Phototransformations of Some 2-Substituted 4 H-Chromen-4-ones (4-Chromones) Related to the Antitumor Antibiotic Hedamycin

The 2-substituted 4 H-chromen-4-ones (4-chromones) 2 and 3 have epoxysubstituted side chains at C(2) resembling that of the antibiotic hedamycin (1). They were chosen as model compounds and subjected to photolysis either in the presence or in the absence of oxygen. The products obtained were isolated by repeated HPLC., and their structures were determined by spectroscopic methods, mainly ¹H- and ¹³C-NMR. Especially noteworthy are the oxygen dependent formation of the tertiary alcohols 11 and 12 as well as the transformation of the diepoxychromone 3 to the allylic alcohols 13 and 14 , the spiro compounds 15 and 16 , and the 2-ethylchromone 19 .     

Identification of the related substances of tilmicosin by liquid chromatography/ion trap mass spectrometry

Structures of seven impurities of the veterinary drug tilmicosin have been elucidated by multiple fragmentation with ion trap tandem mass spectrometry. All related compounds possess the main lactone ring of tilmicosin. The differences in their structures are due to the hydroxyl, mycaminose, 3,5-dimethylpiperidine and mycinose groups connected to C(3), C(5), C(6), C(14) of the lactone ring, respectively. The following compounds of the impurity profile of tilmicosin were identified: B - tilmicosin with a hydroxyl group at C(3); C - tilmicosin without a methyl group at the N-atom connected to C(3) of the mycaminose ring; D - tilmicosin with a hydroxyl group at C(6) of the mycaminose ring; E - tilmicosin with a methoxy group at C(3), F - desmicosin; G - 20-dihydrodesmicosin; and H - tilmicosin without a mycaminose ring. Isomers of the compounds B, C, D, E and H were identified by their mass chromatograms and retention times. The concentrations of the impurities varied in the range of 0.1% to 2.9%.     

First synthesis and isolation of the E- and Z-isomers of some new Schiff bases. Reactions of 6-azido-5-formyl-2-pyridone with aromatic amines

Some novel Schiff bases have been prepared by reacting 6-azido-5-formyl-2-pyridone 1 with a series of aromatic amines 2a-f. 5-Arylaminomethylene-6-(E)-aryl-iminopyridones 3a-e were obtained by reaction of 1 with 2a-e at room temperature, whereas with 2f, the 6-azido-5-naphthalen-2-yl-iminomethylpyridone derivative 4 was formed. On the other hand, heating 1 with 2a-d at 140-150 degrees C yielded two sets of isomeric products, (E)-3a-d and (Z)-5a-d. Refluxing compounds (Z)-3a,c with hydroxyl-amine in methanol gave the corresponding hydroxyliminopyridones 8a,c. Heating of (E)-3a-d with excess POCl3 at reflux did not give the expected tricyclic compound 9, but rather the isomeric products (Z)-5a-d were obtained. The structures of all these products have been characterized using IR and 1H- and 13C-NMR spectroscopy.     

Reaction modes and mechanism in indolizine photooxygenation reactions

Photooxygenations of 1,2-, 1,3-, and 2,3-di- and 1,2,3-trisubstituted indolizines 1a-1f under different reaction conditions in methanol and acetonitrile have been investigated to establish the general reaction pattern and mechanism in indolizine photooxygenation in view of the influence of the ring substituents and substitution pattern. Photooxygenations of 1-acyl-2-phenylindolizines 1a and 1b and 1,3-dibenzoyl-2-phenylindolizine (1d) are self-sensitized, while those of 1-(p-nitrobenzoyl)-2-phenylindolizine (1c) and 2-phenyl-3-(p-chlorobenzoyl)indolizine (1e) need to be sensitized by rose bengal (RB) or methylene blue (MB). These reactions proceed via a singlet oxygen mechanism yet follow different pathways in methanol and in acetonitrile, with peroxidic zwitterion D (in methanol) and dioxetane E across the indolizine C2-C3 bond (in acetonitrile) as the intervening intermediates. Methanol trapping of the peroxidic zwitterion results in C3-N bond cleavage and pyrrole ring opening to give the corresponding (E)- and (Z)-3-(2-pyridinyl)-3-benzoylpropenoic acid methyl esters (2 and 3) and 4-(2-pyridinyl)-3-phenyl-5-aryl-5-hydroxyfuran-2-one (4) as products in methanol, while O-O bond homolysis of the dioxetane furnishes 3-(2-pyridinyl)-3-benzoyl-2-phenyloxirane-2-carboxaldehyde (6) and 1-(6-methyl-2-pyridinyl)-2-phenylethanedione (5) as products in acetonitrile. 3-Benzoyl-1-indolizinecarboxylic acid methyl ester (1f) is unreactive toward singlet oxygen; however, it could be photooxygenated under electron transfer conditions with 9,10-dicyanoanthracene (DCA) as a sensitizer. This reaction takes place by the combination of the indolizine cation radical with the superoxide anion radical (or molecular oxygen) to give the pyridine ring oxidized methyl 3-benzoyl-5-methoxy-8-hydroxy-1-indolizinecarboxylate (9f), dimethyl 2-(2-pyridinyl)fumarate (8f), and dimethyl 2-(2-pyridinyl)maleate (7f) as products.     

The structure of the antibiotic hedamycin—III : C NMR spectra of hedamycin and kidamycin

The ¹³C NMR spectra of hedamycin, kidamycin and some of their derivatives have been fully assigned. Proton coupling constants and ¹³C NMR acetylation shifts indicate that the conformations of the highly substituted tetrahydropyran rings in solution are chair forms for ring E, as well as for ring F in isokidamycins, but a twist form for ring F in hedamycins and kidamycins.     

On the Products of Cholesterol Autoxidation in Phospholipid Bilayers and the Formation of Secosterols Derived Therefrom

In homogenous solution, cholesterol autoxidation leads to a mixture of epimers of 5 primary products, whose concentrations vary in the presence/absence of antioxidants, such as vitamin E. Two of the products (5α‐OOH and 6β‐OOH) undergo Hock fragmentation to yield electrophilic secosterols implicated in disease. Herein, we show that the product distribution is similar in phospholipid bilayers, in that the 7‐OOHs are the major products, but the presence/absence of vitamin E has no effect on the distribution. Cholesterol 7α‐OOH, but not 7β‐OOH, undergoes Hock fragmentation to yield a mixture of unprecedented A‐ring cleavage products and 6,7‐epoxides. When subjected to typical derivatization conditions, 7α‐OOH yields products with essentially indistinguishable chromatographic and spectroscopic features from the previously identified secosterols, casting further doubt on their controversial origin from endogenous O₃.     

Generation of 1-aryl-3-methoxycarbonylnitrilimines and their reactions with unsaturated hydrocarbons

Thermolysis of 1-(4-methoxyphenyl)- and 1-(4-fluorophenyl)heptamethoxycarbonyl-3a,7a-dihydroindazoles at 135?C140 °C resulted in the elimination of hexamethyl benzenehexacarboxylate and in the generation of 1-aryl-3-methoxycarbonylnitrilimines, which were trapped by alkenes and dienes to give the corresponding (1) pyrazolines via 1,3-dipolar cycloaddition and (2) 2-oxoalken-1-oic acid hydrazones via allylic proton migration to the nitrogen atom. The reaction with tetramethylethene unexpectedly yielded substituted 5-(1-hydroxy-1-methylethyl)- or 5-acetylpyrazolinecarboxylates as the main products. The formation of the latter compounds suggests initial abstraction of the H atom from tetramethylethene and probable participation of a water molecule that supplies one more oxygen atom to the reaction products.     

HPLC and 1H-NMR Studies of Alkaline Hydrolysis of Some 7-(Oxyiminoacyl)cephalosporins

Alkaline hydrolysis (pH 10.5) of the three 7-(oxyiminoacyl)cephalosporins 1a–c (cefuroxime, ceftazidime, and ceftriaxone) was studied at 37° using HPLC and ¹H-NMR techniques. The 7-epicephalosporin 2 , the 3-methylidene compound 3 , and the 6-epimer 4 of the 3-methylidene compound 3 were identified for each cephalosporin as the major degradation products under the conditions used; ceftazidime ( 1b ) yielded also the Δ²-isomer 5b (Scheme 1). A kinetic scheme was developed to account for the production of these compounds, and the different kinetic constants involved in the process were calculated. The experimental results show that the presence of a pyridinio group at position C–C(3) favours the appearance of the Δ²-isomer, which was detected mainly in cephalosporins bearing an ester function at C(4). The presence of an oxyimino group at C? CONH? C(7) facilitates epimerization at C(7) (→ 2 ), whereas that of an electron-withdrawing group at C? C(3) results in a increased formation constant for the 3-methylidene compound 3 . The 3-methylidene compounds 3a–c produced by the three cephalosporins on cleavage of the β-lactam ring all underwent epimerization at C(6) to yield the corresponding 6-epimer 4 .     

Spectroscopic characterization of the 1-substituted 3,3-diphenyl-4-(2'-hydroxyphenyl)azetidin-2-ones: application of (13)C NMR, (1)H-(13)C COSY NMR and mass spectroscopy

The article deals with spectroscopic characterization of azetidin-2-ones. The presence of substituents like hydroxyl, fluoro, methoxy and benzhydryl, etc., on the azetidin-2-one ring significantly affects the IR absorption and (13)C NMR frequencies of the carbonyl group present in these compounds. The presence of an ester carbonyl group or too many methine protons in the molecule has been observed to limit the scope of IR and (1)H NMR spectroscopy in unambiguous assignment of the structure. The application of (13)C NMR, 2D NMR ((1)H-(13)C COSY) and mass spectroscopy in characterization of complex azetidin-2-ones is discussed. An application of the latter two techniques is described in deciding unequivocally between an azetidin-2-one ring and chroman-2-one ring structure for the product obtained by treatment of the 1-substituted 3,3-diphenyl-4-[2'-(O-diphenylacyl)hydroxyphenyl]-2-azetidinones with ethanolic sodium hydroxide at room temperature.     

(±)-12-乙基-13-甲氧基-8,11,13-罗汉松三烯-7-酮和(±)-12-乙基-13-甲氧基-8,11,13-罗汉松三烯的全合成

以α-环柠檬醛(1)为A环合成子,以季盐(2)为C环合成子,经缩合及分子内环化反应得到关键中间体(5).为引入乙基,进行了Friedel-Crafts反应和脱氧反应等,共经7步反应得到了(±)-12-乙基-13-甲氧基-8,11,13-罗汉松三烯-7-酮[(±)-nimbonone](9)及(±)-12-乙基-13-甲氧基-8,11,13-罗汉松三烯(10).     

Photochemische Reaktionen. 83. Mitteilung. Verbindungen der 3,4-Dihydrojonon-Reihe als Modelle zur Photochemie γ, δ- bzw. δ, ϵ-ungesättigter Ketone und Aldehyde

Compounds of the 3,4-dihydro-ionone series as models for the photochemistry of γ, δ- and δ,?- unsaturated ketones and aldehydes . The photochemistry of γ, δ- and δ,?-unsaturated carbonyl compounds of the dihydro-ionone series has been studied, with special attention to the investigation of oxetane formation versus hydrogen abstraction. UV.-irradiation of the dihydro-β-ionone compounds with structure A ( 1 , 7 , 14 , 18 , 24 , 29 ) led to isomeric ethers with structures B ( 2 , 8 , 15 , 19 , 25 , 30 ), C ( 3 , 9 , 16 , 20 , 26 , 31 ) and D ( 4 , 21 , 27 ), isomeric bicyclic alcohols with structure E ( 5 , 10 , 17 , 22 , 28 ), and photoreduction products with structure F ( 6 , 11 , 12 , 13 ). Photolysis of dihydro-γ-ionone ( 32 ) gave a complex mixture containing fragmentation product 35 , hydrocarbon 36 , β-ambrinol ( 34 ), oxetane 33 , as well as dihydro-β-ionone ( 1 ) and three of its photoproducts ( 2 , 3 , 5 ). The dihydro-α-ionone compounds 37 and 40 gave mixtures of fragmentation products and the oxetanes 38 and 41 . Irradiation of the side-chain homologues 42 and 45 yielded 43 , which photo-cyclizes to 44 . In contrast, 3 , 4 -dihydro-3′,4′-dehydro-β-ionone ( 46 ) gave merely the isomeric open-chain triene-ketone 47 . The structures assigned to the ethers 2 , 3 , 33 , 38 and to the alcohols 5 , 10 , 13 could be confirmed by chemical reactions and mutual interconversions. The structure of the ether 21 had to be established by X-ray analysis, details of which are described. A novel intramolecular hydrogen transfer is involved in formation of ethers B . The photocyclization A → D probably proceeds by addition of the carbonyl-C atom to the double bond ( A → h ), followed by methyl (1 → 2)-shift ( h → i ). Process A → h may also be involved in formation of compounds of type C and E .     

The synthesis, structure and properties of N-acetylated derivatives of ethyl 3-amino-1H-pyrazole-4-carboxylate

Ethyl 3-amino-1H-pyrazole-4-carboxylate (1) was yielded through total synthesis and reacted with acetic anhydride to give the acetylated products 2-6. Compounds 1-6 were studied with HPLC, X-ray, FT-IR, (1)H-NMR, (13)C-NMR and MS. Acetylation was carried out in solvents of various polarity, namely; chloroform; dioxane; DMF; acetic anhydride, at room temperature and at boiling points; and in the presence and absence of DMAP. The acetylated products are mainly nitrogen atoms in the ring. The position of the ring proton in the solution was based on NOESY; multinuclear HMBC, HSQC spectra and calculations. For equivalent amounts (1-1.5 mol) of acetic anhydride at room temperature two products of monoacetylation are produced in the ring: 2 and 3, ca. 2 : 1 and at the same time only small amount of the third product of monoacetylated, 5 in DMF, as well the product diacetylated, 4. The greatest amount of the product 4 is produced during the reaction with chloroform. However, in this solvent and in dioxane no product 5 is produced. Compound 2 is, largely, formed in dimethylformamide, in the presence DMAP, 0.2 eq. In the presence of this catalytic base, for the first hour, there is a mixture 2 and 3 to the ratio ca. 95 : 5. With 8 eq of Ac(2)O at reflux, after another hour, the compounds 3, 4 and 6 appear about equal amounts. After a longer time, the compound, which appears most in this mixture is triacetylated derivative 6. The structural and spectroscopic characteristics of compounds 1-6 have been given and the methods for their preparation have been provided.     

Solution 1H NMR characterization of axial interactions of the proximal and distal His in the cyanomet complexes of the isolated chains and the 65 kDa intact tetramer of human hemoglobin A.

Solution 1H NMR has been used to investigate the axial bonding of the proximal His and the hydrogen-bonding of the distal His to the bound ligand in the isolated chains as well as the subunits of intact, tetrameric, cyanomet human hemoglobin A. The complete proximal His, including all ring protons necessary to monitor bonding in each subunit, could be definitively assigned by 1D/2D methods despite the large size (approximately 65 kDa) and severe relaxation (to T(1) approximately 3 ms, line width approximately 1.5 kHz) of two of the protons. The complete distal His E7 ring was assigned in the alpha-chain and alpha-subunit of HbA, and the dipolar shifts and relaxation were analyzed to reveal a disposition intermediate between the positions adopted in HbCO and HbO2 that is optimal for forming a hydrogen bond with bound cyanide. The lability of the alpha-subunit His E7 NepsilonH is found to be similar to that in sperm whale cyanomet myoglobin. The orientation of the distal His E7 in the beta-subunit is found to be consistent with that seen in either HbCO or HbO2. While the His E7 labile NepsilonH proton signal could not be detected in either the beta-chain or subunit, it is concluded that this more likely reflects increased lability over that of the alpha-subunit, and not the absence of a hydrogen bond to the bound ligand. Analysis of the heme mean methyl hyperfine shift, which has been shown to be very sensitive to the presence of distal hydrogen bonds to bound cyanide (Nguyen, B. D.; Xia, Z.; Cutruzzolá, F.; Travaglini Allocatelli, C.; Brancaccio, A.; Brunori, M.; La Mar, G. N. J. Biol. Chem. 2000, 275, 742-751), directly supports the presence of a distal His E7 hydrogen bond to cyanide in the beta-chain and beta-subunit which is weaker than the same hydrogen bond in the alpha-subunit. The potential for the proximal His hyperfine shifts in serving as indicators of axial strain in the allosteric transition of HbA is discussed.     

Reaction of oligomethylene di(3-oxobutanoate) with 1,1-disubstituted alkenes and molecular oxygen in the presence of manganese(II and/or IE) acetate

The reactions of 1,1-disubstituted ethenes with oligomethylene di(3-oxobutanoate) in the presence of manganese(II and/or III) acetate and atmospheric oxygen yielded an ω-(3-oxobutanoyloxy)alkyl 6,6-diaryl-3-hydroxy-3-methyl-1,2-dioxane-4-carboxylate, oligomethylene di(6,6-diaryl-3-hydroxy-3-methyl-1,2-dioxane-4-carboxylate)s, ω-hydroxyalkyl 6,6-diaryl-3-hydroxy-3-methyl-1,2-dioxane-4-carboxylates, an ω-(3-oxobutanoyloxy)alkyl 5,5-diaryl-2-methyl-4,5-dihydrofuran-3-carboxylate, oligomethylene di(5,5-diaryl-2-methyl-4,5-dihydrofuran-3-carboxylate)s, ω-hydroxyalkyl 5,5-diaryl-2-methyl-4,5-dihydrofuran-3-carboxylates, and an ohgomethylene diester bearing a substituted 1,2-dioxane ring and a substituted 4,5-dihydrofuran ring. The reaction of the 1,2-dioxan-3-ols with acid gave the corresponding compounds bearing furan rings. The reaction of 1,1,6,6-tetraaryl-1,5-hexadienes with oligomethylene di(3-oxobutanoate) in the presence of manganese(III) acetate yielded macrocyclic diesters bearing two 4,5-dihydrofuran rings.     

Skeletal rearrangements resulting from reactions of 1,6:2,3- and 1,6:3,4-dianhydro-β-D-hexopyranoses with diethylaminosulphur trifluoride

A complete series of eight 1,6:2,3- and 1,6:3,4-dianhydro-β-D-hexopyranoses were subjected to fluorination with DAST. The 1,6:3,4-dianhydropyranoses yielded solely products of skeletal rearrangement resulting from migration of the tetrahydropyran oxygen (educts of D-altro and D-talo configuration) or of the 1,6-anhydro bridge oxygen (D-allo, D-galacto). The major products yielded by the 1,6:2,3-dianhydropyranoses were compounds arising from nucleophilic substitution, with configuration at C4 either retained (D-talo, D-gulo) or inverted (D-manno), or from C6 migration (D-allo). The minor products in the 1,6:2,3-series resulted from migration of the tetrahydropyran oxygen (D-gulo) or the oxirane oxygen (D-manno), or from nucleophilic substitution with retention of configuration (D-manno). The structure of most of the rearranged products was verified by X-ray crystallography.     

Access to the noryohimban [6,5,6,5,6] ring system via an intramolecular furan Diels-Alder reaction

Polycyclic indolic compounds containing the [6,5,6,5,6] ring system were prepared via an intramolecular furan Diels-Alder reaction of α,β-unsaturated amides generated by the N-acylation of 1-(2-furyl)-β-tetrahydrocarbolines. This chemistry can provide access to D(14)-noryohimban derivatives by exploiting the functionality on the C,D,E ring system of the corresponding cycloadducts.     

Drüsenfarbstoffe aus tropischen Labiaten: Parviflorone aus Plectranthus strigosus BENTH.

Red-Coloured Abietanoids from Leaf-Glands of Plectranthus strigosus BENTH . Chromatographic examination of the red-coloured diterpenoids from the South-African title plant yielded the following compounds: parviflorone A(1) , parviflorone B (2) , parviflorone C(3) , parviflorone E (4) parviflorone D (5) , parviflorone F (6) , parviflorone G (7) , and parviflorone H (8) . Compounds 7 and 8 represent new variants of these quinone methides.     

Cycloalkylations of N-(ω-Halogenoalkyl)-substituted Macrocyclic Imides

With ω-halogenoalkyl isocyanates, 2-oxocyclododecane-l-carbonitrile is transformed under ring enlargement to 1-(ω-halogenoalkyl)-2,14-dioxo-1-azacyclotetradecane-3-carbonitriles. In the presence of base, these products undergo O- or C-alkylation leading to bicyclic compounds. The C-alkylation product 7 undergoes solvolysis to form a sixteen-membered ring compound.     

A further study of the cytotoxic constituents of a milnamide-producing sponge

A reinvestigation of Auletta sp. yielded the novel compound milnamide C (3) plus the known compounds milnamide A (1), milnamide B (hemiasterlin) (2), jasplakinolide (5), and geodiamolides A (6), D (7), E (8), and G (9). The isolation work was guided by cytoskeletal bioactivity data. Compounds 2 and 3 were shown to cause microtubule depolymerization, and 6-9 were shown to cause microfilament disruption. This biological activity and the structural elucidation of 3, including X-ray analysis, are reported here. [structure: see text]     

THE PHOTOCHEMISTRY OF p-AMINOBENZOIC ACID

We have studied the photoreactions occurring when p-aminobenzoic acid (PABA), a component of some sunscreens, is irradiated in aqueous solution. These studies were carried out in the presence and absence of oxygen, using light of lambda = 254 nm as well as light of wavelengths greater than 290 nm. In deoxygenated solution between pH 7.5 and 11.0, we found two photoproducts that were identified as 4-(4'-aminophenyl)aminobenzoic acid (I) and 4-(2'-amino-5'-carboxyphenyl)aminobenzoic acid (V); we used 1H and 13C NMR, electron impact mass spectrometry and synthesis by an independent route to identify each of these compounds. Rapid discoloration of the photolyzed sample was observed when PABA was irradiated in aerated solution. Although a number of products were detected under these conditions, the three most abundant stable compounds have been isolated and identified as 4-amino-3-hydroxybenzoic acid, 4-aminophenol and 4-(4'-hydroxyphenyl)aminobenzoic acid (IV). The latter compound was shown to result from rapid photo-induced oxidation of I in the presence of oxygen. Even in the presence of trace amounts of oxygen, the yield of I was significantly reduced in favor of IV. Studies of the thermal oxidation of I, coupled with evidence gathered from studies of the photochemistry of incompletely deoxygenated PABA solutions, indicate that 4-(2,5-cyclohexadien-4-one)iminobenzoic acid (III) is an intermediate on the pathway between I and IV. Qualitatively, we found that the photochemical reactions resulting from irradiation of PABA solutions with lambda = 254 nm light and light with lambda greater than 290 nm were the same. The quantum yields for formation of I and V are highly pH dependent, both being less than 10(-4) at pH 7 and rising steadily to values greater than 10(-3) at pH 11. The detailed pH dependence suggests that the deprotonated PABA radical cation may be an important intermediate entering into the reactions forming I and IV.