zinc-dependent endopeptidase Neprilysin has been developed that feature binding affinities (IC₅₀ values) in the upper nanomolar range. The imidazole moieties of the central benzimidazole or imidazo[4,5-c]pyridine (see picture) scaffolds act as efficient peptide-bond isosters.

We report the synthesis and structural characterization of modified Cram-type, resorcin[4]arene-based cavitands. Two main loci on the cavitand backbone were selected for structural modification: the upper part (wall domain) and the lower part (legs). Synthesis of unsymmetrically bridged cavitands with different wall components (i.e., 7, 8, and 14–18) was performed by stepwise bridging of the four couples of neighboring, H-bonded OH-groups of octol 1a (Schemes 1, 2, 4, and 5). Cavitands with modified legs (i.e., 20, 24, 27, and 28), targeted for surface immobilization, were synthesized by short routes starting from suitable aldehyde starting materials incorporating either the fully preformed leg moieties or functional precursors to the final legs (Schemes 7–10). The new cavitand substitution patterns described in this paper should enable the construction of a wide variety of functional architectures in the future. X-Ray crystallography afforded the characterization of cavitands 2c (Fig. 3) and 24 (Fig. 7) in the vase conformation, with 2c featuring a well-ordered CH₂Cl₂ guest molecule in its cavity. A particular highlight is the X-ray crystal-structure determination of octanitro derivative 19 (Scheme 6), which, for the first time, shows a cavitand, lacking substituents in the ortho-position to the two O-atoms of the four resorcinol moieties, in the kite-conformation (Fig. 5).

The synthesis of azoacetylenes (=dialkynyldiazenes) 1 and 2 has been investigated. They represent a still elusive class of chromophores with potentially very interesting applications as novel bistable photochemical molecular switches or as antitumor agents (Fig. 1). Our synthetic efforts have led us alongside three different approaches (Scheme 1). In a first route, it was envisioned to generate the azo (=diazene) bond by photolysis of N,N′-dialkynylated 1,3,4-thiadiazolidine-2,5-diones that are themselves challenging targets (Scheme 2). Attempts are described to obtain the latter by alkynylation of the parent heterocycle with substituted alkynyliodonium salts. In a conceptually similar approach, the no-less-challenging dialkynylated 9,10-dihydro-9,10-diazanoanthracene (29) was to be generated by alkynylation of the unsubstituted hydrazine 28 (Scheme 6). In a second route, the generation of the NN bond from Br-substituted divinylidenehydrazines (ketene-azines) 35 was attempted in a synthetic scheme involving an aza-Wittig reaction between azinobis(phosphorane) 36 and (triisopropylsilyl)ketene 37 (Scheme 7). Finally, a third approach, based on the formation of the central azo bond as the key step, was explored. This route involved the extrapolation of a newly discovered condensation reaction of N,N-disilylated anilines with nitroso compounds (Scheme 11, and Tables 1 and 2) to the transformation of N,N-disilylated ynamine 55 and nitroso-alkyne 54 (Scheme 13).

We report the synthesis of modified Cram-type cavitands bearing one or two fluorescent labels for single-molecule spectroscopic studies of vasekite conformational switching (Scheme 3). Syntheses were performed by stepwise bridging of the four couples of neighboring H-bonded OH groups of resorcin[4]arene bowls (Schemes 2 and 3). The new substitution patterns enable the construction of a large variety of future functional architectures. ¹H-NMR Investigations showed that the new partially and differentially bridged cavitands feature temperature- and pH-triggered vasekite conformational isomerism similar to symmetrical cavitands with four identical quinoxaline bridges (Table). It was discovered that vasekite switching of cavitands is strongly solvent-dependent.

Plasmepsin II (PMII), a malarial aspartic protease involved in the catabolism of hemoglobin in parasites of the genus Plasmodium, and renin, a human aspartic protease, share 35% sequence identity in their mature chains. Structures of 4-arylpiperidine inhibitors complexed to human renin were reported by Roche recently. The major conformational changes, compared to a structure of renin, with a peptidomimetic inhibitor were identified and subsequently modeled in a structure of PMII (Fig. 1). This distorted structure of PMII served as active-site model for a novel class of PMII inhibitors, according to a structure-based de novo design approach (Fig. 2). These newly designed inhibitors feature a rigid 7-azabicyclo[2.2.1]heptane scaffold, which, in its protonated form, is assumed to undergo ionic H-bonding with the two catalytic Asp residues at the active site of PMII. Two substituents depart from the scaffold for occupancy of either the S1/S3 or S2′-pocket and the hydrophobic flap pocket, newly created by the conformational changes in PMII. The inhibitors synthesized starting from N-Boc-protected 7-azabicyclo[2.2.1]hept-2-ene (6; Schemes 1–5) displayed up to single-digit micromolar activity (IC₅₀ values) toward PMII and good selectivity towards renin. The clear structureactivity relationship (SAR; Table) provides strong validation of the proposed conformational changes in PMII and the occupancy of the resulting hydrophobic flap pocket by our new inhibitors.

A new class of nonpeptidic inhibitors of the malarial aspartic protease plasmepsin II (PMII) with up to single-digit micromolar activities (IC₅₀ values) was developed by structure-based de novo design. The active-site matrix used in the design was based on an X-ray crystal structure of PMII, onto which the major conformational changes seen in the structure of renin upon complexation of 4-arylpiperidines – including the unlocking of a new hydrophobic (flap) pocket – were modeled. The sequence identity of 35% between mature renin and PMII had prompted us to hypothesize that an induced-fit adaptation around the active site as observed in renin might also be effective in PMII. The new inhibitors contain a central 11-azatricyclo[6.2.1.0^2,7]undeca-2(7),3,5-triene core, which, in protonated form, undergoes ionic H-bonding with the two catalytic Asp residues at the active site of PMII (Figs. 1 and 2). This tricyclic scaffold is readily prepared by a DielsAlder reaction between an activated pyrrole and a benzyne species generated in situ (Scheme 1). Two substituents with naphthyl or 1,3-benzothiazole moieties are attached to the central core (Schemes 1–4) for accommodation in the hydrophobic flap and S1/S3 (or S2′, depending on the optical antipode of the inhibitor) pockets at the active site of the enzyme. The most-potent inhibitors (±)-19a–19c (IC₅₀ 3–5 μM) and (±)-23b (2 μM) (Table) bear an additional Cl-atom on the 1,3-benzothiazole moiety to fully fill the rear of the flap pocket. Optimization of the linker between the tricyclic scaffold and the 1,3-benzothiazole moiety, based on detailed conformational analysis (Figs. 3 and 4), led to a further small increase in inhibitory strength. The new compounds were also tested against other aspartic proteases. They were found to be quite selective against renin, while the selectivity against cathepsin D and E, two other human aspartic proteases, is rather poor (Table). The detailed SARs established in this investigation provide a valuable basis for the design of the next generations of more-potent and -selective PMII inhibitors with potential application in a new antimalarial therapy.

This paper describes the development of novel aromatic platforms for supramolecular construction. By the Suzuki cross-coupling protocol, a variety of functionalized m-terphenyl derivatives were prepared (Schemes 1–4). Macrolactamization of bis(ammonium salt) (S,S)-6 with bis(acyl halide) 7 afforded the macrocyclic receptor (S,S)-2 (Scheme 1), which was shown by ¹H-NMR titration studies to form ‘nesting' complexes of moderate stability (K_a between 130 and 290 M⁻¹, 300 K) with octyl glucosides 13–15 (Fig. 2) in the noncompetitive solvent CDCl₃. Suzuki cross-coupling starting from 3,3′,5,5′-tetrabromo-1,1′-biphenyl provided access to a novel series of extended aromatic platforms (Scheme 5) for cleft-type (Fig. 1) and macrotricyclic receptors such as (S,S,S,S)-1. Although mass-spectral evidence for the formation of (S,S,S,S)-1 by macrolactamization between the two functionalized 3,3′,5,5′-tetraaryl-1,1′-biphenyl derivatives (S,S)-33 and 36 was obtained, the ¹H- and ¹³C-NMR spectra of purified material remained rather inconclusive with respect to both purity and constitution. The versatile access to the novel, differentially functionalized 3,3′,5,5′-tetrabromo-1,1′-biphenyl platforms should ensure their wide use in future supramolecular construction.

The formation of the new optically active C₃-symmetrical receptors (S,S,S)-2–4 (Fig. 1), incorporating 1,3,5-triphenylbenzene and 1,3,5-tris(phenylethynyl)benzene platforms as ‘floors' and ‘ceilings', is described. The tris(phenylethynyl)benzene derivatives 9 and (S,S,S)-10 (Scheme 1) for the three-fold peptide coupling to yield the macrocyclic skeletons (Scheme 2) were prepared starting from 1,3,5-triethynylbenzene by the Sonogashira cross-coupling reaction. The optical rotations of the three macrocycles (S,S,S)-2–4, two of which ((S,S,S)-2 and (S,S,S)-3) are constitutional isomers, differ significantly, which is explained by differential twists induced into the macrocyclic skeletons by the leucine spacer in these bridges. 1 : 1 Host–guest complexes of (S,S,S)-2–4 with octyl glucosides (Fig. 3) in CDCl₃ are of modest stability (K_a≤270 M⁻¹ at 300 K). In these complexes, the monosaccharides are most probably nesting on one of the H-bonding faces of the receptor rather than being accommodated in the cavity.

Zwischenmolekulare Wechselwirkungen unter Beteiligung aromatischer Ringe sind Schlüsselvorgänge sowohl in chemischen als auch in biologischen Erkennungsprozessen. Ihr Verständnis ist für das rationale Wirkstoffdesign und für die Leitstrukturoptimierung in der Medizinischen Chemie essenziell. Unterschiedliche Ansätze werden für ein tiefergehendes Verständnis der strukturellen und energetischen Parameter einzelner Erkennungsarten mit aromatischen Substraten verfolgt: erwähnt seien biologische Untersuchungen, Studien der molekularen Erkennung mit künstlichen Rezeptoren, Suchen in kristallographischen Datenbanken, Gasphasenstudien und theoretische Untersuchungen. Dieser Aufsatz versucht, diese Wissensgebiete zu vereinen und die aus zahlreichen Untersuchungen gewonnenen Erkenntnisse zusammenzufassen. Er widmet sich hauptsächlich Beispielen mit biologischer Relevanz mit dem Ziel, die für die Wirkstoffentwicklung wichtigen Kenntnisse der molekularen Erkennung zu vertiefen.

Ein scharfes Maximum in der Struktur-Aktivitäts-Beziehung, ein überraschend starker Einfluss der hydrophoben Teilstruktur auf DNA-Bindung und -Transport und ein ungewöhnlicher Serum-Effekt auf die relativen Transfektionsaktivitäten wurden in ersten biologischen Studien an einer Serie von vier amphiphilen Dendrimeren gefunden, die als Transfektionsagentien entwickelt wurden. Das Dendrimer der niedrigsten Generation, 1, erwies sich als das aktivste.

Die hohe Fluorophilie der HC_αCO-Einheit von Asn 98 im aktiven Zentrum von Thrombin zeigt sich bei der röntgenstrukturanalytischen Charakterisierung eines Komplexes mit einem künstlichen Inhibitor (siehe Bild, Abstände in Å). Auch in den Röntgenstrukturanalysen zahlreicher kleiner Moleküle werden an HC_αCO-Carbonyleinheiten kleine CF⋅⋅⋅HC_α- und CF⋅⋅⋅CO-Abstände gefunden.

Up to fifteen electrons are reversibly accommodated in a triply fused porphyrin dimer conjugated to two [60]fullerene moieties. Its photophysical properties differ completely from those of the many known porphyrin–fullerene dyads: Photoexcitation of the C₆₀ moieties results in quantitative sensitization of the low-lying (about 1 eV) and very short lived lowest singlet level of the porphyrin sheet (see scheme).

Ein dreifach verbrücktes Porphyrindimer, das mit zwei [60]Fulleren-Einheiten konjugiert ist, kann bis zu fünfzehn Elektronen reversibel aufnehmen. In seinen photophysikalischen Eigenschaften unterscheidet es sich grundlegend von den bislang bekannten Porphyrin-Fulleren-Konjugaten: Photochemische Anregung der C₆₀-Einheiten führt zur quantitativen Sensibilisierung des tiefliegenden (ca. 1 eV) und sehr kurzlebigen niedrigsten Singulett-Zustands des Porphyrinteils (siehe Schema).

Intermolecular interactions involving aromatic rings are key processes in both chemical and biological recognition. Their understanding is essential for rational drug design and lead optimization in medicinal chemistry. Different approaches—biological studies, molecular recognition studies with artificial receptors, crystallographic database mining, gas-phase studies, and theoretical calculations—are pursued to generate a profound understanding of the structural and energetic parameters of individual recognition modes involving aromatic rings. This review attempts to combine and summarize the knowledge gained from these investigations. The review focuses mainly on examples with biological relevance since one of its aims it to enhance the knowledge of molecular recognition forces that is essential for drug development.

A sharp maximum in the structure–activity relationship, a surprisingly strong influence of the hydrophobic part on DNA binding and transport, and an unusual serum effect on relative transfection activities were found in preliminary biological data on a series of four amphiphilic dendrimers designed as transfection agents. The lowest generation dendrimer 1 was found to be the most active.

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.

A new hybrid organic–inorganic material has been obtained by the incorporation of a manganese(III) porphyrin into a mesoporous aerogel matrix. The new heterogeneous catalyst was active in the epoxidation of a variety of olefins and polycyclic aromatic hydrocarbons, using iodosylbenzene as oxidizing agent. The catalyst was stable, readily recovered, and re-used without loss of activity. The hybrid aerogel catalyst was more active than the corresponding metalloporphyrin in homogeneous solution.

Ausgedehnte π-Elektronenacceptoren wie 1 wurden durch die Aneinanderreihung von neuartigen Cyanoethinylethenen hergestellt. Elektrochemische Analysen zeigen, dass die Acceptorstärke von der Länge der π-Elektronenkonjugation abhängt und eine lineare Korrelation zwischen der Elektronenaffinität (B3LYP, 3-21G) und dem ersten Reduktionspotential besteht.

Das Titelbild zeigt das erste expandierte Cuban mit einem C₅₆-Kern. Formal abgeleitet durch Insertion von Buta-1,3-diindiyl-Einheiten in sämtliche zwölf C-C-Einfachbindungen von Octamethoxycuban, verläuft seine Entstehung über die Bildung von Ecken, Kanten und Flächen als Schlüsselbausteine. Das expandierte Cuban ist hoch gespannt und explodiert beim Kratzen auf der Oberfläche. Unter den Bedingungen der Fourier-Transformations-Ionenzyklotronresonanz-Massenspektrometrie lagert es sich in Fullerene um, die im Positivionenmodus unter Fullerenkoaleszenz reagieren. Nähere Einzelheiten beschreiben Diederich et al. in ihrer Zuschrift auf S. 4515 ff.

A selection of mono- and diacetylenic dithiafulvalenes was synthesized and employed for the construction of extended tetrathiafulvalenes (TTFs) with hexa-2,4-diyne-1,6-diylidene or deca-2,4,6,8-tetrayne-1,10-diylidene spacers between the two 1,3-dithiole rings. By stepwise acetylenic scaffolding using (E)-1,2-diethynylethene (DEE) building blocks, an extended TTF containing a total of 18 C(sp) and C(sp²) atoms in the spacer was prepared. The versatility of the acetylenic dithiafulvene modules was also established by the efficient synthesis of a thiophene-spaced TTF, employing a palladium-catalyzed cross-coupling reaction. The developed synthetic protocols allow functionalization of the extended TTFs in three general ways: with 1) peripheral substituents on the fulvalene cores, 2) alkynyl moieties laterally appended to the spacer, and 3) cobalt clusters involving acetylenic moieties. Strong chromophoric properties of the extended TTFs were revealed by linear and nonlinear optical spectroscopies. Extensive electrochemical studies and calculations on these compounds are also reported, as well as X-ray crystallographic analyses.

Rebek imides (3), formed from Kemp's triacid, were developed in the mid-1980's as model receptors for adenine derivatives. We report here the first account of their hydrogen-bonding preferences upon binding 9-ethyladenine (1 a) in the solid state. Structural analysis begins with simple imides 3 a–e that form discrete dimers, while bis-imide 4 forms ribbon-like structures in the crystalline phase. The hydrogen-bonding interface within each of the representative assemblies features short intermolecular N(3)_imide⋅⋅⋅O(8*)_imide* distances (ca. 2.95 Å), indicative of two-point hydrogen bonding. Imides 3 f–h could be co-crystallized with 1 a; single-crystal X-ray analysis of the resulting complexes reveals hydrogen-bonding geometries nearly identical to those observed in nucleobase complexes of adenine and pyrimidine derivatives. Imides 3 f and 3 g form 2:1 ternary assemblies with 1 a; the complex of the former, (3 f)₂⋅1 a, displays both Watson–Crick- and Hoogsteen-type hydrogen bonding, whereas the complex of the latter, (3 g)₂⋅1 a, shows the Hoogsteen motif and imide hydrogen bonding to N(3) of the purine base (N(3)_adenine⋅⋅⋅N(3″)_imide=3.07(1) Å). Imide 3 h forms a 1:1 complex with 1 a (3 h⋅1 a⋅CHCl₃) and displays Hoogsteen binding exclusively. All of the 3⋅1 a assemblies show C_adenine⋅⋅⋅O_imide distances (3.38–3.75 Å) that are consistent with C-H⋅⋅⋅O hydrogen bonding. Base-pairing preferences for the Rebek imides are further explored in solution by ¹H NMR one-dimensional NOE experiments and by computational means; in all cases the Hoogsteen motif is modestly favored relative to its Watson–Crick counterpart.

Die formale Insertion von Buta-1,3-diindiyl-Einheiten in die zwölf C-C-Einzelbindungen von Octamethoxycuban führt zu dem explosiven aufgeweiteten Cuban 1. Die Fourier-Transformations-Ionenzyklotronresonanz(FT-ICR)-Massenspektrometrie zeigt, dass 1 leicht seine acht MeO-Gruppen abgibt und sich anschließend in Fulleren-Ionen umlagert, die im Positivionenmodus unter Fullerenkoaleszenz reagieren.

Extended π-electron acceptors, such as 1, have been constructed by the acetylenic scaffolding of a series of novel cyanoethynylethenes. Electrochemical analysis shows that acceptor strength is a function of π-electron conjugation length, and that a linear correlation exists between the electron affinities (B3LYP, 3-21G) and their first reduction potential.

The cover picture shows the first expanded cubane with a C₅₆ core. Formally derived by insertion of buta-1,3-diynediyl moieties into all 12 CC single bonds of octamethoxycubane, its synthesis actually proceeds by the formation of corners, edges, and faces as key building blocks and intermediates. The expanded cubane is highly strained and explodes upon scraping. Under conditions of Fourier-transform ion-cyclotron-resonance mass spectrometry it rearranges into fullerenes, which, in the positive-ion mode, undergo fullerene coalescence reactions. Full details are described by Diederich et al. on p. 4339 ff.

Pocket change: A new family of plasmepsin II inhibitors (see scheme) was developed by taking advantage of the putative flexibility of plasmepsin II and employment of a structure-based de novo design approach based on molecular recognition principles. A newly accessible hydrophobic pocket unlocked by conformational changes that occur upon bonding of adequate inhibitors was proposed. This site was targeted by nonpeptidic plasmepsin II inhibitors, which displayed single-digit micromolar activity in an enzyme assay.

Acetylenic scaffolding with derivatives of tetraethynylethene (TEE, 3,4-diethynylhex-3-ene-1,5-diyne) and (E)-1,2-diethynylethene (DEE, (E)-hex-3-ene-1,5-diyne) provides carbon-rich compounds with interesting physicochemical properties. Thus, these modules are building blocks for monodisperse, linearly π-conjugated oligomers [polytri(acetylene)s, PTAs] extending in length beyond 10nm, and for large, macrocyclic, all-carbon cores (dehydroannulenes and expanded radialenes) exhibiting strong chromophoric properties. The advanced materials' properties were strongly influenced by the presence of electron-donating substituents at the lateral positions, decreasing the decreasing the (HOMO–LUMO) gap in both PTAs and expanded radialenes. Arylated TEEs were found to undergo photochemically induced cis–trans isomerization, paving the way for applications as light-driven molecular switches in optoelectronic devices. Derivatives of 1,3-diethynylallene are new modules that offer the prospect of scaffolding in an orthogonal manner; that is, they represent precursors for helical oligomers. © 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 2: 189–198,2002: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.10022

A lipophilic pocket at the tRNA-guanine transglycosylase (TGT) enzyme active site was discovered and a substantial contribution to the substrate binding free energy was observed when this pocket was filled by apolar side chains. A family of new inhibitors of TGT was developed by employing the principles of molecular recognition and structure-based de novo design, and shown to display up to submicromolar binding affinity. Two X-ray structures of TGT–inhibitor complexes confirmed the binding mode predicted in the design stage. An exceptional ”point mutation” effect on binding affinity was observed upon substitution of X=CH₂ in 1 with O or S.

The cover picture shows the X-ray crystal structure of an expanded [6]radialene which adopts a chair-like conformation. Expanded radialenes exhibit remarkable electronic properties owing to a considerable degree of macrocyclic cross-conjugation. In the upper left corner is shown the “radiating” solar disk of the old Egyptian Sun-god Aton. The study on the synthesis and properties of different radialenes is described in more detail by F. Diederich et al. on p. 3263 ff.

A selection of dimeric tetraethynylethenes (TEEs) and perethynylated expanded radialenes, containing different donor/acceptor substitution patterns, have been prepared and fully characterized. The first X-ray crystal structure of an expanded [6]radialene, with twelve peripheral 3,5-di(tert-butyl)phenyl substituents, is presented. This macrocycle, the all-carbon core of which is isomeric with fullerene C₆₀, adopts a non-planar, “chair-like” conformation. Also a TEE dimer, carrying N,N-dimethylaniline donor substituents, has been subjected to an X-ray crystallographic analysis. The electronic properties were studied by UV/Vis spectroscopy and electrochemistry, providing fundamental insight into mechanisms of π-electron delocalization in the acyclic and macrocyclic chromophores. Donor or donor–acceptor-substituted dimeric TEE derivatives show very strong absorptions extending over the entire UV/Vis region; their longest wavelength absorption bands have high charge-transfer character. Macrocyclic cross-conjugation in the expanded radialenes becomes increasingly efficient with increasing donor–acceptor polarization. A dual, strongly solvent-polarity-dependent fluorescence was observed for a tetrakis(N,N-dimethylaniline)-substituted dimeric TEE; this interesting emission behavior is explained by the twisted intramolecular charge-transfer (TICT) state model. Donor-substituted expanded radialenes display huge resonance-enhanced third-order nonlinear optical coefficients.

The series of monodisperse Pt-bridged TEE oligomers 3 a–f was prepared by oxidative Glaser–Hay oligomerization of monomer 7 under end-capping conditions. These novel molecular rods extend in length from 3.3 nm (monomeric 3 a) to 12.1 nm (hexameric 3 f). Their isolation was achieved by high performance gel permeation chromatography (GPC), and their purification was best monitored by analytical GPC in combination with matrix-assisted laser-desorption-ionization mass spectrometry (MALDI-TOF MS). The mass spectra of each oligomer revealed the molecular ion or its sodium complex as parent ion together with a clean, highly characteristic fragmentation pattern. Delayed addition of the end-capping reagent PhC≡CH to the oligomerization mixture afforded polymer 10 with an average of ≈32 repeat units and a remarkably narrow molecular weight distribution (M_w/M_n=1.06), which is indicative of a living polymerization process. UV/Vis spectral data as well as measurements of the second hyperpolarizability γ by third harmonic generation (THG) revealed a nearly complete lack of π-electron delocalization along the oligomeric backbone. The Pt atoms act as true insulating centers, and the Pt−C(sp) bonds hardly possess any π character. The synthesis of the molecular rods 3 a–f provides another demonstration of the power of oxidative acetylenic homocouplings for the preparation of unusual nanoarchitecture.

Mit einem IC₅₀-Wert von 9 nM ist 1 der wirksamste bekannte Disubstrat-Inhibitor für Catechol-O-Methyl-Transferase (COMT). Die Inhibierung von COMT ist für die Therapie der Parkinson-Krankheit interessant, da hierdurch gewährleistet ist, dass ein größerer Prozentsatz von – in Form von Dopamin – oral verabreichtem L-Dopa den Rezeptor im Gehirn erreicht. Die Struktur eines Komplexes aus COMT und 1 wurde mit einer Auflösung von 2.6 Å aufgeklärt.

With an IC₅₀ value of 9 nM, 1 is the most potent known disubstrate inhibitor for catechol-O-methyltransferase (COMT). Inhibition of COMT is of significant interest in the therapy of Parkinsonapos;s disease since it ensures that a larger percentage of orally administered L-dopa reaches—in the form of dopamine—its target in the brain. The X-ray crystal structure of a complex formed by COMT and 1 has been solved at 2.6-Å resolution.

The C₃-symmetrical [60]fullerene-cyclotriveratrylene (CTV) tris-adducts (±)-1 (with a trans-3,trans-3,trans-3 addition pattern) and (±)-2 (with an e,e,e addition pattern) were prepared in 11 and 9% yield, respectively, by the regio- and diastereoselective tether-directed Bingel reaction of C₆₀ with the tris-malonate-appended CTV derivative (±)-3 (Scheme). This is the first example for tris-adduct formation by a one-step tether-directed Bingel addition. Interchromophoric interactions between the electron-rich CTV cap and the electron-attracting fullerene moiety have a profound effect on the electrochemical behavior of the C-sphere (Fig. 4 and Table 1). The fullerene-centered first reduction potentials in compounds (±)-1 and (±)-2 are by 100 mV more negative than those of their corresponding tris[bis(ethoxycarbonyl)methano][60]fullerene analogs that lack the CTV cap. A particular interest in (±)-1 and (±)-2 arises from the topological chirality of these molecules. A complete topology study is presented, leading to the conclusion that the four possible classical stereoisomers of the e,e,e regioisomer are topologically different, and, therefore, there exist four different topological stereoisomers (Fig. 6). Interestingly, in the case of the trans-3,trans-3,trans-3 tris-adduct, there are four classical stereoisomers but only two topological stereoisomers (Fig. 7). An example of a target molecule representing a topological meso-form is also presented (Fig. 8).

Die Acetylenkupplung erfährt derzeit eine der intensivsten Erforschungs- und Anwendungsphasen in ihrer langen Geschichte. Di- und Oligoacetylene sind als starre, sterisch anspruchslose Struktureinheiten in einer Reihe von Naturstoffen anzutreffen und finden als versteifende, strukturgebende Bausteine in synthetischen Rezeptormolekülen zunehmend Anwendung für molekulare Erkennung. Interessante elektronische und optische Eigenschaften von Molekülen mit ausgedehnten konjugierten π-Elektronensystemen haben das Forschungsinteresse auf neue lineare Oligoalkine und sp-hybridisierte Kohlenstoffallotrope gerichtet. Im Gegenzug hat die Beschäftigung mit diesen präparativen Herausforderungen zur Entdeckung einer Reihe neuer Kupplungsmethoden geführt. Homokupplungen von Acetylenen werden weiterhin häufig unter den klassischen Glaser-Bedingungen durchgeführt, doch prägten Heterokupplungen, wegen des zunehmenden Bedarfs an selektiveren Bedingungen, die Forschung der letzten Jahrzehnte. Weitere Fortschritte bei der Entwicklung dieser Methoden werden durch das noch geringe Verständnis des Mechanismus dieser Prozesse behindert. In neuerer Zeit führte die Entdeckung Palladium-katalysierter Kupplungsmethoden zu deutlichen Steigerungen der Effizienz und Selektivität von Homo- und Heterokupplungen von Acetylenen, was deren Verwendung zum Aufbau immer komplizierterer Systeme ermöglichte. In diesem Aufsatz wird erstmals die Vielfalt existierender Methoden zur Durchführung von Alkin-Alkin-Kupplungen zusammen mit den aktuellen mechanistischen Vorstellungen sowie Anwendungen in der Naturstoffsynthese und anderen zielgerichteten Synthesen zusammenfassend diskutiert. Schwerpunkte bilden dabei neuere Methoden und ihre Verwendung zum Aufbau komplexer makromolekularer Strukturen.

The novel mixed bis-adducts of C₆₀, (±)-4-(±)-8 and 9, with a bis(ethoxycarbonyl)methano addend (Bingel addend) and a second addend ([1,2]benzeno, but[2]eno, methaniminomethano, or diarylmethano) bridging 6,6-closed bonds of the carbon sphere were synthesized in two-step reactions. Each bis-adduct was exhaustively electrolyzed at the potential of the second fullerene-centered reduction step, resulting in the selective removal of the Bingel addend (retro-Bingel reaction) to produce the corresponding mono-adducts, which were isolated in yields of over 60 %. These results open up the possibility of using the Bingel addend as a temporary protecting and directing group in the construction of multiple adducts of C₆₀ with unusual addition patterns. The Bingel-type mono-adduct of C₇₀10 and the constitutionally isomeric bis-adducts 11, (±)-12, and (±)-13 were also included in this investigation. A large difference in the electrochemical behavior between C₇₀ bis-adducts and the corresponding C₆₀ derivatives was observed. Thus, the intramolecular “walk-on-the-sphere” isomerization which occurs readily with Bingel-type bis-adducts of C₆₀ under the conditions of two-electron controlled potential electrolysis (CPE) is only a minor reaction pathway in the series of C₇₀ derivatives. The latter preferentially undergo retro-Bingel reaction.

Two series of monodisperse, terminally donor–donor [D–D, D=4-(dimethylamino)phenyl] and acceptor–acceptor [A–A, A=4-nitrophenyl] functionalized poly(triacetylene) (PTA) oligomers ranging from monomer to hexamer were synthesized by oxidative Hay oligomerization under end-capping conditions. The corresponding D–D and A–A end-substituted polymers with an average degree of polymerization (DP) of n ≈18 and n ≈12, respectively, were also prepared and served as reference points for the corresponding infinitely long polymers. These terminally functionalized PTA oligomers and polymers are yellow- to orange-colored compounds, displaying excellent solubility in aprotic solvents with melting points above 200 °C for the hexamers. For the 4-(dimethylamino)phenyl substituted compounds, a consistent first oxidation potential around +0.42 V versus Fc/Fc⁺ (ferrocene/ferricinium) was observed, whereas the 4-nitrophenyl functionalized systems underwent a reversible reductive two-electron transfer around −1.40 V versus Fc/Fc⁺. The nature of the end-groups has a dramatic influence on the electronic absorption spectra. Saturation of the linear optical properties in the D–D series occurs at significantly shorter chain-length [effective conjugation length (ECL) of n ≈4 monomer units] than in the A–A substituted or the previously reported Me₃Si- and Et₃Si-end-capped PTA oligomer series (ECL: n ≈10 monomer units). Similar observations with respect to the ECL were made by measurement of the Raman-active _(C≡C) stretches. Third-harmonic generation (THG) and degenerate four-wave mixing (DFWM) experiments showed that shorter oligomers of terminally D–D or A–A functionalized PTAs display higher second hyperpolarizabilities γ than the corresponding R₃Si-end-capped series (R=alkyl). Moreover, they disclose a distinct peak of the nonlinearity per monomer unit at intermediate backbone lengths. In THG experiments, the second hyperpolarizabilities for long D/A-functionalized PTA oligomers attained the same saturation values as observed for the corresponding R₃Si-end-capped rods. The nonlinearities measured by DFWM of the D–D and A–A substituted PTAs were found to be larger than for the silylated ones, which can be explained by the closeness of the two-photon resonance.

A series of monodisperse Et₃Si-end-capped poly(triacetylene) (PTA) oligomers ranging from monomer to hexadecamer was prepared by a fast and efficient statistical deprotection–oxidative Hay oligomerization protocol. The PTA oligomers exhibit an increasingly deep-yellow color with lengthening of the π-conjugated backbone, feature excellent solubility in aprotic solvents, and exhibit melting points up to >220 °C for the hexadecameric rod. This new dramatically extended oligo(enediyne) series now enables to investigate the evolution of the physico-chemical effects in PTAs beyond the linear 1/n versus property regime into the higher oligomer region where saturation becomes apparent. We report the results of joint experimental and theoretical studies, including analysis of the ¹³C NMR spectra, evaluation of the linear (UV/Vis) and nonlinear [third-harmonic generation (THG) and degenerate four-wave mixing (DFWM)] optical properties, and characterization of the redox properties with cyclic and steady-state voltammetry. Up to the hexadecameric rod, an increasingly facile one-electron reduction step is observed, showing at the stage of the dodecamer, a leveling off tendency from the linear correlation between the inverse number of monomer units and the first reduction potential. The effective conjugation length (ECL) determined by means of UV/Vis spectroscopy revealed a π-electron-delocalization length of about n=10 monomeric units, which corroborates well with the oligomeric length for which in the ¹³C NMR spectrum C(sp²) and C(sp) resonances start to overlap. Third-harmonic generation (THG) and degenerate four-wave mixing (DFWM) measurements revealed for the second-order hyperpolarizability γ a power law increase γ⋅α⋅n^a for oligomers up to the octamer with exponential factors a=2.46±0.10 and a=2.64±0.20, respectively, followed by a smooth saturation around n=10 repeating units. The power law coefficient a calculated with the help of the valence effective Hamiltonian (VEH) method combined to a sum-over-states (SOS) formalism corroborates well with the values found by both THG and DFWM experiments. Up to the PTA heptamer, INDO (intermediate neglect of differential overlap)-calculated gas-phase ionization potentials and electron affinities obey a linear relationship as a function of the inverse number of monomer units displaying a strong electron-hole symmetry. The onset of saturation for the electron affinity is calculated to occur around the octamer, in accordance with experimentally obtained results from electrochemical measurements.

The cyclophane-type molecular dyads 1⋅2 H and 1⋅Zn, in which a doubly bridged porphyrin donor adopts a close, tangential orientation relative to the surface of a fullerene acceptor, were prepared by Bingel macrocylization. The porphyrin derivatives 2⋅2 H and 2⋅Zn with two appended, singly linked C₆₀ moieties were also formed as side products. NMR investigations revealed that the latter compounds strongly prefer conformations with one of the carbon spheres nesting on the porphyrin surface, thereby taking a similar orientation to that of the fullerene moiety in the doubly bridged systems. Cyclic voltammetric measurements showed that the mutual electronic effects exerted by the fullerene on the porphyrin and vice versa are only small in all four dyads, despite the close proximity of the donor and acceptor components. The steady-state and time-resolved absorption and luminescence properties of 1⋅Zn and 2⋅Zn were investigated in toluene solution and it was shown that, upon light excitation, both the porphyrin- and the fullerene-centered excited states are deactivated to a lower-lying CT state, emitting in the IR spectral region (λ_max=890 and 800 nm at 298 and 77 K, respectively). In the more polar solvent benzonitrile, this CT state is still detected but, owing to its very low energy (below 1.4 eV), is not luminescent and shorter-lived than in toluene. The remarkable observation of similar photophysical behavior of 1⋅Zn and 2⋅Zn suggests that a tight donor-acceptor distance cannot only be established in doubly bridged cyclophane-type structures but also in singly bridged dyads, by taking advantage of favourable fullerene-porphyrin ground-state interactions.

Le diadi molecolari ciclofaniche 1⋅2 H e 1⋅Zn, ove una porfirina elettron-donatrice viene a trovarsi vicina, e in posizione tangenziale, rispetto alla superficie di un fullerene elettro-accettore, sono state preparate mediante reazione di macrociclizzazione di Bingel. Come prodotti secondari di reazione sono stati ottenuti i derivati porfirinici 2⋅2 H and 2⋅Zn, che presentano alle estremità due unità fullereniche appese di tipo monosostituito. Gli studi NMR evidenziano che in questi ultimi è favorita una conformazione in cui una sfera fullerenica si posiziona in stretta vicinanza alla superficie della porfirina, analogamente a quanto accade per le diadi ciclofaniche 1⋅2 H e 1⋅Zn. Misure di voltammetria ciclica indicano che la mutua interazione tra il fullerene e la porfirina sono modeste in tutti e quattro i casi, nonostante la stretta vicinanza dei componenti e le loro complementari proprietà elettroniche. Le proprietà di assorbimento ed emissione di 1⋅Zn e 2⋅Zn, sia allo stato stazionario che risolte nel tempo, sono state studiate in toluene. E′ stato così dimostrato che, a seguito di assorbimento di luce, sia gli stati eccitati localizzati sulla porfirina che quelli localizzati sul fullerene vengono disattivati verso un più basso livello elettronico di trasferimento di carica (CT), che emette nel vicino infrarosso (λ_max=890 e 800 nm a 298 e 77 K, rispettivamente). In un solvente più polare, quale benzonitrile, lo stato CT è ancora osservato ma, a causa del basso contenuto energetico (meno di 1.4 eV), non è luminescente e presenta un tempo di vita più breve che in toluene. Risulta di particolare rilevanza la somiglianza tra il comportamento fotofisico di 1⋅Zn e 2⋅Zn; questo suggerisce che una stretta vicinanza tra il donatore e l′accettore può realizzarsi non solo nelle strutture forzatamente affacciate di tipo ciclofanico, ma anche nei sistemi “non costretti” con due unità fullereniche, sfruttando favorevoli interazioni donatore-accettore allo stato fondamentale.

The fullerene-crown ether conjugates (±)-1 to (±)-3 with trans-1 ((±)-1), trans-2 ((±)-2), and trans-3 ((±)-3) addition patterns on the C-sphere were prepared by Bingel macrocyclization. The trans-1 derivative (±)-1 was obtained in 30% yield, together with a small amount of (±)-2 by cyclization of the dibenzo[18]crown-6(DB18C6)-tethered bis-malonate 4 with C₆₀ (Scheme 1). When the crown-ether tether was further rigidified by K⁺-ion complexation, the yield and selectivity were greatly enhanced, and (±)-1 was obtained as the only regioisomer in 50% yield. The macrocyclization, starting from a mixture of tethered bis-malonates with anti (4) and syn (10) bisfunctionalized DB18C6 moieties, afforded the trans-1 ((±)-1, 15%), trans-2 ((±)-2, 1.5%), and trans-3 ((±)-3, 20%) isomers (Scheme 2). Variable-temperature ¹H-NMR (VT-NMR) studies showed that the DB18C6 moiety in C₂-symmetrical (±)-1 cannot rotate around the two arms fixing it to the C-sphere, even at 393 K. The planar chirality of (±)-1 was confirmed in ¹H-NMR experiments using the potassium salts of (S)-1,1′-binaphthalene-2,2′-diyl phosphate ((+)-(S)-19) or (+)-(1S)-camphor-10-sulfonic acid ((+)-20) as chiral shift reagents (Fig. 1). The DB18C6 tether in (±)-1 is a true covalent template: it is readily removed by hydrolysis or transesterification, which opens up new perspectives for molecular scaffolding using trans-1 fullerene derivatives. Characterization of the products 11 (Scheme 3) and 18 (Scheme 4) obtained by tether removal unambiguously confirmed the trans-1 addition pattern and the out-out geometry of (±)-1. VT-NMR Studies established that (±)-2 is a C₂-symmetrical out-out trans-2 and (±)-3 a C₁-symmetrical in-out trans-3 isomer. Upon changing from (±)-1 to (±)-3, the distance between the DB18C6 moiety and the fullerene surface increases and, correspondingly, rotation of the ionophore becomes increasingly facile. The ionophoric properties of (±)-1 were investigated with an ion-selective electrode membrane (Fig. 2 and Table 2), and K⁺ was found to form the most stable complex among the alkali-metal ions. The complex between (±)-1 and KPF₆ was characterized by X-ray crystal-structure analysis (Figs. 3 and 4), which confirmed the close tangential orientation of the ionophore atop the fullerene surface. Addition of KPF₆ to a solution of (±)-1 resulted in a large anodic shift (90 mV) of the first fullerene-centered reduction process, which is attributed to the electrostatic effect of the K⁺ ion bound in close proximity to the C-sphere (Fig. 5). Smaller anodic shifts were measured for the KPF₆ complexes of (±)-2 (50 mV) and (±)-3 (40 mV), in which the distance between ionophore and fullerene surface is increased (Table 3). The effects of different alkali- and alkaline-earth-metal ion salts on the redox properties of (±)-1 were investigated (Table 4). These are the first-ever observed effects of cation complexation on the redox properties of the C-sphere in fullerene-crown ether conjugates.

Programmedwith an unusual number of functions, the tetraethynylethene derivative 1 exhibits three addressable switching subunits, which can undergo individual reversible switching cycles that are controllable by pH and light. Three “write/erase” processes and one “AND” logic gate process can be separately addressed, and in each case an efficient nondestructive readout is possible.

The pure enantiomers of D₂-C₈₄ as well as a third constitutional isomer of this higher fullerene were produced by a retro-Bingel reaction on the first organic derivatives of C₈₄ (see scheme). These derivatives were synthesized by Bingel cyclopropenation of C₈₄, separated, and unambiguously structurally characterized.

MiteinerungewöhnlichenZahl an Funktionen ist das Tetraethinylethenderivat 1 ausgestattet: Es weist drei adressierbare Untereinheiten auf, die individuelle reversible, durch den pH-Wert und Licht kontrollierbare Schaltcyclen eingehen. Drei „Schreib/Lösch”-Prozesse sowie eine logische Gatterfunktion des „AND”-Typs können einzeln adressiert werden, wobei in jedem Fall ein effizientes, zerstörungsfreies Ablesen möglich ist.

Mit16C-C-Doppel-und32C-C-Dreifachbindungen und einer Länge von 11.9 nm ist ein hexadecameres Poly(triacetylen) (PTA) vom Typ 1 der bisher längste linear π-konjugierte molekulare Draht, der keine aromatischen Wiederholungseinheiten aufweist. Über eine schnelle und effiziente statistische Entschützungs-Oligomerisierungs-Sequenz wurde eine vom Monomer bis zum Hexadecamer reichende Serie von PTA-Oligomeren 1 hergestellt; die effektive Konjugationslänge, bei der Sättigung der molekularen Eigenschaften auftritt, wurde sowohl UV/Vis- als auch Raman-spektroskopisch zu n = 10 (n = Zahl der Monomereinheiten) bestimmt.

Für das Ermitteln von Struktur-Funktions-Beziehungen, deren Kenntnis zum Verständnis der Eigenschaften hochmolekularer linear π-konjugierter Polymere beiträgt, haben sich monodisperse Oligomere als äußerst nützlich erwiesen. Eine große Vielfalt spektakulärer molekularer Architekturen wurde entwickelt, wobei derzeit ein Höhepunkt mit der Herstellung von über 10 nm langen molekularen Drähten wie 1 als potentiellen Bausteinen für die molekulare Elektronik erreicht ist.

Der quantitative Nachweis des Einflusses einer isolierenden Dendrimerhülle auf die Redoxeigenschaften eines eingelagerten Eisenporphyrinkerns ließ sich erstmals mit den schematisch dargestellten wasserlöslichen dendritischen Komplexen mit kovalent fixierten axialen Imidazol-Liganden führen. Damit sind diese Komplexe, deren Redoxpotentiale chemisch und elektrochemisch in Lösungsmitteln unterschiedlicher Polarität (CH₂Cl₂, MeCN, H₂O) bestimmt wurden, aussagekräftige Modellverbindungen für Cytochrome.

The quantitative evaluation of the effect of an insulating dendritic shell on the redox properties of an embedded iron porphyrin core has been achieved for the first time using water-soluble dendritic iron porphyrins with tethered axial ligands (shown schematically). Thus, these complexes, whose redox properties have been determined by chemical and electrochemical methods in solvents of different polarity (CH₂Cl₂, MeCN, H₂O), are valid mimics for cytochromes.

Die reinen Enantiomere vonD₂-C₈₄ sowie ein drittes Konstitutionsisomer dieses höheren Fullerens wurden durch Retro-Bingel-Reaktion der ersten organischen C₈₄-Derivate erhalten (siehe Schema). Diese wurden durch Bingel-Cyclopropanierung von C₈₄ synthetisiert und konnten getrennt und strukturell eindeutig zugeordnet werden.

The development of structure–property relationships for monodisperse oligomers has been extremely useful to rationalize the properties of high molecular weight linear π-conjugated polymers. A great variety of spectacular molecular architecture has been generated, culminating in the recent preparation of molecular wires such as 1 with lengths exceeding 10 nm that have potential applications in molecular electronics.

With16C−Cdoubleand32C−Ctriplebonds and a length of 11.9 nm, the hexadecameric poly(triacetylene) (PTA) of type 1 is currently the longest linear fully π-conjugated molecular wire that does not contain aromatic repeat units. A series of PTA oligomers 1 extending from monomer to hexadecamer was prepared by a rapid and efficient statistical deprotection–oligomerization sequence; the effective conjugation length at which saturation of molecular properties occurs was determined as n=10 (n=number of monomeric units) by both UV/Vis and Raman spectroscopies.

Zufällig entdeckt wurde bei elektrochemischen Untersuchungen zur Stabilität von Anionen von 1 eine präparativ nützliche Methode: die Retro-Bingel-Reaktion, eine elektrochemische Methode zur Entfernung der Bis(alkoxycarbonyl)methano-Bücken von Methanofullerenen. Sie wurde dazu verwendet, um die ersten Proben von enantiomerenreinem D₂-C₇₆ mit gesicherter optischer Reinheit herzustellen.

Die Selbstorganisation zweier C₆₀-Hexakisaddukte, die je eine Di(4-pyridyl)methanogruppe tragen, mit zwei Pt^II-Zentren führte zum zweikernigen Metallacyclophan 1 als erstem Repräsentanten einer neuen Klasse supramolekularer Multifullerenverbindungen. Der Röntgenstrukturanalyse von 1 zufolge bilden die beiden Pt^II-Zentren und die beiden quartären C-Atome der Dipyridylmethanogruppen auf Kosten beträchtlicher Winkelspannung ein perfekt planares Parallelogram.

Serendipitously discovered during electrochemical investigations on the stability of anion 1, a preparatively useful electrochemical procedure, the retro-Bingel reaction, has been identified as a method for removing di(alkoxycarbonyl)methano bridges from methanofullerenes. This procedure was applied to prepare the first samples of enantiomerically pure D₂-C₇₆ with unambiguous optical purity.

Self-assembly of two C₆₀hexakis-adducts, each bearing one di(4-pyridyl)methano addend, and two Pt^II centers afforded the dinuclear cyclophane 1, which represents the first example of a new class of supramolecular multifullerene arrays. The X-ray crystal structure of 1 revealed that the four vertex atoms of the cyclophane—the two Pt^II centers and the two quaternary C atoms of the dipyridylmethano groups—form a perfectly planar parallelogram at the cost of substantial angle strain.

A supermolecular array consisting of a coordinating ring, a copper(I) centre and a difunctionalized fragment threaded inside the ring is treated with a C₆₀ derivative to afford a rotaxane with two fullerenes as stoppers (right). The changes in the photophysical properties of the rotaxane with respect to the individual components, a methanofullerene and a Cu^I complex, were assigned to the occurrence of intercomponent energy- and electron-transfer processes.

Die regioselektive Bingel-Makrocyclisierung der C₆₀-Kohlenstoffkugel mit einem Bismalonat, das einen Dibenzo[18]krone-6-Spacer enthält, eröffnet erstmals einen allgemeinen Zugang zu trans-1-Fulleren-Bisaddukten wie (±)-1. Die Komplexierung von Kaliumionen durch (±)-1 hat einen starken Einfluß auf die Redoxeigenschaften des Fullerens infolge der engen räumlichen Nähe zwischen der Fullerenoberfläche und dem kronenethergebundenen Kation, die sich aus der doppelten Verbrückung ergibt.

Multinanometergroße Assoziate (M_r>14 000) wurden durch das Einfädeln molekularer Stäbe in dendritische Cyclophane (Dendrophane) erhalten. Diese Stäbe enthalten zwei Testosteron-Endgruppen, die über starre Spacer mit einem zentralen, durch zwei quartäre Ammoniumsubstituenten funktionalisierten Phenylring verknüpft sind. Die Bildung definierter Aggregate, in denen zwei Dendrophane spezifisch die Steroidgerüste einschließen (siehe Bild), wird durch eine Kombination von unpolaren Wechselwirkungen, hydrophober Desolvatisierung und Ionenpaarbildung begünstigt und hängt sehr von der Länge der Spacer ab.

Dendrimers provide a unique nanoscale environment in which to model biological function. These highly branched macromolecules can be viewed as mimics of both enzymes and more complex, self-asssembled biological architectures. This Concepts article focuses on dendrimers in which the intriguing nature of the dendritic environment plays an active role in generating or controlling properties observed in biological systems, such as those illustrated.

Eine Vier-Puls-Version des gepulsten Doppel-Elektron-Elektron-Resonanz(DEER)-Experimentes wurde auf eine Serie von TEMPO-Diradikalen mit definierten Interradikalabständen im Bereich von 1.4 bis 2.8 nm angewendet (siehe Bild). Diese neue Pulssequenz ermöglicht es, breite Verteilungen von Elektron-Elektron-Abständen ohne Totzeitartefakte zu bestimmen.

Regioselective Bingel macrocyclization of C₆₀ with a bis-malonate containing a novel dibenzo[18] crown-6 tether provides a versatile access to trans-1 fullerene bis-adducts such as (±)-1. Complexation of a potassium ion by (±)-1 has a pronounced effect on the redox properties of the carbon sphere as a result of the close proximity of the fullerene surface to the crown ether bound cation, which is enforced by the double bridging.

A four-pulse version of the pulsed double electron electron resonance (DEER) experiment has been applied to a series of TEMPO diradicals with well-defined interradical distances ranging from 1.4 to 2.8 nm (see picture). The new pulse sequence allows broad distributions of electron–electron distances to be measured without dead-time artifacts.

Multinanometer-sized assemblies with molecular weights exceeding 14 000 are obtained by the threading of two dendritic cyclophanes (dendrophanes) onto molecular rods in which two testosterone termini are attached by rigid spacers to a central phenyl ring bearing two quaternary ammonium side chains. The formation of these structurally defined aggregates, in which the dendrophanes preferentially encapsulate the steroid termini (see picture), is driven by a combination of apolar interactions, hydrophobic desolvation, and ion pairing, and depends strongly on the length of the spacer.

A Möbius aromatic transition state with a highly anisotropic magnetic susceptibility is involved in the thermal extrusion of dinitrogen from the adduct of benzene with diazomethane ([Eq. (1)]). A similar mechanism is proposed for the formation of 6–5-open methanofullerenes by thermal extrusion of dinitrogen from the pyrazolines that are obtained by 1,3-cycloaddition of diazoalkanes to fullerenes.

Oligopyridine ligands with attached methanofullerene C₆₀units have been prepared (e.g., 1) and their coordination behaviour investigated. The electrochemical properties of the resulting ruthenium(II) complexes are also described.