Four new ginkgolic acids from Ginkgo biloba

Four new compounds, 2-hydroxy-6-(12′-hydroxyheptadec-13′(E)-en-1-yl)benzoic acid (1), 2-hydroxy-6-(13′-hydroxyheptadec-11′(E)-en-1-yl)benzoic acid (2), 2-hydroxy-6-(10′-hydroxypentadec-11′(E)-en-1-yl)benzoic acid (3), and 2-hydroxy-6-(11′-hydroxypentadec-9′(E)-en-1-yl)benzoic acid (4) were isolated from the leaves of Ginkgo biloba and the structures of new ginkgolic acids were deduced on the basis of spectroscopic methods and chemical means. Compounds 1 and 2, and 3 and 4 examined as an inseparable mixture of hydroxyl and double bond positional isomers, were ultimately defined by total synthesis. Compounds 1–4 showed moderate lipid droplets accumulation inhibitory activity on mouse pre-adipocyte cell line, MC3T3-G2/PA6.     

3-Oxyanthranilic acid derivatives from Actinomadura sp. BCC27169

Eight new compounds including 9′-[2-amino-3-(4″-O-methyl-α-rhamnopyranosyloxy) phenyl]nonanoic acid (1), 9′-[2-amino-3-(4″-O-methyl-α-ribopyranosyloxy)phenyl] nonanoic acid (2), 11′-[2-amino-3-(4″-O-methyl-α-rhamnopyranosyloxy)phenyl]undecanoic acid (3), 11′-[2-amino-3-(4″-O-methyl-α-ribopyranosyloxy)phenyl]undecanoic acid (4), 8-(4′-O-methyl-α-rhamnopyranosyloxy)-3,4-dihydroquinolin-2(1H)-one (5), 8-(4′-O-methyl-α-ribopyranosyloxy)-3,4-dihydroquinolin-2(1H)-one (6), 8-(4′-O-methyl-α-rhamnopyranosyloxy)-2-methyquinoline (7), and 8-(4′-O-methyl-α-ribopyranosyloxy)-2-methylquinoline (8) were isolated from Actinomadura sp. BCC27169. The chemical structures of these compounds were determined based on NMR and high-resolution mass spectroscopy. The absolute configurations of these monosaccharides were revealed by the hydrolysis of compounds 7 and 8. Compounds 3 and 8 exhibited antitubercular activity at MIC 50 μg/mL. Only compound 3 showed cytotoxicity against KB cell at IC₅₀ 18.63 μg/mL, while other isolated compounds were inactive at tested maximum concentration (50 μg/mL).     

Synthesis and characterization of polybinaphthalene incorporating chiral (R) or (S)-1,1′-binaphthalene and oxadiazole units by Heck reaction

Chiral conjugated polymers P-1 and P-2 were synthesized by the polymerization of (R)-3,3′-diiodo-2,2′-bisbutoxy-1,1′-binaphthalene ((R)-M-1) and (S)-3,3′-diiodo-2,2′-bisbutoxy-1,1′-binaphthalene ((S)-M-1) with 2,5-bis(4-vinylphenyl)-1,3,4-oxadiazole (M-2) under Pd-catalyzed Heck coupling reaction, respectively. Both monomers and polymers were analysed by NMR, MS, FT-IR, UV, DSC-TG, fluorescent spectroscopy, GPC and CD spectra. The chiral conjugated polymers exhibit strong Cotton effect in their circular dichroism (CD) spectra indicating a high rigidity of polymer backbone. CD spectra of polymers P-1 and P-2 are almost identical and have opposite signs for their position. These polymers have strong blue fluorescence.     

Efficient synthesis of novel dipyridoimidazoles and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives

Novel dipyrido[1,2-a;3′,4′-d]imidazoles 7a-d, dipyrido[1,2-a;4′,3′-d]imidazoles 8a,c and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives 9a-d were synthesized by two pathways: thermal electrocyclic reaction of 3-alkenylimidazopyridine-2-oximes 10 and direct condensation of ethyl glycinate (or hydrazine) with 2,3-dicarbonylimidazo[1,2-a]pyridines 11.     

Aigialomycins and related polyketide metabolites from the mangrove fungus Aigialus parvus BCC 5311

Reinvestigation of the secondary metabolites from the marine mangrove fungus Aigialus parvus BCC 5311 led to the isolation of six new nonaketide metabolites, aigialomycins F (4) and G (5a/5b), 7′,8′-dihydroaigialospirol (7), 4′-deoxy-7′,8′-dihydroaigialospirol (8), and rearranged macrolides 9 and 10, along with six previously described compounds, hypothemycin (1), aigialomycins A (2) and B (3), aigialospirol (6), 4-O-demethylhypothemycin (11), and aigialone (12). The structures of the new compounds were elucidated by analyses of the NMR spectroscopic and mass spectrometry data in combination with chemical means.     

Enantioselective synthesis of axially chiral 1-(1-naphthyl)isoquinolines and 2-(1-naphthyl)pyridines through sulfoxide ligand coupling reactions

Racemic 1-(1′-isoquinolinyl)-2-naphthalenemethanol rac-12 was prepared through a ligand coupling reaction of racemic 1-(tert-butylsulfinyl)isoquinoline rac-7 with the 1-naphthyl Grignard reagent 10. Resolution of rac-12 was achieved through chromatographic separation of the Noe-lactol derivatives 14 and 15, providing (R)-(−)-12 of >99% ee and (S)-(+)-12 of 90% ee. The ligand coupling reaction of optically enriched sulfoxide (S)-(−)-7 (62% ee) with Grignard reagent 10 furnished rac-12, with the absence of stereoinduction resulting from competing rapid racemisation of the sulfoxide 7. Reaction of optically enriched (S)-(−)-7 with 2-methoxy-1-naphthylmagnesium bromide was also accompanied by racemisation of the sulfoxide 7, and furnished optically active (+)-1-(2′-methoxy-1′-naphthyl)isoquinoline (+)-3b in low enantiomeric purity (14% ee). The absolute configuration of (+)-3b was assigned as R using circular dichroism spectroscopy, correcting an earlier assignment based on the Bijvoet method, but in the absence of heavy atoms. Optically active 2-pyridyl sulfoxides were found not to undergo racemisation analogous to the 1-isoquinolinyl sulfoxide 7, with the ligand coupling reactions of (R)-(+)- and (S)-(−)-2-[(4′-methylphenyl)sulfinyl]-3-methylpyridines, (R)-(+)-17 and (S)-(−)-17, with 2-methoxy-1-naphthylmagnesium bromide providing (−)- and (+)-2-(2′-methoxy-1′-naphthyl)-3-methylpyridines, (−)-18 and (+)-18, in 53 and 60% ee, respectively. The free energy barriers to internal rotation in 3b and 18 have been determined, and the isoquinoline (R)-(−)-12 examined as a ligand in the enantioselectively catalysed addition of diethylzinc to benzaldehyde; (R)-(−)-12 was also converted to (R)-(−)-N,N-dimethyl-1-(1′-isoquinolinyl)-2-naphthalenemethanamine (R)-(−)-19, and this examined as a ligand in the enantioselective Pd-catalysed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate.     

Asymmetric Friedel-Crafts alkylation of activated benzenes with methyl (E)-2-oxo-4-aryl-3-butenoates catalyzed by [Pybox/Sc(OTf)3]

The asymmetric Friedel-Crafts reaction between methyl (E)-2-oxo-4-aryl-3-butenoates (1a-c) and activated benzenes (2a-d) has been efficiently catalyzed by the Sc^III triflate complex of (4′S,5′S)-2,6-bis[4′-(triisopropylsilyl) oxymethyl-5′-phenyl-1′,3′-oxazolin-2′-yl]pyridine (pybox 3). The 4,4-diaryl-2-oxo-butyric acid methyl esters (4) are usually formed in good yields and the enantioselectivity is up to 99% ee. The sense of the stereoinduction can be rationalized with the same octahedral complex (10) between 1, pybox 3 and Sc triflate already proposed for other reactions involving pyruvates, and catalyzed by the same complex.     

Synthesis and properties of novel 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-triones: methodology for synthesizing cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates

Novel condensation reaction of tropone with N-substituted and N,N′-disubstitued barbituric acids in Ac₂O afforded 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (8a-f) in moderate to good yields. The ¹³C NMR spectral study of 8a-f revealed that the contribution of zwitterionic resonance structures is less important as compared with that of 8,8-dicyanoheptafulvene. The rotational barriers (ΔG^‡) around the exocyclic double bond of mono-substituted derivatives 8a-c were obtained to be 14.51-15.03 kcal mol⁻¹ by the variable temperature ¹H NMR measurements. The electrochemical properties of 8a-f were also studied by CV measurement. Upon treatment with DDQ, 8a-c underwent oxidative cyclization to give two products, 7 and 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates (11a-c·BF₄⁻ and 12a-c·BF₄⁻) in various ratios, while that of disubstituted derivatives 8d-f afforded 7,9-disubstituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborate (11d-f·BF₄⁻) in good yields. Similarly, preparation of known 5-(1′-oxocycloheptatrien-2′-yl)-pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (14a-d) and novel derivatives 14e,f was carried out. Treatment of 14a-c with aq. HBF₄/Ac₂O afforded two kinds of novel products 11a-c·BF₄⁻ and 12a,c·BF₄⁻ in various ratios, respectively, while that of 14d-f afforded 11d-f. The product ratios of 11a-c·BF₄⁻ and 12a-c·BF₄⁻ observed in two kinds of cyclization reactions were rationalized on the basis of MO calculations of model compounds 20a and 21a. The spectroscopic and electrochemical properties of 11a-f·BF₄⁻ and 12a-c·BF₄⁻ were studied, and structural characterization of 11c·BF₄⁻ based on the X-ray crystal analysis and MO calculation was also performed.     

Thermal decomposition of the tert-butyl perester of thymidine-5′-carboxylic acid. Formation and fate of the pseudo-C4′ radical

Thermal decomposition of the tert-butyl perester of thymidine-5′-carboxylic acid 1 carried out at 85 °C in different solvents affords the tert-butylacetal 4a, deriving from in cage decomposition, and pseudo C4′ radicals 2. Radicals 2 can be reduced to 5 by hydrogen atom abstraction from thiol (thiophenol or glutathione) or THF, or can be oxidized to cations 8 by dioxygen or perester 1 itself. Cations 8 are stereoselectively trapped by the nucleophilic solvent (tert-butanol, methanol, water) to give acetals 4a-c.     

Cytotoxic and anti-HIV-1 constituents from leaves and twigs of Gardenia tubifera

Two new natural cycloartanes, tubiferolide methyl ester (1) and tubiferaoctanolide (2), together with the known coronalolide (3) and coronalolide methyl ester (4) have been isolated from leaves and twigs of Gardenia tubifera. In addition, a new flavone 5,3′,5′-trihydroxy-7,4′-dimethoxyflavone (5), five known flavones 6-10 and hexacosyl 4′-hydroxy-trans-cinnamate (11) were also obtained from the same source. The structures were assigned on the basis of spectroscopic methods. Compounds 3, 7, 9, and 10 showed significant cytotoxic activities only in P-388 cell line. Compound 1 was cytotoxic against P-388, KB, Col-2 and Lu-1, while 4 was active in P-388 and BCA-1. Compounds 3 and 4 displayed significant anti-HIV activities in the HIV-1RT assay; compound 7 showed moderate activity in this assay. Compounds 5-10 were also found to be active in the ^ΔTat/RevMC 99 syncytium assay.     

Synthesis of (3′R,5′S)-3′-hydroxycotinine using 1,3-dipolar cycloaddition of a nitrone

To synthesize (3′R,5′S)-3′-hydroxycotinine [(+)-1], the main metabolite of nicotine (2), cycloaddition of C-(3-pyridyl)nitrones 3a, 3c, and 15 with (2R)- and (2S)-N-(acryloyl)bornane-10,2-sultam [(2R)- and (2S)-8] was examined. Among them, l-gulose-derived nitrone 15 underwent stereoselective cycloaddition with (2S)-8 to afford cycloadduct 16, which was elaborated to (+)-1.     

Application and details of photoinduced oxidative cyclization of 5-(4′,9′-methanocycloundeca-2′,4′,6′,8′,10′-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-triones and related compounds

As novel methodology for synthesizing the furan ring, a photoinduced oxidative cyclization of 5-(4′,9′-methanocycloundeca-2′,4′,6′,8′,10′-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-triones (7a-c) and related compounds 9a-c was accomplished to give 5,10-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1,3H)-dionylium tetrafluoroborates (8a-c⁺·BF₄⁻) and related compounds 2a-c⁺·BF₄⁻, respectively. In the photoinduced oxidative cyclization, the molecular oxygen in air is used as oxidant and the reaction proceeds under mild conditions to give desired products without byproducts, and thus, it is interesting from the viewpoint of the green chemistry. On the reactions of the mono-substituted derivatives 7d,e and 9e,f, the selectivity of the photoinduced cyclizations were reversed as compared with those of the DDQ-promoted oxidative cyclizations. By the NMR monitoring of the reactions of 7a and deuterated compound 7a-D₂ under degassed conditions, the details of the reaction pathway were clarified and rationalized on the basis of the MO calculation by the 6-31G^∗ basis set of the MP2 levels as well.     

Synthetic studies of erythromycin derivatives: 6-O-methylation of (9S)-12,21-anhydro-9-dihydroerythromycin A derivatives

Synthetic studies on methylation of erythromycin derivatives were conducted. Methylation of 6 resulted in the formation of the C-3′ quaternary ammonium salts with a rate faster than 6-O-methylation. In dipolar aprotic solvent and under strong base conditions, 6-O-methylation, C-3′ quaternary ammonium salts formation and 2-C-methylation proceeded simultaneously to yield a mixture of three different products 7, 8 and 9. The quaternary ammonium salts were converted back to the corresponding tertiary amines 2, 10 and starting material 6 by employing sodium 4-pyridinethiolate as a N-demethylation reagent. The 6-O-methylation was eventually achieved in a good yield when a carbobenzyloxy (Cbz) group was utilized to protect the C-3′-dimethylamino group of 4. In this report, we will discuss the details of different reaction courses in the methylation of (9S)-12, 21-anhydro-9-dihydroerythromycin A derivatives.     

Synthesis of planar-chiral bridged bipyridines and terpyridines by metal-mediated coupling reactions of pyridinophanes

We have accomplished efficient synthesis of planar-chiral bridged 2,2′-bipyridine (S)-6, C₂-symmetric bipyridinophane (S,S)-7, bridged 2,2′:6′,2″-terpyridines (S)-11, and C₂-symmetric terpyridine (S,S)-12 by metal-mediated biaryl cross-coupling or homo-coupling reactions of the corresponding 6-halo[10](2,5)pyridinophanes. Stille-type and Negishi cross-coupling reactions are particularly useful for the syntheses of 6, 11, and 12. On the other hand, nickel-mediated homo-coupling reaction worked best for achieving the synthesis of structurally unique bipyridinophane 7.     

On the relative stereochemistry of atomaric acid and related compounds

The stereochemistry at C-3 of the known compounds atomaric acid 2a, 5′a-desmethyl-5′-acetylatomaric acid 4a, and stypoquinonic acid 5a is revised to 2, 4, and 5 on the basis of a careful study of 2D NOESY experiments and also from comparison of their ¹H and ¹³C chemical shifts with those of the related metabolites 6 and 7 isolated from Stypopodium zonale. Compound 7 is a novel unusually functionalized 1-keto-5′a-desmethyl atomaric acid derivative whose structure and stereochemistry were determined by spectroscopic means.     

Synthesis and evaluation of fully (5-amidoisophthalic acid)-functionalised polyacrylamides as selective inhibitors of the beta crystal polymorph of l-glutamic acid

Poly-N-5-acrylamidoisophthalic acid (4), poly-N-(5-(N′-(3,5-dicarboxyphenyl)carbamoyl)pentyl)acrylamide (10a) and poly-N-(11-(N′-(3,5-dicarboxyphenyl)carbamoyl)undecyl)acrylamide (10b) were prepared and assessed as polymorph-selective crystallization inhibitors of the stable β form of l-glutamic acid. Polymerization was carried out as the final step in the preparation of 10a and 10b to ensure the preparation of fully functionalized polymers. Polymers 4, 10a and 10b were effective as complete inhibitors of the stable β form of l-glutamic acid in quantities of 0.5% w/w or greater, whereas the corresponding ‘monomeric’ additives 2 and 11 required quantities of 3% or greater to completely inhibit the β form, demonstrating a cooperative binding effect by the polymeric additives. Within the series of polymers 4, 10a and 10b, polymer 10a, which features a short tethering chain, was the most effective.     

Synthesis of ‘thianthrene dimer’ by the coupling reaction of stannylthianthrenes in the presence of copper catalysts

The coupling reaction of 1-tributylstannylthianthrene (5) and 2-tributylstannylthianthrene (7) in the presence of copper catalysts at rt afforded the thianthrene dimer 1,1′-bithianthrene (3), 2,2′-bithianthrene (8), and 1,2′-dithianthrene (9) in high yields. Also we obtained thianthrene oxide dimer (R,R) (S,S)-1-(10-S-monoxythianthrene-1-yl)thianthrene-10-S-monoxide (12) and (R,S) (S,R)-1-(10-S-monoxythianthrene-1-yl)thianthrene-10-S-monoxide (13) from 1-tributylstannyl-10-S-monoxythianthrene (10) under the same reaction condition. The final structural conformation of 3, 8, 9, and 12 was performed by X-ray crystallographic analysis. Further, the solvent effects in the coupling reactions were also examined.     

Bioactive meroditerpenes and indole alkaloids from the soil fungus Neosartorya fischeri (KUFC 6344), and the marine-derived fungi Neosartorya laciniosa (KUFC 7896) and Neosartorya tsunodae (KUFC 9213)

Two new metabolites including a new aszonalenin analogue (1c) and a new meroditerpene (3) were isolated, together with aszonalenin (1a), acetylaszonalenin (1b), 13-oxofumitremorgin B (2), aszonapyrone A (4b) and helvolic acid, from the culture of the soil fungus Neosartorya fischeri (KUFC 6344). While the ethyl acetate extract of the culture of the diseased coral-derived fungus Neosartorya laciniosa (KUFC 7896) furnished aszonapyrone B (4a), aszonapyrone A (4b), tryptoquivaline L and 3′-(4-oxoquinazolin-3-yl) spiro[1H-indole-3,5′-oxolane]-2,2′-dione, the ethyl acetate extract of the culture of the marine sponge-associated fungus Neosartorya tsunodae (KUFC 9213) yielded a new analogue of chevalone C (5) and helvolic acid. The structures of the new compounds were established based on 1D and 2D NMR spectral analysis as well as HR-ESIMS. Compounds 1a–c, 2, 3, 4a, 4b and 5 were evaluated for their in vitro growth inhibitory activity on the MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and A375-C5 (melanoma) cell lines by the protein binding dye SRB method.     

Determination of the absolute configuration of the male aggregation pheromone, 2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol, of the stink bug Erysarcoris lewisi (Distant) as 2Z,6R,1′S,5′S by its synthesis

Lipase-catalyzed asymmetric acetylation of a mixture of (6R,1′S,4′S,5′R)- and (6R,1′R,4′R,5′S)-7′-norsesquisabinen-4′-ol (3) afforded a separable mixture of the recovered former and the acetate of the latter. The recovered alcohol was oxidized to (6R,1′S,5′R)-sesquisabina ketone (2), whose absolute configuration could be assigned by its CD comparison with (1R,5S)-sabina ketone (4). Conversion of (6R,1′S,5′R)-sesquisabina ketone (2) to the bioactive pheromone revealed the stereostructure of the male aggregation pheromone of the stink bug Erysarcoris lewisi (Distant) to be (2Z,6R,1′S,5′S)-2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol (sesquisabinen-1-ol, 1).     

Separation and identification of three epimeric pairs of new C-glucosyl anthrones from Rumex dentatus by on-line high performance liquid chromatography–circular dichroism analysis

Six C-glucosyl anthrones were characterized as three pairs of epimers by on-line high performance liquid chromatography–circular dichroism (HPLC–CD) analysis and isolated from the roots of Rumex dentatus by column chromatography. Their structures were elucidated by mass spectrometry, nuclear magnetic spectroscopy and HPLC–CD analysis. They are 10R-C-β-d-glucosyl-10-hydroxyemodin-9-anthrone (rumejaposide E, 1) and 10S-C-β-d-glucosyl-10-hydroxyemodin-9-anthrone (rumejaposide F, 2), 10R-C-β-d-glucosylemodin-9-anthrone (rumejaposide G, 3) and 10S-C-β-d-glucosylemodin-9-anthrone (rumejaposide H, 4), 10S-C-β-d-glucosyl-10-hydroxychrysophanol-9-anthrone (cassialoin, 5) and 10R-C-β-d-glucosyl-10-hydroxychrysophanol-9-anthrone (rumejaposide I, 6). Rumejaposides F–I (2–4 and 6) were new C-glucosyl anthrones. Rumejaposide E (1) and cassialoin (5) were isolated for the first time in Rumex plants. On-line HPLC–UV–CD analysis was a useful tool for structure elucidating epimeric C-glycosides anthrones 3–6 because of the poor stability of the pure isomers (3 and 4) and the minute quantity of 5 and 6 in the mixture.