On the implications of the structure of 3′-azido-3′-deoxythymidine and related compounds to antiviral activity

We report structure–activity relation studies on 3′-azido-3′-deoxythymidine (AZT) and the implications to the biological activity of this class of compounds. The adiabatic potential surface (APS ) of the title compound has been examined with the LCAO –MO –SCF method within the AMI approximation. This study has shown at least 13 minima, all separated by small energy differences and barriers. We have found that the equilibrium favors the anti,gg conformations, in variance to previous studies that predicted the syn,gg conformers to be the most stable forms. The most stable conformation (A) is favored by about 0.5 kcal/mol. However, calculations simulating a bulk-water environment suggest that the three lowest energy conformations (A, B, and C) become almost degenerate in solution. We suggest that the crystallographic conformation (L), characterized by a high dipole moment, and analogous to C, undergoes a strong stabilization upon rotation of the 3′-azido group and that these two conformers, C and L, are the only ones in which the hydroxyl proton is free of steric hindrance. This last point has some relevance from the biological point of view since it is generally accepted that this site must be phosphorylated in order for AZT to achieve its therapeutic effects. The above results suggest that, once in solution, conformer L isomerizes to C, which is the bioactive form of AZT. © 1992 John Wiley & Sons, Inc.     

Tetranaphthyleno[5,6‐bcd:11,12‐b′c′d′:17,18‐b′′c′′d′′:23,24‐b′′′c′′′d′′′]tetrafuran

The title compound, C₄₀H₁₆O₄ or [C₁₀H₄O]₄, is a planar tetrameric cyclooligomer which crystallizes in the monoclinic space group P2₁/n. The compound is located on an inversion center with the asymmetric unit consisting of half of the molecule. The compound displays an interesting packing structure, where the cyclooligomer displays both layered packing with respect to nearest neighbors and a rotation of adjacent planar rings that results in additional interactions. The geometric parameters of the compound agree well with those of comparable cyclooligomers, while the packing reveals some similarities and differences.     

Oxydative Aryl-Aryl-Verknüpfung von 6,6′,7,7′-Tetramethoxy-1,1′,2,2′,3,3′,4,4′-octahydro-1,1′-biisochinolin-Derivaten

Oxidative Aryl-Aryl-Coupling of 6,6′,7,7′-Tetramethoxy-1,1′,2,2′,3,3′,4,4′-octahydro-1,1′-biisoquinoline Derivatives We describe the synthesis of 2 by intramolecular oxidative coupling of 1, 1′-biisoquinoline derivatives 1 (Scheme 1). This heterocyclic system can be considered as a union of two apomorphine molecules and may thus exhibit dopaminergic activity. - The readily available tetrahydrobiisoquinoline 6 was methylated to 11 (Scheme 4) and reduced (with NaBH₃CN) to rac- 7 and (catalytically) to meso- 7 (Scheme 3). Reduction of 11 with NaBH₄ and of the biurethane rac- 9 with LiAlH₄/AlCl₃ afforded meso- and rac- 10 , respectively (Scheme 4). Demethylation of 6 , meso- 10 , meso- and rac- 7 led to 12 , meso- 14 , meso- and rac- 13 , respectively (Scheme 5). The latter two phenols were converted with chloroformic ester to the hexaethoxycarbonyl derivatives meso- and rac- 15 and subsequently saponified to the biurethanes meso- and rac- 16 , respectively (Scheme 5). - In order to assure proximity of the two aromatic rings, the ethano-bridged derivatives meso- and rac- 18 were prepared by condensing meso- and rac- 7 with oxalic ester and reducing the oxalyl derivatives meso- and rac- 17 with LiAlH₄/AlCl₃, respectively (Scheme 6). The ¹H-NMR, spectra at different temperatures showed that rac- 18 populated two conformers but rac- 17 only one, all with C₂-symmetry, and that meso- 17 as well as meso- 18 populated two enantiomeric conformers with C₁-symmetry. Whereas both oxalyl derivatives 17 were fairly rigid due to the two amide groupings, the ethano derivatives 18 exhibited coalescence temperatures of -20 and 30°. - The intramolecular coupling of the two aromatic rings was successful under ‘non-phenolic oxidative’ conditions with the tetramethoxy derivatives 7, 10 and 18 , the rac-isomers leading to the desired dibenzophenanthrolines, the meso-isomers, however, mostly to dienones (Scheme 9): With VOF₃ and FSO₃H in CF₃COOH/CH₂Cl₂ rac- 7 was converted to rac- 19 , rac- 18 to rac- 21 and rac- 10 to a mixture of rac- 20 and the dienone 23b of the morphinane type. Under the same conditions meso- 10 was transformed to the dienone 23a of the morphinane type, whereas meso- 18 yielded the dienone 24 of the neospirine type, both in lower yields. The analysis of the spectral data of the six coupling products offers evidence for their structures. With the demethylation of rac- 20 and rac- 21 to rac- 25 and rac- 26 , respectively, the synthetic goal of the work was reached, but only in the rac-series (Scheme 10). - In the course of this work two cleavages of octahydro-1,1′-biisoquinolines at the C(1), C(1′)-bond were observed: (1) The biurethanes 9 and 16 in both the meso- and rac-series reacted with oxygen in CF₃COOH solution to give the 3,4-dihydroisoquinolinium salts 27 and 28 ; the latter was deprotonated to the quinomethide 30 (Scheme 11). (2) Under the Clarke-Eschweiler reductive-methylation conditions meso- and rac- 7 were cleaved to the tetrahydroisoquinoline derivative 32 .     

Conformational dimorphism of the spiropyran 1′,3′,3′‐trimethylspiro[2H‐1‐benzopyran‐2,2′‐indoline]‐6‐carbaldehyde)

The title compound, C₂₀H₁₉NO₂, crystallizes from an acetone–heptane solution as two dimorphs in the space groups C2/c and Cc. Each dimorph has two molecules in the asymmetric unit. The four molecules adopt slightly different conformations expressed by the degree of bending around a vector connecting the O and C atoms attached to the bridgehead C atom of the pyran ring. Due to the fact that all four molecules are chemically identical, the difference in bending is attributed to packing forces. This is evident from the close contacts of neighbouring molecules perpendicular to the plane of the benzopyran moiety observed in the Cc structure and not in the C2/c structure. These observations provide a unique example that shows how packing forces can affect the conformation of a specific molecule.     

Highly Soluble and Green Indigo Dyes: 4,4′,7,7′‐Tetraalkoxy‐5,5′‐diaminoindigotins

Two new types of 4,4′,7,7′‐tetraalkoxyindigotins, 1a – f and 2a – f along with the new N‐substituted indigotins 4e – f , were synthesized from dinitrobenzaldehydes 5a – f , which were prepared from 2‐hydroxy‐5‐methoxybenzaldehyde ( 7 ) via dialkoxybenzaldehydes 6a – f (Scheme). The new dialkoxyindigotin 3g was obtained from dialkoxybenzaldehyde 6g via nitrobenzaldehyde 8g . The 1,4‐dialkoxy‐2,3‐dinitrobenzenes 9 were isolated as by‐products. The 4,4′,7,7′‐tetraalkoxy‐5,5′‐diaminoindigotins 1 are soluble in organic solvents, and their solutions are green, which is highly uncommon for indigotins and is primarily caused by electronic effects of substituents, steric effects playing a minor role. The indigotins 1 produce a strong red shift of the longest‐wavelength absorption and negative solvatochromism indicating the predominance of polar resonance structures in the ground state. Tautomeric structures were excluded. These indigotins are valuable compounds for technical applications, for synthetic purposes, and for analytical studies. SANS (Small‐angle neutron scattering) experiments showed that certain 4,4′,7,7′‐tetraalkoxy‐5,5′‐diaminoindigotins 1 form rod‐like aggregates in solution. The similarly substituted 4,4′,7,7′‐tetraalkoxy‐5,5′‐dinitroindigotins 2 are far less soluble. They produce red monoanions (preferably dimers) and bluish‐purple dianions in organic solvents.     

Facile synthesis of novel spiro[azetidine-2,4′(1′H)-isoquinoline-1′,3′,4(2′H)-triones]

A convenient general method for the synthesis of a new heterocycle, spiro[azetidine-2,4′(1′H)-iso-quinoline-1′,3′,4(2′H)-trione] is described. The key intermediate 2 was prepared by direct halogenation of position-4 of acid 3 with thionyl chloride, and subsequent treatment of the generated 4-Cl, 4-acetyl chloride 11 with a THF/NH₃ solution at low temperature.     

The 1H NMR spectra of zinc complexes of pyridine-2-carbaldehyde 2′-pyridylhydrazone

Proton magnetic resonance spectra at 100 MHz are described for some zinc complexes of the E- and Z-isomers of pyridine-2-carbaldehyde 2′-pyridylhydrazone in d₆-dimethylsulphoxide solution. Chemical shift data are discussed qualitatively in relation to factors such as the charge on the metal ion, the anisotropy of ligand nitrogen atoms, electric field effects caused by the dipole moment of nitrogen lone pairs, metal-nonbonded-hydrogen interactions, ring current effects and the conformational changes undergone by each isomer on coordination.     

Synthesis of Some Novel Phenyl Substituted Oxothiazolidin- 1’’,3’’,4’’-thiadiazolo-[3’,4’-b]thiazoline of 3β-Substituted Cholestane

Three title compounds 4a—4c have been synthesized by the cyclodehydration of 1’-benzylidine-4’-(3β-substituted-5α-cholestane-6-yl)thiosemicarbazones 2a—2c with thioglycolic acid followed by the treatment with cold conc. H2SO4 in dioxane. The compounds 2a—2c were prepared by condensation of 3β-substituted-5α-cholestan- 6-one-thiosemicarbazones 1a—1c with benzaldehyde. These thiosemicarbazones 1a—1c were obtained by the reaction of corresponding 3β-substituted-5α-cholestan-6-ones with thiosemicarbazide in the presence of few drops of conc. HCl in methanol. The structures of the products have been established on the basis of their elemental, analytical and spectral data.     

7‐Halogenated 7‐Deazapurine 2′‐Deoxyribonucleosides Related to 2′‐Deoxyadenosine, 2′‐Deoxyxanthosine,and 2′‐Deoxyisoguanosine: Syntheses and Properties

A series of 7‐fluorinated 7‐deazapurine 2′‐deoxyribonucleosides related to 2′‐deoxyadenosine, 2′‐deoxyxanthosine, and 2′‐deoxyisoguanosine as well as intermediates 4b – 7b, 8, 9b, 10b , and 17b were synthesized. The 7‐fluoro substituent was introduced in 2,6‐dichloro‐7‐deaza‐9H‐purine ( 11a ) with Selectfluor (Scheme 1). Apart from 2,6‐dichloro‐7‐fluoro‐7‐deaza‐9H‐purine ( 11b ), the 7‐chloro compound 11c was formed as by‐product. The mixture 11b / 11c was used for the glycosylation reaction; the separation of the 7‐fluoro from the 7‐chloro compound was performed on the level of the unprotected nucleosides. Other halogen substituents were introduced with N‐halogenosuccinimides ( 11a → 11c – 11e ). Nucleobase‐anion glycosylation afforded the nucleoside intermediates 13a – 13e (Scheme 2). The 7‐fluoro‐ and the 7‐chloro‐7‐deaza‐2′‐deoxyxanthosines, 5b and 5c , respectively, were obtained from the corresponding MeO compounds 17b and 17c , or 18 (Scheme 6). The 2′‐deoxyisoguanosine derivative 4b was prepared from 2‐chloro‐7‐fluoro‐7‐deaza‐2′‐deoxyadenosine 6b via a photochemically induced nucleophilic displacement reaction (Scheme 5). The pK_a values of the halogenated nucleosides were determined (Table 3). ¹³C‐NMR Chemical‐shift dependencies of C(7), C(5), and C(8) were related to the electronegativity of the 7‐halogen substituents (Fig. 3). In aqueous solution, 7‐halogenated 2′‐deoxyribonucleosides show an approximately 70% S population (Fig. 2 and Table 1).     

Synthesis of nitrogen‐containing heterocycles 9. Preparation and carbon‐carbon bond cleavage of spiro[cycloalkane[1′,2′,4′]‐triazolo[1′,5′‐a][1′,3′,5′]triazine] derivatives and related compounds

Diaminomethylenehydrazones of cyclic ketones 1–5 reacted with ethyl N‐cyanoimidate (I) at room temperature or with bis(methylthio)methylenecyanamide (II) under brief heating to give directly the corresponding spiro[cycloalkane[1′,2′,4′]triazolo[1′,5′,‐a][1′,3′‐5′]triazine] derivatives 7–12 in moderate to high yields. Ring‐opening reaction of the spiro[cycloalkanetriazolotriazine] derivatives occurred at the cycloalkane moiety upon heating in solution to give 2‐alkyl‐5‐amino[1,2,4]triazolotriazines 13–16. Diaminomethylenehydrazones 17–19, of hindered acyclic ketones, gave 2‐methyl‐7‐methylthio[1,2,4]‐triazolo[1,5‐a][1,3,5]triazines 21–23 by the reaction with II as the main products with apparent loss of 2‐methylpropane from the potential precursor, 2‐tert‐butyl‐2‐methyl‐7‐methylthio[1,2,4]triazolo[1,5‐a]‐[1,3,5]triazines 20, in good yields. In general, bis(methylthio)methylenecyanamide II was found to be a favorable reagent to the one‐step synthesis of the spiro[cycloalkanetriazolotriazine] derivatives from the diaminomethylenehydrazones. The spectral data and structural assignments of the fused triazine products are discussed.     

4′‐Vinyl‐2,2′:6′,2′′‐ter­pyridine

The title compound, C₁₇H₁₃N₃, is a versatile precursor for polymeric ter­pyridine derivatives and their metal complexes. The mol­ecule has transoid and near‐coplanar pyridine rings. However, the vinyl group is forced out of the plane of the terpyridyl moiety by a close H?H contact.     

Synthesis and photophysical properties of 2,5,8,11‐tetrakis(5‐hexylthiophen‐2‐yl)tetrathieno[2,3‐a:3′,2′‐c:2′′,3′′‐f:3′′′,2′′′‐h]naphthalene

The title compound, C₅₈H₆₄S₈, has been prepared by Pd‐catalysed direct C—H arylation of tetrathienonaphthalene (TTN) with 5‐hexyl‐2‐iodothiophene and recrystallized by slow evaporation from dichloromethane. The crystal structure shows a completely planar geometry of the TTN core, crystallizing in the monoclinic space group P2₁/c. The structure consists of slipped π‐stacks and the interfacial distance between the mean planes of the TTN cores is 3.456 (5) Å, which is slightly larger than that of the comparable derivative of tetrathienoanthracene (TTA) with 2‐hexylthiophene groups. The packing in the two structures is greatly influenced by both the aromatic core of the structure and the alkyl side chains.     

Synthesis and Characterization of Fluorinated Polyimide Derived from 3,3′‐Diisopropyl‐4,4′‐diaminodiphenyl‐3′′,4′′‐difluorophenylmethane

A novel aromatic diamine monomer, 3,3′‐diisopropyl‐4,4′‐diaminodiphenyl‐3′′,4′′‐difluorophenylmethane (PAFM), was successfully synthesized by coupling of 2‐isopropylaniline and 3,4‐difluorobenzaldehyde. The aromatic diamine was adopted to synthesize a series of fluorinated polyimides by polycondensation with various dianhydrides: pyromellitic dianhydride (PMDA), 3,3′,4,4′‐biphenyltetracarboxylic dianhydride (BPDA), 4,4′‐oxydiphthalic anhydride (ODPA) and 3,3′,4,4′‐benzophenone tetracarboxylic dianhydride (BTDA) via the conventional one‐step method. These polyimides presented excellent solubility in common organic solvents, such as N,N‐dimethylformamide (DMF), N,N‐dimethyl acetamide (DMAc), dimethyl sulfoxide (DMSO), N‐methyl‐2‐pyrrolidone (NMP), chloroform (CHCl₃), tetrahydrofuran (THF) and so on. The glass transition temperatures (T_g) of fluorinated polyimides were in the range of 260–306°C and the temperature at 10% weight loss in the range of 474–502°C. Their films showed the cut‐off wavelengths of 330–361 nm and higher than 80% transparency in a wavelength range of 385–463 nm. Moreover, polymer films exhibited low dielectric properties in the range of 2.76–2.96 at 1 MHz, as well as prominent mechanical properties with tensile strengths of 66.7–97.4 MPa, a tensile modulus of 1.7–2.1 GPa and elongation at break of 7.2%–12.9%. The polymer films also showed outstanding hydrophobicity with the contact angle in the range of 91.2°–97.9°.     

4′‐Iodo‐2,2′:6′,2′′‐terpyridine

In the nearly planar title compound, C₁₅H₁₀IN₃, the three pyridine rings exhibit transoid conformations about the interannular C—C bonds. Very weak C—H...N and C—H...I interactions link the molecules into ribbons. Significant π–π stacking between molecules from different ribbons completes a three‐dimensional framework of intermolecular interactions. Four different packing motifs are observed among the known structures of simple 4′‐substituted terpyridines.     

Monoclinic and orthorhombic polymorphs of 4,4′,6,6′‐tetrachloro‐2,2′‐(piperazine‐1,4‐diyldimethylene)diphenol

The title compound, C₁₈H₁₈Cl₄N₂O₂, crystallizes as monoclinic and orthorhombic polymorphs from CHCl₃–CH₃OH solution. In both polymorphic forms, the molecule lies on a crystallographic centre of inversion (at the piperazine ring centroid) and exhibits an intramolecular O—H...N hydrogen bond. In the monoclinic polymorph (space group P2₁/c), the molecules are linked by intermolecular C—H...Cl hydrogen bonds into a ribbon sheet built from R₈⁸(34) rings. In the orthorhombic polymorph (space group Pbcn), the molecules are linked by intermolecular C—H...O hydrogen bonds into a ribbon sheet of R₆⁶(34) rings. The sheets in the orthorhombic polymorph are crosslinked into a three‐dimensional framework by π–π stacking interactions.     

2,2′:3′,2′′‐Terthiophene‐Based all‐Thiophene Dendrons and Dendrimers: Synthesis,Structural Characterization,and Properties

The synthesis of generational dendritic oligothiophenes (DOTs) has been successfully achieved by a divergent/convergent approach that involves halogenation, boronation, and palladium‐catalyzed Suzuki coupling reactions. The key point in the presented synthetic approach is the use of trimethylsilyl (TMS) protecting groups, which allow for the core‐lithiation and subsequent boronation of the dendrons and for the peripheral ipso‐substitution with iodine monochloride or N‐bromosuccimide. In addition, the TMS protecting groups can be completely removed by using tetrabutylammonium fluoride, thus yielding only‐thiophene‐based dendrons and dendrimers. Due to their highly branched structure, all these synthesized DOTs are soluble in organic solvents. Chemical structures were confirmed by NMR spectroscopic, mass spectrometric, and elemental analysis. Concentration‐dependent ¹H NMR spectroscopic investigations revealed that the higher generation compounds tend to aggregate in solution. Such an aggregation behavior was further confirmed by measuring with MALDI‐TOF MS. Both MALDI‐TOF MS and gel‐permeation chromatography (GPC) analyses confirmed the monodispersity of the DOTs. Furthermore, GPC results revealed that these DOT molecules adopt a condensed globular molecular shape. Their optical and electronic properties were also investigated. The results indicated that these DOTs comprise various conjugated α‐oligothiophenes with different chain lengths, which results in the higher generation compounds showing broad and featureless UV/Vis absorption spectra and ill‐defined redox waves.     

2′,3′‐Dehydrosalannol

The title compound, methyl (2aS,3R,5R,5aS,6S,6aS,8R,9aS,10aR,10bR,10cS)‐8‐(3‐furyl)‐2a,4,5,5a,6,6a,8,9,9a,10a,10b,10c‐dodeca­hydro‐3‐hydroxy‐2a,5a,6a,7‐tetra­methyl‐5‐(3‐methylbut‐2‐enoyl­oxy)‐2H,3H‐cyclo­penta­[4′,5′]­furo­[2′,3′:6,5]benzo[cd]­isobenzo­furan‐6‐acetate, C₃₂H₄₂O₈, was isolated from uncrushed green leaves of Azadirachta indica A. Juss (neem) and has been found to possess antifeedant activity against Spodptera litura. The conformations of the functional groups are similar to those of 3‐des­acetyl­salannin, which was isolated from neem kernels. The mol­ecules are linked into chains by intermolecular O—H?O hydrogen bonds.     

Synthesis and Properties of Sodium and Europium(III) Cryptates Incorporating the 2,2′-Bipyridine 1,1′-Dioxide and 3,3′-Biisoquinoline 2,2′-Dioxide Units

The sodium and europium cryptates of the new macrobicyclic ligands 2 and 3 incorporating the 2,2′-bipyri dine 1,1′-dioxide and 3,3′-biisoquinoline 2,2′-dioxide units, respectively, have been prepared. The Eu^III complexes present characteristic ¹H-NMR spectra, showing large shifts, and are strongly luminescent in aqueous solution. These markedly improved luminescent properties, compared to the europium cryptate of the parent macrobicyclic ligand 1 , may be ascribed at least in part to a better shielding of the bound cation by the N-oxide sites.     

A second triclinic modification of 2′,6′‐di­methoxy­flavone

Crystals of a second triclinic modification of the title compound, 2‐(2,6‐di­methoxy­phenyl)‐4H‐1‐benzo­pyran‐4‐one, C₁₇H₁₄O₄, were grown from a hot cyclo­hexane solution. In the mol­ecule, the O—C—C—C torsion angle at the junction between the benzo­pyran and phenyl rings is 67.6 (3)°.