Synthesis of a novel series of tetracyclic opioid antagonists incorporating an 8-aminobicyclo[3.2.1]oct-6-ene sub-unit

The bridged bicyclo[3.2.1]oct-ene and -ane amines 9-13 have been prepared via [3+2]cycloaddition of allylic alcohols 6 to alkynes 7, and assessed as ligands at opioid receptors. Amine 10b is a potent antagonist at μ receptors.     

Synthesis and self-assembly of novel calix[4]arenocrowns: formation of calix[4]areno[2]catenanes

A series of novel calix[4]arenocrowns 1a-c were efficiently synthesized by a one-pot reaction of calix[4]monohydroquinone diacetate 5 with ditosylate 6 and its analogues in the presence of sodium hydroxide. It was found that the calix[4]arenocrowns could form stable pseudorotaxane-type complexes 2a-c with paraquat, and further self-assemble into calix[4]areno[2]catenanes 3a-c with dicationic salt 8 and p-bis(bromomethyl)benzene.     

Convenient synthesis of [3]catenane by olefin metathesis dimerizations

[3]Catenane 5a and 5b were synthesized conveniently by olefin metathesis dimerization of pseudorotaxanes 3a and 3b. The yields of 5a and 5b were influenced by concentrations of 3a and 3b, and a ring size of a center wheel of [3]catenane.     

Calix[8]arene-based glycoconjugates as multivalent carbohydrate-presenting systems

An efficient approach for the introduction of eight mono- or disaccharide sugar moieties (d-glucose, N-acetyl-d-glucosamine, d-galactose, l-fucose, d-maltose and d-cellobiose) at the upper rim of calix[8]arene 1, using thioureido linkers, is reported. The obtained water-soluble, nanosized glycocalix[8]arenes 5b-10b may act as biomimetic carbohydrate systems and as hosts for highly polar organic molecules. Preliminary ¹H NMR complexation experiments of octaglycosyl derivative 7b and 10b with ionic guests are also reported.     

Transformation of octadehydrodibenzo[12]annulene to benzonaphthopentalene by successive nucleophilic and electrophilic transannular cyclizations

A nucleophile-induced cyclization of octadehydrodibenzo[12]annulene derivative 1b was investigated. Treatment of 1b with BuLi gave fused 5–9-membered ring products, dibenzobicyclo[7.3.0]tetraenediynes 2a and 2b, formed via a single transannular cyclization reaction. The reason why double cyclization did not occur is ascribed to the structure of a plausible anionic intermediate in which a negative charge locates apart from the remaining triple bond carbons. The second cyclization did not take place even when once-isolated product 2b was treated with BuLi because of the higher reactivity toward a nucleophile of the fulvene moiety compared to the triple bonds. On the other hand, heating a chlorobenzene solution of 2b containing cyclohexa-1,4-diene gave products 3a–c possessing a benzonaphthopentalene framework via a Bergman cyclization pathway albeit in low yields after inter- or intramolecular hydrogen abstraction. Moreover, iodine-induced transannular cyclization of 2b afforded the corresponding diiodide 3d.     

Azobenzene-bridged calix[8]arenes

An azobenzene bridge was introduced into the lower (or smaller) rim of p-tert-butylcalix[8]arene (1) and 1,5-calix[8]crown-3 (2) to form 1,4-singly bridged (3) and 1,5:3,7-doubly bridged (4) calix[8]arene derivatives, respectively. Trans and cis isomers of conformationally rigid 4 were isolated. The quantum yields of the trans-cis photoisomerisation reactions have been measured.     

Novel diaminoaluminum halides and a diaminoaluminum hydride: 1,3,2-Diazaalumina-[3]ferrocenophanes

The dilithiated derivative 2 of 1,1′-bis(trimethylsilylamino)ferrocene (1) reacts with the pyridine adducts of the aluminum trihalides AlX₃ (X = Cl, Br, I) to give the respective 1,3,2-diazaalumina-[3]ferrocenophanes (4b, c, d) as pyridine adducts. The fluoride 4a could not be obtained in this way. The reaction of 1,1′-bis(trimethylsilylamino)ferrocene (1) with the dimethyl(ethyl)amine- or pyridine adduct of aluminium trihydride gave the 1,3,2-diazaalumina-[3]ferrocenophanes (5) and (6) as the amine and pyridine adducts, respectively. Treatment of 5 with trimethyltin fluoride afforded the adduct 7 with an Al–F function. Addition of pyridine converted 7 into the desired pyridine adduct of the fluoride (4a). The molecular structures of the pyridine adducts 4a, 4b, 4c and 6 were determined by X-ray analysis. The pyridine is in the trans-position relative to the N–Si bond vectors, and temperature dependent solution-state NMR spectra prove that prominent structural features are retained in solution.     

Synthesis and phototransformations of novel styryl-substituted furo-benzobicyclo[3.2.1]octadiene derivatives

Novel cis- and trans-(o-H/Me/vinyl) substituted styryl furo-benzobicyclo[3.2.1]octadiene derivatives (7a,b, 8) were prepared and transformed to the novel naphthofuran derivatives of benzobicyclo[3.2.1]octadiene (6a,b) and novel phenanthrene-benzobicyclo[3.2.1]octadiene derivative (11) by photochemical electrocyclic ring closure in the presence of iodine and by intramolecular photoinduced [4+2] cycloaddition, respectively. These novel annelated bicyclo[3.2.1]octadiene derivatives (6a,b, 11) are especially interesting for their rigid methano-bridged junction of two aromatic units at defined geometrical arrangement and thereby as potentials for molecular clips.     

Calix[4]quinones. Part 4: The ClO2 oxidation of calix[4]arene dialkyl ethers

Except for the special case of calix[4]arene diethyl ether 1, the chlorine dioxide oxidation of dialkyl ethers 2-5 yielded only the corresponding calix[4]diquinone dialkyl ethers 8-11. Chlorine dioxide oxidation of calix[4]arene diethyl ether 1 produced two isomeric products 6 and 7, which were stable enough to be isolated by column chromatography. However, a slow conformational interconversion between isomeric pair 6 and 7 was observed at room temperature, and the equilibrium was reached after 400 h at 18 °C with an amount of 5:3 in favor of syn-isomer.     

[4+2] Cycloaddition reactions of 4-sulfur-substituted 2-pyridones with electron-deficient dienophiles

[4+2] Cycloaddition reactions of 4-(phenylthio)-1-tosyl-2-pyridone (6a) and 4-(phenylsulfonyl)-1-tosyl-2-pyridone (6b) with electron-deficient dienophiles 7 (N-methylmaleimide, N-phenylmaleimide, and methyl acrylate) gave new isoquinuclidine products 8-10. The N-tosyl group of 6a and 6b was also efficiently converted to N-alkyl derivatives 6c-f, which showed different stereoselectivity toward reactions with dienophiles 7. Several other dienophiles 15 (dimethyl acetylenedicarboxylate, methyl vinyl ketone, ethyl vinyl ether, and methyl methacrylate) were found not to react with 6a or 6b, but led to the formation of tosyl migration products 4-(phenylthio)-O-tosyl-pyridinol (16a) and 4-(phenylsulfonyl)-O-tosyl-2-pyridinol (16b), respectively. The reactivity, regioselectivity, and stereoselectivity of the cycloaddition reactions were also compared with semi-empirical calculations.     

Unusual reactivity of bicyclo[2.2.1]heptene derivatives during the ozonolysis

This paper describes mechanistic studies on the ozonolysis of bicyclo[2.2.1]heptene derivatives 6 and 7 obtained from (R)-(+)-pulegone through the cyclopentadiene 5 and its Diels-Alder reaction with maleic anhydride. The ozonolysis of the tricyclic diol 7 led to the ketone 8 with the same skeleton while the anhydride 6 gave rise to the epoxide 10 and the bis-lactone 11. The structure of 8, 10 and 11 are confirmed by X-ray analysis. These unexpected results are discussed in terms of a π complex between ozone and the double bond.     

Synthesis of new compounds containing the 2,3-dihydro[1,4]dioxino[2,3-b]pyridine heterocyclic system as a substructure

2,3-Dihydro-spiro[1,4]dioxino[2,3-b]pyridine-3,3′-pyrrolidine (8A) and 2,3-dihydro-spiro[1,4]dioxino[2,3-b]pyridine-3,4′-piperidine (9A) have been synthesized from 2-chloro-3-pyridinol. The corresponding 2,3′ (8B) and 2,4′ (9B) isomers were obtained via the Smiles rearrangement, while 9B was also selectively synthesized from 2-nitro-3-pyridinol. The separation of the isomers A and B under the sulfamide form was carried out by flash column chromatography. Subsequent transformations of the corresponding dioxinopyridine derivatives were described.     

[4+2]-Annulations leading to configurationally homogeneous bicyclo[4.4.0]decanediones with five new stereocenters

Bicyclo[4.4.0]decanediones 16 and 21 were prepared in 3-step sequences and their congener 23 as well as bicyclo[4.4.0]decanetrione 24 by subsequent modification. In step 1 the cesium enolate of γ,δ-unsaturated β-ketoester 13 was annulated to the ester-substituted cyclohexenones 6 (achiral; simple diastereoselectivity observed) and 18 (chiral; simple and induced diastereoselectivity observed). In step 2, Pd-catalyzed fragmentation provided bicyclo[4.4.0]decanediones 15 and 20, respectively. De(methoxycarbonylation) of the latter in step 3 furnished compounds 16 and 21.     

Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]thienopyridazines

Two new types of pyrido-fused tris-heterocycles (1a,b and 2a,b) have been prepared from 3-aminopyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4-b]thieno[2,3- and 3,2-d]pyrroles (1a,b) and pyrido[4,3-e]thieno[2,3- and 3,2-c]pyridazines (2a,b) has been studied. The Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids (3,4) and 4-bromo-3-pyridylpivaloylamide (9) afforded the biaryl coupling products (10,11) in high yields (85%). Diazotization of the hydrolysed (2-thienyl)-coupling product (12) and azide substitution gave the 3-azido-4-(2-thienyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine (15) was prepared by exchanging the previous order of reactions. The desired β-carboline thiophene analogues (1a,b) were obtained via the nitrene by thermal decomposition of the azido precursors (14,15). By optimising conditions for intramolecular diazocoupling, the corresponding pyridazine products (72-83%, 2a,b) were afforded.     

Production mechanism of proepitheaflagallin, a precursor of benzotropolone-type black tea pigment, derived from epigallocatechin via a bicyclo[3.2.1]octane-type intermediate

An unstable intermediate proepitheaflagallin B (2), a precursor of proepitheaflagallin (3), was isolated as an enzymatic oxidation product of (−)-epigallocatechin (1), and the structure of 2 was determined based on spectroscopic data. The structure and its decomposition revealed that the detailed production mechanism of proepitheaflagallin (3) via a bicyclo[3.2.1]octane-type intermediate was related to that of major black tea pigments, theaflavins.     

Conversion of novel palladacycles into oxopyrrolo[3,4-b]quinolines

The quinolinylcyclopalladated complexes 3a–b were synthesised in good yields (81% and 77%) by the insertion reaction of the prepared dinuclear palladium complexes [Pd(C,N-2-C₉H₄N-CHO-3-R-6)Cl(PPh₃)]₂ [(R = H (2a), R = OMe (2b)] with isonitrile XyNC (Xy = 2,6-Me₂C₆H₃). The cyclopalladated complexes 3a–b were also obtained in low yields (39% and 33.5%) via a one pot oxidative addition reaction of quinoline chloride 1a–b with isonitrile XyNC:Pd(dba)₂ (4:1). The reactions of 3a–b with Tl(TfO) (TfO = triflate, CF₃SO₃) in the presence of H₂O or EtOH causes depalladation reactions of the complexes to provide the corresponding organic compounds 4a–b, 5a–b and 6a–b in yields (41%, 27% and 18–19%). The products were characterized by satisfactory elemental analyses and spectral studies (IR, ¹H, ¹³C and ³¹P NMR). The crystal structures of 2a, 3a and 3b were determined by X-ray diffraction studies.     

A preparative microwave method for the isomerisation of 4,16-dibromo[2.2]paracyclophane into 4,12-dibromo[2.2]paracyclophane

4,16-Dibromo[2.2]paracyclophane (4) is isomerised to 4,12-dibromo[2.2]paracyclophane (1) by the application of microwaves in DMF solution.     

Selective synthesis of bis[1,2]dithiolo[1,4]thiazines from 4-isopropylamino-5-chloro-1,2-dithiole-3-ones

Reaction of 4-isopropylamino-5-chloro-1,2-dithiole-3-ones 3 and S₂Cl₂ in acetonitrile gave selectively 3-oxo-bis[1,2]dithiolo[1,4]thiazine-5-thiones 1 by the addition of triethylamine and bis[1,2]dithiolo[1,4]thiazine-3,5-diones 5 under the action of formic acid. 3,5-Diones 5 were also obtained by intramolecular cyclization of N,N-bis(5-chloro-3-oxo[1,2]dithiol-4-yl)amines 6 with S₂Cl₂ in the presence of Et₃N.     

Synthesis of functionalized bicyclo[3.2.1]octan-6-ones for diterpenoids: allylsilane directed Pummerer reaction: insertion reactions of diazoketones

The sulfide 5 underwent Pummerer cyclization to give 6, whereas the allyl silane analog 10 produced the bicyclo[3.2.1]octanones 11 and 11a. Extension of this methodology to 15 resulted in 16 without the necessity for allyl silane activation. The intermediate diazoketone 14 on treatment with BF₃·OEt₂ gave 17, 18 and 19, whereas the saturated adduct 22 on treatment with Rh₂(OAc)₄ gave 23.     

Synthesis of conformationally locked carbocyclic nucleosides built on an oxabicyclo[3.1.0]hexane system

The rigid 6-oxobicyclo[3.1.0]hexane scaffold, characteristic of the natural antibiotic neplanocin C (3), was used to build prototypes of conformationally locked deoxynucleosides in the North hemisphere of the pseudorotational cycle. The purine analogues 6 and 7 are conformationally equivalent to carbocyclic nucleosides built with the bicyclo[3.1.0]hexane template. The pyrimidine nucleosides were unstable and underwent a facile intramolecular epoxide ring-opening reaction leading to heterocycle 22. Only the deoxyguanosine analogue 7 showed antiviral activity against EBV.