Five novel norcembranoids from Sinularia leptoclados and S. parva

Three new norcembrane-based diterpenoids, leptocladolides A (1), B (4) and C (5), along with five known metabolites 6-10, have been isolated from the dichloromethane extract of a Taiwanese soft coral Sinularia leptoclados. Furthermore, a chemical investigation on the dichloromethane extract of S. parva has resulted in the isolation of two new related isomers, 1-epi-leptocladolide A (2) and 7E-leptocladolide A (3), in addition to 1 and 7. The structures of new metabolites 1-5 were elucidated on the basis of extensive spectroscopic analyses and their relative stereochemistries were determined by NOESY experiments. The new metabolites 1 and 3 have been shown to exhibit significant cytotoxic activity against KB and Hepa59T/VGH cancer cell lines.     

6,7-Seco-ent-kaurane-type diterpenoids from Isodon eriocalyx var. laxiflora

Twenty nine 6,7-seco-ent-kaurane-type diterpenoids including 18 new ones, laxiflorolides C–T (1–18), along with 21 known ones were obtained from Isodon eriocalyx var. laxiflora. Laxiflorolides E–G (3–5) are the first identified naturally occurring 6,7-seco-ent-kauranoids that feature a 3,6-epoxy unit, and laxiflorolide M (11) is the first identified naturally occurring 6-nor-6,7-seco-ent-kauranoid. The absolute configurations of compounds 1, 3, 6, and 11 were determined by single-crystal X-ray diffraction analyses. The cytotoxic activity of the isolates was evaluated by an MTT assay.     

Lyconadins C and F, new Lycopodium alkaloids from Lycopodium complanatum

New Lycopodium alkaloids, lyconadins C (1) and F (2), were isolated from the club moss Lycopodium complanatum. Lyconadin C (1) is a new C₁₆N₂-type Lycopodium alkaloid possessing unique fused-tetracyclic ring system consisting of a cycloheptene ring fused to a decahydroquinoline and pyridone rings. Lyconadin F (2) possesses a primary amide moiety in its molecular, which is the first example of Lycopodium alkaloids. Biogenetically, lyconadins C (1) and F (2) might be related to lyconadins A (4) and B (5). The structures and relative stereochemistry of 1 and 2 were elucidated on the basis of spectroscopic data. The absolute stereochemistry of 2 was elucidated by chemical correlations with lyconadin B (5) through hemiaminal form of lyconadin F (3).     

Sesquiterpenoids from Ligularia virgaurea spp. oligocephala

Four novel eremophilane-type sesquiterpene lactones, 6β,10α-dihydroxy-1-oxoeremophila-7(11),8(9)-dien-12,8-olide (1), 6β-acetyl-2-oxoeremophila-1(10),7(11), 8(9)-trien-12,8-olide (2), 6β,8β-diacetyl-2-oxoeremophila-1(10),7(11)-dien-12,8-olide (3), dimeric eremophilane ligulolide B (5), and known sesquiterpenoid, 6β,8α-diacetyleremophila-1(10),7(11)-dien-12,8-olide (4), were isolated from an extract of the whole plant of Ligularia virgaurea spp. oligocephala. The structure of 1 was confirmed by NMR spectra and single crystal X-ray crystallography investigation, as well as 2, 3, and 5 were elucidated by spectroscopic methods including 1D and 2D NMR spectra. A discussion of biogenesis of 5 was described. Cytotoxicities of compound 1 were measured in vitro against selected cancer cells human promyelocytic leukemia (HL-60), human ovarian (HO-8910) and human lung epithehial (A-549).     

Calyciphyllines H-M, new Daphniphyllum alkaloids from Daphniphyllum calycinum

Six new Daphniphyllum alkaloids, calyciphyllines H-M (1-6), were isolated from the leaves and stems of Daphniphyllum calycinum (Daphniphyllaceae). The structures and relative stereochemistry of 1-6 were elucidated on the basis of spectroscopic data, and the absolute stereochemistry of 3 was assigned by PGME method.     

Banchromene and other secondary metabolites from the endophytic fungus Fusarium sp. obtained from Piper guineense inhibit the motility of phytopathogenic Plasmopara viticola zoospores

A new chromene, (S)-banchromene (1), together with seven known compounds, ergosterol, beauvericin (2), fusaproliferin (3), radicinin (4), poly(3-hydroxybutyric acid) (PHB, 5), N-methylpyrrolidone and an inseparable mixture of isochromene derivatives 6a, 6b, were isolated from a culture of Fusarium sp. strain CAMKT24b1, an endophytic fungus from the leaves and twigs of Piper guineense (Piperaceae). The structures of these metabolites were elucidated on the basis of their spectroscopic data; the absolute configuration of 1 was determined by ab initio-calculation of the optical rotation. In tests with the zoospores of the grapevine downy mildew pathogen Plasmopara viticola, compounds 1–4 showed moderate to high levels of motility-impairing activity at concentrations as low as 2.5 μg/mL. Compound 2 was the most active, exhibiting both motility-halting and lytic activities. Furthermore, compounds 2 and 3 displayed significant cytotoxic activity against brine shrimp larvae (Artemia salina) at 10 μg/mL. This is the first report on motility inhibitory and lytic activities of metabolites from an endophytic Fusarium species against the zoospores of the downy mildew pathogen P. viticola.     

Naupliolide, a sesquiterpene lactone with a novel tetracyclic skeleton from Nauplius graveolens subsp. odorus

The aerial parts of Nauplius graveolens subsp. odorus (Schousb) Wikl. afforded a novel sesquiterpene lactone (1) named naupliolide together with the known 6,7,9,10-tetradehydroasteriscanolide 2 and asteriscunolides A-D 3a-d. The structure of compound 1 corresponds to a novel skeleton of 14,15-dimethyl-7,13-dioxotricyclic[6.4.0.0^9,11]dodeca-12,13-olide, and was established on the basis of spectroscopic methods including 2D-NMR. The coexistence of naupliolide 1 together with the structurally related sesquiterpene lactones asterisculolides A-D (3a-d) and 6,7,9,10-tetradehydroasteriscanolide 2, seems to indicate their biosynthetic relationship.     

Synthesis of (4R,15R,16R,21S)- and (4R,15S,16S,21S)-rollicosin

A convergent synthesis of (4R,15R,16R,21S)-rollicosin (1) and (4R,15S,16S,21S)-rollicosin (2) was accomplished. Hydroxy lactone 6a and/or 6b were synthesized from 4-pentyn-1-ol, and α,β-unsaturated lactone 7 was synthesized from γ-lactone 8 and 5-hexen-1-ol. Inhibitory activity of these compounds was examined with bovine heart mitochondrial complex I.     

Two novel diterpenoids from Isodon rubescens var. lushanensis

Two novel diterpenoids, luanchunins A (1) and B (2), along with their precursor, kamebakaurin (3), had been isolated from the stems and leaves of Isodon rubescens var. lushanensis. Their structures were elucidated on the basis of extensive spectroscopic analyses. Compounds 1 and 2 showed potent cytotoxic activity against HL-60 with IC₅₀ values of 4.81 μM and 3.52 μM, respectively. Plausible pathways for the biosynthesis of 1 and 2 were also postulated.     

Structures and cytotoxicities of fascaplysin and related alkaloids from two marine phyla—Fascaplysinopsis sponges and Didemnum tunicates

The structural variations and bioactivity properties of the alkaloids in the fascaplysin (1) and the reticulatine (3) families were examined. Four organisms were analyzed consisting of two collections of the sponge Fascaplysinopsis reticulata and two collections of the tunicate Didemnum sp. Reported are the isolation of three new compounds: 3-bromofascaplysin (2), 14-bromoreticulatine (4), and 14-bromoreticulatate (6) along with reticulatate (5) previously known as a semi-synthetic product of 1. Compounds 1 and 5 showed selectivity in a cell based cytotoxicity assay.     

Trypanocidal constituents of Dracocephalum komarovi

Trypanocidal constituents of Dracocephalum komarovi were investigated. Under guidance of the in vitro trypanocidal activity against epimastigotes of Trypanosoma cruzi, the causative agent of Chagas' disease, two new diterpenes, dracocequinones A (1) and B (2), and two known triterpene acids, ursonic acid and ursolic acid, were isolated as trypanocidal constituents, in addition to previously reported diterpenes, cyclocoulterone (4), komaroviquinone (5), dracocephalone A (6) and komarovispirone (7). Furthermore a new diterpene, komarovinone A (3), was isolated, together with four known terpenes. Among these compounds, komaroviquinone (5) showed the most potent activity with minimum lethal concentration of 0.4 μM. Structure elucidation of the new diterpenes 1-3 was described.     

Facile synthesis of 4-phenylquinolin-2(1H)-one derivatives from N-acyl-o-aminobenzophenones

An efficient synthesis of 4-phenylquinolin-2(1H)-one derivatives has been achieved in a one-pot reaction from N-acyl-o-aminobenzophenones 1a-c (a: acyl=acetyl; b: acyl=propanoyl; c: acyl=heptanoyl) using NaH as a base. Treatment of 1 with NaH provided the quinolones 2a-c with 62-83% yields, whereas the reaction in the presence of alkyl iodide (alkyl=methyl, ethyl, n-octyl) gave the corresponding N-alkylated quinolones 3a-g in 75-95% yields. The alkylation reaction of 4-phenylquinolin-2(1H)-one 2a with alkyl halide gave a mixture of N-alkylated and O-alkylated products. Comparison of IR and NMR data of the N-alkylated and O-alkylated compounds with those of 2a-c indicated that 2a-c exist as the lactam form.     

Anti-Pseudomonas aeruginosa xanthones from the resin and green fruits of Cratoxylum cochinchinense

Cochinchinones I-L (1-3 and 13) along with 11 known xanthones (4-12, 14, and 15) were isolated from the resin and green fruits of Cratoxylum cochinchinense. In addition, four new acetylated compounds (16-19) were derivatized from 7-geranyloxy-1,3-dihydroxyxanthone (14) and 3-geranyloxy-1,7-dihydroxyxanthone (15). All compounds were characterized on the basis of spectroscopic analyses. The structures of cochinchinone I (1), a monoacetate (18) and a dibrosylate (20), were also confirmed by X-ray diffraction analysis. The antibacterial and antifungal activities of selected compounds were evaluated as well.     

Synthesis of N,N′-bis and N,N,N′,N′-tetra-[(3,5-di-substituted-1-pyrazolyl)methyl]para-phenylenediamines: new candidate ligands for metal complex wires

A series of tridentate ligands N,N-bis-[(di-substituted-1-pyrazolyl)methyl]arylamines 2-3a,b and benzylamine 4a,b, tetradentate N,N′-bis-[(di-substituted-1-pyrazolyl)methyl]para-phenylenediamines 7a,b and hexadentate N,N,N′,N′-tetra-[(di-substituted-1-pyrazolyl)methyl]para-phenylenediamines 8a,b has been prepared in good yield by condensation of arylamines, benzylamine or para-phenylenediamine with N-hydroxymethyl disubstituted pyrazoles 1a,b. The synthesis and characterisation of these various polydentate ligands are described.     

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.     

Solvent-free reactions of N,N′-thiocarbonyldiimidazole with ferrocenylcarbinols

The efficient and simple routes for the synthesis of various ferrocenyl derivatives from ferrocenylcarbinols and N,N′-thiocarbonyldiimidazole (TCDI) are described. It involves grinding the two substrates in a Pyrex tube with a glass rod at room temperature. The reaction of ferrocenylmethanol (1a) provided S,S-bis(ferrocenylmethyl)dithiocarbonate (1b), whose crystal structure and a plausible mechanism for its formation are also reported. The reaction of 1-ferrocenyl-1-phenylmethanol (2a) and 1-ferrocenylbutanol (2b) gave the products 2c and 2d, respectively. The reaction of ω-ferrocenyl alcohols 4-ferrocenylphenol (3a) and 6-ferrocenylhexan-1-ol (3b) yielded the products 3c and 3d, respectively. Reaction of 1,1′-ferrocenedimethanol (3e) afforded 3f in moderate yield, and by contrast, it was not similar to 1b. Reaction of [4-(trifluoromethyl)phenyl]methanol (4a) provided the thiocarbonate 4b in good yield.     

An efficient synthesis of furano analogs of duocarmycin C1 and C2: seco-iso-cyclopropylfurano[e]indoline-trimethoxyindole and seco-cyclopropylfurano[f]quinoline-trimethoxyindole

seco-Iso-cyclopropylfurano[e]indoline-trimethoxyindole 1 and seco-cyclopropylfurano[f]quinoline-trimethoxyindole 2 are potent cytotoxic agents. Previous synthesis of these compounds was inefficient and the approach required separation of a mixture containing the isomeric indoline and quinoline intermediates 11 and 12, formed from radical cyclization of allylic bromide 10. Reported herein is an efficient and selective synthesis of either intermediate 11 or 12, thus product 1 or 2, as needed. The conditions of the Stobbe condensation, bromination, 5-exo-trig radical cyclization, amine-carboxylic acid coupling, and debenzylation were optimized for multi gram scale. As a result, the reaction times were shortened, the products were readily isolated, and the yields and purity improved.     

Endo and exo cyclometallated iron carbonyl complexes derived from N-(N′-methyl-2-pyrrolylmethylidene)-2-thienylmethylamine

The reaction of N-(N′-methyl-2-pyrrolylmethylidene)-2-thienylmethylamine (1) with Fe₂(CO)₉ in refluxing toluene gives endo cyclometallated iron carbonyl complexes 2 and 5, exo cyclometallated iron carbonyl complex 3, and unexpected iron carbonyl complex 4. Complexes 2, 3, and 5 are geometric isomers. Complex 5 differs from complex 2 in the switch of the original substituent from α to β position of the pyrrolyl ring, and the pyrrolyl ring bridges to the diiron centers in μ-(3,2-η¹:η²) coordination mode in stead of μ-(2,3-η¹:η²). In complex 4, the pyrrolyl moiety of the original ligand 1 has been displaced by a thienyl group, which comes from the same ligand. Single crystals of 2, 3, and 5 were subjected to the X-ray diffraction analysis. The major product 2 undergoes: (i) thermolysis to recover the original ligand 1; (ii) reduction to form a hydrogenation product, 6, of the original ligand; (iii) substitution to form a monophosphine-substituted complex 7; (iv) chemical as well as electrochemical oxidation to produce a carbonylation product, γ-butyrolactam 8.     

New cytotoxic sesquiterpenes from the red algae Laurencia obtusa and Laurencia microcladia

Three new sesquiterpenes (1-3), along with five known (5-9), were isolated from the organic extract of the red alga Laurencia obtusa, collected from the coastal rocks of Serifos in the Aegean Sea. A new dimeric sesquiterpene of the cyclolaurane-type (4) along with four previously reported (7, 10-12) metabolites, were isolated from the extract of Laurencia microcladia, collected at Chios island in the North Aegean Sea. The structures and the relative stereochemistry of the compounds are proposed on the basis of their spectral data. The cytotoxicity of the isolated metabolites was evaluated against several cell lines including human tumor cell lines.     

Caldaphnidines A-F, six new Daphniphyllum alkaloids from Daphniphyllum calycinum

Six new Daphniphyllum alkaloids, namely caldaphnidines A-F (1-6), together with eight known ones, deoxycalyciphylline B, deoxyisocalyciphylline B, bukittiggine, calycicine A, methyl homosecodaphniphyllate, daphnilactone B, and daphnezomines L-M, were isolated from the leaves and the seeds of Daphniphyllum calycinum. The structure of 1 was determined by a single-crystal X-ray diffraction study, and the structures of 2-6 were established by spectral methods, especially two-dimensional NMR techniques (¹H-¹H COSY, HMQC, HMBC, and NOESY).