Dendrophanes: Water-soluble dendritic receptors as models for buried recognition sites in globular proteins

Water-soluble dendritic cyclophanes (dendrophanes) of first ( 1 , 4 ), second ( 2 5 ), and third generation ( 3 6 ) with poly(ether amide) branching and 12, 36, and 108 terminal carboxylate groups, respectively, were prepared by divergent synthesis, and their molecular recognition properties in aqueous solutions were investigated. Dendrophanes 1 – 3 incorporate as the initiator core a tetraoxa[6.1.6.1]paracyclophane 7 with a suitably sized cavity for inclusion complexation of benzene or naphthalene derivatives. The initiator core in 4 – 6 is the [6.1.6.1]cyclo-phane 8 shaped by two naphthyl(phenyl) methane units with a cavity suitable for steroid incorporation. The syntheses of 1 – 6 involved sequential peptide coupling to monomer 9 , followed by ester hydrolysis (Schemes 1 and 4), Purification by gel-permeation chromatography (GPC; Fig. 3) and full spectral characterization were accomplished at the stage of the intermediate poly(methyl carboxylates) 10 – 12 and 23 – 25 , respectively. The third-generation 108-ester 25 was also independently prepared by a semi-convergent synthetic strategy, starting from 4 (Scheme 5). All dendrophanes with terminal ester groups were obtained in pure form according to the ¹³C-NMR spectral criterion (Figs, 1 and 5). The MALDI-TOF mass spectra of the third-generation derivative 25 (mol. wt. 19328 D) displayed the molecular ion as base peak, accompanied by a series of ions [M – n(1041 ± 7)]⁺, tentatively assigned as characteristic fragment ions of the poly(ether amide) cascade. A similar fragmentation pattern was also observed in the spectra of other higher-generation poly(ether amide) dendrimers. Attempts to prepare monodisperse fourth-generation dendrophanes by divergent synthesis failed. ¹H-NMR and fluorescence binding titrations in basic aqueous buffer solutions showed that dendrophanes 1 – 3 complexed benzene and naphthalene derivatives, whereas 4 – 6 bound the steroid testosterone. Complexation occurred exclusively at the cavity-binding site of the central cyclophane core rather than in fluctuating voids in the dendritic branches, and the association strength was similar to that of the complexes formed by the initiator cores 7 and 8 , respectively (Tables 1 and 3). Fluorescence titrations with 6-(p-toluidino)naphthalene-2-sulfonate as fluorescent probe in aqueous buffer showed that the micropolarity at the cyclophane core in dendrophanes 1 - 3 becomes increasingly reduced with increasing size and density of the dendritic superstructure; the polarity at the core of the third-generation compound 3 is similar to that of EtOH (Table 2). Host-guest exchange kinetics were remarkably fast and, except for receptor 3 , the stabilities of all dendrophane complexes could be evaluated by ¹H-NMR titrations. The rapid complexation-decomplexation kinetics are explained by the specific attachment of the dendritic wedges to large, nanometer-sized cyclophane initiator cores, which generates apertures in the surrounding dendritic superstructure.     

New Cyclophanes as Initiator Cores for the Construction of Dendritic Receptors: Host-guest complexation in aqueous solutions and structures of solid-state inclusion compounds

Cyclophanes 3 and 4 were prepared as initiator cores for the construction of dendrophanes (dendritic cydophanes) 1 and 2 , respectively, which mimic recognition sites buried in globular proteins. The tetra-oxy[6.1.6.1]paracyclophane 3 was prepared by a short three-step route (Scheme 1) and possesses a cavity binding site shaped by two diphenylmethane units suitable for the inclusion of flat aromatic substrates such as benzene and naphthalene derivatives as was shown by ¹H-NMR binding titrations in basic D₂O phosphate buffer (Table 1). The larger cyclophane 4 , shaped by two wider naphthyl(phenyl)methane spacers, was prepared in a longer, ten-step synthesis (Scheme 2) which included as a key intermediate the tetrabromocyclophane 5 . ¹H-NMR Binding studies in basic borate buffer in D₂O/CD₃OD demonstrated that 4 is an efficient steroid receptor. In a series of steroids (Table 1), complexation strength decreased with increasing substrate polarity and increasing number of polar substituents; in addition, electrostatic repulsion between carboxylate residues of host and guest also affected the binding affinity strongly. The conformationally flexible tetrabromocyclophane 5 displayed a pronounced tendency to form solid-state inclusion compounds of defined stoichiometry, which were analyzed by X-ray crystallography (Fig. 2). 1,2-Dichloroethane formed a cavity inclusion complex 5a with 1:1 stoichiometry, while in the 1:3 inclusion compound 5b with benzene, one guest is fully buried in the macrocyclic cavity and two others are positioned in channels between the Cyclophanes in the crystal lattice. In the 1:2 inclusion compound 5c , two toluene molecules penetrate with their aromatic rings the macrocyclic cavity from opposite sides in an antiparallel fashion. On the other hand, p-xylene (= 1,4-dimethylbenzene) in the 1:1 compound 5d is sandwiched between the cyclophane molecules with its two Me groups penetrating the cavities of the two macrocycles. In the 1:2 inclusion compound 5e with tetralin (= 1,2,3,4-tetrahydronaphthalene), both host and guest are statically disordered. The shape of the macrocycle in 5a – e depends strongly on the nature of the guest (Fig. 4). Characteristic for these compounds is the pronounced tendency of 5 to undergo regular stacking and to form channels for guest inclusion; these channels can infinitely extend across the macrocyclic cavities (Fig. 6) or in the crystal lattice between neighboring cyclophane stacks (Fig. 5). Also, the crystal lattice of 5c displays a remarkable zig-zag pattern of short Br…?O contacts between neighboring macrocycles (Fig. 7).     

Catalytic Cyclophanes. Part XI. A flavo-thiazolio-cyclophane as a biomimetic catalyst for the preparative-scale electro-oxidation of aromatic aldehydes to methyl esters

Flavo-thiazolio-cyclophane 6 was prepared on a gram scale by an 18-step synthesis (Schemes 3 and 4). This pathway involved the very efficient preparation of bromo-cyclophane 32 (37% yield over 13-steps), which can be readily modified to create various multiply functionalized receptors. This bromide 32 was subsequently converted into the corresponding boronic acid and connected to the 7-bromoflavin 10 (Scheme 2) via Suzuki coupling to give flavo-cyclophane 36 . The thiazolium unit was then introduced after quaternization of the tertiary amino groups of 36 . Flavo-thiazolio-cyclophane 6 , with both prosthetic groups attached in proximity to the well-defined cyclophane binding site, is a functional model for the enzyme pyruvate oxidase. In basic methanolic solution, 6 catalyzes the oxidation of aromatic aldehydes to their corresponding methyl esters. Cyclophane 6 shows saturation kinetics, and the turnover number calculated for the oxidation of naphthalene-2-carbaldehyde to methyl naphthalene-2-carboxylate (k_cat = 0.22 s⁻¹) is one of the highest reported for an artificial enzyme. Control experiments showed that the catalytic advantages of 6 result from the macrocyclic binding and reaction site as well as from the covalent attachment of both cofactors to this site. The catalytic cycle is completed by electrochemical re-oxidation of the reduced flavin moiety at a low working electrode potential (- 0.3 V vs. Ag/AgCl), and up to ca. 100 catalytic cycles can be performed on a preparative scale, The intramolecular nature of the electron transfer from the active aldehyde intermediate to the flavin is particularly conducive to the oxidation of unreactive aldehydes.     

Dendrophanes: Water-Soluble Dendritic Receptors. Preliminary communication

The dendritic cyclophanes (dendrophanes ) 1–3 containing a [6.1.6.1]paracyclophane as the initiator core embedded in dendritic poly(ether-amide) shells of first ( 1 ), second ( 2 ), and third ( 3 ) generation were prepared and characterized. The X-ray crystal-structure analyses of esters 7 and 4 , derivatives of cyclophane core 9 and first-generation dendrophane 1 , respectively, displayed open cavity binding sites suitable for the inclusion complexation of aromatic substrates. With their carboxylate surface groups, dendrophanes 1–3 were readily soluble in aqueous phosphate buffer (pH 8.0), and the complexation of naphthalene derivatives was investigated by ¹H-NMR and fluorescence titrations. The binding studies demonstrated that the cyclophane cavity remains open and accessible to appropriate substrates even at higher dendritic generations. The 1:1 complexes formed in aqueous buffer were of similar stability to those formed by the unbranched core 9 (K_a between 1000 and 10000 1 mol^?1, 300 K). Investigations with the fluorescent probe 6-(p-toluidino)naphthalene-2-sulfonate ( 12 ) showed that the micropolarity at the dendrophane core decreases with increasing generation number.     

Macrotricyclic Steroid Receptors by Pd°-Catalyzed Cross-Coupling Reactions: Dissolution of cholesterol in aqueous solution and investigations of the principles governing selective molecular recognition of steroidal substrates

Three double-decker cyclophane receptors, (±)- 2 , (±)- 3 , and (±)- 4 with 11–13-Å deep hydrophobic cavities were prepared and their steroid-binding properties investigated in aqueous and methanolic solutions. Pd°-Catalyzed cross-coupling reactions were key steps in the construction of these novel macrotricyclic structures. In the synthesis of D₂-symmetrical (±)- 2 , the double-decker precursor (±)- 7 was obtained in 14% yield by fourfold Stille coupling of equimolar amounts of bis(tributylstannyl)acetylene with dibromocyclophane 5 (Scheme 1). For the preparation of the macrotricyclic precursor (±)- 15 of D₂-symmetrical (±)- 3 , diiodocylophane 12 was dialkynylated with Me₃SiC?CH to give 13 using the Sonogashira cross-coupling reaction; subsequent alkyne deprotection yielded the diethynylated cyclophane 14 , which was transformed in 42% yield into (±)- 15 by Glaser-Hay macrocyclization (Scheme 2). The synthesis of the C₂-symmetrical conical receptor (±)- 4 was achieved via the macrotricyclic precursor (±)- 25 , which was prepared in 20% yield by the Hiyama cross-coupling reaction between the diiodo[6.1.6.1]paracyclophane 19 and the larger, dialkynylated cyclophane 17 (Scheme 4). Solid cholesterol was efficiently dissolved in water through complexation by (±)- 2 and (±)- 3 , and the association constants of the formed 1:1 inclusion complexes were determined by solid-liquid extraction as K_a = 1.1 × 10⁶ and 1.5 × 10⁵ l mol^?1, respectively (295 K) (Table 1). The steroid-binding properties of the three receptors were analyzed in detail by ¹H-NMR binding titrations in CD₃OD. Observed steroid-binding selectivities between the two structurally closely related cylindrical receptors (±)- 2 and (±)- 3 (Table 2) were explained by differences in cavity width and depth, which were revealed by computer modeling (Fig. 4). Receptor (±)- 2 , with two ethynediyl tethers linking the two cyclophanes, possesses a shallower cavity and, therefore, is specific for flatter steroids with a C(5)?C(6) bond, such as cholesterol. In contrast, receptor (±)- 3 , constructed with longer buta-1,3-diynediyl linkers, has a deeper and wider hydrophobic cavity and prefers fully saturated steroids with an aliphatic side chain, such as 5α-cholestane (Fig. 7). In the 1:1 inclusion complexes formed by the conical receptor (±)- 4 (Table 3), testosterone or progesterone penetrate the binding site from the wider cavity side, and their flat A ring becomes incorporated into the narrower [6.1.6.1]paracyclophane moiety. In contrast, cholesterol penetrates (±)- 4 with its hydrophobic side chain from the wider rim of the binding side. This way, the side chain is included into the narrower cavity section shaped by the smaller [6.1.6.1]paracyclophane, While the A ring protrudes with the OH group at C(3) into the solvent on the wider cavity side (Fig. 8). The molecular-recognition studies with the synthetic receptors (±)- 2 , (±)- 3 , and (±)- 4 complement the X-ray investigations on biological steroid complexes in enhancing the understanding of the principles governing selective molecular recognition of steroids.     

Insulated Molecular Wires: Dendritic Encapsulation of Poly(triacetylene) Oligomers,Attempted Dendritic Stabilization of Novel Poly(pentaacetylene) Oligomers,and an Organometallic Approach to Dendritic Rods

Multinanometer‐long end‐capped poly(triacetylene) (PTA) and poly(pentaacetylene) (PPA) oligomers with dendritic side chains were synthesized as insulated molecular wires. PTA Oligomers with laterally appended Fréchet‐type dendrons of first to third generation were prepared by attaching the dendrons ( 8 , 13 , and 17 , respectively, Scheme 1) to (E)‐enediyne 18 by a Mitsunobu reaction and subsequent Glaser‐Hay oligomerization under end‐capping conditions (Scheme 2). Whereas first‐generation oligomers up to the pentamer were isolated ( 1a – e ), for reasons of steric overcrowding, only oligomers up to the trimer ( 2a – c ) were formed at the second‐generation level, and only the end‐capped monomer and dimer ( 3a , b ) were isolated at the third‐generation level. By repetitive sequences of hydrosilylation (with the Karstedt catalyst), followed by allylation or vinylation, a series of carbosilane dendrons were also prepared (Schemes 3 and 4). Attachment of the second‐generation wedge 40 to (E)‐enediyne 18 , followed by deprotection and subsequent end‐capping Hay oligomerization, provided PTA oligomers 4a – d with lateral carbosilane dendrons (Scheme 5). UV/VIS Studies (Figs. 5 – 10) demonstrated that the insulating dendritic layers did not alter the electronic characteristics of the PTA backbone, even at the higher‐generation levels. Despite distortion from planarity due to the bulky dendritic wedges, no loss of π‐electron conjugation along the PTA backbone was detected. A surprising (E)→(Z) isomerization of the diethynylethene (DEE) core in the third generation derivative 3a was observed, possibly photosensitized by the bulky Fréchet‐type dendritic wedge. Electrochemical investigations by steady‐state voltammetry and cyclic voltammetry showed that the first reduction potential of the PTA oligomer with Fréchet‐type dendrons is shifted to more negative values as the dendritic coverage increases. With compounds 5a – c , the first oligomers with a poly(pentaacetylene) backbone were obtained by oxidative Hay oligomerization under end‐capping conditions (Scheme 6). The synthesis of dendritic PPA oligomers by oxidative coupling of (E)‐enetetrayne 60 under end‐capping conditions provided oligomers 61a – d , which were formed as mixtures of stereoisomers due to unexpected thermal (E)→(Z) isomerization (Scheme 8). In another novel approach towards dendritic encapsulation of molecular wires with a Pt‐bridged tetraethynylethene (TEE) oligomeric backbone, the trans‐dichloroplatinum(II) complex trans‐ 67 with dendritic phosphane ligands (Fig. 14) was coupled under Hagihara conditions to mono‐deprotected 69 under formation of the extended monomer 65 (Scheme 12). Again, an unexpected thermal (E)→(Z) isomerization, possibly induced by steric strain between TEE moieties and dendritic phosphane ligands in the unstable complex, led to the isolation of 65 as an isomeric mixture only.     

Zum Mechanismus der Photochemie des Benzfurazans

Mechanistic studies on the photochemical reactions of benzfurazan . From other works it is known that irradiation of benzfurazan ( 1 ) in methanol gives the carbaminacid-ester 4 , whereas in benzene the azepinederivative 3 is obtained (Scheme 1). The compounds 5–8 (Scheme 2) have been proposed as intermediates. In our investigations we detected and characterized by means of UV.- and IR.-spectroscopy the two species 5 and 8 . Irradiation of 1 with 350 nm light at room temperature in a strongly polar solvent (e.g. H₂O) yields exclusively 5 (Fig. 1) with a quantum yield of 0.48. In non polar solvents (e.g. hexane) 5 isomerizes in a second photochemical step to 8 (quantum yield 0.43) (Fig. 3). Thermally, 5 can be converted back to 1 . The rate constant for this reaction at room temperature is 2 · 10^–5s^–1. The transformation 5 → 8 was also investigated at low temperature. There was no direct evidence for any intermediates of the type oxazirene ( 6 ) or nitrene ( 7 ). However, the formation of azepine 3 upon irradiation of 5 in benzene suggests as intermediate the nitrene 7 which could be converted into 8 in a fast thermal reaction (Scheme 3).     

New Results in the Synthesis of Styrylazulene Derivatives: Application of the ‘Anil synthesis’ to the preparation of azulenes substituted with styryl groups at the seven-membered ring

The synthesis of 4,6,8-trimethyl-1-[(E)-4-R-styryl]azulenes 5 (R=H, MeO, Cl) has been performed by Wittig reaction of 4,6,8-trimethylazulene-1-carbaldehyde ( 1 ) and the corresponding 4-(R-benzyl)(triphenyl)phosphonium chlorides 4 in the presence of EtONa/EtOH in boiling toluene (see Table 1). In the same way, guaiazulene-3-carbaldehyde ( 2 ) as well as dihydrolactaroviolin ( 3 ) yielded with 4a the corresponding styrylazulenes 6 and 7 , respectively (see Table 1). It has been found that 1 and 4b yield, in competition to the Wittig reaction, alkylation products, namely 8 and 9 , respectively (cf. Scheme 1). The reaction of 4,6,8-trimethylazulene ( 10 ) with 4b in toluene showed that azulenes can, indeed, be easily alkylated with the phosphonium salt 4b . 4,6,8-Trimethylazulene-2-carbaldehyde ( 12 ) has been synthesized from the corresponding carboxylate 15 by a reduction (LiAlH₄) and dehydrogenation (MnO₂) sequence (see Scheme 2). The Swern oxidation of the intermediate 2-(hydroxymethyl)azulene 16 yielded only 1,3-dichloroazulene derivatives (cf. Scheme 2). The Wittig reaction of 12 with 4a and 4b in the presence of EtONa/EtOH in toluene yielded the expected 2-styryl derivatives 19a and 19b , respectively (see Scheme 3). Again, the yield of 19b was reduced by a competing alkylation reaction of 19b with 4b which led to the formation of the 1-benzylated product 20 (see Scheme 3). The ‘anil synthesis’ of guaiazulene ( 21 ) and the 4-R-benzanils 22 (R=H, MeO, Cl, Me₂N) proceeded smoothyl under standard conditions (powered KOH in DMF) to yield the corresponding 4-[(E)-styryl]azulene derivatives 23 (see Table 4). In minor amounts, bis(azulen-4-yl) compounds of type 24 and 25 were also formed (see Table 4). The ‘anil reaction’ of 21 and 4-NO₂C₆H₄CH=NC₆H₅ ( 22e ) in DMF yielded no corresponding styrylazulene derivative 23e . Instead, (E)-1,2-bis(7-isopropyl-1-methylazulen-4-yl)ethene ( 27 ) was formed (see Scheme 4). The reaction of 4,6,8-trimethylazulene ( 10 ) and benzanil ( 22a ) in the presence of KOH in DMF yielded the benzanil adducts 28 to 31 (cf. Scheme 5). Their direct base-catalyzed transformation into the corresponding styryl-substituted azulenes could not be realized (cf. Scheme 6). However, the transformation succeeded smoothly with KOH in boiling EtOH after N-methylation (cf. Scheme 6).     

Catalytic Enantioselective Hydrosilylation of Ketones with Rhodium-Phosphite Complexes Containing a TADDOLate and a Dihydrooxazole Unit

New types of chiral phosphorus/nitrogen ligands, capable of forming six-membered-ring metal chelates have been prepared from α,α,α′,α′-tetraaryl-1,2-dioxolane-4,5-dimethanols (TADDOLs), PCl₃, and dihydrooxazole alcohols (from amino acids) ( 7 in Scheme 1). The X-ray crystal structure of a Rh complex of one of these ligands, 8b , has been determined (Scheme 2 and Fig.). Enantioselective hydrosilylations of dialkyl and aryl alkyl ketones with Ph₂SiH₂/0.01 equiv. Rh^I⋅ 7 have been studied and found to provide secondary alcohols in enantiomer ratios of up to 97 : 3 (Scheme 3 and Table). The ligand prepared from (R,R)-TADDOL and the (R)-valine-derived (R)-α,α-dimethyl-4-isopropyl-4,5-dihydrooxazole-2-methanol gives better results than the (R,R,S)-isomer ( 7d vs. 7c in Scheme 3), and an i-Pr group on the 4,5-dihydrooxazole ring gives rise to a slightly better selectivity than a Ph group. With the (R,R,R)-ligands the hydrogen transfer occurs from the Re face of the oxo groups (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.     

Colchicine models: Synthesis and Antitubulin Activity of 2′-Monosubstituted and 2′, 5-Disubstituted 2,3,4,4′-Tetramethoxy-1,1′-biphenyls. Synthesis of 4,4′, 5′, 6′-tetramethoxy-1,1′-biphenyl-2,3′-dicarboxylic acid

Reductive amination of 2,3,4,4′-tetramethoxtybiphenyl-2-carbaldehyde ( 4 ) with MeNH₂ afforded methylamine 5 (Scheme 1), Hydroxymethylation of amine 8 , prepared similarly from 4 by reductive amination with benzylamine followed by N-methylation, afforded alcohol 12 which was converted the 5-methyl-substituted methylamine 14 by conventional chemical reactions (Scheme 2), Methylamine 14 was also obtained from ester 16 after hydroxymethylation to alcohol 17 and conventional manipulation of alcohol and ester functions (Scheme 2). Both amines 5 and 14 as well as the 2′, 5-dimethyl-substituted biphenyl 26 prepared from the dialdehyde 25 by a Wolff-Kishner reduction, did not show noteworthy activity in the tubulin binding assay or as inhibitors of tubulin polymerization (Table). However, the 2′ethyl-substituted biphebyl 11 prepared from 4 by reaction with MeLi followed by dehyderation and catalytic reduction of styrene 10 (Scheme 1) showed appreciable activity in both assays, coming close to that of known phenyltropolone models. The X-ray analysis of 14 ·HCl and 11 showed significant difference in the orientation of the rings with respect to one another (Fig.).     

Synthesis of Dendritic Metalloporphyrins with Distal H‐Bond Donors as Model Systems for Hemoglobin

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^II? O₂ 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^II? O₂ 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.     

Enantioselective Preparation of β2‐Amino Acids with Aspartate,Glutamate, Asparagine,and Glutamine Side Chains

(S)‐β²‐Homoamino acids with the side chains of Asp, Glu, Asn, and Gln have been prepared and suitably protected (N‐Fmoc, CO₂^tBu, CONHTrt) for solid‐phase peptide syntheses. The key steps of the syntheses are: N‐acylation of 5,5‐diphenyl‐4‐isopropyl‐1,3‐oxazolidin‐2‐one (DIOZ) with succinic and glutaric anhydrides (Scheme 2), alkylation of the corresponding Li‐enolates with benzyl iodoacetate and Curtius degradation (Scheme 4), and removal of the chiral auxiliary (Scheme 5). In addition, numerous functional‐group manipulations (CO₂H?CO₂^tBu, CO₂Bn?CO₂H, CbzNH→FmocNH, CO₂H→CO₂NH₂→CONHTrt; Schemes 2, 4, 5, and 6) were necessary, in order to arrive at the four target structures. The configurational assignments were confirmed by X‐ray crystal‐structure determinations (Scheme 2 and Fig. 3). The enantiomeric purities of a β²hAsn and of a β²hGln derivative were determined by HPLC on a Chiralcel column to be 99.7 : 0.3 and >99 : 1, respectively (Fig. 4). Notably, it took up to twelve steps to prepare a suitably protected trifunctional product with a single stereogenic center (overall yield of 10% from DIOZ and succinic anhydride)!     

Chiral Lithiated Phosphoric Triamides: Structure,Reactivity, and Salt Effects

The theoretical structure of a cyclic phosphoric triamide 3 and of its monolithiated isomers 4 – 6 was calculated by ab initio methods (Fig. 1, Tables 1 and 2). The global minimum in 4 consists of a five-membered Li−C−N−P−O chelate. The intermediates 5 and 6 are, relative to 4 , energetically unfavorable by 15 and 18 kcal mol⁻¹, respectively, due to distortion in order to accommodate the N-complexation of the Li⁺ ions. NMR Investigations (¹H, ¹³C, ³¹P, and ⁷Li) of the lithiated bicyclic phosphoric triamide 1 were performed (Tables 3 – 5). The lithium aminomethanide 2 is characterized by a sp³-hybridized anion supporting Li−C contacts. The anions exist in a monomer-dimer equilibrium in solution (Scheme 2). Trapping reactions of rac- 2 with carbonyl compounds generated the corresponding amino-alcohol derivatives with high diastereoselectivities (Scheme 3, Table 6). A rational for the stereochemical outcome is given (Fig. 4). In the presence of LiBr, a P−N bond cleavage occurred on reaction of rac- 2 with aldehydes, which allowed the synthesis of (1-hydroxylalkyl)phosphonic diamides (Scheme 5, Table 7).     

Oligosaccharide Analogues of Polysaccharides,Part 23 , Synthesis of a Dimeric Acetyleno Cyclodextrin from a Mannopyranose‐Derived Dialkyne

The 1,4‐cis‐diethynylated α‐D ‐mannopyranose analogue 11 has been prepared from 1,6 : 2,3‐dianhydro‐β‐D ‐allopyranose ( 6 ) by alkynylating epoxide and acetal opening (Scheme 2). Eglinton coupling of 11 gave the cyclodimer 18 (Scheme 3). Crystal‐structure analysis of the corresponding bis(methanesulfonate) 19 revealed substantially bent butadiyne moieties; one mannopyranosyl ring adopts the ⁴C₁ and the other one a slightly distorted ^OS₂ conformation (Fig. 1). Hydrogenation of 18 , followed by deprotection, gave the stable butane‐1,4‐diyl‐bridged cyclodimer 21 (Scheme 3). Crystal‐structure analysis shows the ⁴C₁ conformation of the mannopyranosyl units (Fig. 2). The two butane fragments are characterised by a combination of gauche and antiperiplanar arrangements.     

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).     

Nonreductive Enantioselective Ring Opening of N-(Methylsulfonyl)dicarboximides with Diisopropoxytitanium α,α,α′,α′-Tetraaryl-1,3-dioxolane-4,5-dimethanolate

The bicyclic and tricyclic meso-N-(methylsulfonyl)dicarboximides 1a–f are converted enantioselectively to isopropyl [(sulfonamido)carbonyl]-carboxylates 2a–f by diisopropoxytitanium TADDOLate (75–92% yield; see Scheme 3). The enantiomer ratios of the products are between 86:14 and 97:3, and recrystallization from CH₂Cl₂/hexane leads to enantiomerically pure sulfonamido esters 2 (Scheme 3). The enantioselectivity shows a linear relationship with the enantiomer excess of the TADDOL employed (Fig.3). Reduction of the ester and carboxamide groups (LiAlH₄) and additional reductive cleavage of the sulfonamido group (Red-Al) in the products 2 of imide-ring opening gives hydroxy-sulfonamides 3 and amino alcohols 4 , respectively (Scheme 4). The absolute configuration of the sulfonamido esters 2 is determined by chemical correlation (with 2a,b ; Scheme 6), by the X-ray analysis of the camphanate of 3e (Fig. 1), and by comparative ¹⁹F-NMR analysis of the Mosher esters of the hydroxy-sulfonamides 3 (Table 1). A general proposal for the assignment of the absolute configuration of primary alcohols and amines of Formula HXCH₂CHR¹R², X = O, NH, is suggested (see 11 in Table 1). It follows from the assignment of configuration of 2 that the Re carbonyl group of the original imide 1 is converted to an isopropyl ester group. This result is compatible with a rule previously put forward for the stereochemical course of reactions involving titanium TADDOLate activated chelating electrophiles ( 12 in Scheme 7). A tentative mechanistic model is proposed ( 13 and 14 in Scheme 7).     

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).     

Fluorescent sensors based on 2-substituted imidazolidines

A number of 2-substituted imidazolidines were synthesized from N,N′-dibenzylethane-1,2-diamine derivatives and benzaldehyde, naphthalene-1-carbaldehyde, 2-hydroxynaphthalene-1-carbaldehyde, and anthracene-9-carbaldehyde. Examination of the obtained compounds by spectral methods revealed selective sensor properties of 2-(anthracen-9-yl)-1,3-dibenzylimidazolidine and 2-(anthracen-9-yl)-1,3-bis(2-hydroxybenzyl)-imidazolidine for Hg²⁺ and Cu²⁺ ions.     

Preparation and Characterization of New C2‐ and C1‐Symmetric Nitrogen,Oxygen, Phosphorous,and Sulfur Derivatives and Analogs of TADDOL. Part III

A brief overview is presented of the field of organocatalysis using chiral H‐bond donors, chiral Brønsted acids, and chiral counter‐anions (Fig. 1). The role of TADDOLs (=α,α,α′,α′‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanols) as H‐bond donors and the importance of an intramolecular H‐bond for acidity enhancement are discussed. Crystal structures of TADDOLs and of their N‐, S‐, and P‐analogs (Figs. 2 and 3) point the way to proposals of mechanistic models for the action of TADDOLs as organocatalysts (Scheme 1). Simple experimental two‐step procedures for the preparation of the hitherto strongest known TADDOL‐derived acids, the bicyclic phosphoric acids ( 2 in Scheme 2) and of a phosphoric‐trifluorosulfonic imide ( 9 in Scheme 4), are disclosed. The mechanism of sulfinamide formation in reactions of TADDAMIN with trifluoro‐sulfonylating reagents is discussed (Scheme 3). pK_a Measurements of TADDOLs and analogs in DMSO (reported in the literature; Fig. 5) and in MeO(CH₂)₂OH/H₂O (described herein; Fig. 6) provide information about further possible applications of this type of compounds as strong chiral Brønsted acids in organocatalysis.