Total Synthesis,Absolute Configuration,and Biological Activity of Xyloallenoide A

The novel natural product xyloallenoide A, isolated from the marine mangrove endophytic fungus from the South China Sea, and its diastereoisomer xyloallenoide A1, which contain N‐methyl‐substituted amino acids, were synthesized. The absolute configurations of the amino acid units of xyloallenoide A were finally confirmed to be L ‐Lys, Me‐D ‐Val, and Me‐L ‐Ala. This report represents a practical and attractive alternative for the synthesis of N‐methyl‐substituted cyclotripeptides. In the preliminary bioassay, synthetic xyloallenoide A showed marginal activities against KB (IC₅₀=9.6 μM ) and KBv200 cells (IC₅₀=10.3 μM ), and xyloallenoide A1 was inactive against KB and KBv200 cells.     

Total Synthesis of the Proposed Structure of Ardimerin,and Proposal for its Structural Revision

We report the first total synthesis of the proposed structure of ardimerin, which was achieved in 14 steps starting from 2,3,4‐trimethoxybenzoic acid. The key steps include the β‐selective formation of the crucial C‐glycoside linkage and stepwise construction of the strained eight‐membered salicylide core. The synthesis revealed that the proposed structure 1 does not match the natural product. A proposal is made for reassigning the isolated natural product to the already known structure of bergenin. Interesting properties of the synthetic eight‐membered salicylides are documented, including their susceptibility toward nucleophilic ring opening and the bowl chirality.     

Total Synthesis Confirms Laetirobin as a Formal Diels–Alder Adduct

Laetirobin, isolated from a parasitic fungus host–plant relationship, was synthesized in six practical steps with an overall yield of 12 % from commercially available 2,4‐dihydroxyacetophenone. Because the product is a pseudosymmetric tetramer of benzo[b]furans, each step of the synthesis was designed to involve tandem operations. Highlights include: 1) the double Sonogashira reaction of a bis(alkyne), 2) the practical copper(I)‐mediated formation of a bis(benzo[b]furan), and 3) the biomimetic [4+2] dimerization and unexpected cationic [5+2] annulation of gem‐diaryl alkene precursors. Preliminary structure–activity relationship data between the isomeric [4+2] and [5+2] tetramers revealed only the natural product to possess promising anticancer potential. Specifically, laetirobin is capable of blocking tumor cell division (mitosis) and invoking programmed cell death (apoptosis).     

Benzodiazepine Alkaloids from Marine‐Derived Endophytic Fungus Aspergillus ochraceus

A new fungus‐derived benzodiazepine analogue, 2‐hydroxycircumdatin C ( 1 ), and a compound which has been isolated from a natural resource for the first time, but has been previously synthesized, namely (11aS)‐2,3‐dihydro‐7‐methoxy‐1H‐pyrrolo[2,1‐c][1,4]benzodiazepine‐5,11(10H,11aH)‐dione ( 2 ), along with five structurally related known alkaloids ( 3 – 7 ), were isolated from Aspergillus ochraceus, an endophytic fungus derived from the marine brown alga Sargassum kjellmanianum. Their structures were established on the basis of spectroscopic methods. The absolute configuration of 1 was determined through CD evidence. Compound 1 displayed significant DPPH radical‐scavenging activity with an IC₅₀ value of 9.9 μM , which is 8.9‐fold more potent than that of butylated hydroxytoluene (BHT), a well‐known synthetic positive control.     

Antimicrobial Depsides Produced by Cladosporium uredinicola,an Endophytic Fungus Isolated from Psidium guajava Fruits

Four depsides, all of them new as natural products, were isolated from Cladosporium uredinicola solid‐media culture and identified as 3‐hydroxy‐2,5‐dimethylphenyl 2,4‐dihydroxy‐3,6‐dimethylbenzoate ( 1 ), 3‐hydroxy‐2,4,5‐trimethylphenyl 2,4‐dihydroxy‐3,6‐dimethylbenzoate ( 2 ), 3‐hydroxy‐2,5‐dimethylphenyl 3‐[(2,4‐dihydroxy‐3,6‐dimethylbenzoyl)oxy]‐6‐hydroxy‐2,4‐dimethylbenzoate ( 3 ), and 3‐hydroxy‐2,4,5‐trimethylphenyl 3‐[(2,4‐dihydroxy‐3,6‐dimethylbenzoyl)oxy]‐6‐hydroxy‐2,4‐dimethylbenzoate ( 4 ). The endophytic fungus was isolated from Psidium guajava fruits and cultivated over sterilized rice. The compounds 1 – 4 were purified by classical chromatographic procedures, and the chemical structures were identified by spectroscopic studies, mainly 1D‐ and 2D‐NMR and LC/ESI‐MS/MS. Three of the isolated depsides exhibited moderate bacteriostatic and/or bactericide effects on Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Bacillus subtillis.     

Guignardic Acid,a Novel Type of Secondary Metabolite Produced by the Endophytic Fungus Guignardia sp.: Isolation,Structure Elucidation,and Asymmetric Synthesis

A UV‐guided fractionation of the AcOEt extract of the fermentation broth of Guignardia sp., an endophytic fungus from the leaves of the tropical tree Spondias mombin, resulted in the identification of the new metabolite (−)‐(2S,5Z)‐2‐(1‐methylethyl)‐4‐oxo‐5‐(phenylmethylene)‐1,3‐dioxolane‐2‐carboxylic acid ( 1 ), isolated as NH salt 1a . The metabolite 1 was designated (−)‐(S)‐guignardic acid. This first member of a new class of natural compounds contains a dioxolanone moiety formed by fusion of 2‐oxo‐3‐phenylpropanoic acid (phenylpyruvic acid) and 3‐methyl‐2‐oxobutanoic acid (dimethylpyruvic acid), products of the oxidative deamination of phenylalanine and valine, respectively. The structure of 1a was deduced from spectral data (UV, IR, MS, ¹H‐ and ¹³C‐NMR) and confirmed by asymmetric synthesis.     

An efficient high‐speed countercurrent chromatography method for preparative separation of javanicin from Fusarium solani,a fungus isolated from the fruiting body of the mushroom Trametes trogii

To develop an efficient method for large preparation of javanicin from Fusarium solani, a rapid and simple method by high‐speed countercurrent chromatography was established based on average polarity (P′ values) and partition coefficients (K values) of crude samples. A suitable solvent system for high‐speed countercurrent chromatography was selected from many possible biphasic solvent systems. HSCCC was successfully applied to separate and purify javanicin, the main bioactive component of solid cultures of the fungus F. solani isolated from the fruiting body of Trametes trogii, with petroleum ether–ethyl acetate–methanol–water (4:3:2:1, v/v) as solvent system. A total amount of 40.6 mg of javanicin was obtained from 100 mg crude sample. The purity of javanicin was 92.2% with a recovery of 95.1%, as determined by high‐performance liquid chromatrography. The molecular structure was identified primarily by NMR and MS methods. The results indicated that high‐speed countercurrent chromatography could be a powerful technology for separating naphthoquinones from the solid cultures of the fungus F. solani. It is also of significance that the separation of javanicin from natural source was carried out for the first time utilizing high‐speed countercurrent chromatography.     

A Convergent Synthesis of a Twelve‐Membered Macrolide Natural Product, (6R,12S)‐6‐Hydroxy‐12‐methyl‐1‐oxacyclododecane‐2,5‐dione

A new polyketide metabolite, the twelve‐membered macrolide 1 , isolated from the endophytic fungal strain Cladosporium tenuissimum LR 463 of Maytenus hookeri, whose structure had been determined as (6R,12S)‐6‐hydroxy‐12‐methyl‐1‐oxacyclododecane‐2,5‐dione, was synthesized for the first time by a convergent strategy via Yamaguchi esterification of 2 with 3 and ring‐closing metathesis (RCM) to afford the cyclic ester 1 that was eventually transformed to the target molecule. However, the total synthesis revealed that the assigned structure of the natural product is not correct.     

Biomimetic Synthesis of Rhytidenone A and Mode of Action of Cytotoxic Rhytidenone F

The rhytidenone family comprises spirobisnaphthalene natural products isolated from the mangrove endophytic fungus Rhytidhysteron rufulum AS21B. The biomimetic synthesis of rhytidenone A was achieved by a Michael reaction/aldol/lactonization cascade in a single step from the proposed biosynthetic precursor rhytidenone F. Moreover, the mode of action of the highly cytotoxic rhytidenone F was investigated. The pulldown assay coupled with mass spectrometry analysis revealed the target protein PA28γ is covalently attached to rhytidenone F at the Cys92 residue. The interactions of rhytidenone F with PA28γ lead to the accumulation of p53, which is an essential tumor suppressor in humans. Consequently, the Fas‐dependent signaling pathway is activated to initiate cellular apoptosis. These studies have identified the first small‐molecule inhibitor targeting PA28γ, suggesting rhytidenone F may serve as a promising natural product lead for future anticancer drug development.     

Discovery,Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide,a Symmetrical Glycosylated Macrolide Dimer from Marine Cyanobacteria

A new dimeric macrolide xylopyranoside, cocosolide ( 1 ), was isolated from the marine cyanobacterium preliminarily identified as Symploca sp. from Guam. The structure was determined by a combination of NMR spectroscopy, HRMS, X‐ray diffraction studies and Mosher's analysis of the base hydrolysis product. Its carbon skeleton closely resembles that of clavosolides A–D isolated from the sponge Myriastra clavosa, for which no bioactivity is known. We performed the first total synthesis of cocosolide ( 1 ) along with its [α,α]‐anomer ( 26 ) and macrocyclic core ( 28 ), thus leading to the confirmation of the structure of natural 1 . The convergent synthesis featured Wadsworth–Emmons cyclopropanation, Sakurai annulation, Yamaguchi macrocyclization/dimerization reaction, α‐selective glycosidation and β‐selective glycosidation. Compounds 1 and 26 potently inhibited IL‐2 production in both T‐cell receptor dependent and independent manners. Full activity requires the presence of the sugar moiety as well as the intact dimeric structure. Cocosolide also suppressed the proliferation of anti‐CD3‐stimulated T‐cells in a dose‐dependent manner.     

Dicitrinol,a Citrinin Dimer,Produced by Penicillium janthinellum

A citrinin dimer, named dicitrinol ( 3 ), was isolated from extracts obtained from a rice cultivation of Penicillium janthinellum, a fungus found in fruits of Melia azedarach. Dicitrinol ( 3 ) was isolated by classical chromatographic procedures, and identified by MS, and 1D‐ and 2D‐NMR data. A biosynthetic scheme is proposed for this new dimerization of citrinin. Dicitrinol ( 3 ) was shown to be slightly weaker than citrinin regarding bacterial inhibition.     

A New Hydrolyzable Tannin from Balanophora harlandii with Radical‐Scavenging Activity

One new hydrolyzable tannin, 1‐O‐[(E)‐p‐coumaroyl]‐3‐O‐galloyl‐β‐D ‐glucopyranose ( 1 ), was isolated from the rhizome of Balanophora harlandii, together with 18 known phenolic compounds. Their structures were determined by detailed spectroscopic analysis. Of the known compounds, 3‐O‐caffeoyl‐D ‐glucopyranose ( 6 ) was obtained as a natural product for the first time, and compounds 2 – 6 and 8 – 19 were identified for the first time from this plant. The radical‐scavenging activity of the isolated compounds was tested by a DPPH assay.     

Two-Photon Absorption and Cell Imaging of Fluorene-Functionalized Epicocconone Analogues

Epicocconone 1 is a natural chromophore isolated from the fungus Epicoccum nigrum that has shown applications in proteomics and fluorescent microscopy thanks to its unique pro-fluorescence properties. The modification of the skeleton of the natural product by replacing the triene side chain by a fluorenyl scaffold can noticeably increase the fluorophore's absorption coefficient. The synthesis of the analogues of the natural product has been made possible by the use of a palladium-catalyzed carbonylation reaction, allowing the construction of the β-keto-dioxinone key intermediate. Two-photon absorption cross-section measurements of the fluorenyl epicocconone analogues show a structure dependency with values ranging from 60 to 280 GM and live cell imaging show intense staining of intracellular vesicle-like structures around the nucleus.     

A Novel Endophytic Taxol-Producing Fungus <Emphasis Type="Italic">Chaetomella raphigera</Emphasis> Isolated From a Medicinal Plant, <Emphasis Type="Italic">Terminalia arjuna</Emphasis>

Taxol is the most important member of the clinically useful natural anticancer drug. An endophytic fungus Chaetomella raphigera (strain TAC-15) was isolated from a medicinal plant Terminalia arjuna and screened for its potential in Taxol production. The fungus was identified based on the morphology of the fungal culture and the characteristics of the spores. This fungus was grown in MID liquid medium and analyzed by chromatographically and spectrometrically for the presence of Taxol. The amount of Taxol produced by this endophytic fungus was quantified by HPLC which showed that it produced 79.6 μg/L, and further confirmative analyses were done by using UV, IR, FAB mass spectroscopy, and NMR spectroscopy. Thus, the fungus can serve as a potential material for fungus engineering to improve the production of Taxol.     

Bacterial production of the fungus‐derived cholesterol‐lowering agent mevinolin

Forty‐five strains from two different species (Salinispora arenicola and Salinispora pacifica) were isolated from three different marine sponge species in the Great Barrier Reef region of Australia. We found that two of the strains of Salinispora arenicola (MV0335 and MV0029) produced mevinolin, a fungus‐derived cholesterol‐lowering agent. Compound structure was determined using an integrated approach: (a) high performance liquid chromatography‐quadrupole time‐of‐flight‐mass spectrometric analysis with multimode ionization (electrospray ionization and atmospheric pressure chemical ionization) and fast polarity switching; and (b) database searching and matching of monoisotopic masses, retention times and mass spectra of the precursor and product ions of the compounds of interest and the authentic reference standards thereof. Copyright © 2014 John Wiley & Sons, Ltd.     

Structure and Absolute Configuration of Aspergilumamide A,a Novel Lumazine Peptide from the Mangrove‐Derived Fungus Aspergillus sp.

A novel lumazine peptide, aspergilumamide A ( 1 ), as well as a known analog penilumamide ( 2 ), were isolated from the mycelia of a marine‐derived fungus Aspergillus sp. (33241), obtained from the mangrove Bruguiera sexangula var. rhynchopetala collected from the South China Sea. The structure of 1 was identified by comprehensive spectroscopic analysis, including 1D‐ and 2D‐NMR, ESI‐MS, and MS/MS experiments. The absolute configuration of 1 was determined by Marfey's method.     

Scobidiynediol的合成及绝对构型

本文报道了以光学活性乳酸为手性元对目标化合物的所有可能的四个异构体所进行的合成。根据合成样品与天然产物的核磁及旋光数据比较，标题化合物的相对及绝对构型都得以完全确立，其完整结构定为(2S,3S)-4,6-庚二炔-2,3-二醇。     

Unprecedented 1,14‐seco‐Crotofolanes from Croton insularis: Oxidative Cleavage of Crotofolin C by a Putative Homo‐Baeyer–Villiger Rearrangement

EBC‐162 isolated from Croton insularis, obtained from the northern rainforest of Australia, was structurally affirmed as crotofolin C ( 4 ). Novel oxidative degradation products, EBC‐233 and EBC‐300, which are the first crotofolane endoperoxides, were also isolated. Both endoperoxides were found to be stable intermediates, which are proposed to undergo an unprecedented homo‐Baeyer–Villiger biosynthetic rearrangement to give a new class of 1,14‐seco‐crotofolane diterpenes. Prolonged storage of all isolates assisted in authenticating their natural product status. Anticancer activities of reported compounds are presented.     

Xanthones and Oxepino[2, 3‐b]chromones from Three Endophytic Fungi

Three new metabolites, microsphaeropsones A–C ( 1 – 3 ) with a unique oxepino[2,3‐b]chromen‐6‐one (ring‐enlarged xanthone) skeleton, were isolated from the endophytic fungus Microsphaeropsis species, co‐occurring with their putative biogenetic anthraquinoide precursors citreorosein ( 4 ) and emodin ( 5 ). From another Microsphaeropsis species, large amounts of fusidienol A ( 8 a ), smaller amounts of emodin ( 5 ), the known aromatic xanthones 9 a and 9 b , the new 3,4‐dihydrofusidienol A ( 8 b ), and the new aromatic xanthone 9 c were isolated. The endophyte Seimatosporium species produced a new aromatic xanthone, seimatoxanthone A ( 10 ), and 3,4‐dihydroglobosuxanthone A ( 12 ), closely related to α‐diversolonic ester ( 13 ) from Microdiplodia sp.. The structures were determined mainly by extensive 1D and 2D NMR experiments and supported by X‐ray single‐crystal analysis of 1 and the oxidation product 7 . The absolute configurations of the microsphaeropsones A–C ( 1 – 3 ) were established by comparison of the electronic and vibrational circular dichroism (ECD and VCD) spectra of 1 with time‐dependent DFT (TDDFT) and DFT calculations by using either the solid‐state structures or DFT‐optimized geometries as inputs. Preliminary studies indicated that 1 , 2 , and enone 7 showed antibacterial, fungicidal, and algicidal properties.     

First Total Synthesis of Desmosdumotin C †

Abstract

Desmosdumotin C (1), a novel compound isolated from the roots of Desmos dumosus, was synthesized from 2,4,6‐trihydroxyacetophenone (2), confirming the assigned structure of the natural product.