Lipase-mediated kinetic resolution of rigid clofibrate analogues with lipid-modifying activity

The lipase-catalysed kinetic resolution of methyl esters of (±)-5-chloro-2,3-dihydro-1-benzofuran-2-carboxylic acid, (±)-6-chloro-2,3-dihydro-4H-1-benzopyran-2-carboxylic acid, and (±)-6-chloro-2,3-dihydro-4H-1-benzopyran-3-carboxylic acid, rigid analogues of clofibrate, was effected with fair to moderate enantioselectivities (E=1.0–4.8), enantiomeric excesses of up to 86% and workable reaction rates. Enantiomerically pure (R)- and (S)-5-chloro-2,3-dihydro-1-benzofuran-2-carboxylic acids were obtained by fractional crystallisation of the diastereomeric salts of the corresponding racemic acid with (+)- and (−)-amphetamine from ethanol; the absolute configuration of the products were established by chemical correlation.     

Two pairs of enantiomeric neolignans from Lobelia chinensis

A pair of new enantiomeric neolignans, ethyl 3-[(2R,3S)-2-(4-hydroxy-3-methoxyphenyl)-3-(hydroxymethyl)-7-methoxy-2,3-dihydro-1-benzofuran-5-yl] propanoate (+) (1) and ethyl 3-[(2S,3R)-2-(4-hydroxy-3-methoxyphenyl)-3-(hydroxymethyl)-7-methoxy-2,3-dihydro-1-benzofuran-5-yl] propanoate (-) (1), together with a pair of known enantiomeric neolignans (+) (2) and (-) (2), as well as five known lignans (3-7) were isolated from the ethanol extract of Lobelia chinensis. Their structures were elucidated on the basis of extensive spectroscopic analyses, including 1D and 2D NMR, HR-ESI-MS and CD spectra.     

Expeditious synthesis of 2,3-dihydro-2-alkoxy-3-methylenebenzofurans from N-benzofuran-3-ylmethyl N,N,N-trialkylammonium bromides: a new approach to access the natural product, 2-hydroxy-3-methylene-6-methyl-2, 3-dihydrobenzofuran

A highly efficient strategy was developed to construct a natural product-based library of 2-alkoxy-3-methylene-2,3-dihydrobenzofurans from N-benzofuran-3-ylmethyl N,N,N-trialkylammonium bromides.     

Condensed diazepines. synthesis of 1-aryl-3,5-dihydro-4H-1-benzofuro-[2,3-<Emphasis Type="Italic">d</Emphasis>][1,2]diazepin-4-ones

The cyclocondensation of (2-aroyl-1-benzofuran-3-yl)acetic acids and their methyl esters with hydrazine hydrate under various experimental conditions has been studied. Optimal conditions have been found for obtaining 1-aryl-3,5-dihydro-4H-1-benzofuro[2,3-d][1,2]diazepin-4-ones.     

Synthesis of Some New Thieno[2,3-b]pyridines,Pyrimidino[4′,5′:4,5]thieno[2,3-b]-pyridines,and 2,3-Dihydro-1,3,4-thiadiazoles

Thieno[2,3-b]pyridines were synthesized from 6-benzofuran-2-yl-4-phenyl-2-sulfanylpyridine-3-carbonitrile and each of chloro acetone, ethyl chloroacetate, ω -bromoacetophenone, and chloroacetonitrile. These compounds were conveniently converted into novel pyrido[4′,5′:4,5]thieno[3,2-d]pyrimidines. Also, 2,3-dihydro-1,3,4-thiadiazole was synthesized from hydrazonoyl halides and 2-benzofuran-2-yl-3-(phenylamino)-3-thioxopropanenitrile. The structures of the products have been elucidated by elemental analyses, spectral data studies, and alternative syntheses whenever possible. The newly synthesized compounds were tested towards microorganisms.     

Polynucleotide analogues. VI. Synthesis and characterization of alternating copolymers of maleic anhydride and dihydropyran containing guanine derivatives

2-Amino-6-chloropurine was reacted with 2-(tosyloxymethyl)-2,3-dihydro-2H-pyran to give 2-(2-amino-6-chloropurin-9-ylmethyl)-2,3-dihydro-2H-pyran ( 3 ) and its N⁷-isomer ( 4 ), which were treated with 5% aqueous trimethylamine to result in 2-(guanin-9-ylmethyl)-2,3-dihydro-2H-pyran ( 5 ) and its N⁷-isomer ( 6 ), respectively. 2-(N²-Acetylguanin-9-yl-methyl)-3,4-dihydro-2H-pyran ( 7 ) and 2-(N²-acetylguanin-7-ylmethyl)-3,4-dihydro-2H-pyran ( 8 ), obtained by acetylation of compounds 5 and 6 , were copolymerized with maleic anhydride to give the alternating copolymers 9 and 10 , and they were hydrolyzed to result in poly[ {2-(guanin-9-ylmethyl)tetrahydropyran-5,6-diyl} {1,2-dicarboxyethylene}] ( 11 ) and poly[ {2-(guanin-7-ylmethyl)tetrahydropyran-5,6-diyl} {1,2-dicarboxyethylene}] ( 12 ), re-spectively. Polymer 11 showed hypochromicity whereas 12 exhibited hyperchromicity in aqueous solutions. Polymers 11 and 12 in aqueous solutions showed very strong excimer fluorescence with the maximum intensities at 432 and 446 nm, respectively, at room tem-perature. The two polymers showed polyelectrolyte effects, e.g., very high GPC molecular weights as well as reduced viscosities at low concentrations in water. Normal behavior was retained by addition of inorganic salts. Sodium salts of polymers 11 and 12 migrated to the anode by electrophoresis and both showed two bands. © 1995 John Wiley & Sons, Inc.     

A Regioselective Synthesis of Novel Functionalized Organochalcogen Compounds by Chalcogenocyclofunctionalization Reactions Based on Chalcogen Halides and Natural Products

The regioselective synthesis of novel functionalized condensed organochalcogen compounds by chalcogenocyclofunctionalization reactions based on chalcogen halides and the natural products thymol and carvacrol has been developed. The reactions of selenium dibromide with allyl thymol and allyl carvacrol proceeded in methylene chloride at room temperature in the presence of NaHCO₃ affording bis[(7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl] and bis[(4-isopropyl-7-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl] selenides in 90–92% yield. Similar sulfides were obtained in 70–72% yields by the reaction of sulfur dichloride in chloroform under reflux. Trihalotellanes containing the same organic moieties were synthesized from allyl thymol, allyl carvacrol and tellurium tetrachloride or tetrabromide in quantitative yields. Corresponding functionalized ditellurides were prepared in 91–92% yields by the reduction of the trichlorotellanes with sodium metabisulfite in two-phase solvent system. The comparison of reactivity of sulfur, selenium and tellurium halides in chalcogenocyclofunctionalization and distinguishing features of each reaction were discussed.     

Electron impact mass spectrometry of some 2,3-dihydro-1-benzofuran-3-acetic acids

The mass spectrometric behaviour of four 2,3-dihydro-1-benzofuran-3-acetic acids has been studied in detail with the aid of exact mass measurements, linked scans, collisionally activated decomposition, mass analysed ion kinetic energy spectra and labelling experiments. Unusual fragmentation pathways are emphasized for which mechanisms are proposed.     

Reaction of Dimethyl Sulfoxide with 4-Acyloxycoumarins

Dimethyl sulfoxide converts 4-acetoxycoumarin (1) exclusively to 2-(2-hydroxybenzoyl)-2-[(methylthio)methyl]-2,3-dihydro-4 H-furo[3,2-c]chromen-4-one (3) at 180°C under a nitrogen atmosphere, but in the absence of nitrogen, the products obtained are dicoumarol and its dehydrative cyclization products 7 H-bis[1]benzopyrano[4,3-b: 3′,4′-c]pyran-6,8-dione (9) and (3). Under similar conditions, 4-benzoyloxycoumarin (1a) affords benzoic acid, 4-hydroxy-3-({2-[(methylthio)methyl]-3-oxo-2,3-dihydro-1-benzofuran-2-yl}methyl)-2H-chromen-2-one (7), and 3-(2-hydroxybenzoyl)-3,4-dihydro-2H,5H-pyrano[2,3-b] chromen-5-one (8).     

Unexpected course of rearrangement of substituted S-(1(3H)-isobenzofuranone-3-yl)isothiuronium bromides

Three series of S-(1(3H)-isobenzofuranone-3-yl)isothiuronium bromides differing in substitution at the isothiuronium moiety (none, one or two methyl groups) and at the benzene ring were prepared and characterized. These salts were then treated with various bases (acetate, triethylamine, Na₂CO₃) to give either 1-hydroxy-3-oxo-1,3-dihydro-2H-isoindol-2-carbothioamides or the product of S to N isobenzofuranone-3-yl migration, i.e., 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thioureas. If ammonia was used in reaction with N,N′-dimethyl isothiuronium salts then 3-hydroxy-2,3-dihydro-1H-isoindol-1-ones were formed together with 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thioureas in parallel reaction with the yields increasing with ammonia concentration. The formation of isoindolones takes place in two steps with an aldehyde intermediate, which can be trapped with N,N-dimethylhydrazine.     

Studies on quinazolinones. 2. Synthesis of 2-(4-benzylpiperazin-1-ylmethyl)-2,3-dihydro-5H-oxazolo[2,3–6]quinazolin-5-one and -2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one

To search for novel antihypertensive heterocycles in the condensed quinazoline series, two representative compounds were synthesized via a suitable reaction sequences. Treating anthranilonitrile with allyl isocyanate gave 2-(allylureido)benzonitrile ( 10 ) in a quantitative yield. Compound 10 was cyclized to 3-allylquinazoline-2(1H, 4(3H)-dione ( 11 ). Bromination of 11 in carbon tetrachloride converted it into the corresponding 3-(2,3-dibromopropyl) derivative ( 12 ) in 92% yield. Ring closure of 12 was effected by the action of alkali to afford 2-bromomethyl-2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-one ( 13 ). The title compound, 2-(4-benzylpiperazin-1-ylmethyl)-2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-one ( 7 ) could be obtained by a reaction of either 12 or 13 with 1-benzylpiperazine respectively. Starting from the readily available 3-allyl-2H-thioxoquinazolin-4(3H)-one ( 16 ) via the analogous reactions gave the 2-bromomethyl-2,3-dihydro-5H-thiazolo[2,3-b]-quinazolin-5-one ( 19 ) in good yield. However, the reaction of 19 with 1-benzylpiperazine provided another target compound, 2-(4-benzylpiperazin-1-ylmethyl)-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one ( 8 ) only in poor yield (8%). As major product, the dehydrobrominated compound, 2-methylene-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one ( 22 ) was isolated. A preliminary pharmacological evaluation revealed that both compounds 7 and 8 are devoid of the antihypertensive activity.     

Isolation of tetraprenyltoluquinols from the brown alga Sargassum thunbergii

Thunbergols A (4) and B (5), tetraprenyltoluquinols, along with three known compounds (1-3) have been isolated from the brown alga Sargassum thunbergii. The structures of these two new compounds were determined to be 9-(3,4-dihydro-2,8-dimethyl-6-hydroxy-2H-1-benzopyran-2-yl)-6-methyl-2-(4-methyl-3-pentenyl)-(2E,6E)-nonadienoic acid (4) and 10-(2,3-dihydro-5-hydroxy-7-methyl-1-benzofuran-2-yl)-10-hydroxy-6-methyl-2-(4-methyl-3-pentenyl)-(2E,6E)-undecadienoic acid (5), respectively, by combined spectroscopic methods. Both of them exhibited significant scavenging activities on radical and potently inhibited generation of ONOO(-) from morpholinosydnonimine (SIN-1).     

3-Hydroxydihydrobenzofuran glucosides from Gnaphalium polycaulon

A new 3-hydroxydihydrobenzofuran glucoside, gnaphaliol 9-O-β-D-glucopyranoside (2), was isolated from the aerial parts of Gnaphalium polycaulon together with 1-{(2R*,3S*-3-(β-D-glucopyranosyloxy)-2,3-dihydro-2-[1-(hydroxyl methyl)vinyl]-1-benzofuran-5-yl}-ethanone or gnaphaliol 3-O-β-D-glucopyranoside (1), (Z)-3-hexenyl O-β-D-glucopyranoside (3) and adenosine (4). The absolute configurations at C-2 and C-3 positions of compound 1 were determined to be 2R and 3R. The structures of these compounds were elucidated on the basis of their physical and spectroscopic data.     

Novel routes to 1-aryl-1,4-dihydro-3(2H)-isoquinolinones and 2-substituted or 2,3-disubstituted benzofurans by intramolecular cyclizations

N-(α-Benzotriazolylalkyl)arylacetamides, readily available from an arylacetamide, an aldehyde and benzotriazole, undergo intramolecular cyclization under acidic conditions to give 1-aryl-1,4-dihydro-3(2H)-isoquinolinones in good to excellent yields. Similarly, 2-(benzotriazol-1-yl)-2-(o-hydroxyphenyl)ethanols, obtained by lithiation of 2-(benzotriazol-1-ylmethyl)phenols followed by quenching with aldehydes or ketones, eliminate a molecule of water and a molecule of benzotriazole yielding 2-substituted and 2,3-disubstituted benzofurans.     

Energetic and conformational changes upon complexation of gelatin with sodium dodecyl sulfate

The effect of sodium bis(2-ethylhexyl)sulfosuccinate/isooctane/water microemulsions on the stability of 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl methylcarbamate (carbofuran, CF), 3-hydroxy-2,3-dihydro-2,2-dimethylbenzofuran-7-yl methylcarbamate (3-hydroxycarbofuran, HCF) and 3-keto-2,3-dihydro-2,2-dimethylbenzofuran-7-yl methylcarbamate (3-ketocarbofuran, KCF) in basic media has been studied. The presence of these microheterogeneous media implies a large basic hydrolysis of CF and HCF on increasing surfactant concentration and, also, on increasing water content in the microemulsion. The hydrolysis rate constants are approximately 2- and 10-fold higher than those in pure water for HCF and CF, respectively. In contrast, a steep descent in the rate of decomposition for KCF was observed. These behaviours can be ascribed to the presence of CF derivatives both in the hydrophilic phase and in the lipophilic phase, while the hydroxyl ions are only restricted to the water pool of the microemulsion (hydrophilic phase). The kinetic rate constants for the basic hydrolysis in AOT-based microemulsions have been obtained on the basis of a pseudophase model. Taking into account that an important part of soils are colloids, the possibility of the presence of restricted water environments implies that soil composition and its structure will play an important role in the stability of these carbamates. In fact, we observed that the presence of these restricted aqueous media in the environment, in particular in watersheds and in wastewaters, could reduce significantly the half-life of these pesticides (33% and 91% for HCF and CF, respectively).     

A new method for the synthesis of novel 1-aryl-3-heteroaryl-1H-pyrazolo[3,4-b]quinoxalines

The reaction of 3-(2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline 4 with o-chlorobenzenediazonium chloride gave 3-[α-(o-chlorophenylhydrazono)-2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-ylmethyl]-2-oxo-1,2-dihydroquinoxaline 6 , whose refluxing in phosphoryl chloride/pyridine afforded 1-(o-chlorophenyl)-3-(2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-yl)-1H-pyrazolo[3,4-b]quinoxaline 7. The reactions of 6 and 7 with nitrous acid resulted in sulfur extrusion to provide 1-(o-chlorophenyl)-3-(4-methyl-4H-1,2,4-triazol-5-yl)1H-pyrazolo[3,4-b]quinoxaline 8 and 3-[α-(o-chlorophenylhydrazono)-4-methyl-4H-1,2,4-triazol-5-ylraethyl]-2-oxo-1,2-dihydroquinoxaline 9 , respectively.     

Condensed isoquinolines 32. Synthesis of 4H-thieno-[3′,2′:5,6]-and-[2′,3′: 5,6]pyrimido-[1,2-b]isoquinolines and 6,12-dihydro-5H-isoquino-[2,3-a]quinazoline-5,12-dione derivatives

Treatment of 2-(4-oxo-3,4-dihydrothieno[2,3-d]-and-[3,2-d]pyrimidin-2-ylmethyl)benzoic acids and 2-(4-oxo-3,4-dihydro-2-quinazolinylmethyl)benzoic acid with acetic anhydride gave thieno[3′,2′:5,6]-and-[2′,3′:5,6]pyrimido[1,2-b]isoquinoline-4,11-diones and isoquino[2,3-a]quinazoline-5,12-dione respectively. NMR spectroscopy showed that an intramolecular acylation of the above acids occurs at the atom N-1 of the pyrimidinone part of the bicycle. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1053–1061, July, 2008.     

Rhenium tricarbonyl core complexes of thymidine and uridine derivatives

Thymidine and uridine were modified at the C2' and C5' ribose positions to form amine analogues of the nucleosides (1 and 4). Direct amination with NaBH(OAc)3 in DCE with the appropriate aldehydes yielded 1-{5-[(bis(pyridin-2-ylmethyl)amino)methyl]-4-hydroxytetrahydrofuran-2-yl}-5-methyl-1H-pyrimidine-2,4-dione (L1), 1-{5-[(bis(quinolin-2-ylmethyl)amino)methyl]-4-hydroxytetrahydrofuran-2-yl}-5-methyl-1H-pyrimidine-2,4-dione (L2), and 1-[3-(bis(pyridin-2-ylmethyl)amino)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-1H-pyrimidine-2,4-dione (L5), while standard coupling procedures of 1 and 4 with 5-(bis(pyridin-2-ylmethyl)amino)pentanoic acid (2) and 5-(bis(quinolin-2-ylmethyl)amino)pentanoic acid (3) in the presence of HOBT-EDCI in DMF provided a second novel series of bifunctional chelators: 5-(bis(pyridin-2-ylmethyl)amino)pentanoic acid [(3-hydroxy-5-(5-methyl-4-oxo-3,4-dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-yl)methyl] amide (L3), 5-(bis(quinolin-2-ylmethyl)amino)pentanoic acid [(3-hydroxy-5-(5-methyl-4-oxo-3,4-dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-yl)methyl] amide (L4), 5-(bis(pyridin-2-ylmethyl)amino)pentanoic acid [2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl] amide (L6), and 5-(bis(quinolin-2-ylmethyl)amino)pentanoic acid [2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl] amide (L7). The rhenium tricarbonyl complexes of L1-L4, L6, and L7, [Re(CO)3(LX)]Br (X=1-4, 6, 7: compounds 5-10, respectively), have been prepared by reacting the appropriate ligand with [NEt4][Re(CO)3Br3] in methanol. The ligands and their rhenium complexes were obtained in good yields and characterized by common spectroscopic techniques including 1D and 2D NMR, HRMS, IR, cyclic voltammetry, UV, and luminescence spectroscopy and X-ray crystallography. The crystal structure of complex 6.0.5NaPF6 displays a facial geometry of the carbonyl ligands. The nitrogen donors of the tridentate ligand complete the distorted octahedral spheres of the complex. Crystal data: monoclinic, C2, a = 24.618(3) A, b = 11.4787(11) A, c = 15.5902(15) A, beta = 112.422(4) degrees , Z = 4, D(calc) = 1.562 g/cm3.     

Reaction of 2,3-Dihydro-1,5-benzothiazepines and Phenylacetyl Chloride in the Presence of Triethylamine： A New Aspect on the Formation Mechanism of Dihydro-1,3-oxazin-4-one Derivatives

2a,4-Disubstituted 2,2a,3,4-tetrahydro-2-phenyl-1H-azeto[2,1-d][ 1,5]benzothiazepin-1-ones, as well as 2-substi-tuted 2,3-dihydro-3-phenylacetyl-2-styryl-benzothiazoles and 4a,6-disubstituted 3- .benzyl-4a,5-d/hydro-2-phenyl-1H,6H-[1,3]oxazino[2,3-d][1,5]benzothiazepin-1-ones, were obtained from the reaction of 2,4-disubstituted 2,3-dihydro-1,5-benzothiazepines with phenylacetyl chloride in the presence of triethylamine. The mechanism for the formation of 4a,5-dihydro-1H,6H-[1,3]oxazino[2,3-d][1,5]benzothiazepin-1-ones, 2,3-dihydro-1,3-oxazin-4-one derivatives, was suggested.     

两种含杂环的氨基萘醌化合物的合成

以2,3-二氯-1,4-萘醌为主要原料,分别与吗啡啉和糠胺在一定条件下反应生成2种含杂环的氨基萘醌类化合物。2,3-二氯-1,4-萘醌与吗啡啉及2,3-二氯-1,4-萘醌与糠胺物质的量比均为1∶2,反应温度为60℃,溶剂为乙醇。2,3-二氯-1,4-萘醌与吗啡啉反应时间为1 h,产物2-氯-3-吗啡啉基萘-1,4-二酮(a)收率为93.5%;2,3-二氯-1,4-萘醌与糠胺反应时间为4 h,产物N~2,N~3-二(2-呋喃甲基)-1,4-二((2-呋喃甲基)亚胺)-1,4-二氢化萘-2,3-二氯化铵(d)收率为46.7%。对产物进行IR、Uv、MS和H-NMR等分析表征。