One-pot synthesis of macrocyclic compounds possessing two cyclobutane rings by sequential inter- and intramolecular [2+2] photocycloaddition reactions

Sensitized photocycloaddition reactions of 6,6′-dimethyl-4,4′-[1,3-bis(methylenoxy)phenylene]-di-2-pyrone (1) with electron-poor α,ω-diolefins such as ethylene diacrylate (2a) and polyoxyethylene dimethacrylates (2b-d) afforded site- and stereoselective macrocyclic dioxatetralactones (3a-d) and (4b) having 18- to 25-membered rings across the C5-C6 and C5′-C6′ double bonds, or C5-C6 and C3′-C4′ double bonds in 1, respectively. Similar photoreactions of 1 with electron-rich α,ω-diolefins such as poly(ethylene glycol)divinyl ether (2e and 2f) afforded crown ether-type macrocyclic compounds (5e and 5f) having 18- and 21-membered rings across the C3-C4 and C3′-C4′ double bonds in 1, respectively. The stereochemical features of 3b, 5e-xx, and 5e-nn were determined by the X-ray crystal analysis. The reaction mechanism was inferred by MO methods.     

Synthesis and structure of 8-hydroxy-6-methoxy-3,7-dimethylisochromane and its analogues

The title compound 1 was obtained by the reaction of alcohol 18 and triethyl orthoformate catalyzed by aluminum chloride followed by catalytic hydrogenation in good yield. Similarly, compounds 1 and 3 were obtained by intramolecular cyclization of MOM ether 19 with titanium(IV) chloride in moderate yields and isochromanes 1, 3, 26 and 27 by intramolecular cyclization of ether 20 with titanium(IV) chloride in high yields. The structures of compounds 1-3 were elucidated by analysis of spectroscopic data and chemical reactions. The mechanisms on the formation of 1 and 3 are discussed.     

Synthesis and properties of novel crown ether-annelated 4′,5′-diaza-9′-(1,3-dithiole-2-ylidene)-fluorenes and their ruthenium(II) complexes

Two novel redox-active 1,3-dithiole (DT) ring-fused 4,5-diazafluorene ligands with crown ether moieties (L1 and L2) were synthesized and characterized. The crystal structure of L1 was studied. The electrochemical and spectroscopic properties of these new ligands, as well as the corresponding bis(bipyridine)ruthenium(II) complexes [4: Ru L1(bpy)₂ and 5: Ru L2(bpy)₂], were also been investigated.     

Novel organosoluble and colorless poly(ether imide)s based on 1,1-bis[4-(3,4-dicarboxyphenoxy)phenyl]cyclohexane dianhydride and trifluoromethyl-substituted aromatic bis(ether amine)s

A series of novel fluorinated poly(ether imide)s (IV) having inherent viscosities of 0.70-1.08 dL/g were prepared from 1,1-bis[4-(3,4-dicarboxyphenoxy)phenyl]cyclohexane dianhydride (I) and various trifluoromethyl (CF₃)-substituted aromatic bis(ether amine)s II_a-g by a standard two-step process with thermal and chemical imidization of poly(amic acid) precursors. These poly(ether imide)s showed excellent solubility in many organic solvents and could be solution-cast into transparent, flexible, and tough films. These films were essentially colorless, with an ultraviolet-visible absorption edge of 375-380 nm and a very low b^∗ value (a yellowness index) of 5.5-7.3. They also showed good thermal stability with glass-transition temperatures of 207-269 °C, 10% weight loss temperatures in excess of 474 °C, and char yields at 800 °C in nitrogen more than 62%. In comparison with analogous V series poly(ether imide)s without the -CF₃ substituents, the IV series polymers showed better solubility, lower color intensity, and lower dielectric constants.     

Oxymethylcrowned chromene: photoswitchable stoichiometry of metal ion complex and ion-responsive photochromism

Chromene derivatives bearing oxymethyl-12-crown-4 (1), -15-crown-5 (2), -18-crown-6 (3) ether moieties, and non-cyclic analogue (4) were synthesized, and their metal ion binding properties and photochromism were examined. NMR titration with alkali metal ions revealed that 1 formed a 1:2 complex (metal ion: ligand) with Na⁺, while Li⁺ afforded a 1:1 complex of 1. In cases of K⁺ and Rb⁺, the complexes were a mixture of 1:1 and 1:2 complexes, but the formation of 1:1 complex was observed again with Cs⁺. Under UV irradiation, however, the complex stoichiometry of 1 with all alkali metal ions was 1:1. As a comparison of NMR spectra between the Li⁺ and Na⁺ complexes of 1 indicated considerable upfield shift for the chromene moiety of the Na⁺ complex, π-π stacking of the chromene moiety seems to induce formation of the 1:2 complex. These results indicate that the chromene moiety is not only to show photochromism but also to induce aggregation to form the 1:2 complex resulted in switching of the complex stoichiometry by UV irradiation. The formation of 1:2 complex appeared only with 1 because flexibility of the crown moieties for 2 and 3 interfered the formation of 1:2 complex. Studies on photochromism in the presence of a metal ion demonstrated that the chromene derivatives bearing crown ether moieties show ion-responsive photochromism depending on the metal ion binding ability of their crown ether moieties.     

Structural and thermosensitive properties of novel octopus shape cyclotriphosphazenes

Three novel compounds (3–5) were synthesized from the reactions of non-geminal cis-2,4,6 diethylene glycol monobutyl ether substituted cyclotriphosphazene (2a) with ethylamine, hexylamine and dodecylamine. Compounds 3–5 were characterized by ³¹P NMR, MS and elemental analysis. The thermosensitive properties of compounds 3–5 were investigated. Compound 3 showed thermosensitive properties which might enable it to be used as a biomedical material.     

Periphery-modified crown ethers. Synthesis of bis-5,8-dimethoxy-1,4-methanonaphthalene-fused crown ethers

The easily accessible and multi-functionalized 5,8-dimethoxy-6,7-dihydroxy methyl-1,4-dihydro-1,4-methanonaphthalene (1) has been utilized as the basic building material to synthesize the symmetric bis-methanonaphthalene-fused crown ethers 14a-d (BMN-16-crown-4, BMN-22-crown-6, BMN-28-crown-8, and BMN-34-crown-10), that are constructed based on the connection between the α,β-bis-benzylic carbon atoms of diol 1 and oligoethylene glycols (9a-d) via two synthetic routes keyed upon the method of Williamson ether synthesis.     

Synthesis of bis-(3,5)pyrazolophanes via double cycloadditive macrocyclisation

Double cycloadditive macrocyclisation of bis-hydrazonoyl chlorides 5 were performed with bis-allyl ethers 9 and 10, bis-vinyl ether 14 and bis-propargyl ether 18. The title compounds having a 18-, 19-, 22- or 24- membered ring annulated to the pyrazole units were obtained with good overall yield.     

A new cavitand ionophore bearing two rigid crown ether groups

A new cavitand (1) bearing two rigid crown ether groups has been synthesized from tetrahydroxycavitand (2). The binding properties of this cavitand towards alkali metal ions as well as ammonium ion were also examined.     

Synthesis of novel C2-symmetric chiral crown ethers and their application to enantioselective trifluoromethylation of aldehydes and ketones

Synthesis of novel C2-symmetric chiral crown ethers and their application to enantioselective trifluoromethylation of aldehydes and ketones are discussed. The use of a series of C2-symmetric chiral crown ethers 2 or 3 derived from commercially available (R)-1,1′-bi-2-naphthol for the enantioselective trifluoromethylation of 2-naphthyl aldehyde 1a with (trifluoromethyl)trimethylsilane in the presence of a base was attempted. Iodo-substituted crown ether 2b was found to be the most effective in the model reaction. Moderate enantioselectivities were observed for the trifluoromethylation of both aryl or alkyl aldehydes and alkyl aryl ketones in 21-44% ees. Although the ees are still improvable, this is the first example of a chiral crown ether-catalyzed enantioselective trifluoromethylation reaction.     

Oxidation of sulfides with hydrogen peroxide catalyzed by synthetic flavin adducts with dendritic bis(acylamino)pyridines

The catalytic activities of the cationic synthetic flavin adduct 1 with various dendritic and non-dendritic 2,6-bis(acylamino)pyridines 2 were examined for the oxidation of organic sulfides with H₂O₂. The adduct of 5-ethyllumiflavinium perchlorate 1a with 2b–d bearing poly(benzyl ether) dendron units acts as an efficient organocatalyst for the oxidative transformation of sulfides to the corresponding sulfoxides under mild conditions.     

The synthesis of 2,4-dienyl fluoroalkyl ketones by a tandem three-stage sequence of propargyl 2-fluoroalkylvinyl ether formation, Claisen rearrangement, and allene-to-conjugated diene isomerization

A tandem three stages process to a series of trifluoromethyl and halodifluoromethyl 2,4-unsaturated ketones 4a-c is described. This process started with the preparation of 2-fluoroalkyl substituted propargyl vinyl ether 3a-d by treatment of a mixture of individual ethyl α-per(poly)fluoroalkyl acetates 1a-d and propargyl alcohol 2 in CH₂Cl₂ with the mixed base (Na₂CO₃/TEA) at ambient temperature. When heated in toluene at 80°C, these ethers readily underwent a tandem propargyl-allenyl Claisen rearrangement and isomerization of the resultant 3,4-dienone to give 2,4-unsaturated fluoroalkyl ketones 4a-c (Z/E mixture). The reaction of ethyl α-per(poly)fluoroalkyl acetate 1 with 1-phenyl propargyl alcohol 5 in refluxing CH₂Cl₂ in the presence of the mixed base (Na₂CO₃/TEA) directly afforded the corresponding unsaturated fluoroalkyl ketone 6a-c in one pot. In the presence of NaH, the reaction of ethyl 3-halo-3-fluoroalkylacrylates 8a-b with 1,1-dimethyl propargyl alcohol 9 at −50°C to 0°C also gave the unsaturated fluoroalkyl ketones 10a-b in one pot. The difluorovinyl propargyl ether 11 produced by reduction of 2-bromodifluoromethyl substituted propargyl vinyl ether 3b rearranged in hot benzene to give the corresponding allene 12 bearing a gem-difluoromethylene group in the middle of the aliphatic chain.     

A color version of the Hinsberg test: permethylated cyclodextrin and crown-appended azophenol for highly selective sensing of amines

Azophenol dyes 1-5 having the permethylated cyclodextrin and/or crown moieties have been synthesized. Compounds 1 and 2 provide critical information for discrimination among 1°-3° amines by unique color changes. Addition of 1° and 2° amines to solutions of 1 or 2 in chloroform shifts the absorbance maximum of the initial solutions from 380 nm to ∼580 nm and ∼530 nm, respectively, but no change is observed with 3° amines. The high selectivity of 1 is mainly due to H-bonding between the ammonium H atoms of the amine and oxygen atoms of the crown-6. The selectivity of 1 possessing the β-cyclodextrin moiety toward amines was higher than that of 2 possessing the α-cyclodextrin moiety. On the other hand, chloroform solutions of 3 or 4, which lack the crown ether moiety, changed from yellow (380 nm) to pink (500 nm) with the addition of 1° and 2° amines, but with no selectivity. These results indicate that the crown unit in 1 or 2 plays an important role in discriminating among the types of amines.     

An efficient synthesis of 4,4′,5,5′-tetraiododibenzo-24-crown-8 and its highly conjugated derivatives

4,4′,5,5′-Tetraiododibenzo-24-crown-8 (9), a practical building block, was prepared under efficient and mild reaction conditions starting from the simple starting material, catechol (1). Highly conjugated 4,4′,5,5′-tetraethynyldibenzo-24-crown-8 (10a,b) were prepared via a Sonogashira coupling reaction from tetraiodocrown ether 9. These highly conjugated crown ethers form complexes in CD₂Cl₂ with dibenzylammonium hexafluorophosphate in a 1:1 ratio. Emission spectrum of pseudorotaxane 11 shows a dramatic shift from the non-complexed precursor.     

Color modulation for intramolecular charge-transfer-induced chemiluminescence of bicyclic dioxetanes bearing a 3-hydroxy-5-naphthylphenyl moiety in the coordination sphere

Bicyclic dioxetanes 2a, 2b, and 3, bearing a 3-hydroxy-5-naphthylphenyl moiety underwent charge-transfer-induced decomposition with accompanying emission of light, the color of which changed from red to blue responding to a complex of crown ether with potassium t-butoxide used as a base. Furthermore, they afforded unusual chemiluminescence, the spectra of which displayed two peaks in some cases. It was observed for chemiluminescences in the coordination sphere with crown ether that their spectra did not coincide with the spectra of authentic emitters.     

Synthesis of 10 stereochemically distinct bis-tetrahydrofuran intermediates for creating a library of 64 asimicin stereoisomers

Stereoselective synthesis of 10 unique bifunctional stereoisomeric adjacent bis-THF intermediates (R = Bz), including 5.1-5.4, 5.7-5.9, 5.11, and 5.15-5.16, of 16 possible compounds, is described. The key steps used in the synthesis of these compounds included the rhenium(VII) oxide-mediated and the Co(modp)₂-catalyzed trans oxidative cyclizations (OCs), the OsO₄-catalyzed cis OC, and the Williamson’s type etherification reactions. The remaining six bis-THF intermediates (R = Bn) can be prepared from 5.7-5.9, 5.11, and 5.15-5.16 (R = Bz) in two steps, including protection of the free alcohol as benzyl ether followed by the benzoate deprotection. These intermediates should provide access to all 64 asimicin stereoisomers and their analogs.     

Two novel 3,4-seco-trinorlanostane triterpenoids isolated from Ganoderma fornicatum

Two novel 3,4-seco-25,26,27-trinorlanostane triterpeniod compounds, fornicatins A and B (1 and 2) have been isolated from the fruiting body of G. fornicatum. The structural elucidation of 1 and 2 were accomplished by extensive NMR analysis. The relative stereochemistry of 2 was established by single crystal X-ray crystallography, which also confirmed the novel carbon skeleton of the new triterpenoid. An ether linkage of C-4 with C-7 in 1 is unprecedented in natural triterpenoids. Both compounds were tested for their inhibitory effects on rabbit platelet aggregation induced by PAF, ADP, or AA.     

Fluorescence emission control and switching of oxymethylcrowned spirobenzopyrans by metal ion

Oxymethylcrowned spirobenzopyran 1 and pyrenylspirobenzopyran 2 were synthesized, and fluorescence emission of their corresponding merocyanine form was examined in the presence of metal ions. For 2, fluorescence emission derived from the pyrene moiety was completely quenched by photoinduced electron transfer (PET) of the nitrogen atom when the merocyanine form was not produced, namely, without metal ions. However, when 2 was converted to the merocyanine form by the complexation of its crown ether with a metal ion, fluorescence resonance energy transfer (FRET) from the pyrene to the merocyanine moieties took place to produce fluorescence emission. This result demonstrates that the spirobenzopyran isomerization can function as a fluorescence emission switch. Fluorescence quantum yield measurement for 1 and 2 showed that fluorescence emission depends on the binding metal ion in which the fluorescence quantum yield generally increased with the increase of metal ion radius.     

Synthesis of new tropinone derivatives by palladium-catalyzed couplings of 8-azabicyclo[3.2.1]oct-2-enyl nonaflates

Whereas tropinone derived nonaflate 3 was no suitable precursor for Heck-reactions, the related carbamate 7 was an excellent substrate for palladium-catalyzed processes. Nonaflate 7 was either isolated in excellent yield by LDA treatment of ketone 5 followed by trapping with NfF (nonafluorobutanesulfonyl fluoride) or generated in situ by fluoride-catalyzed reaction of silyl enol ether 6 with NfF. The desired 1,3-diene 8 was prepared by conventional Heck-reaction of nonaflate 7 with methyl acrylate in almost quantitative yield. Alternatively, the one-pot nonaflation-Heck protocol starting from silyl enol ether 6 provided 8 in good yield. The couplings of acrylonitrile or phenyl vinyl sulfone were also performed with in situ generated 7 and they afforded the expected 1,3-dienes 9 and 10 in good yields. The Sonogashira-reaction with phenylacetylene also started from silyl enol ether 6 and provided enyne 11 via 7 in good yield. A Diels-Alder reaction of 1,3-diene 8 with N-phenyl maleimide at 100 °C furnished tetracyclic adduct 12 in good yield, with excellent diastereofacial selectivity, but with low endo-exo-selectivity. Nonaflate 14 was easily obtained from the corresponding unsaturated bicyclic ketone 13. It behaved differently in an attempted Heck-reaction and mainly led to fragmentation products 15 and 16, whereas the expected 1,3-diene 17 was formed only as minor component. However, 14 could successfully be used in a Sonogashira-reaction with phenylacetylene to afford compound 18. These transformations demonstrate the great potential of tropinone derived alkenyl nonaflates for diversity oriented syntheses of interesting compounds containing an 8-azabicyclo[3.2.1]octane scaffold.     

Chemical characterisation of oxidative degradation products of Δ-THC

The chemical analysis of a sample of Δ⁹-THC, which had been stored in an ethanol/propylene glycol solution for 5 years, resulted in the isolation of several hydroxylated Δ⁹-THC derivatives, the main of which were trans-cannabitriol monoethyl ether (4) and trans-propanediol ethers 7 and 8. cis-Cannabitriol monoethyl ether (5) and the oxidised derivatives 3 and 6 were detected in lesser amounts. The structure elucidation of the unprecedented cannabinoids 3, 5, 7 and 8 was achieved mainly by NMR techniques. Full NMR assignment of compounds 4 and 6 were also made. The detection of cannabitriol (6) and the corresponding solvent-adduct analogues (compounds 4-8) was in agreement with the decomposition mechanisms previously proposed for Δ⁹-THC. The isolation of the endoperoxide 3 represents indirect evidence of the existence of unstable precursors that were suspected to be intermediates in the non-enzymatic oxidation pathway of Δ⁹-THC. Both isomers of cannabitriol monoethyl ether exhibited weak affinity at either CB₁ (K_i=2.25, 6.30 μM) or CB₂ cannabinoid receptors (K_i=1.97, 3.13 μM), the trans isomer always being more potent than the cis isomer.