Preparation,isomerisation et configuration absolue des “hydrates” de thymidine

The (+) and (?) cis-6-hydroxy-5,6-dihydrothymidines 4a and 5a have been prepared by mild reduction of (+) and (?) trans-5-bromo-6-hydroxy-5,6-dihydrothymidine 2a and 3a. The trans “hydrates” 6a and 7a have been prepared by warming 4a or 5a in alkaline aqueous solution at 60°C. The isomerization of 4a, 5a, 6a and 7a involved the opening of the pyrimidine ring at 1,6 position and subsequent keto-enolisation. The characterization of the configurations of “hydrates” is based on the specific formation of the enantiomeric forms of 6-hydroxy-5,6-dihydrothymine by radiation-induced degradation of 4a, 5a, 6a, 7a and 5,6-dihydrothymine 5S8b.     

Metabolites of fusidium coccineum

Nine cometabolites of the antibiotic fusidic acid (1a) have been identified. These include the fusidane derivatives (5a, 6a, 7a, 8a, 9a, 10a, and 12a), 7,8-dehydropseudofusidic acid (11a), and fusilactidic acid (13a).     

Steroide—XL: 16,17-azido- und 16,17-aminoalkohole des östra-1,3,5(10)-trien-3-methyläthers

The four epimeric azido alcohols of estra-1,3,5(10)-trien-3-methyl ether with nitrogen at C-16 and oxygen at C-17 were prepared by the following reactions: cleavage of the 16α,17α-epoxide 1 with sodium azide affords the 16β,17α-azido alcohol 2a. The analogous reaction of the 16β,17β-epoxide 4 gives the 17α,16β-azido alcohol 5a and the desired 16α,17β-azido alcohol 6a in low yield. 6a is obtained in a smooth reaction by substitution of the 16β,17β-bromohydrine 8 with sodium azide. Sodium borohydride reduction of the 16β-azido-17-ketone 9 yields the 16β,17β-azido alcohol 10a, reduction of 16α-azido-17-ketone 13 with lithium borohydride gives the 16α,17α-azido alcohol 14a. From the azido alcohols the corresponding amino alcohols 3a, 7a, 11a and 15a are prepared with hydrazine hydrate/Raney nickel. The amino alcohols give the acetic anhydride the corresponding acetylamino alcohols. The cis-amino alcohols 11a and 15a react with acetone to the corresponding oxazolidines 12 and 16.     

Synthesis,antimicrobial and anticancer activities of some new N-methylsulphonyl and N-benzenesulphonyl-3-indolyl heterocycles: 1st Cancer Update

A series of 1-(N-methyl 2a–c and N-benzenesulphonyl-1H-indol-3-yl)-3-aryl-prop-2-ene-1-ones 3a–c were prepared and allowed to react with urea, thiourea or guanidine and gave the pyrimidine derivatives 4a–c to 9a–c. Base catalyzed reaction of 2a–c or 3a–c with ethyl acetoacetate gave cyclohexanone derivatives 10a–c and 11a–c, respectively. Reaction of the latter compounds with hydrazine hydrate afforded indazole derivatives 12a–c and 13a–c, respectively. On the other hand, condensation of 2c or 3c with some hydrazine derivatives namely, hydrazine hydrate, acetyl hydrazine, phenyl hydrazine and benzyl hydrazine hydrochloride gave pyrazole derivatives 14a,b-17a,b, respectively. Moreover, reaction of 2c or 3c with hydroxyl amine hydrochloride gave isoxazole derivatives 18a,b. The newly synthesized compounds were tested for their antimicrobial activity and showed that, compounds 14a, 14b, 15a and 15b were found to be the most active ones of all the tested compounds toward Salmonella typhimurium (ATCC 14,028) compared to the reference drug chloramphenicol. Eighteen new compounds namely, pyrimidin-2(1H)-ones 4a–c and 5a–c, pyrimidin-2(1H)-thiones 6a–c and 7a–c and pyrimidin-2-amines 8a–c and 9a–c were tested for their in vitro cytotoxicity against human liver carcinoma (HEPG2), human breast cancer (MCF7) and human colon cancer (HCT-116) cell lines and showed that, compounds 4c, 5c, 6c, 8c and 9c were found to be the highly active compounds compared to the reference drug doxorubicin.     

Synthesis of azepane and nojirimycin iminosugars: the Sharpless asymmetric epoxidation of d-glucose-derived allyl alcohol and highly regioselective epoxide ring opening using sodium azide

The Sharpless asymmetric epoxidation of d-glucose-derived allyl alcohol 4 afforded α- and β-epoxides 5a and 5b in high stereoselectivity. The epoxide ring opening in 5a/5b was studied with different nucleophilic azido reagents, under various reaction conditions, and was found to be highly regioselective to give the preferential formation of 6-azido diol 6a/6b over 5-azido-diol 7a/7b. The 6-azido diol 6a/6b and 5-azido diol 7a/7b thus obtained were converted to the corresponding seven- and six-membered iminosugar, namely, azepane 1a/1b and 1-deoxy-nojirimycin 2a/2b.     

Dipole-dipole transfer between acetone solvates of chlorophyll a and chlorophyll a dihydrate dimers in water/acetone mixtures. A model for P680 sensitized excitation

We describe a simple model for P680 sensitized excitation in photosynthesis. Chl a fluorescence quenching effects observed when water is added to Chl a solutions in acetone are shown to be the result of resonant transfer between acetone solvates of monomeric Chl a, Chl a·Ac, and dimers of Chl a dihydrate. The presence of (Chl a·2H₂O)₂ is evidenced by a 678 nm difference absorbance (ΔA band obtained on conversion of a 680 nm absorption shoulder to polycrystalline Chl a precipitate, (Chl a·H₂O)_n. The equilibration between (Chl a·2H₂O)₂ and Chl a·Ac as a principal mechanism for Chl a·Ac fluorescence quenching is supported by theoretical fits of the data.     

Studies on Indian medicinal plants—XXXIX : Reinvestigation of the lactones and bromo derivative of betulinic acid

Isobornyloxy aluminium dichloride reduction of the ketolactone 2a of betulinic acid (1a) gave the axial alcohol 2b as the preponderant product. Hydroxylactone B of 1a therefore must have the equatorial OH function contrary to our previous conclusion. The so-called “hydroxylactone A” has been found to be the ring A rearranged product 3a. Reexamination of earlier work has shown that 1a yields a mixture of 2e and 5a in presence of HBr-AcOH, and a mixture of 2d and 3a with refluxing formic acid. Bromination of 1a affords 1e.     

Cabralea eichleriana dc. (meliaceae)—I structure and stereochemistry of wood extractives

From Cabralea eichleriana DC. (Meliaceae) nine compounds having a dammarane skeleton have been isolated and identified. They are cabraleone 2, ocotillone 3, cabraleadiol 4a, cabralealactone 5, cabraleahydroxylactone 6a, eichlerianic acid 7a, shoreic acid 8a, dammarenolic acid 9a and eichlerialactone 10a. The only limonoid present is fissinolide1. Compounds 7a and 10a are hereby reported for the first time as occurring in Nature. Configurations of ocotillone and cabraleone are revised and have been assigned 20S, 24S and 20S, 24R respectively.     

Novel pyrimidine and its triazole fused derivatives: Synthesis and investigation of antioxidant and anti-inflammatory activity

In the present study, we have carried out the synthesis of novel dihydropyrimidinecarbonitrile (1a–c), its dimethylated adduct (2a–c), and hydrazine derivative (3a–c) of 2a–c and its triazole fused derivatives (4a–c, 5a–c and 6a–c). The structure of newly synthesized compounds was confirmed by IR, ¹H NMR, mass spectral data and elemental analysis. Further the novel derivatives were investigated for their in vitro antioxidant and anti-inflammatory activity. The results revealed that some of the tested compounds showed potent antioxidant and anti-inflammatory activity. The mass spectral pattern of 6a has been investigated in order to elucidate the structure.     

Rearrangements of 3-heterobicyclo[3.2.0]hept-6-enes

Studies directed at a synthesis of dihydrothiepin 1b have resulted in the elucidation of several factors which effect cyclobutene ring opening in the 3-heterobicyclo[3.2.0]hept-6-ene ring system. We report the unexpected rearrangement of 4a, 4b, 13b and 13c to the synthetically useful a-vinyl-2,5-dihydrothiophenes 7a, 7b, 15a and 15b, respectively. Conversion of 4a to 6 is suggested to occur by a 1,3-rearrangement of 4a to isomeric 3-thiabicyclo[3.2.0]hept-6-ene 19 followed by cyclobutene ring opening in 19.     

Stereospecific conversion of cyclic phosphorothioates into chlorophosphates

The reaction of the individual diastereoisomeric cyclic phosphorothioates 2a, 2b in the trans-2,4,7-trioxa-3-phosphabicyclo (4.4.0) decane and 4a, 4b in the trans-2,4,7-trioxa-3-phosphabicyclo (4.3.0) nonane series with sulphuryl chloride affords the corresponding sulphenyl chlorides 5a, 5b, 6a, 6b with retention of the configuration of the phosphorus atom. The reaction of the latter with phosphorus trichloride leads stereospecifically to the chlorophosphates 7a, 7b, 8a and 8b with full retention of configuration at phosphorus.     

17α-Konfigurierte 20-methylpregnan-derivate

A mixture of 1a+1b (17α), obtained by C-17-epimerization of pregnenolone (1a) was converted into 3a+3b by Wittig-reaction. 3a+3b were acetylated to a mixture of 4a+4b, from which 4b was isolated by cristallization of 3a and following AgNO₃-chromatography of the mother-liquors. Δ²⁰⁽²²⁾ → Δ¹⁷-doublebond-isomerization occurs by hydrogenation (Pd/C) of 3a (17β) to give 5. Hydrogenation (Pt-catalyst) of 4b (17α) leads to 8b, which was converted into the 20-methylpregnane-derivatives 7b, 9b–13b. By comparison with the 17β epimers 1a–4a, 7a–13a a spectroscopic determination of the relative configuration on C-17 of 17-alkylsubstituted steroids was possible.     

1,4-Bis(phosphine)-2,5-difluoro-3,6-dihydroxybenzenes and their P-oxides: Syntheses, structures, ligating and electronic properties

Reactions of 1,4-difluoro-2,5-dimethoxybenzene with LDA (1:2) at low temperatures generated organodilithio intermediates; quenching the reaction mixtures with chlorophosphines ClPR₂ produced 1,4-bis(phosphino)-2,5-difluoro-3,6-dimethoxybenzenes 1a (R = Ph) and 1b (R = iPr). Demethylation of 1a–b was accomplished by BBr₃, yielding bis(phosphino)hydroquinones 2a–b. Treating 2a–b with excess hydrogen peroxide produced bis(phosphinyl)hydroquinones 3a–b. The binucleating properties of 2a were established by the formation of a bimetallic nickel complex upon reaction with Ph₂Ni(PMe₃)₂. Electrochemical activity of hydroquinones 2a–b and 3a–b was examined by cyclic voltammetry. In addition, compounds 2a, 3a and 3b were obtained in crystalline form and characterized by single-crystal X-ray diffraction. The influence of the fluorine substituents on the composition of the frontier orbitals of 2a and 3a was examined by computational methods.     

Synthesis, photophysical properties and sugar-dependent in vitro photocytotoxicity of pyrrolidine-fused chlorins bearing S-glycosides

Eight S-glycosylated 5,10,15,20-tetrakis(tetrafluorophenyl)porphyrins (1a′, 1b′, 1a and 1b (a: S-glucosylated, b: S-galactosylated)) and their 1,3-dipolar cycloadducts, i.e. chlorins 2a′, 2b′, 2a and 2b were prepared by nucleophilic substitution of the pentafluorophenyl groups with S-glycoside. These photosensitizers were characterized by ¹H, ¹³C and ¹⁹F NMR spectroscopies and elemental analysis. The photocytotoxicity of the S-glycosylated photosensitizers and the parent porphyrin (1) and chlorin (2) was examined in HeLa cells. Photosensitizers 1, 2, 1a′, 1b′, 2a′ and 2b′ showed no significant photocytotoxicity at the concentration of 0.5 μM, while the deprotected photosensitizers 1a, 1b, 2a and 2b were photocytotoxic. The strong inhibition by sodium azide of the photocytotoxicity of these photosensitizers suggested that ¹O₂ is the main mediator. The S-glucosylated photosensitizers 1a and 2a showed higher photocytotoxicity than S-galactosylated 1b and 2b, respectively. The cellular uptake of 1a and 2a increased up to 24 h, while that of 1b and 2b was saturated by 12 h.     

Synthesis of some alkoxy based bisthiadiazolines

The bisthiadiazolines 3a–3h built around the alkyl chains of varying lengths have been synthesized in good yields by refluxing bisthiosemicarbazones 2a–2h in acetic anhydride. The reactions of bisaldehydes 1a–1h with thiosemicarbazide in alcoholic medium provided 2a–2h and the former were obtained by using the reported methods. The formation and stereochemical features of the bisthiadiazolines 3a–3h are found to be independent of the internal spacer length. The intermediates 2a–2h and bisheterocyclic compounds 3a–3h have been characterized by means of IR, ¹H NMR, ¹³C NMR, Mass (ESI) and elemental analysis.     

Transformations photochimiques d'endoperoxydes dérivés d'hydrocarbures aromatiques polycycliques—I : Cas du photooxyde de diphényl-9,10 anthracène; obtention et propriétés du diépoxyde isomère

When irradiated at long wavelengths (λ ? 435 nm), the 9,10-endoperoxide of 9,10-diphenylanthracene 1a isomerizes to the 4a,10: 9,9a-diepoxide 4a, which can be isolated at low temperature. On warming at 20–25° c, 4a gives only the benzocyclobutenic diether 6a by electrocyclic ring opening and cyclisation, whereas under irradiation it undergoes, degradation to 10-hydroxy-10-phenyl-9-anthrone 7a and isomerizations to the bicyclic acetal 8a and to the benzofuro(3,2-b] benzofuran 9a. These transformations of 4a explain previous results obtained when irradiating 1a under various conditions; their mechanisms are discussed.     

Benzisoxazolium cations—II : Reaction with anthranilic acid: Intramolecular reaction of an N-aroyl-N-alkylsalicylamide

Reaction of 2-ethylbenzisoxazolium fluoborate (1) with anthranilic acid gives O-aroylsalicylamide (5a) and the quinazolone (6a), whose structure is established by an unambiguous synthesis of its methyl ether (6b). The O-aroyl amide (5a), formed via the ketoketenimine (Scheme 1) from the salt 1, undergoes O→N migration to the imide (8) which through an intramolecular reaction followed by dehydration is converted to the quinazolone 6a (Scheme 2). Independently the O-aroyl amide (5a) could be transformed to the quinazolone (6a) under basic conditions. The formation of quinazolone (6a) suggests the labile N-alkyl-N-aroyl isomer (8), which is expected to be in equilibrium with the O-aroyl isomer (5a), is captured. (Scheme 2).     

Steric constraints against [3,3]-sigmatropic rearrangement of allylic azides. A convenient approach to β-l-4-aminopent-2-enoglyceropyranosides

Starting from alkyl α-d-4-O-methanesulphonylpent-2-enoglyceropyranosides 13a–c, nucleophilic substitution carried out with polymer-supported azide ion led to regioisomeric mixtures of the azides 14a–c and 15a–c. An analogous result, due to a [3,3]-sigmatropic rearrangement, was observed starting from methyl α-d-hex-2-enoerythropyranoside derivatives 6a and 6b. On the contrary, starting from alkyl β-d-4-O-methanesulphonylpent-2-enoglyceropyranosides 21a–c, azides 22a–c were exclusively obtained, and subsequently converted into the corresponding amino derivatives 23a–c. The behaviour of β-anomers 21a–c was ascribed to steric interactions in the cyclic transition state, as supported by ab initio calculations.     

Copper and palladium complexes with N-heterocyclic carbene ligands functionalised with carboxylate groups

The new imidazolium salts functionalised with the trimethylsilyl ester group 1a–c, were easily obtained by quaternisation of alkyl- or aryl-imidazoles with trimethylsilyl bromoacetate. Salt 1a was isolated and fully characterised. It reacted with mesityl copper (Cu₅Mes₅) under trimethylsilyl abstraction to form the complex 2. Methanolysis of 1a–c gave good yields of the carboxylic acid functionalised imidazolium salts 3a–c. Deprotonation of the latter in liquid ammonia led to the zwitterionic imidazolium carboxylates 4a–c. Reaction of 4a with (Cu₅Mes₅) gave solutions from which the insoluble polymeric 5a crystallised slowly. Generation of the carboxylate-functionalised NHC in situ followed by reaction with Pd(OOCCH₃)₂ gave the new complex 6a in which the NHC-carboxylate ligand is chelate bidentate.     

Transformations thermiques des photooxydes meso des acenes—III: Dimeres de l'o-quinodimethane issu du photooxyde d'anthracene

Thermolysis of the anthracene photooxide 1a, in solution, can afford successively three dimers (I→II→III) the structures of which have been established by NMR and X-ray analysis for the first one. Their origin is the unstable o-quinodimethane diether 3a, coming from 1a by isomenzation, which at 80° dimerizes to 8a (dimer I) by an unusual [_π8_s+_π6_s] concerted cycloaddition. Above 110°, 8a isomerizes into 9a (dimer II) by a concerted [1,5] suprafacial sigmatropic migration. Finally, at higher temperature (~200°), both dimers are partly converted into the symetrical dimer 10a (dimer III), probably by a radical pathway. Thermolysis runned in presence of N-methylmaleimide show the non-reversibility of these reactions, giving two adducts, 15a and 16a, derived from 9a, the structures of which are deduced from NMR data. An explanation of the nature and high selectivity of the proceeding processes is given by considering orbital factors.