Molecular Clefts Derived from 9,9′-spirobi[9H-fluorene] for enantioselective complexation of pyranosides and dicarboxylic acids

The molecular clefts (R)- and (S)- 3 , incorporating 9,9′-spirobi[9H-fluorene] as a spacer and two N-(5,7-dimethyl-1,8-naphthyridin-2-yl)carboxamide (CONH(naphthy)) units as H-bonding sites were prepared via the bis(succinimid-N-yl esters) of (R)-and (S)-9,9′-spirobi[9H-fluorene]-2,2′-dicarboxylic acid ( 5 ). Derivative 6 , with one CONH(naphthy) unit and one succinimid-N-yl ester residue allowed easy access to spirobifluorene clefts with two different H-bonding sites, as exemplified by the synthesis of 4 . Binding studies with (R)- and (S)- 3 and optically active dicarboxylic acids in CDCl₃ exhibited differences in free energy of the formed diastereoisomeric complexes (Δ(ΔGº)) between 0.5 and 1.6 kcal mol^?1 (T 300 K). Similar enantioselectivities were observed with the spirobifluorene clefts (R)- and (S)- 1 , bearing two N-(6-methylpyridin-2-yl)carboxamide (CONH(py)) H-bonding sites. The thermodynamic quantities ΔHº and ΔSº for the recognition processes with (R)- and (S)- 1 were determined by variable-temperature ¹H-NMR titrations and compared to those with (R)- and (S)- 2 , which have two CONH(py) moieties attached to the 6,6′-positions of a conformationally more flexible 1,1′-binaphthyl cleft. All association processes showed high enthalpic driving forces which are partially compensated by unfavorable changes in entropy. Pyranosides bind to the optically active clefts 1 and 3 in CDCl₃ with ?ΔGº = 3.0–4.3 kcal mol^?1. Diastereoisomeric selectivities up to 1.2 kcal mol^?1 and enantioselectivities up to 0.4 kcal mol^?1 were observed. Cleft 4 and N-(5,7-dimethyl-1,8-naphthyridin-2-yl)acetamide ( 25 ) complexed pyranosides 22–24 as effectively as 3 indicating that only one CONH(naphthy) site in 3 associates strongly with the sugar derivatives. Based on the X-ray crystal structure of 3 , a computer model for the complex between (S)- 3 and pyranoside 22 was constructed. Molecular-dynamics (MD) simulations showed that differential geometrical constraints are at the origin of the high enantioselectivity in the complexation of dicarboxylic acid (S)- 7 by (R)- and (S)- 1 and (R)- and (S)- 3 .     

Synthesis,Crystal Structures,and Modelling of β-Oligopeptides Consisting of 1-(Aminomethyl)cyclopropanecarboxylic Acid: Ribbon-Type Arrangement of Eight-Membered H-Bonded Rings

Partially and fully protected, and unprotected β-oligopeptides ( 3 – 9 ) were prepared from 1-(aminomethyl)cyclopropanecarboxylic acid, which, in turn, is readily available from cyanoacetate and dibromoethane. N-Boc and C-OMe protection were applied for the fragment-coupling (1-hydroxy-1H-benzotriazole (HOBt)/1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC)) solution synthesis. X-Ray crystal structures of the dimer ( 3 ), trimer ( 5 ), and tetramer ( 6 ) are described, and compared with those of the Boc-protected building blocks ( 2 ) and of the corresponding trimer ( 10 ) consisting of 1-(aminomethyl)cyclohexanecarbonyl residues (cf. Figs. 1 and 2). While the cyclohexane derivative forms ten-membered hydrogen-bonded rings, the characteristic secondary-structural motif in the cyclopropane derivatives is an eight-membered ring with H-bonding between next neighbors (Fig. 1). All cyclopropanecarbonyl moieties in the reported structures have the – generally more stable – s-cis (`bisected') conformation of the C=O groups on the three-membered rings (not preferred with the cyclohexane analog, the exocyclic CO group of which may be in an s-trans, a perpendicular, an axial, or an equatorial position). The bisecting effect and the large exocyclic bond angle (120°) in the cyclopropane units are proposed to provide the `ordering' elements – on top of the staggering effect of the C(2)−C(3) ethane bond in all β-peptides – which lead to the observed substituent-induced turn formation. A high degree of intramolecular H-bonding is evident also from IR spectroscopy (Fig. 3), and concentration- and temperature-dependent NMR measurements (Fig. 4) of CHCl₃ and CD₂Cl₂ solutions, indicating that the boat-type arrangement of the eight-membered rings with their unusual H-bonding geometry (Fig. 1, f ) is also present in solution. A possible structure of a poly[1-(aminomethyl)cyclopropane-carboxylic acid] consisting of a flight of stairs formed by folded H-bonded eight-membered rings is modelled, using the oligomer X-ray data (Fig. 5). The type of secondary structure found in the solid state of the β^2,2-peptides reported here is unprecedented in the realm of α-peptides and proteins.     

Mimicking the Vancomycin Carboxylate Binding Site: Synthetic receptors for sulfonates,carboxylates, and N-protected α-amino acids in water

The novel H₂O-soluble cyclophanes 1 and 2 incorporating different anion-recognition sites were prepared in short synthetic routes (Schemes 1 and 2) as first-generation mimics of the natural, D -Ala-D -Ala binding antibiotic vancomycin. The X-ray crystal structure of 1 , a tris(hydrochloride)salt, revealed an open, preorganized cavity of sufficient size for the incorporation of small aliphatic residues (Fig. 3). In the crystal, molecules of 1 are arranged in parallel stacks, generating two types of channels, an ‘intra-stack’ channel passing through the cyclophane cavities and an ‘inter-stack’ channel located between cyclophane stacks (Fig. 4). The strongest intermolecular interactions between macrocycles in the crystal are C?O…?H? N H-bonds between the carboxamide residues of adjacent cyclophanes in neighboring stacks (Fig. 5). The ‘intra-’ and ‘inter-stack’ channels incorporate the three ordered Cl^? counterions and several, partially ordered solvent molecules (4 MeOH, 1 H₂O) (Fig. 6). Counterion Cl(2) is located within the ‘intra-stack’ channel and interacts with a protonated piperazinium N-atom and both ‘intra-stack’ MeOH molecules. The two other counterions, Cl(1) and Cl(3), are located within the ‘inter-stack’ channel. They are connected to two MeOH and one H₂O molecules and also interact both with the NH group of the protonated spiropiperidinium ring in 1 , forming an infinite, chain-like H-bonding network …?Cl(1)…?HOH…?MeOH…?Cl(3)…?HNH…?Cl(1′)…?. Both ‘intra-’ and ‘inter-stack’ MeOH molecules undergo weak CH…?π interactions with neighboring aromatic rings. Cyclophane 1 complexed aromatic sulfonates in 0.5M KCl/DCl buffer in D₂O, whereas the tetrakis(quaternary ammonium) receptor 2 bound the sodium salts of aliphatic and aromatic carboxylates and sulfonates, of N-acylated α-amino acids as well as of N-acetyl-D -alanyl-D -alanine (Ac-D -Ala-D -Ala), a substrate of vancomycin, in pure H₂O. In all of these complexes, ion pairing between the cationic recognition site in the periphery of the cyclophane receptor and the anionic substrates represents the major driving force for host-guest association. The ¹H-NMR analysis of complexation-induced changes in chemical shift clearly demonstrated that, in solution, this ion pairing exclusively takes place outside the cavity. Nevertheless, the macrocyclic bridges are essential for the efficiency of the anion-recognition sites in the two cyclophane receptors 1 and 2 . Control compounds 3 and 4 possess nearly the same anion-recognition sites than 1 and 2 , but lack their macrocyclic preorganization; as a consequence, they do not form stable ion-pairing complexes with mono-anionic substrates in the considered concentration ranges ( < 50 mM ) in D₂O.     

Negative Cooperativity in the Molecular Recognition of Excitatory Amino-Acid Derivatives by Synthetic Allosteric 1,1′-Binaphthalene Receptors

The optically active allosteric receptors (−)-(R,R)- 3 and (+)-(R,R)- 4 were synthesized for the molecular recognition of the N-(benzyloxy)carbonyl (N-Cbz)-protected excitatory amino acids aspartic acid (Asp, 1 ) and glutamic acid (Glu, 2 ). These macrocyclic structures consist of two 1,1′-binaphthalene moieties connected by two but-2-yne-1,4-diyl (for (−)-(R,R)- 3 ) or p-xylylene (for (+)-(R,R)- 4 ) bridges between the O-atoms in the minor grooves. Each 1,1′-binaphthalene moiety contains two 2-acetamidopyridin-6-yl (CONH(py)) H-bonding sites in the major groove to bind excitatory amino-acid derivatives via two COOH█bk█⋅⋅⋅█ek█CONH(py) H-bonding arrays and additional secondary electrostatic interactions. The formation of stable complexes with 1 : 2 host-guest stoichiometry was proven by the evaluation of fluorescence binding titrations using a multiple-wavelength nonlinear least-squares curve-fitting procedure, Job plot analysis, and solubilization experiments. Complexation of the first excitatory amino-acid guest at binding site 1 reduces the affinity for the second guest at binding site 2. As measures for the negative cooperativity between the two sites, the ratios of the association constants for the first and second binding events, {K_a(1 : 1)/K_a(1 : 2)}_corr. (corrected for the statistical preference of the 1 : 1 complex formation), were found to adopt values between 1.4 and 2.4, and the Hill coefficients n_H varied between 0.49 and 0.59.     

Three-Component Reactions with Sterically Crowded 2,2,4,4-Tetramethyl-3-thioxocyclobutanone,Phenyl Azide,and Electron-Deficient C,C-Dipolarophiles

In order to trap ‘thiocarbonyl-aminides’ A , formed as intermediates in the reaction of thiocarbonyl compounds with phenyl azide, a mixture of 2,2,4,4-tetramethyl-3-thioxocyclobutanone ( 1 ), phenyl azide, and fumarodinitrile ( 8 ) was heated to 80° until evolution of N₂ ceased. Two interception products of the ‘thiocarbonylaminide’ A (Ar?Ph) were formed: the known 1,4,2-dithiazolidine 3 (cf. Scheme 1) and the new 1,2-thiazolidine 12 (Scheme 2). The structure of the latter was established by X-ray crystallography (Fig.1). The analogous ‘three-component reaction’ with dimethyl fumarate ( 9 ) yielded, instead of 8 , in addition to the known interception products 3 and 6 (Scheme 1), two unexpected products 15 and 16 (Scheme 3), of which the structures were elucidated by X-ray crystallography (Fig.2). Their formation is rationalized by a primary [2 + 3] cycloaddition of diazo compound 18 with 1 to give 19 , followed by a cascade of further reactions (Scheme 4).     

Cyclophane-Type Fullerene-dibenzo[18]crown-6 Conjugates with trans-1, trans-2, and trans-3 Addition Patterns: Regioselective Templated Synthesis,X-Ray Crystal Structure,Ionophoric Properties,and Cation-Complexation-Dependent Redox Behavior

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.     

Complexes of the Triolide from (R)-3-Hydroxybutanoic Acid with Sodium,Potassium, and Barium Salts: Crystal Structures,Ester Chelates and Ester Crowns,Crystal Packing,Bonding, and Electron-Localization Functions

The triolide of (R)-3-hydroxybutanoic acid ((R,R,R,))-3,7,11-trimethyl-2,6,10-trioxadodecane-1,5,9-trione; ( 1 ), readily available from the corresponding biopolymer P(3-HB) in one step, forms crystalline complexes with alkali and alkaline earth salts. The X-ray crystal structures of three such complexes, (3 NaSCN)·4 1 ( 2 ), (2 KSCN)·2 1 · H₂O ( 3 ), and (2) Ba(SCN)₂ · 2 1 · 2 H₂O · THF ( 4 ), have been determined and are compared. The triolide is found in these structures (i) as a free molecule, making no contacts with a cation (clathrate-type inclusion), (ii) as a monodentate ligand coordinated to a single ion with one carbonyl O-atom only, (iii) as a chelator, forming an eight-membered ring, with two carbonyl O-atoms attached to the same ion, (iv) as a linker, using two carbonyl O-atoms to bind to the two metals of an ion-X-ion unit (ten-membered ring), and (v), in a crown-ester complex, in which an ion is sitting on the three unidirectional C?O groups of a triolide molecule (Figs. 1–3). The crystal packing is such that there are columns along certain axes in the centers of which the cations are surrounded by counterions and triolide molecules, with the non-polar parts of 1 on the outside (Fig. 4). In the complexes 2–4 , the triolide assumes conformations which are slightly distorted, with the carbonyl O-atoms moved closer together, as compared to the ‘free’ triolide 1 (Fig. 5). These observed features are compatible with the view that oligo (3-HB) may be involved in the formation of Ca polyphosphate ion channels through cell membranes. A comparison is also made between the triolide structure in 1–4 and in enterobactin, a super Fe chelator (Fig. 5). To better understand the binding between the Na ion and the triolide carbonyl O-atoms in the crown-ester complex, we have applied electron-localization function (ELF) calculations with the data set of structure 2 , and we have produced ELF representations of ethane, ethene, and methyl acetate (Figs. 6–9). It turns out that this theoretical method leads to electron-localization patterns which are in astounding agreement with qualitative bonding models of organic chemists, such as the ‘double bond character of the CO? OR single bond’ or the ‘hyperconjugative n → σ* interactions between lone pairs on the O-atoms and neighbouring σ-bonds’ in ester groups (Fig. 8). The noncovalent, dipole/pole-type character of bonding between Na⁺ and the triolide carbonyl O-atoms in the crown-ester complex (the Na? O?C plane is roughly perpendicular to the O? C?O plane) is confirmed by the ELF calculation; other bonding features such as the C?N bond in the NaSCN complex 2 are also included in the discussion (Fig. 9).     

Dendroclefts: Optically Active Dendritic Receptors for the Selective Recognition and Chiroptical Sensing of Monosaccharide Guests

The enantiomerically pure dendritic receptors with cleft-type recognition sites (dendroclefts) of generation zero ((−)- G0 ), one ((−)- G1 ), and two ((−)- G2 ) (Fig. 1) were prepared for the complexation of monosaccharides via H-bonding. They incorporate a rigid, optically active 9,9′-spirobi[9H-fluorene] core bearing 2,6-bis(carbonylamino)pyridine moieties as H-bonding sites in the 2,2′-positions. The dendritic shells in (−)- G1 and (−)- G2 are made out of a novel type of dendritic wedges of the first ( 8 ; Scheme 2) and second ( 13 ; Scheme 3) generations, which contain only donor O-atoms and are attached to the H-bonding edges of the core via glycine spacers (Scheme 4). The formation of stable 1 : 1 complexes (association constants K_a between 100 and 600 M ⁻¹, T=298 K; Table 2) between the three receptors and pyranosides in CHCl₃ was confirmed by ¹H-NMR and CD binding titrations as well as by Job plot analyses. The degree of dendritic branching was found to exert a profound effect on the stereoselectivity of the recognition processes. The binding enantioselectivity decreases with increasing degree of branching, whereas the diastereoselectivity increases. The ¹H-NMR analysis showed that the N−H⋅⋅⋅O H-bonds between the amide NH groups around the core and the sugar O-atoms become weakened with increasing dendritic generation, presumably due to steric factors and competition from intramolecular H-bonding between these amide groups and the O-atoms of the dendritic shell. The chiroptical properties of the dendroclefts respond to guest binding in a stereoselective manner. Whereas large differential changes are seen in the circular dichroism (CD) spectra of (−)- G0 and (−)- G1 upon complexation of the enantiomeric monosaccharides (Figs. 3 and 4), the CD spectra of the higher-generation derivative (−)- G2 respond to a lesser extent to guest complexation (Fig. 5). This is indicative of a different binding geometry, more remote from the core chromophore. With their higher masses, the dendroclefts (−)- G1 and (−)- G2 are readily recycled from host-guest solutions by gel-permeation chromatography. The strong CD sensory response and the easy recyclability suggest applications of chiral dendroclefts as sensors for biologically important molecules.     

Revidierte Struktur des Makrodiolids Colletodiol

Revised Structure of the Macrodiolide Colletodiol An X-ray analysis shows that the vicinal glycol unit of colletodiol has the threo-rather than the previously assigned erythro-configuration (see 1 , Fig. 1 and Fig. 3). Together with the correlative assignments of (2R)- and (8R)-absolute configurations by MacMillan & Simpson the centers of chirality of colletodiol 1 are now established to be (2R, 8R, 10R, 11R).     

A Molecular‐Dynamics Simulation Study of the Conformational Preferences of Oligo(3‐hydroxyalkanoic acids) in Chloroform Solution

The GROMOS96 molecular‐dynamics (MD) program and force field was used to calculate the conformations at 298 K in CHCl₃ solution of two hexakis(3‐hydroxyalkanoic acids). One consists of (R)‐3‐hydroxybutanoate (HB) residues only: H−(OCH(Me)−CH₂−CO)₆−OH ( 1 ). The other one carries the side chains of valine, alanine, and leucine: H−(OCH(CHMe₂)CH₂−CO−O−CH(Me)−CH₂−CO−O−CH(CH₂ CHMe₂)−CH₂−CO)₂−OH ( 2 ), with homochiral 3‐hydroxyalkanoate (HA) moieties. In both cases, the conformational equilibria were sampled 2500 times for 25 ns. Other than clusters of arrangements with inter‐residual hydrogen bonding (between the O‐ and C‐terminal OH and COOH groups, and with chain‐bound ester carbonyl O‐atoms; Fig. 6), there are no preferred backbone conformations in which the molecules 1 and 2 spend more than 5% of the time. Specifically, neither the 2₁‐ nor the 3₁‐helical conformation of the oligoester backbone (found in stretched fibers, in lamellar crystallites, and in single crystals of polymers PHB and of oligomers OHB) is sampled to any significant extent (Fig. 8 and 9), in spite of the high population, in both oligomers, of the (−)‐synclinal conformation around the C(2)−C(3) bond (angle ϕ₂ in Fig. 2). In contrast to β‐oligopeptides, for which strongly preferred secondary structures are found after a few ns, and for which the number of conformations levels off with time, the number of conformational clusters of the corresponding oligoesters found by our force‐field MD calculations increases steadily over the observation time of 25 ns (Fig. 5). Thus, the conclusion from biological and physical‐chemical studies, according to which the PHB chain is extremely flexible, is confirmed by our computational investigation: in CHCl₃ solution, the hexakis(3‐hydroxyalkanoate) chain samples its conformational space randomly!     

Cyclische Oligomere von (R)-3-Hydroxybuttersäure: Herstellung und strukturelle Aspekte

Cyclic Oligomers of (R)-3-Hydroxybutanoic Acid: Preparation and Structural Aspects The oligolides containing three to ten (R)-3-hydroxybutanoate (3-HB) units (12-through 40-membered rings 1–8 ) are prepared from the hydroxy acid itself, its methyl ester, its lactone (‘monolide’), or its polymer (poly(3-HB), mol. wt. ca. 10⁶ Dalton) under three sets of conditions: (i) treatment of 3-HB ( 10 ) with 2,6-dichlorobenzoyl chloride/pyridine and macrolactonization under high dilution in toluene with 4-(dimethylamino)pyridine (Fig. 3); (ii) heating a solution (benzene, xylene) of the β-lactone 12 or of the methyl ester 13 from 3-HB with the tetraoxadistanna compound 11 as trans-esterification catalyst (Fig. 4); (iii) heating a mixture of poly(3-HB) and toluene-sulfonic acid in toluene/1,2-dichloroethane for prolonged periods of time at ca. 100° (Fig. 6). In all three cases, mixtures of oligolides are formed with the triolide 1 being the prevailing component (up to 50% yield) at higher temperatures and with longer reaction times (thermodynamic control, Figs. 3–6). Starting from rac-β-lactone rac- 12 , a separable 3:1 to 3:2 mixture of the l,u- and the l,l-triolide diasteroisomers rac- 14 and rac- 1 , respectively, is obtained. An alternative method for the synthesis of the octolide 6 is also described: starting from the appropriate esters 15 and 17 and the benzyl ether 16 of 3-HB, linear dimer, tetramer, and octamer derivatives 18–23 are prepared, and the octamer 23 with free OH and CO₂H group is cyclized (→ 6 ) under typical macrolactonization conditions (see Scheme). This ‘exponential fragment coupling protocol’ can be used to make higher linear oligomers as well. The oligolides 1–8 are isolated in pure form by vacuum distillation, chromatography, and crystallization, an important analytical tool for determining the composition of mixtures being ¹³C-NMR spectroscopy (each oligolide has a unique and characteristic chemical shift of the carbonyl C-atom, with the triolide 1 at lowest, the decolide 8 at highest field). The previously published X-ray crystal structures of triolide 1 , pentolide 3 , and hexolide 4 (two forms), as well as those of the l,u-triolide rac- 14 , of tetrolide ent- 2 , of heptolide 5 , and of two modifications of octolide 6 described herein for the first time are compared with each other (Figs. 7–10 and 12–15, Tables 2 and 5–7) and with recently modelled structures (Tables 3 and 4, Fig. 11). The preferred dihedral angles τ₁ to τ₄ found along the backbone of the nine oligolide structures (the hexamer and the larger ones all have folded rings!) are mapped and statistically evaluated (Fig. 16, Tables 5–7). Due to the occurrence of two conformational minima of the dihedral angle O? CO? CH₂? CH (τ₃ = + 151 or ?43°), it is possible to locate two types of building blocks for helices in the structures at hand: a right-handed 3₁ and a left-handed 2₁ helix; both have a ca. 6 Å pitch, but very different shapes and dispositions of the carbonyl groups (Fig. 17). The 2₁ helix thus constructed from the oligolide single-crystal data is essentially superimposable with the helix derived for the crystalline domains of poly(3-HB) from stretched-fiber X-ray diffraction studies. The absence of the unfavorable (E)-type arrangements around the OC? OR bond (‘cis-ester’) from all the structures of (3-HB) oligomers known so far suggests that the model proposed for a poly(3-HB)-containing ion channel (Fig. 2) must be modified.     

Double-Bond Shifts in [4n]Annulenes as a New Principle for Molecular Switches: First Results with Dimethyl Heptalene-1,2- and -4,5-dicarboxylates

A new concept for molecular switches, based on thermal or photochemical double-bond shifts (DBS) in [4n]annulenes such as heptalenes or cyclooctatetraenes, is introduced (cf. Scheme 2). Several heptalene-1,2- and -4,5-dicarboxylates (cf. Scheme 4) with (E)-styryl and Ph groups at C(5) and C(1), or C(4) and C(2), respectively, have been investigated. Several X-ray crystal-structure analyses (cf. Figs. 1–5) showed that the (E)-styryl group occupies in the crystals an almost perfect s-trans-conformation with respect to the C?C bond of the (E)-styryl moiety and the adjacent C?C bond of the heptalene core. Supplementary ¹H-NOE measurements showed that the s-trans-conformations are also adopted in solution (cf. Schemes 6 and 9). Therefore, the DBS process in heptalenes (cf. Schemes 5 and 8) is always accompanied by a 180° torsion of the (E)-styryl group with respect to its adjacent C?C bond of the heptalene core. The UV/VIS spectra of the heptalene-1,2- and -4,5-dicarboxylates illustrated that it can indeed be differentiated between an ‘off-state’, which possesses no ‘through-conjugation’ of the π-donor substituent and the corresponding MeOCO group and an ‘on-state’ where this ‘through-conjugation’ is realized. The ‘through-conjugation’, i.e., conjugative interaction via the involved s-cis-butadiene substructure of the heptalene skeleton, is indicated by a strong enhancement of the intensities of the heptalene absorption bands I and II (cf. Tables 3–6). The most impressive examples are the heptalene-dicarboxylates 11a , representing the off-state, and 11b which stands for the on-state (cf. Fig.8).     

From Colchicine and Some of Its Derivatives to 1,2,3,9,10-Pentamethoxybenzo[a]heptalenes

A two-step synthesis of 4-methylcolchicine ( 13 ), starting from colchicine ( 2 ), has been developed (Scheme 5). In three steps, 4-ethylcolchicine ( 28 ) is also accessible from 2 (Scheme 8). Colchicine ( 2 ) and its derivatives 13 and 28 have been transformed into the benzo[a]heptalene derivatives 9 , 18 , and 34 , respectively, by Hofmann degradation of the corresponding deacetylcolchiceine 3, 19 , and 29 , respectively, followed by methylation of the two O-functions first with diazomethane and then with trimethoxonium tetrafluoroborate (Scheme 2 and 6). The thus formed tropylium salts gave, on deprotonation with Me₃N in CHCl₃, the expected pentamethoxybenzo[a]heptalenes 9, 18 , and 34 , respectively. X-Ray crystal-structure analysis of 9 (Fig.3) and 18 (Fig. 7), determination of the vicinal coupling constants of the H-atoms at the heptalene skeleton as well as the measurement of the racemization rate of the new benzo[a]heptalenes revealed a marked influence of the substituent at C(4) on the degree of twisting of the heptalene skeleton. The absolute configuration of the resolved heptalenes was deduced from their long-wavelength CD maxima around 350 nm. The heptalenes with a negative maximum in this range possess (7aP)-configuration.     

Molecular Recognition and Enantiomer Separations on a novel chiral stationary phase based on a 9,9′-spirobi[9H-fluorene]-derived molecular cleft

An optically active molecular cleft incorporating a 9,9′-spirobi[9H-fluorene] spacer and two N-(5,7-dimethyl-1,8-naphthyridin-2-yl)carboxamide: (CONH(naphthyr)) moieties as H-bonding sites was covalently bound to silica gel to provide the new chiral stationary phase (CSP) (R)- 16 (Scheme 2). Previous solution-binding studies in CDCl₃ had shown that the anchored molecular cleft was capable of complexing optically active dicarboxylic acids with differences in free energy of the formed diastereoisomeric complexes (Δ(ΔG⁰)) between 0.5 and 1.6 kcal mol^?1 (T = 300 K). The optical resolution of racemic dicarboxylic acids, that are bound with a high degree of enantioselectivity in the liquid phase, was now achieved by HPLC on the CSP (R)- 16. The order of enantiomer elution was as predicted from the solution studies, and the separation factor α varied between 1.18 and 1.24. A series of 1,1′-binaphthalene-2,2′-diol derivatives were also resolved on the new CSP, in some cases with baseline separation. The order of enantiomer elution under normal-phase chromatographic conditions was rationalized by computer modeling of the association between the solute enantiomers and the immobilized molecular cleft. HPLC Separations with eluents of different polarity suggested that the attractive interactions between solute and immobilized chiral selector are a combination of H-bonding, which prevails in apolar eluents, and aromatic π--π stacking, which dominates in polar eluents.     

In search for mixed transition metal/lanthanide single-molecule magnets: Synthetic routes to NiII/TbIII and NiII/DyIII clusters featuring a 2-pyridyl oximate ligand

Employing the mononuclear complex [Ni{(py)C(Me)NO}₂{(py)C(Me)NOH}] (1) as ‘ligand’ [(py)C(Me)NOH = methyl 2-pyridyl ketone oxime], the use of the ‘metal complexes as ligands’ approach has led to the synthesis of the mixed Ni^II/Ln^III complexes [NiTb{(py)C(Me)NO}₂(NO₃)₃{(py)C(Me)NOH}] (2), [Ni₂Ln₂{(py)C(Me)NO}₆(NO₃)₄] (Ln = Dy, 3; Ln = Tb, 4) and [Ni₂Tb{(py)C(Me)NO}₆](NO₃) (5). The structures of 2, 3, and 5, and the magnetic properties of 2 and 5 are briefly discussed.     

Regioselective One‐Step Synthesis and Topological Chirality of trans‐3, trans‐3,trans‐3 and e,e,e [60]Fullerene‐Cyclotriveratrylene Tris‐adducts: Discussion on a Topological meso‐Form

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).     

Organocatalyzed Michael Addition of Aldehydes to Nitro Alkenes – Generally Accepted Mechanism Revisited and Revised

The amine‐catalyzed enantioselective Michael addition of aldehydes to nitro alkenes (Scheme 1) is known to be acid‐catalyzed (Fig. 1). A mechanistic investigation of this reaction, catalyzed by diphenylprolinol trimethylsilyl ether is described. Of the 13 acids tested, 4‐NO₂? C₆H₄OH turned out to be the most effective additive, with which the amount of catalyst could be reduced to 1 mol‐% (Tables 2–5). Fast formation of an amino‐nitro‐cyclobutane 12 was discovered by in situ NMR analysis of a reaction mixture. Enamines, preformed from the prolinol ether and aldehydes (benzene/molecular sieves), and nitroolefins underwent a stoichiometric reaction to give single all‐trans‐isomers of cyclobutanes (Fig. 3) in a [2+2] cycloaddition. This reaction was shown, in one case, to be acid‐catalyzed (Fig. 4) and, in another case, to be thermally reversible (Fig. 5). Treatment of benzene solutions of the isolated amino‐nitro‐cyclobutanes with H₂O led to mixtures of 4‐nitro aldehydes (the products 7 of overall Michael addition) and enamines 13 derived thereof (Figs. 6–9). From the results obtained with specific examples, the following tentative, general conclusions are drawn for the mechanism of the reaction (Schemes 2 and 3): enamine and cyclobutane formation are fast, as compared to product formation; the zwitterionic primary product 5 of C,C‐bond formation is in equilibrium with the product of its collapse (the cyclobutane) and with its precursors (enamine and nitro alkene); when protonated at its nitronate anion moiety the zwitterion gives rise to an iminium ion 6 , which is hydrolyzed to the desired nitro aldehyde 7 or deprotonated to an enamine 13 . While the enantioselectivity of the reaction is generally very high (>97% ee), the diastereoselectivity depends upon the conditions, under which the reaction is carried out (Fig. 10 and Tables 1–5). Various acid‐catalyzed steps have been identified. The cyclobutanes 12 may be considered an off‐cycle ‘reservoir’ of catalyst, and the zwitterions 5 the ‘key players’ of the process (bottom part of Scheme 2 and Scheme 3).     

Preparation of the PdCl2 Complex of TADDOP,the Bis(diphenylphosphinite) of TADDOL: Use in enantioselective 1,3-diphenylallylations of nucleophiles and discussion of the mechanism

Reaction of the tartrate-derived diol (R,R)-α,α,α′,α′-tetraphenyl-2,2-dimethyl-1,3-dioxolane-4,5-dimethanol (TADDOL) with chlorodiphenylphosphane gives a new bis(diphenylphosphanyl) ligand (TADDOP). The complex 4 formed with PdCl₂ has been crystallized and its structure determined by X-ray diffraction (Fig.1). The complex is used for Pd-catalyzed enantioselective 1,3-diphenylallylations of various nucleophiles which give products with enantiomer ratios of up to 88:12 (Scheme 2). Crystallization procedures lead to the enantiomerically pure (> 99:1) product 11 derived from dimethyl malonate. The structure of the TADDOP complex 4 is compared with those of other transition-metal complexes containing chelating bis(diphenylphosphanyl) ligands (Fig.2). A crystallographic data base search reveals that the structures of transition-metal complexes containing two Ph₂P groups (superpositions in Fig.3) fall into one of two categories: one with approximate C₂ symmetry and the other with C₁ symmetry (20 and 19 examples, resp.). A mechanistic model is proposed which correlates the conformational chirality (δ or λ) of the four Ph groups' arrangement in such complexes with the topicity of nucleophile approach on Pd-bound trans,trans-1,3-diphenylallyl groups (Scheme 3 and Table).     

β-Thiopeptides: Synthesis,NMR Solution Structure,CD Spectra,and Photochemistry

To test the effect of NH−C=S groups (Scheme 1) on the stability of β-peptide secondary structures, we have synthesized three β-thiohexapeptide analogues of H-(β-HVal-β-HAla-β-HLeu)₂-OH ( 1 ) with one, two, and three C=S groups in the N-terminal positions (cf. 2 – 4 and model in Fig. 1). The first C=S group was introduced selectively by treatment with Lawesson reagent of Boc-β-dipeptide esters ( 6 and 8 ). A series of fragment-coupling steps (with reagents as for the corresponding sulfur-free building blocks) and another thionation reaction led to the title compounds with a C=S group in residues 1, 1, and 3, as well as 1, 2, and 3 of the β-hexapeptide (Schemes 2 and 3). The sulfur derivatives, especially those with three C=S groups, were much more soluble in organic media than the sulfur-free analogues (>1000-fold in CHCl₃; Table 1). The UV and CD spectra (in CHCl₃, MeOH, and H₂O) of the new compounds were recorded and compared with those of the parent β-hexapeptide 1 (Figs. 2 – 4); they indicate the presence of more than one secondary structure under the various conditions. Most striking is a pronounced exciton splitting (Δλ ca. 20 nm, amplitude up to +121000) of the ππ*_C=S band near 270 nm with the β-trithiohexapeptide (with and without terminal protecting groups), and strong, so-called `primary solvent effects', in the CD spectra. The CD spectrum of the β-dithiohexapeptide 3 undergoes drastic changes upon irradiation with 266-nm laser light of a MeOH solution (Fig. 5). The NMR structure in CD₃OH of the unprotected β-trithiohexapeptide 4 was determined to be an (M)-3₁₄-helix (Fig. 7), very similar to that of the non-thionated analogue (cf. 1 ). NMR and mass spectra of the β-hexapeptides with C=S and with C=O groups are compared (Figs. 6 and 8).     

Stereoselective Formation of Ternary Copper(II) Complexes of (S)-Amino-acid Amides and (R)- or (S)-Histidine and (R)- or (S)-Tyrosine in Aqueous Solution

Formation constants of ternary complexes of Cu^II with (S)-amino-acid amides ((S)-phenylalaninamide, (S)-prolinamide, and (S)-tryptophanamide) and (R)- or (S)-histidine and (R)- or (S)-tyrosine were determined potentiometrically in aqueous solution. Significant stereoselectivity was presented by all three amides towards histidine, the diastereoisomeric complexes with ‘heterochiral’ ligands being more stable than those with ‘homochiral’ ligands (see Table 3). The stereoselectivity observed with (S)-phenylalaninamide and (S)-tryptophanamide may be explained on the basis of hydrophobic stacking interactions between 1H-imidazole and the aromatic side chain, favoured by the terdentate behaviour of histidine (see Fig.2), whereas repulsive effects seem to be prevalent with (S)-prolinamide. Only (S)-prolinamide and (S)-phenylalaninamide show appreciable stereoselectivity with tyrosine, which is bidentate, probably on account of repulsive interactions. The present results on the stability of ternary complexes in solution allow to draw some conclusions on the mechanism of chiral discrimination performed by Cu^II complexes of (S)-amino-acid amides added to the mobile phase in HPLC (reversed phase).