Chloctanspirones A and B, novel chlorinated polyketides with an unprecedented skeleton, from marine sediment derived fungus Penicillium terrestre

Two novel chlorinated sorbicillinoids named chloctanspirones A (1) and B (2), possessing an unprecedented bicyclo[2.2.2]octane-2-spiro cyclohexane skeleton, together with their quasi-precursors terrestrols K (3) and L (4), two additional new chlorinated compounds, were isolated from a marine sediment derived fungus Penicillium terrestre. Their structures including absolute stereochemistries were elucidated by analysis of NMR, MS data, and TDDFT CD calculations. The cytotoxic effects of 1-4 were preliminarily evaluated in HL-60 and A-549 cells. Compound 1 was active against both HL-60 and A-549 cells with IC₅₀s 9.2 and 39.7 μM, respectively, while 2 showed weaker activity only against HL-60 cells (IC₅₀ 37.8 μM).     

Aspergiolide A, a novel anthraquinone derivative with naphtho[1,2,3-de]chromene-2,7-dione skeleton isolated from a marine-derived fungus Aspergillus glaucus

Aspergiolide A (1), an anthraquinone derivative with naphtho[1,2,3-de]chromene-2,7-dione skeleton, has been isolated from cultures of a marine-derived fungus Aspergillus glaucus. The structure and stereochemistry of 1 was determined by NMR and X-ray diffraction analyses. Compound 1 showed selective cytotoxicities against A-549, HL-60, BEL-7402, and P388 cell lines.     

Penilactones A and B, two novel polyketides from Antarctic deep-sea derived fungus Penicillium crustosum PRB-2

Two highly oxygenated polyketides, penilactones A and B (1 and 2), containing a new carbon skeleton formed from two 3,5-dimethyl-2,4-diol-acetophenone units and a γ-butyrolactone moiety, together with five known compounds (3-7) were isolated from an Antarctic deep-sea derived fungus Penicillium crustosum PRB-2. Penilactones A and B possess antipodal absolute stereochemistries. Their structures were elucidated by spectroscopic methods, and their absolute configurations were assigned by single-crystal X-ray diffraction and CD analyses. A plausible biogenetic pathway for 1-2 is proposed.     

An NMR study of sequential intermediates and collateral products in the conversion of 1,3,6,8-tetraazatricyclo[4.4.1.1]dodecane (TATD) to 1,3,6,8-tetraazatricyclo[4.3.1.1]undecane (TATU)

In situ ¹H nuclear magnetic resonance spectroscopy was used to investigate the processes that occur during the synthesis of 1,3,6,8-tetraazatricyclo[4.3.1.1^3,8]undecane (TATU). NMR analysis showed a reaction mixture containing more than one compound. The production of these intermediates and collateral products was rationally supported by a careful ¹H NMR monitoring study. We characterized 1,3,5-triazabicyclo[3.2.1]octane (TABO, 4) and 3-(2-aminoethyl)-1,3,5-triazabicyclo[3.2.1]octane (AETABO, 7) by ¹H and ¹³C NMR in D₂O solution inside the NMR sample tube, as an intermediate and collateral product of the reaction, respectively. Further, a reaction of 1,3,6,8-tetraazatricyclo[4.4.1.1^3,8]dodecane (TATD) with ¹⁵N-labeled ammonium chloride was carried out. The ¹⁵N NMR and GC-MS experiments indicated that ¹⁵N was incorporated into TATU, TABO, and urotropine.     

Novel carbon-bridged citrinin dimers from a volcano ash-derived fungus Penicillium citrinum and their cytotoxic and cell cycle arrest activities

Three novel carbon-bridged citrinin dimers, dicitrinones A-C (1-3), were isolated from a volcano ash-derived fungus Penicillium citrinum. Their structures were elucidated by spectroscopic methods. Dicitrinone A (1) and B (2) are two atropisomeric mixtures, which were verified by both NMR and quantum chemical calculations. Their cytotoxicity against four tumor cell lines (HL-60, MOLT-4, A-549, and BEL-7402) was evaluated by SRB and MTT methods. Dicitrinone B (2) arrested the HL-60 cell cycle at the G2/M phase, which was analyzed using flow cytometry.     

Biosynthesis of aspergiolide A, a novel antitumor compound by a marine-derived fungus Aspergillus glaucus via the polyketide pathway

Aspergiolide A, a novel antitumor compound, was produced by a marine-derived filamentous fungus Aspergillus glaucus. The biosynthesis of it was unambiguously determined by feeding experiments using [l-¹³C]sodium acetate, [2-¹³C]sodium acetate, and [1,2-¹³C₂]sodium acetate precursors followed by ¹³C NMR spectroscopic investigation of the isolated products. Analysis of the patterns of ¹³C-enrichment revealed that all 25 carbon atoms in skeleton of aspergiolide A were derived from labeled acetate. And among them, 12 carbon atoms were labeled from the carboxylic group of acetate, while the other 13 carbon atoms were labeled from the methylic group of acetate. Besides, the labeling pattern of [1,2-¹³C₂]sodium acetate feeding experiment demonstrated that 12 intact acetate units were incorporated in aspergiolide A by polyketide pathway.     

Shimalactone A, a novel polyketide, from marine-derived fungus Emericella variecolor GF10

Shimalactone A (1), a novel polyketide having bicyclo[4.2.0]octadiene and oxabicyclo[2.2.1]heptane units, was isolated from a cultured marine fungus of Emericella variecolor GF10. The stereo structure of 1 was deduced from 2D NMR and X-ray crystallographic analyses of 1 and its derivatives. The absolute structure of 1 was determined by application of the CD allylic benzoate rule to the benzoate derivative of 1. Shimalactone A (1) induced neuritogenesis at 10 μg/mL against neuroblastoma Neuro 2A cells.     

A facile approach to tricyclo[6.4.0.04,9]-dodecane framework

The unusual tricyclo[6.4.0.0^4.9]dodecane framework was constructed in eight linear steps in 13%overall yield.An innovative strategy accessing the framework from bicyclo[3.3.1]nonanes was employed.The key steps involve a Robinson annulation,a base induced decarboxylation and epimerization in a single step,and an intramolecular alkylation.     

Benzopyranone,benzophenone, and xanthone derivatives from the soil fungus Penicillium citrinum PSU-RSPG95

Two new benzopyranones, named coniochaetones E (1) and F (2), one new xanthone, penicillone C (3), and one new benzophenone, penicillanone (4), are isolated from the soil fungus Penicillium citrinum PSU-RSPG95, together with ten known compounds. Their structures are identified on the basis of spectroscopic data. The isolated compounds are evaluated for their cytotoxic activity.     

Penioxalamine A,a novel prenylated spiro-oxindole alkaloid from Penicillium oxalicum TW01-1

Penioxalamine A (1), a novel prenylated spiro-oxindole alkaloid having a unique seven-membered nitrogen heterocycle system, was isolated from the fungus Penicillium oxalicum TW01-1. The structure of 1 was elucidated on the basis of the spectral data, single-crystal X-ray diffraction, and CD analysis. Compound 1 showed moderate cytotoxicity against HL-60 cell line. The possible biosynthetic pathway of 1 was also proposed.     

Simple NMR method for assigning relative stereochemistry of bridged bicyclo[3.n.1]-2-enes and tricyclo[7.n.1.0]-2-enes

The stereochemistry of syn and anti-forms of bridged bicyclo[3.n.1]-2-ene, tricyclo[7.n.1.0]-2-ene (n=1-3) and bicyclo[4.3.1]dec-7-ene derivatives can be assigned from the ¹³C chemical shift difference of the double bond. Both syn-9-R-bicyclo[3.3.1]non-2-enes and syn-13-R-tricyclo[7.3.1.0^2,7]tridec-2(7)-enes have a large shielding difference between sp² carbons, while the corresponding anti-forms have a smaller one. In contrast, 8-R-bicyclo[3.2.1]oct-2-enes and 12-R-tricyclo[7.2.1.0^2,7]dodec-2(7)-enes have an inverse correlation. The reason of this specificity is the influence of the γ-gauche effect on the chemical shift of C(2) atom. The GIAO theory has been applied to investigate the ¹³C chemical shifts. The conformational equilibrium in the formamide group of 13-formylamino-tricyclo[7.3.1.0^2,7]tridec-2(7)-enes has been studied.     

A novel transformation of 1-exo-substituted 2a-aroyl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones with sulfoxonium ylide to highly strained 2a-(1-arylethenyl)-1,2,2a,7b-tetrahydrocyclobuta[b]benzofurans

When 1-substituted 2a-aroyl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones (1) were treated with dimethylsulfoxonium methylide, 1-endo isomers (endo-1) gave 1-substituted 3-aroyl-1,2,4a,9b-tetrahydrodibenzofuran-4-ols (2) exclusively as expected. On the other hand, 1-exo isomers (exo-1) underwent a novel transformation to 1-substituted 2a-(1-arylethenyl)-1,2,2a,7b-tetrahydrocyclobuta[b]benzofurans (3), together with 2.     

Neoverataline A and B, two antifungal alkaloids with a novel carbon skeleton from Veratrum taliense

Bioassay-guided fractionation of the ethanol extract of the roots and rhizomes of Veratrum taliense yielded two new and thirteen known steroidal alkaloids. The structures of the two new compounds, neoverataline A and B, were established by extensive spectroscopic analyses to be 3,4-secocevane-4,9-olid-14,15,16,20-tetra-ol-3-oic acid and 3,4-secocevane-4,9-olid-7,14,15,16,20-penta-ol-3-oic acid, respectively, and are a novel carbon skelton. All of the fifteen alkaloids were subjected to in vitro antifungal assays, which showed that the verazine- (veramitaline, stenophylline B, stenophylline B-3-O-β-d-glucopyranoside, veramiline-3-O-β-d-glucopyranoside) and jerveratrum-type (jervine, jervine-3-O-β-d-glucopyranoside) alkaloids exhibited strong antifungal activities against the phytopathogenic fungus Phytophthora capisis with MICs of 160, 120, 160, 80, 80 and 120 μg·L⁻¹, respectively. Furthermore, the verazine-type alkaloids stenophylline B, stenophylline B 3-O-β-d-glucopyranoside and veramiline 3-O-β-d-glucopyranoside were shown to also inhibit the growth of another fungal phytopathogen Rhizoctonia cerealis with MICs of 160, 120 and 120 μg mL⁻¹. The MICs of triadimefon (an antifungal agrochemical used herein as a positive control) against P. capisis and R. cerealis were 120 and 80 μg mL⁻¹, respectively. A preliminary structure-activity relationship regarding these alkaloids has been formulated.     

One pot synthesis of imidazo[2,1-b]thiazoles and benzo[d]thiazolo[3,2-a]imidazoles

A series of imidazo[2,1-b]thiazole and benzo[d]thiazolo[3,2-a]imidazole analogues were synthesized by stirring an equimolar mixture of dibenzoylacetylene with imidazole/thiazole derivatives in toluene or acetonitrile at room temperature. The products were generated in good yields and characterized by standard analytical techniques such as IR, ¹H NMR, ¹³C NMR and mass spectrometry. The structure of products 19, 20, 22, 24 and 25 were also unambiguously confirmed by single crystal X-ray analysis.     

Preparation of novel pyridine-fused tris-heterocycles; pyrido[4,3-e]pyrrolo-/pyrido[4,3-e]furano[2,3-c]pyridazines and pyrido[3,4-b]pyrrolo[3,2-d]pyrrole

Three novel pyrido-fused tris-heterocycles have been prepared based on a Suzuki coupling and subsequent cyclisation approach. Pyrido[4,3-e]pyrrolo[2,3-c]pyridazine (3b, 77%) and pyrido[4,3-e]furano[2,3-c]pyridazine (5b, 76%) were obtained by intramolecular diazocoupling. Successful diazocoupling of furan (5b) is thus reported for the first time by NOBF₄ generation of the diazonium intermediate. N-TIPS-pyrido[3,4-b]pyrrolo[3,2-d]pyrrole (TIPS-4b) was synthesised by thermal cyclisation of pyridyl nitrene in considerably higher yield (71%) than previously experienced from similar cyclisations, due to TIPS-activation.     

Microwave-assisted synthesis of novel N-(4-phenylthiazol-2-yl)-benzo[d]thiazole-, thiazolo[4,5-b]pyridine-, thiazolo[5,4-b]pyridine- and benzo[d]oxazole-2-carboximidamides inspired by marine topsentines and nortopsentines

We report the synthesis of novel N-(4-phenylthiazol-2-yl)-substituted benzo[d]thiazole-, thiazolo[4,5-b]pyridine-, thiazolo[5,4-b]pyridine- and benzo[d]oxazole-2-carboximidamides, which were inspired by marine topsentines and nortopsentines. Condensation of 4,5-dichloro-1,2,3-dithiazolium chloride (Appel salt) with various ortho-halogenated anilines, aminopyridines and aminophenols gave the corresponding aryliminodithiazoles in good to excellent yields. Copper(I)-mediated or nucleophilic-assisted cyclization of aryliminodithiazoles furnished cyano-functionalized benzo[d]thiazoles, thiazolo[4,5-b]- and thiazolo[5,4-b]-pyridines and benzo[d]oxazoles. The latter were condensed with substituted 4-phenylthiazol-2-amines to furnish twenty seven new polyaromatic carboximidamides in moderate to good yields.     

Zyzzyanone A, a novel pyrrolo[3,2-f]indole alkaloid from the Australian marine sponge Zyzzya fuliginosa

A new dipyrroloquinone, zyzzyanone A 1, having a pyrrolo[3,2-f]indole-4,8(1H,7H)-dione skeleton, was isolated from the Australian marine sponge Zyzzya fuliginosa, along with the known pyrroloquinoline alkaloids, makaluvamines C, E, G, H, and L, and damirones A and B. The structure of 1 was determined by spectroscopic data. Zyzzyanone A 1 shows moderate cytotoxic activity against mouse Ehrlich carcinoma cells (IC₅₀ 25 μg/mL), inhibits the cell division of fertilized sea urchin eggs at a concentration of 25 μg/mL, and exhibits UV-A and UV-B absorbing activity.     

2-Oxobenzo[h]chromene: a novel entry for the concise and efficient synthesis of indeno[1,2-c]phenanthrenes

An efficient and concise synthesis of 7-sec-amino-5,13-dihydro-6H-indeno[1,2-c]phenanthrene-8-carbonitriles is described through base catalyzed ring transformation of 4-sec-amino-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles with 1-indanone in moderate to good yields.     

Enantiospecific approach to the tricyclic core structure of tricycloillicinone, ialibinones, and takaneones via ring-closing metathesis reaction

Enantiospecific synthesis of the tricyclic core structure present in the biologically active natural products tricycloillicinone, ialibinones, and takaneones, starting from the readily available campholenaldehyde employing a transannular RCM reaction as the key step, has been accomplished.     

A simple and effective approach to the synthesis of pyrido[4,3,2-mn]pyrrolo[3,2,1-de]acridine skeleton of arnoamines A and B, pentacyclic marine alkaloids from the ascidian Cystodytes sp.

Starting from ethyl 5-hydroxy-2-methyl-1-phenylindole-3-carboxylate, a simple and effective approach to the synthesis of pyrido[4,3,2-mn]pyrrolo[3,2,1-de]acridine skeleton of arnoamines A and B, unique pentacyclic alkaloids from the ascidian Cystodytes sp., has been developed. Synthesis of this ring system involves seven steps and produces ethyl 4-methoxy-1-methylpyrido[4,3,2-mn]pyrrolo[3,2,1-de]acridine-2-carboxylate in 41.5% overall yield.