The dihydrofuran template approach to furofuran synthesis

Flash vacuum pyrrolysis of vinyl epoxides provides cis-dihydrofuran carboxylic esters in good yields and diastereoselectivities, which, on base-promoted epimerisation afford the complementary trans series. The compounds provide a viable template for a Lewis acid promoted cyclisation to provide the 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane core found in the furofuran series of natural lignans. This strategy is stereodivergent and can be controlled to provide the exo-exo, exo-endo or endo-endo stereochemistries. The approach has been exemplified in syntheses of the sesamyl furofurans (+/-)-epiasarinin and (+/-)-asarinin.     

A general strategy for the diastereoselective synthesis of 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane lignans

A strategy for the stereoselective synthesis of all the possible diastereoisomers of the 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane (furofuran) lignans from a single dihydrofuran precursor is described. The key steps involve a diastereocontrolled templated cationic cyclization followed by stereoselective reduction of the resulting methyl glycoside.     

Furofuranic glycosylated lignans: a gas-phase ion chemistry investigation by tandem mass spectrometry

Alkali metal cation adducts, [M+Alk](+), and [M-H](-) ions of four known glycosylated furofuran lignans, (+)-pinoresinol 4-O-beta-D-glucopyranoside, (+)-phylliroside, (+)-8-hydroxypinoresinol 4-O-beta-D-glucopyranoside, and (+)-8-hydroxypinoresinol 8-O-beta-D-glucopyranoside, recently isolated from Carex distachya, were generated by electrospray ionization and allowed to undergo collisionally activated dissociation (CAD) in a quadrupole ion trap (QIT) and in a triple quadrupole (TQ) mass spectrometer. CAD mass spectra of [M+Na](+) and [M+Li](+) adducts revealed the presence of structurally diagnostic product ions. CAD mass spectra of deprotonated glycosylated furofuran lignans showed the typical neutral loss of 162 Da when the glucose residue was bound to a phenolic oxygen atom. When glycosylation occurred at an alcoholic oxygen, as for (+)-8-hydroxypinoresinol 8-O-beta-D-glucopyranoside, a neutral loss of 180 Da represented the main fragmentation pathway. Selective hydrogen/deuterium (H/D) exchange of all the acidic hydrogen atoms of furofuran glycosides, performed by introducing lignan glycosides in D(2)O/CH(3)OD solutions, were employed to obtain information on the nature of the product ions generated during TQ/CAD processes. Energy-resolved TQ/CAD mass spectra of deprotonated lignan glycosides and their deprotonated aglycones were used in a qualitative way to infer information on the integrated energetic picture of CAD fragmentations and to investigate the mechanism of the predominant dissociation/isomerization processes. On the basis of the hypothesized fragmentation mechanisms, gas-phase features of the furofuran ring were derived. The presence of an OH substituent in the C8 position decreased the electron density in the adjacent C8' position, modifying the fragmentation pathway.     

Furofuran Lignans from Cuscuta chinensis

Three furofuran lignans named neocuscutasides A, B and C were obtained from the ethanolic extract of the dried seeds of Cuscuta chinensis and their structures were characterized by chemical and spectroscopic methods.     

Spurring radical reactions of organic halides with tin hydride and TTMSS using microreactors

Tributyltin hydride-mediated radical reactions of organic halides were successfully carried out in a continuous flow system using a microreactor. The reactions proceeded within a very short period of time, coupled with quickly decomposing radical initiators such as V-65 and V-70. The continuous flow reaction system was applied to gram scale synthesis of a key intermediate for furofuran lignans.     

Oxygen insertion in Sesamum indicum furanofuran lignans. Diastereoselective syntheses of enzyme substrate analogues

The furofuran lignans in sesame seed have an unusual oxygen insertion between their furan and aryl rings. In our continuing investigations on the isolation and characterization of the enzyme(s) involved, the diastereoselective syntheses of various substrate analogues for the oxygen insertion step were developed for future substrate specificity and inhibitor studies. This synthetic strategy also provided entry to so-called furofuranone epoxy-lignans, such as salicifoliol from Bupleurum sp., and acuminatolide from Helichrysum sp.     

Cytotoxic lignans from the stems of Styrax camporum (Styracaceae)

An ethanolic extract from the stems of Styrax camporum Pohl (Styracaceae), a plant traditionally used for gastrointestinal diseases, was fractionated and subjected to flash chromatography and afforded two benzofuran lignans, egonol and homoegonol, and one furofuran lignan, (+/-)syringaresinol, which were identified by spectral data interpretation. Their cytotoxic activities against Hep-2 (larynx epidermoid carcinoma), HeLa (human cervix carcinoma) and C6 (rat glioma) cell lines were evaluated using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay at several concentrations for 24h. Activities could be observed for egonol against C6 (IC50 = 3.2 microg/mL) and Hep-2 (IC50 = 3.6 microg/mL) cell lines, and for homoegonol against C6 (IC50 = 4.9 microg/mL) and HeLa (IC50 = 5.3 microg/mL) cells.     

Regioselective route for arylnaphthalene lactones: convenient synthesis of taiwanin C,justicidin E,and daurinol

Arylnaphthalene lactones are natural products which can be isolated from a wide range of plants and have the significant biological activities including cytotoxicity, antimicrobial, diuretic, and ion channel blocking. The drawback of the previous intramolecular Diels–Alder reaction of 3-arylprop-2-ynyl 3-arylpropiolates was to generate two regioisomers of arylnaphthalene lactone without selectivity. Herein, we report a convenient and regioselective synthesis method in which the intramolecular Diels–Alder reaction of an arylalkene–arylalkyne and subsequent DDQ oxidation was used for Type I and Type II arylnaphthalene lactones, respectively. We demonstrated the synthesis of three lignans, taiwanin C (Type I), justicidin E (Type II), and daurinol (Type I and anti-cancer activity).     

Stereospecific synthesis of endo-endo-3,7-dioxabicyclo[3.3.0]octane lignans using 1,6-bis(dipropylboryl)-2,4-hexadiene

A general methodology for the stereoselective synthesis of compounds of the 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane series was developed. The strategy includes allylboration of aromatic aldehydes with 1,6-bis(dialkylboryl)-2,4-hexadiene, ozonolysis of the thus obtained 1,4-diaryl-2,3-divinyl-1,4-diols, and subsequent intramolecular cyclization. This methodology was used for obtaining the naturally occurring lignans of the furofuran series, viz., diaeudesmin, diayangambin, epiasarinin, epieudesmin, epiyangambin, and asarinin.     

Structural basis for the potential antitumour activity of DNA-interacting benzo[kl]xanthene lignans

The biological properties and possible pharmacological applications of benzo[kl]xanthene lignans, rare among natural products and synthetic compounds, are almost unexplored. In the present contribution, the possible interaction of six synthetic benzo[kl]xanthene lignans and the natural metabolite rufescidride with DNA has been investigated through a combined STD-NMR and molecular docking approach, paralleled by in vitro biological assays on their antiproliferative activity towards two different cancer cell lines: SW 480 and HepG2. Our data suggest that the benzo[kl]xanthene lignans are suitable lead compounds for the design of DNA selective ligands with potential antitumour properties.     

The Synthesis of 4-Arylcarbonyl-3-methoxycarbonyl-2-phenylfurans by Friedel-Crafts Acylation Reactions

Keto esters 8, 4-arylcarbonyl-3-methoxycarbonyl-2-phenylfurans, potential precursors of the synthesis of furofuran lignans, were obtained from dimethyl 2-phenylfuran-3,4-dicarboxylate 2.Diester 2 was selectively hydrolyzed to monoacid 6 followed by converting to its acid chloride 7.Friedel-Crafts acylation reactions of 7 with aromatic compounds afforded keto esters 8.The geometric structures of 8 and its precursors were elucidated and verified by NMR spectra.     

Chromatographic Determination of Lignans (Antioxidants) in Food Products

Interest in lignans is continually growing in recent years because of their strong antioxidant properties and other biological characteristics, positively affecting human health. Methods for the extraction, identification, and determination of lignans are developed; lignan species and their quantity in food products are determined, and databases of lignans in food products have been created in several countries (Finland, Netherlands, United States, Canada, United Kingdom, Japan, and Spain). In this review, we consider chromatographic methods (gas, liquid, supercritical fluid, and thin-layer chromatography) used to identify and determine natural lignans and isolate them in an individual state. Most natural lignans are found in flax and sesame seeds, cereals, some vegetables, fruits, and berries.     

Tetrahydrofuran lignans via tandem oxidative anionic-radical processes or reductive radical cyclizations

Several tetrahydrofuran lignans have become important due to their diverse biological activities. We present initial studies on short syntheses of some of the simplest members of this natural product class. Galgravin and Veraguensin are obtained in only three or four steps from nitroalkenes and allylic alcohols via a new tandem anionic-radical process, and reductive radical cyclizations of beta-nitro ethers derived from the same precursors are suitable to obtain Galgravin as well as Galbelgin and Ganschisandrin.     

The Genus Haplophyllum Juss.: Phytochemistry and Bioactivities—A Review

Herein, a comprehensive review is given focusing on the chemical profiles of the essential oils (EOs), non-volatile compounds, ethnobotany, and biological activities of different Haplophyllum (Rutaceae family) species. To gather the relevant data, all the scientific databases, including Scopus, ISI-WOS (Institute of Scientific Information-Web of Science), and PubMed and highly esteemed publishers such as Elsevier, Springer, Taylor and Francis, etc., were systematically retrieved and reviewed. A wide array of valuable groups of natural compounds, e.g., terpenoids, coumarins, alkaloids, lignans, flavonoids, and organic acids have been isolated and subsequently characterized in different organic extracts of a number of Haplophyllum species. In addition, some remarkable antimicrobial, antifungal, anti-inflammatory, anticancer, cytotoxic, antileishmanial, and antialgal effects as well as promising remedial therapeutic properties have been well-documented for some species of the genus Haplophyllum.     

Characterization of phenolic compounds in the fruits of Forsythia suspensa by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry

Phenolic compounds are the major bioactive constituents of Forsythia suspensa, an important Chinese herbal medicine used for the treatment of various infectious diseases. Fragmentation behaviors of the phenolic compounds in F. suspensa were investigated by using a high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS(n)) method. For common phenylethanoid glycosides, the loss of the caffeoyl moiety was the first fragmentation step, then sequential losses of rhamnose, hexose and water were observed in further fragmentations. If a substituent group presented in the beta position, the fragmentation was triggered by initial loss of a substituent group to form structures such as suspensaside A. Then it underwent the common fragmentation pathways as mentioned above, or eliminated characteristic residues of masses 134 or 152 Da, respectively. The latter pathway is reported here for the first time. The fragmentation behaviors of furofuran lignans displayed a typical cleavage of the tetrahydrofuran ring. However, the presence of a hydroxyl group at C-1 led to the successive loss of 30 Da. Neutral loss of CO(2) and benzyl cleavage were characteristic for lignans with a 2,3-dibenzylbutyrolactone skeleton. A neutral loss of 30 Da was also observed in the fragmentation pattern of flavonols. These fragmentation rules were implemented to analyze phenolic compounds in the fruits of F. suspensa. A total of 51 compounds, including 24 phenylethanoid glycosides, 21 lignans and 6 flavonols, were identified or tentatively characterized based on their retention times, UV spectra and MS fragmentation patterns.     

Lignans and Gut Microbiota: An Interplay Revealing Potential Health Implications

Plant polyphenols are a broad group of bioactive compounds characterized by different chemical and structural properties, low bioavailability, and several in vitro biological activities. Among these compounds, lignans (a non-flavonoid polyphenolic class found in plant foods for human nutrition) have been recently studied as potential modulators of the gut–brain axis. In particular, gut bacterial metabolism is able to convert dietary lignans into therapeutically relevant polyphenols (i.e., enterolignans), such as enterolactone and enterodiol. Enterolignans are characterized by various biologic activities, including tissue-specific estrogen receptor activation, together with anti-inflammatory and apoptotic effects. However, variation in enterolignans production by the gut microbiota is strictly related to both bioaccessibility and bioavailability of lignans through the entire gastrointestinal tract. Therefore, in this review, we summarized the most important dietary source of lignans, exploring the interesting interplay between gut metabolites, gut microbiota, and the so-called gut–brain axis.     

New Lignans from the Aerial Parts of Rudbeckia laciniata

Three new furofuran lignans, (+)‐4,4′‐O‐diangeloylpinoresinol ( 1 ), (+)‐4,4′‐O‐diangeloylmedioresinol ( 2 ), and (+)‐4,4′‐O‐diangeloylsyringaresinol ( 3 ), together with the known compound (+)‐syringaresinol, were isolated from the MeOH extract of Rudbeckia laciniata. The structure elucidation of these compounds were based on 1D‐ and 2D‐NMR, and HR‐ESI‐MS data. The additional structural evidence was obtained from alkaline hydrolysis of the compounds.     

Structural discrimination of isomeric tetrahydrofuran lignan glucosides by tandem mass spectrometry

Due to the possible role in human health, the number of analytical studies on lignans aimed at their quali‐ and quantitative analysis in plant extracts, biological fluids and foods is continuously increasing. However, helpful systematic mass spectrometric investigations on these compounds are few and rather limited to specific lignan sub‐classes. To increase the comprehension of the previously outlined picture of the gas‐phase properties of furofuran lignans, we extended the study to tetrahydrofuran lignans and here we reported the collision‐activated dissociation (CAD) fragmentation patterns of the alkali metal cation adducts, [M+Alk]⁺, and [M–H]^? ions of three isomeric tetrahydrofuran lignans, (+)‐8′‐hydroxylariciresinol 4′‐O‐β‐D ‐glucopyranoside (1), (+)‐7′‐hydroxylariciresinol 7′‐O‐β‐D ‐glucopyranoside (2) and 4‐O‐β‐D ‐glucopyranosyloxy‐3,3′‐dimethoxy‐7,9′‐epoxylignan‐5′,8′,9‐triol (3) investigated by electrospray ionization triple quadrupole mass spectrometry (ESI‐TQMS). Hydrogen/deuterium (H/D) solution exchange experiments, allowing the selective H/D exchange of all the acidic hydrogen atoms, proved to be a very effective tool to obtain information on the nature of fragments generated during TQ/CAD processes. The [M+Na]⁺ CAD mass spectra of the three isomeric tetrahydrofurans revealed four different pathways involving the loss of the glucose moiety, which allowed the assignment of the glycosylation site. In the negative ion mode, the main fragmentation channel of the [M–H]^? ions of O‐glucosylated lignans at the phenolic oxygen atoms is represented by the loss of 162 Da. When the sugar is bound to a benzylic OH group the loss of the sugar as a 180 Da unit occurs eventually following the loss of a water molecule involving both the C(9)H₂OH chain and the sugar. Copyright © 2010 John Wiley & Sons, Ltd.     

Natural products: chemical instruments to apprehend biological symphony

As a striking variety of biological activities are elicited by natural products, these chemicals have been used for decades to study biological phenomena. Understanding how these products interfere with normal cell functions at a molecular level led to a wide range of discoveries including new signaling pathways and proteins. Moreover, as natural products often act as chemical inhibitors, such studies often allow the identification of their binding partners as relevant targets for drug design. This article aims to emphasize how natural products or engineered analogs can be used as chemical tools to apprehend some biological problems from the point of view of a chemical biologist.