Tubular structures bearing channels in organic crystals composed of adamantane-based macrocycles

Five macrocyclic molecules (1–5) were efficiently synthesized from the dimerization and trimerization of di-substituted adamantane derivatives, which were composed of three different aromatic units and two different linker groups. Three single-crystals were obtained from these macrocyclic molecules, including a set of pseudopolymorphs (3a and 3b) of macrocycle 3 and another macrocycle 5 (5a). Single crystal X-ray analysis revealed that the three monocyclic compounds were rectangular or square in shape with solvent molecules in the cavity. Macrocycle 3 in 3a formed stacks to produce tubular structures with channels that assembled into three-dimensional networks through CH/π interactions.     

Anion binding with some 22- and 28-membered selenaaza macrocycles: Structural aspects and Se NMR studies

A series of macrocyclic adducts of the 22- and 28-membered selenaaza macrocycles (1 and 2, respectively) with different counter anions such as halides, sulfate, perchlorate, phosphate, trifluoroacetate and nitrate has been prepared. The adducts have been characterized by elemental analysis, IR, ¹H NMR, ⁷⁷Se NMR and ESI-MS analysis. The ⁷⁷Se NMR spectrum of the adduct (7) shows an upfield shift compared to the parent macrocycle. The bromo (5), iodo (6), sulfate (7), trifluroacetate (10) adducts of the 22-membered selenaaza macrocycle and perchlorate (16), trifluroacetate (18) adducts of the 28-membered selenaaza macrocycle have been structurally characterized. The crystal structures show extensive hydrogen bonding networks. The molecular structures of all the compounds show the macrocycle to be fully protonated except the trifluroacetate adduct of the 22-membered macrocycle (10), which is only diprotonated. The binding constants of the neutral 22-membered selenaaza macrocycle towards, fluoride, bromide, iodide and sulfate ion have been determined by the NMR titration method.     

Using ligand exchange reactions to control the coordination environment of Pt(II) acetylide complexes: applications to conjugated metallacyclynes

Ligand exchange of cis-bis(diphenylphosphino)ethylene (dppee) with trans-(Ph₃P)₂Pt(CCR)₂ easily generates the cis-complexes (dppee)Pt(CCR)₂ in 64-95% yield. This transformation is used to convert pyridine-containing macrocycle 7 to its cis-analogue 8 and the macrocyclic bipyridine analogue 10 to the unique macrocyclic ligand 11. X-ray structural characterization of trans-complexes 5a and 5b and cis-complexes 6a and 6b are reported, as is the structure of the strained macrocycle 8.     

Synthesis and evaluation of bipendant-armed (oligo)thiophene crown ether derivatives as new chemical sensors

Three new (oligo)thiophene bipendant-armed ligands 2a-c, derived from 2-(aminomethyl)-15-crown-5, have been synthesized and characterized. Compounds 2a-c were prepared by reductive amination of the corresponding macrocycle with formyl thiophene derivatives 1a-c in the presence of NaBH(OAc)₃ in fair to good yields. The photophysical properties of ligands 2a-c were studied and they were also evaluated as chemosensors in the presence of Na(I), Ag(I), Pd(II) and Hg(II) cations in acetonitrile solution.     

Synthesis and X-ray crystallographic studies of novel proton-ionizable nitro- and halogen-substituted acridono-18-crown-6 chromo- and fluorogenic ionophores

Starting from acridono-18-crown-6 ligand 1 (Fig. 1) seven new proton-ionizable chromogenic and fluorogenic ionophores 2-8 (Fig. 1) containing NO₂ group(s) and/or Br or Cl atom(s) in the aromatic rings were prepared by electrophilic substitution. The precursor macrocycle 1 was obtained by a modification of the reported procedure which made chromatography unnecessary in purification and gave higher yield. X-ray crystallographic studies of the complexes of acridono-18-crown-6 type ligands 1, 2, 3, 6 and 8 show that the proton-ionizable units are in the acridone tautomeric form and that the ligands invariably bind a water molecule in their cavities by multipodal hydrogen bonding. In two cases (6 and 8) an additional DMF solvent molecule is also bound at the crown perimeter in the solid state.     

Interactions of acyclic and cyclic bis-phenanthridinium derivatives with ss- and ds-polynucleotides

The acyclic bis-phenanthridinium ligands 1, 2 and the cyclic analogue 3 bind to ss-RNA by bis-intercalation. Due to it's shorter linker 1 exhibits mono-intercalative binding to ds-polynucleotides, while a mixed mode of binding with 2 is shown to strongly dependent on the base composition and tertiary structure of ds-DNA and RNA. The cyclic analogue 3 binds to ds-polynucleotides by non-intercalative mode. Comparing the ss-/ds-polynucleotide selectivity obtained for 3 and previously reported for 3,8-linked bis-phenanthridinium analogues, it is clear that the more rigid structure and sterically more restricted cleft of the latter could better distinguish ss- from ds-polynucleotide regions.     

Coordination chemistry of anticrowns: Complexation of cyclic trimeric perfluoro-o-phenylenemercury with nitro compounds

Cyclic trimeric perfluoro-o-phenylenemercury (o-C₆F₄Hg)₃ (1) is capable of reacting with nitromethane to give complex {[(o-C₆F₄Hg)₃](CH₃NO₂)} (2) containing one molecule of the nitro compound per one macrocycle molecule. In this complex, the nitromethane ligand is bound to 1 by its both oxygen atoms, one of which is simultaneously coordinated to all three Hg centres of the macrocycle while the other interacts with a single Hg centre. The complex of similar composition, {[(o-C₆F₄Hg)₃](C₆H₅NO₂)} (3), is produced in the interaction of 1 with nitrobenzene. In this complex too, the both oxygen atoms of the nitro group are involved in the bonding to the macrocycle. A distinctive feature of 3 is that here one oxygen atom of the coordinated nitro derivative is bound by only two Hg centres of 1 whereas the other interacts again with a single Hg site. The reaction of 1 with 5-nitroacenaphthene affords a 1:1 complex, {[(o-C₆F₄Hg)₃](C₁₂H₉NO₂)} (4), having a polydecker sandwich structure in the crystal. Unlike in 3, the aromatic rings of the nitroarene units in 4 are disposed virtually in parallel to the macrocycles. The nitro compound in 4 behaves again as a bidentate ligand, forming three Hg-O bonds with one of the adjacent macrocycles and a single Hg-O bond with another molecule of 1. The complex is characterized also by shortened Hg-C contacts between the Hg centres of 1 and the carbon atoms of the nitroarene moiety as well as shortened C-C contacts between the carbon atoms of the nitroarene and the macrocycle. In the interaction of 1 with 1-nitropyrene, complexes of two compositions, viz. {[(o-C₆F₄Hg)₃](C₁₆H₉NO₂)} (5) and {[(o-C₆F₄Hg)₃](C₁₆H₉NO₂)₃} (6) are formed. An X-ray diffraction study of 6 has shown that in this adduct two of three coordinated molecules of the nitro compound are located on one side of the metallacycle plane while the third nitroarene molecule is disposed on its other side. The aromatic rings of all three nitropyrene ligands in 6 are practically parallel to the mean plane of the macrocycle. In contrast to 2-4, each molecule of the nitroarene in 6 is bonded to 1 by a single oxygen atom which is coordinated only to one Hg centre. In the case of one of the nitropyrene ligands that forms much longer Hg-O bond with 1 than two others, an additional contribution to the bonding is made by shortened Hg-C contacts between the macrocycle and the carbon atoms of the aromatic pyrene core and also by shortened C-C contacts between the carbon atoms of the coordinated nitroarene and 1. The synthesized adducts are the first examples of complexes of an anticrown with nitro compounds.     

Novel thiol-derivatized zinc(II) phthalocyanines

Preparation and characterization of tetrasubstituted zinc(II) phthalocyanines in which sulfur is not linked to the macrocycle are reported herein for the first time. Thioacetic acid S-[3-(3,4-dicyano-phenoxy)-propyl]ester (4) was synthesized in 55% yield from 4-nitrophthalonitrile and thioacetic acid S-(3-hydroxy-propyl)ester (3). Tetrasusbtituted thiol-derivatized zinc(II) phthalocyanine 5 was obtained from 4 and zinc acetate in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene in butanol. Treatment of 5 with sodium methoxide afforded phthalocyanine 6.     

Synthesis of thiophene-capped [2]rotaxanes

Two types of thiophene-capped [2]rotaxanes, i.e., bithienyl (2T)- and bis(3,4-ethylenedioxythiophene)-yl (BEDOT)-capped [2]rotaxanes, were synthesized. The electron-deficient cyclophane of cyclobis(paraquat-p-phenylene) (CBPQT⁴⁺) was used as a macrocycle. Association constants for inclusion complexation of 2T- and BEDOT-derivatives with CBPQT⁴⁺ were obtained by ¹H NMR titration. Due to the donor-acceptor charge transfer absorption band, 2T- and BEDOT-capped [2]rotaxanes have red and green colors, respectively. On the basis of electrochemical analysis, we confirmed that only BEDOT-capped [2]rotaxane is a promising candidate for [3]rotaxane synthesis through oxidation coupling of the thiophene unit.     

Structurally original oxathioethers macrocycles containing an exocyclic double-bond: synthesis,characterization, reactivity,and coordination

New oxathioethers macrocycles have been synthesized and characterized. Each macrocycle consists in structurally defined ether and thioether moieties and an exocyclic double-bond (2a–c) or a hydroxymethyl group (3a–c). Macrocycles (2a–c) have been synthesized by reaction of dianions of thioethers diols (1a–c) with 3-chloro-2-chloromethylprop-1-ene. Their hydroboration/oxidation led to corresponding primary alcohols (3a–c). Structures of compounds (2b) and (3a) have been determined by X-ray diffraction. The reactivity of the hydroxyl group allowed the preparation of oxathioethers macrocycles bearing a polyether chain or a benzyl group (4a,b) and the synthesis of new bicyclic sandwich-type compounds (5a,b). The ability of these functionalized macrocycles to coordinate to palladium has been investigated.     

A hybrid macrocycle containing benzene and pyridine subunits is a better anion receptor than both its homoaromatic congeners

The hybrid tetraamide receptor 3 containing both 2,5-diamidopyridine and 1,3-diamidobenzene anion binding units has been synthesized. NOESY spectroscopy revealed that the new receptor is well preorganized for anion complexation, presumably owing to the macrocyclic topology and the rigidity of the 2,5-diamidopyridine unit. Association constants of 3 with several anions are higher than those determined earlier for its homoaromatic congeners 1 and 2. X-ray crystallographic analysis of the chloride complex of hybrid macrocycle 3 enabled direct comparison of structural aspects of anion recognition by the 2,5-diamidopyridine and 1,3-diamidobenzene moieties.     

Synthesis and evaluation of an Iejimalide-archazolid chimera

Even though the macrolides of the iejimalide family are of marine origin, whereas those of the archazolid series derive from terrestrial myxobacteria, a comparison of their constitution, stereochemistry, and biological activity suggests that these natural products are close structural and functional relatives. Guided by this perception, compound 5 was prepared, which hybridizes the macrolactone core of iejimalide B (2) with the tail of archazolid A (3). The cytotoxicity profile of this chimera, as determined with a panel of 12 human cancer cell lines, corresponds to that of the parent compound 2, although its potency is lower. This outcome may be interpreted on the basis of molecular dynamics calculations, which suggest that the low energy conformations of 2 and 5 are similar but the energetic barriers between the relevant conformers are distinctly higher for the hybrid structure. The synthesis of 5 hinged on a regioselective functionalization of 2,4-dibromothiazole 6, a highly selective CBS-reduction of ketone 8, a Suzuki cross coupling of vinyl boronate 17 with the elaborate alkenyl iodide 16, and a productive closure of the macrocycle by RCM, which requires the selective activation of two out of eight double bonds present in the cyclization precursor 20 by the second-generation Grubbs catalyst 21.     

Synthesis of 12-aza analogs of epothilones and (E)-9,10-dehydroepothilones

N-Boc-12-aza-epothilone analog (azathilone) 1 is a potent inhibitor of human cancer cell growth and represents a structurally new class of natural product-derived microtubule-stabilizing agents. Compound 1 has been prepared employing a convergent strategy that is based on the consecutive assembly of building blocks 3, 4, and 19 into diene 20 and subsequent RCM-mediated macrocycle formation. The aldol reaction between aldehyde 3 and ketone 4 delivered the required 6R,7S diastereoisomer 5 with good selectivity and provided a reliable entry into the stereoselective synthesis of carboxylic acid 12. RCM with diene 20 was highly E-selective, thus giving efficient access to (E)-9,10-dehydro-1 (2). The latter is a key analog in SAR studies with 1.     

Hydrogelation and spontaneous fiber formation of 8-aza-7-deazaadenine nucleoside ‘click’ conjugates

Nucleoside hydrogels based on benzyl azide ‘click’ conjugates of 8-aza-7-deaza-2′-deoxyadenosine bearing 7-ethynyl, 7-octa-(1,7-diynyl), and 7-tri-prop-2-ynyl-amine side chains were synthesized (1, 3, 4). The cycloaddition adduct with the shortest linker (1) yields the most powerful hydrogelator forming stable gels at a concentration of 0.3 wt % of 1 in water. One molecule of 1 catches 7500 water molecules. Cycloaddition of the 8-aza-7-deaza-7-azido-2′-deoxyadenosine (9) and 3-phenyl-1-propyne (10) leads to the isomeric conjugate 2, with a C-N connectivity between the nucleobase and triazole moiety. This gel is less stable than that of the adduct 1. Both gels show a similar stability over a wide pH range (4.0-10.0). Xerogels of 1 and 2 studied by scanning electron microscopy (SEM) reveal that both click adducts (1 and 2) form long fibers spontaneously.     

Improved synthesis of a C3-symmetrical pyridinophane

The formation of the C₃-symmetrical 2,11,20-triaza[3.3.3](2,6)pyridinophane 1 was undertaken with the aim of improving the synthesis of this highly desirable macrocycle, with the future aim of functionalizing 1 with amide pendent arms for the recognition of lanthanide ions. The synthesis of 1 involves the stepwise transformation of pyridine-2,6-dicarboxylic acid into two key intermediates; N,N-bis[(6-hydroxymethyl)pyridin-2-yl]-p-tosylamide 7 and 6-bis[(amino-p-tosyl)methyl]pyridine 5. The macrocyclization of these two intermediates gave 8, from which 1 was formed upon deprotection of the three tosyl groups.     

Regio- and stereoselective synthesis of spiro-pyrrolidine/pyrrolizidine/thiazolidine-grafted macrocycles through intramolecular 1,3-dipolar cycloaddition reaction

Regioselective synthesis of spiropyrrolidine-grafted 11-membered macrocycle was accomplished through an intramolecular [3+2] cycloaddition of azomethine ylides. The key precursor alkenyl diketone (4a–b) was obtained from simple starting materials. The dipole generated from isatin tethered to O-alkyl enone (4a–b) was reacted intramolecularly to yield the spiropyrrolidine-grafted macrocycles (6a–b). The structures of the cycloadducts were assigned by 2D NMR and confirmed by single crystal analysis.     

Triphenylamine-based novel PET sensors in selective recognition of dicarboxylic acids

The triphenylamine-based chemosensors 1 and 2 have been designed and synthesized, for the first time, for the selective recognition of dicarboxylic acids. Carboxylic acid binding takes place through charge neutral pyridyl amide receptor sites with concomitant quenching of fluorescence of the triphenylamine moiety. The bindings were examined using ¹H NMR, fluorescence and UV-vis spectroscopic methods. The receptor 1 was found to be selective for glutaric and adipic acids and the macrocycle 2 was specific for 2,2-dimethylmalonic acid.     

Synthesis and comparison of physicochemical, transport, and antithrombic properties of a cyclic prodrug and the parent RGD peptidomimetic

Cyclic prodrug 1 was derived from RGD peptidomimetic 2 by linking the amino and carboxylic acid groups via an (acyloxy)alkoxy linker. The formation of a cyclic prodrug can transiently alter the physicochemical properties of the RGD peptidomimetic. Cyclic prodrug 1 was synthesized via the key intermediate 8, and the synthesis of this key intermediate was accomplished using two different routes. Cyclic prodrug 1 has a smaller hydrodynamic radius and higher membrane interaction potential than those of the parent RGD peptidomimetic 2. The cell membrane permeation of cyclic prodrug 1 is twice that of the parent peptidomimetic 2. The prodrug-to-drug conversion can be carried out in isolated porcine esterase as well as human plasma. The cyclic prodrug is more stable at pH 4 than pH 7, and is very unstable at pH 10. The cyclic prodrug has antithrombic activity, suggesting that it can be converted to the RGD peptidomimetic in platelet-rich plasma (PRP).     

Synthesis of novel dansyl-labeled Celecoxib derivatives

Four novel dansyl-labeled derivatives of Celecoxib, a cyclooxygenase-2 (COX-2) selective inhibitor, were designed and synthesized. To realize the fluorophore-linker-approach divergent and convergent synthetic strategies were applied. Therefore Celecoxib p-benzoic acid, 8, was synthesized in a new and convenient way. The yield and the synthetic route to Celecoxib, 1, its pyrazolylic acid, 7, and its pyrazolylic methyl ester, 6, were improved. Through a convenient synthesis 1,11-diamino-3,6,9-trioxundecane, 19, was obtained in high yield and purity and used as a linker for the dansyl moiety.     

Synthesis of water-soluble 2-alkylcyclodextrin-C60 conjugates and their inclusion complexation in aqueous solution

Two β-cyclodextrin-C₆₀ conjugates (3 and 4) with a flexible linker at the secondary face of cyclodextrin are synthesized by a single reaction of 2-(ω-azidoundecanyl)-2-O-heptakis (2,3,6-tri-O-methyl)-β-cyclodextrin (2) and C₆₀, both of which display satisfactory water solubility. Structural analyses show that 3 is a closed [5,6] aziridinofullerene, whereas 4 is a bis-adduct derivative. Using rhodamine B (RhB) as a guest molecule, the inclusion complexation behavior of 3 was investigated in aqueous solution.