Synthesis and anticancer properties of 7α-chloro-3-methyl-1,1-dioxoceph-3-em-4-carboxylic acid esters

The tert-butyl esters of 3-azidomethyl-, 3-isocyanatomethyl-, 3-chloromethyl-, and 3-p-nitrophenylvinyl-7α-chloro-1,1-dioxoceph-3-em-4-carboxylic acid, and also esters of 7α-chloro-3-methyl-1,1-dioxoceph-3-em-4-carboxylic acid, and of 7α-chloro-3-methyl-2-dimethylaminomethylene-1,1-dioxoceph-3-em-4-carboxylic acid have been synthesized. Results of cytotoxic screening of these compounds in relation to cancer and normal cells in vitro are correlated and analyzed. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 259–273, February, 2007.     

Synthesis and structural modification of <Emphasis Type="Italic">tert</Emphasis>-butyl ester of 7α-chloro-2-(N,N-dimethylaminomethylene)-3-methyl-1,1-dioxoceph-3-em-4-carboxylic acid

The reaction of tert-butyl 7α-chloro-and 7-β-chloro-7α-isopropoxy-3-methyl-1,1-dioxoceph-3-em-4-carboxylates with the Vilsmeier reagent was carried out with introduction of N,N-dimethylaminomethylene group at position 2 in the E-and Z-isomeric forms. Prolonged treatment of tert-butyl 7α-chloro-3-methyl-2-(N,N-dimethylaminomethylene)-1,1-dioxoceph-3-em-4-carboxylate with hydroxylamine hydrochloride in acetonitrile at 40–50°C gave tert-butyl 10(S)-chloro-6-methyl-5-oxa-1,1,9-trioxo-1-thia-4,8-diazatricyclo[7,2,0,0^2,6]undecane-7(R)-carboxylate which isomerized into 1-tertbutoxycarbonylmethyl-3α-chloro-4-(5-methylisoxazole-4-sulfonyl)azetidin-2-one. In the case of tertbutyl 7β-chloro-7α-isopropoxy-3-methyl-2-(N,N-dimethylaminomethylen)-1,1-dioxoceph-3-em-4-carboxylate the analogous reaction gave tert-butyl 10β-chloro-(2S,6S,7S,10R,11R)-10α-isopropoxy-6-methyl-5-oxa-1,1,9-trioxo-1-thia-4,8-diazatricyclo[7,2,0,0^2,6]undecane-7(R)-carboxylate, the struc-ture of which was determined by 2D-NOESY two-dimensional spectroscopy. The compounds synthesized showed weak or no cytotoxic activity with respect to monolayers of cancer cells in vitro.     

Synthesis and cytotoxic properties of 7α-chloro-3-methyl-1,1-dioxoceph-3-ems, substituted with amide or keto group at position 4

7α-Chloro-3-methyl-1,1-dioxoceph-3-ems with amide or keto group at position 4 have been synthesized by structural modification of 7α-chloro-3-methyl-1,1-dioxoceph-3-em-4-carboxylic acid. Screening of these compounds for cytotoxic activity revealed compounds with specific activity against cancer cells in vitro, capable of effective inhibition of the growth of sarcoma S-180 in vivo. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, 1849–1859, December 2007.     

Bromination of <Emphasis Type="Italic">tert</Emphasis>-Butyl Esters of 7α-Chloro and 7-Alkylidenedeacetoxycephalosporanic Acid Sulfones

The action of N-bromosuccinimide on tert-butyl esters of 7α-chloro- and 7-alkylidenedeacetoxycephalosporanic acid sulfones upon irradiation with visible light leads to the formation of a mixture of the product of allylic bromination of the 3-methyl group, namely, 3-bromomethyldeacetoxycephalosporanate, and the product of replacement of a proton at C₍₂₎ in the latter, namely, 2-bromo-3-bromomethyldeacetoxycephalosporanate. Small amounts of E-isomers were also obtained in the case of the Z-isomer of the 7-(4-nitrobenzylidene) derivative. In the case of the 7α-chloro derivative only substitution of one or two protons at C₍₂₎ occurs during bromination without irradiation, the same as the isomerization of the double bond in the cepheme system.Dedicated to Academician N. K. Kochetkov on the occasion of this ninetieth birthday.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 767–774, May, 2005.     

A study of the Claisen rearrangement of 7-(3-phenyl-2-propenyloxy)-3-phenyl-(4H)-1-benzopyran-4-one derivatives

Summary The Claisen rearrangement of 7-(3-phenyl-2-propenyloxy)-3-phenyl-(4H)-1-benzopyran-4-one (2 a) gave 7-hydroxy-8-(1-phenyl-2-propenyl)-3-phenyl-(4H)-1-benzopyran-4-one (3 a) and 2,3-dihydro-2,6-diphenyl-3-methyl-(7H)furo[2,3-h]-1-benzopyran-7-one (7 a). 2-Methyl-7-(3-phenyl-2-propenyloxy)-3-phenyl-(4H)-1-benzopyran-4-one (2 b) afforded4 b and7 b. 8-Methyl-7-(3-phenyl-2-propenyloxy)-3-phenyl-(4H)-1-benzopyran-4-one (12) gave only the alkali soluble product 7-hydroxy-8-methyl-6-(1-phenyl-2-propenyl)-3-phenyl-(4H)-1-benzopyran-4-one (13).3 a,4 b, and13 were further cyclized in acidic medium to9 a,10 b, and14 followed by dehydrogenation.This paper is dedicated to Dr. F. M. Dean, Department of Organic Chemistry, Robert Robinson Laboratories, University of Liverpool, Liverpool, U. K., on his retirement     

3-(4-Phenyl-1,2,4-triazol-3-yl)chromones

The condensation of 4-phenyl-1,2,4-triazol-3-ylacetonitrile with 2-methyl-, 4-ethylresorcinol, and with pyrogallol gave α-(4-phenyl-1,2,4-triazol-3-yl)-2,4-dihydroxyacetophenones. Upon treatment with acid anhydrides and chlorides and subsequent hydrolysis these form 7-hydroxy-3-(4-phenyl)-1,2,4-triazol-3-yl)chromones with different substituents in both the benzene and the pyrone rings. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1676–1684, November, 2005.     

4-(10-Methyl-10H-phenothiazin-3-yl)-1,4-dihydropyridines, 4,5-dihydroindeno[1,2-<Emphasis Type="Italic">b</Emphasis>]-and 5,5-dioxo-4,5-dihydrobenzo-thieno[3,2-<Emphasis Type="Italic">b</Emphasis>]pyridines

Different modifications of the Hantzsch synthesis using 10-methyl-10H-phenothiazine-3-carbaldehyde gave 4-(10-methyl-10H-phenothiazin-3-yl)-substituted 1,4-dihydropyridine-3,5-di-, 5-oxo-4,5-dihydro-1H-indeno[1,2-b]pyridine-, and 5,5-dioxo-4,5-dihydro-1H-5λ⁶-benzo[4,5]thieno[3,2-b]pyridine-3-carboxylic esters. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 280–288, February, 2007.     

Chemical transformations of reaction products of 2-methyl-3-(4-tolyl)-4(3<Emphasis Type="Italic">H</Emphasis>)-quinazolone with benzil and its 4,4′-derivatives

The reaction of 2-methyl-3-(4-tolyl)-4(3H)-quinazolone with benzil produces 2-[(Z)-3-oxo-2,3-diphenylprop-1-enyl]-3-(4-tolyl)-4(3H)-quinazolone, which is readily transformed into 2-(3,3-diphenylsuccinimido)-N-(4-tolyl)benzamide on dissolution in organic water-containing solvents. The rearrangement mechanism was suggested and investigated by the quantum chemical PM3 method. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 146–151, January, 2007.     

Features of the reaction of unsymmetrical 2-mercapto-imidazoles with aromatic and aliphatic ketones

The cyclization of unsymmetrical 2-mercaptoimidazoles with aliphatic and aromatic ketones has been studied. Using ¹H NMR and X-ray analysis it has been shown that 4-R¹-1H-2-mercaptoimidazoles undergo selective oxidative cyclization to the corresponding 3-R³-2-R²-6-R¹-imidazo[2,1-b][1,3]thiazoles while 6-R⁴-1H-2-mercaptobenzo[d]imidazoles give a mixture of 6-R⁴-3-R²-2-R³-benzo[4,5]imidazo[2,1-b][1,3]thiazole and 7-R⁴-3-R²-2-R₃-benzo[4,5]imidazo[2,1-b][1,3]thiazole in the ratio 1: 1. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 115–122, January, 2007.     

Structure of (Z)-(5R)-methyl-2-(4-phenylbenzylidene)cyclohexanone as chiral component of liquid-crystalline systems

The spatial structure of (Z)-(5R)-methyl-2-(4-phenylbenzylidene)cyclohexanone prepared by photochemical isomerization of the E-isomer was studied by analyzing the magnitudes and temperature dependence of the proton spin-spin coupling constants obtained by ¹H NMR spectroscopy and the results of molecular modeling using semiempirical quantum chemical AM1 and PM3 methods and the density functional theory (DFT). Comparison of the results obtained for the Z-and E-isomers shows that in both cases the conformational equilibrium for both isomers is characterized by significant preference of the chair conformer having an equatorial methyl group, namely, − ΔH (chair a ⇌ chair e) = 1.98–2.12 and 1.36–1.54 kcal mole⁻¹ for the Z-and E-isomers, respectively. Distinctions in the non-planarity of the enone fragment and cyclohexanone ring in the Z-and E-isomers under study following from the results of mathematical modeling were confirmed by the experimental values of the geminal spin-spin coupling constants of protons of the methylene groups in α,α ′-positions with respect to the enone group. Quantum chemical calculations of the Z-isomer revealed the existence of intramolecular hydrogen bond between the carbonyl oxygen and the nearest aromatic proton in ortho-position of the benzene ring. Possible reasons for different helical twisting power of (Z)-(5R)-methyl-2-(4-phenylbenzylidene)cyclohexanone and the E-and Z-arylidene derivatives of 1R, 4R-isomenthone in the mesophase are discussed based on the results of molecular structure studies for these compounds. In the text below the unsaturated ketones under study will be called “arylidene cyclohexanone derivatives” for convenience of comparing the characteristics of methylcyclohexanone and isomenthone derivatives. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 962–972, June, 2006.     

New glycosidic and other constituents from hulls of <Emphasis Type="Italic">Oryza sativa</Emphasis>

Three new compounds, 4-hydroxymethylene-7-(9,9,13-trimethylcyclohexyl)-heptanyl-3′,7′,7′-trimethylcyclohexa-2′,4′-dien-1′-oate (1), 1-(n-hexadec-7-enoxy)-6-(n-octadecanoxy)-β-D-glucopyranoside (2), and (Z)-12-hydroxy-9-octadecenoic acid-12-β-D-glucopyranoside (3), along with the known compound hexacosanoic acid (4), were isolated and identified from the rice hulls of Oryza sativa. Their structures were elucidated by 1D and 2D NMR spectroscopic techniques (¹H-¹H COSY, ¹H-¹³C HETCOR, DEPT) aided by EIMS, FABMS, HRFABMS, and IR spectra. Published in Khimiya Prirodnykh Soedinenii, No. 4, pp. 344–347, July–August, 2007.     

Crystal structures of ethyl-4-(5-bromo-2-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate and ethyl-1-methyl-15-oxo-2-oxa-14,16-diazatetracyclo [11.3.1.0<Superscript>3.12</Superscript>.0<Superscript>6.11</Superscript>]heptadeca-3,5,7,9,11-pentaene-17-carboxylate

The crystal structures of ethyl-4-(5-bromo-2-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate and ethyl-1-methyl-15-oxo-2-oxa-14,16-diazatetracyclo[11.3.1.0^3.12.0^6.11]heptadeca-3,5,7, 9,11-pentaene-17-carboxylate were determined by XRD, and the conformations of their structures were determined.     

Interaction of benzimidazole-2-thione with propargyl bromide and 1,3-dibromopropyne

Interaction of benzimidazole-2-thione with propargyl bromide under found conditions permitted the direct synthesis of 2-(2-propynylsulfanyl)-3H-1,3-benzimidazolium bromide, the base 2-(2-propynylsulfanyl)-1H-1,3-benzimidazole, stable crystalline 2-(1,2-propadienylsulfanyl)-1H-1,3-benzimidazole, and 3-methyl[1,3]thiazolo[3,2-a][1,3]benzimidazole. The reaction of benzimidazole-2-thione with 1,3-dibromopropyne in chloroform or absolute methanol gave 2-(3-bromo-2-propynylsulfanyl)-3H-1,3-benzimidazolium bromide, and in absolute methanole in the presence of a twofold excess of sodium methoxide the reaction proceeded stereo-and regioselectively to give 3-[(Z)-bromomethylidene][1,3]thiazolo[3,2-a][1,3]benzimidazole. Presented to Academician B. A. Trofimov on his 70^th jubilee. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, 1399–1405, September, 2008.     

<Emphasis Type="Italic">tert</Emphasis>-Butyl (2<Emphasis Type="Italic">S</Emphasis>)-(<Emphasis Type="Italic">p</Emphasis>-tolylsulfonyloxy)propionate — a suitable reagent for the direct alkylation of indole derivatives

A new method is proposed for the synthesis of indole derivatives containing a chiral substituent at the nitrogen atom, which includes the direct alkylation of indole derivatives with tert-butyl (2S)-(p-tolylsulfonyloxy)propionate, obtained from commercial ethyl (S)-lactate with subsequent conversion to the corresponding p-toluenesulfonyloxy derivative by hydrolysis, and esterification. Dedicated to Academician B. A. Trofimov on his 70^th birthday. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, 1391–1398, September, 2008.     

An alternative synthesis of a sex pheromone of the dry bean beetleCallosobruchus analis

A formal total synthesis of 3-methylhept-2(Z)-enoic acid, a sex pheromone of the dry bean beetleCallosobruchus analis, was performed on the basis of a highly stereoselective version of the Peterson olefination of ketones developed previously by the authors. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1389–1392, July, 1999.     

4-Hydroxy-2-quinolones. 108. N-R-amides of 9-fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid and their antitubercular activity

The reaction of 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline with triethylmethanetricarboxylate gives di(9-fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinolin-2-yl)methane and ethyl 9-fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate from which alkyl-, dialkylaminoalkyl-, and hetarylamides as well as hydrazides were prepared. The structure and antitubercular properties of the compounds synthesized are discussed. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1391–1407, September, 2006.     

Synthesis and Stereoisomerization of 2-(1-Alkoxyimino-2,2,2-trifluoroethyl)-5-trimethylsilylfurans

2-(1-Alkoxyimino-2,2,2-trifluoroethyl)-5-trimethylsilylfurans were synthesized by the condensation of 2-(trifluoroacetyl)-5-trimethylsilylfuran with alkoxyamines. According to ¹H and ¹⁹F NMR spectroscopic data, the alkoxyimino group in the E-isomers descreens the H-3 and H-4 protons of the furan ring more strongly than in the Z-isomers, shifting their signals downfield. The fluorine atoms of the α-trifluoromethyl group in the Z-isomer are characterized by a downfield shift in relation to the E-isomer. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 834–838, June, 2005.     

Reduction of (<Emphasis Type="Italic">E</Emphasis>)-3-aryl-2-(thiazol-2-yl)acrylonitriles with lithium aluminum hydride

Reduction of (E)-3-aryl-2-(4-arylthiazol-2-yl)acrylonitriles with lithium aluminum hydride in dry ether afforded (Z)-1-amino-3-aryl-2-(thiazol-2-yl)prop-1-ene derivatives in 15 to 40% yields. The structure of (Z)-1-amino-3-(2-chlorophenyl)-2-[4-(4-methylphenyl)thiazol-2-yl]prop-1-ene was confirmed by X-ray diffraction analysis. Dedicated to Academician N. K. Kochetkov on the occasion of his 90th birthday. __________ Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1301–1303, May, 2005.     

New chiral spiro[2.5]octanones as products of methylenation of (3<Emphasis Type="Italic">R</Emphasis>, 6<Emphasis Type="Italic">R</Emphasis>)-2-arylidene-6-isopropyl-3-methylcyclohexanones with dimethylsulfoxonium methylide. Synthesis,stereochemistry, and behavior in liquid-crystalline systems

Methylenation of (3R,6R)-2-(4-X-benzylidene)-6-isopropyl-3-methylcyclohexanones (X = F, Cl, Ph) with dimethylsulfoxonium methylide occurs stereoselectively to give 1(S)-(4-X-phenyl)-5(R)-isopropyl-8(R)-methyl-3(R)-spiro[2.5]octanones, whose stereochemistry was established by ¹H NMR spectroscopy. The configuration of the chiral centers in the cyclohexanone fragment and its preferred conformation (methyl is axial and isopropyl is equatorial) in the products do not change with respect to the starting enones. The mutual trans-arrangement of the carbonyl and aryl groups at the newly formed three-membered ring was established; the aryl group also occupies the trans-position with respect to the axial methyl group of the cyclohexanone fragment. Using methylenation of the compound with X = Ph as an example, a mixture of by-products resulting from oxidative hydroxylation at the α-position relative to the carbonyl group was isolated. The resulting chiral spiro[2.5]octanones induce a helical supramolecular ordering in the nematic mesophase of 4-pentyl-4′-cyanobiphenyl and exhibit a twisting power only somewhat (by 20–30%) lower than the starting enones. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2331–2341, October, 2005.     

Reactions of 2-(4,5-dihydro-3-furyl)-1,3-diphenyl-1,3-diaza-2λ<Superscript>3</Superscript>-phospholidine and 4,5-dihydro-3-furylphosphonous diamides with nitrile imines

Reactions of 2-(4,5-dihydro-3-furyl)-1,3-diphenyl-1,3-diaza-2λ³-phospholidine (1) with nitrile imines are multistep processes involving cleavage of one P-N bond of the diazaphospholidine ring to form substituted 5-(2-chloroethyl)-4-(N,N′-diphenylethylenediamino)-1,4-dihydro-1,2,4λ⁵-diazaphosphorines 4 as final products. Analogs of phospholidine 1, namely, 4,5-dihydro-3-furylphosphonous dipiperidide and dimorpholide, react with C,N-diphenylnitrile imine with retention of both P-N bonds to give 5-(2-hydroxyethyl)-1,2,4-diazaphosphorinium chlorides. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1590–1593, July, 2005.