Polyphenol

      This article is about larger phenolic substances. For smaller molecules, see natural phenol.
      Plant-derived polyphenol, tannic acid, formed by esterification of ten equivalents of the phenylpropanoid-derived gallic acid to a monosaccharide (glucose) core from primary metabolism.
      Neutral phenol substructure "shape". An image of a computed electrostatic surface of neutral phenol, showing neutral regions in green, electronegative areas in orange-red, and the electropositive phenolic proton in blue.
      Phenol-phenolate equilibrium, and resonance structures giving rise to phenol aromatic reactivity. See also the images at the wiki pages for phenols.

      Polyphenols[1][2] (noun, pronunciation of the singular /pɑli'finəl/[3] or /pɑli'fɛnəl/, also known as Polyhydroxyphenols) are a structural class of mainly natural, but also synthetic or semisynthetic, organic chemicals characterized by the presence of large multiples of phenol structural units. The number and characteristics of these phenol structures underlie the unique physical, chemical, and biological (metabolic, toxic, therapeutic, etc.) properties of particular members of the class. They may be broadly classified as phenolic acids, flavonoids, stilbenes, and lignans.[4]

      The name derives from the ancient Greek word πολύς (polus, meaning "many, much") and the word phenol which refers to a chemical structure formed by attaching to an aromatic benzenoid (phenyl) ring, an hydroxyl (-OH) group akin to that found in alcohols (hence the "-ol" suffix). The term polyphenol appears to have been in use since 1894.[3]

      Definition of the term polyphenol

      WBSSH polyphenols, the original high molecular weight class

      The White–Bate-Smith–Swain–Haslam (WBSSH) definition,[5] describes the polyphenol class as:

      • generally moderately water-soluble compounds,
      • with molecular weight of 500–4000 Da,
      • with >12 phenolic hydroxyl groups, and
      • with 5–7 aromatic rings per 1000 Da,

      where the limits to these ranges are somewhat flexible.[1][5] This definition was offered and substantiated by natural product and organic chemist Edwin Haslam and colleagues, building off of earlier natural products research efforts of Edgar Charles Bate-Smith, Anthony Swain and Theodore White that characterized specific structural characteristics common to plant phenolics used in tanning (i.e., the tannins).[citation needed]

      The expansive Quideau polyphenol proposal

      The need for clarity of definition alongside the current enormous literature and ambiguity of the polyphenol term led Stéphane Quideau to offer a definition not yet given formal status by IUPAC or other nomenclature entity (emphasis added):[6]

      "[The] entanglement of structure types is admittedly far from providing a clear picture of the plant polyphenols family. For sure, the presence of more than one hydroxyl group on a benzene ring or other arene systems does not make them “polyphenols”. Catechol, resorcinol, pyrogallol, and phloroglucinol, all di- and trihydroxylated benzene (C6) derivatives, are still defined as “phenols” according to the IUPAC official nomenclature rules of chemical compounds. Many such monophenolics are often quoted as “polyphenols” by the cosmetic and parapharmaceutic industries, but they cannot be by any scientifically-accepted definition. Hydroxytyrosol (i.e. 3,4-dihydroxyphenylethanol) is one flagrant example suffering from such an abuse. The meaning of the chemical term “phenol” includes both the arene ring and its hydroxyl substituent(s). Hence, even if we agree to include in a definition polyphenolic structures with no tanning action, the term “polyphenol” should be restricted, in a strict chemical sense, to structures bearing at least two phenolic moieties independently of the number of hydroxyl groups they each bear. But this definition needs additional restrictions, for many natural products of various biosynthetic origins do contain more than one phenolic unit. It is, for example, the case for many alkaloids derived from the phenylalanine/tyrosine amino acids. The natural occurrence of such alkaloids then gives us a poser in any attempts to propose a definition of polyphenols strickly based on biosynthetic origin(s) grounds, for these amino acids themselves are primary metabolites of the shikimate/phenylpropanoid pathway. So, here is my proposal!

      The term “polyphenol” should be used to define compounds exclusively derived from the shikimate/phenylpropanoid and/or the polyketide pathway, featuring more than one phenolic unit and deprived of nitrogen-based functions.

      This definition lets out all monophenolic structures, as well as all their naturally occurring derivatives such as phenyl esters, methyl phenyl ethers and O-phenyl glycosides. However, investigations on these compounds, which are often the biogenetic precursors of “true” polyphenols, definitely have their place in polyphenol research, but qualifying them as polyphenols is pushing it too far."

      By this definition, all WBSSH polyphenols are "Quideau polyphenols," though the converse is not true. This article covers Quideau and WBSSH polyphenols, with the former providing the least restrictive definition for including chemical substances and their activities in the discussion. Whenever possible, when structures are omitted from the text, these labels make clear which type of phenolic compound is under discussion.

      Examples of phenolic compounds within both WBSSH and Quideau definitions of polyphenols

      Examples of compounds that fall under both the WBSSH and Quideau definitions include the black tea antioxidant theaflavin-3-gallate shown below, and the hydrolyzable tannin, tannic acid, shown above. The historically important chemical class of tannins is a subset of the polyphenols.[1][7]

      Raspberry ellagitannin
      Plant-derived theaflavin-3-gallate, formed by esterification of two equivalents of gallic acid to a theaflavin core. this example meets several of the WBSSH definition points (see below), but not the phenol-count criterion.
      Ellagic acid, a dimer of gallic acid, and a core-type component of polyphenols

      Examples of phenolic compounds that fall between WBSSH and Quideau definitions of polyphenols

      Both the Quideau and the WBSSH definitions differentiate higher molecular weight and more structurally and functionally complex polyphenols from the simple phenolics —monoaromatics such gallic and caffeic acids.[citation needed] The Quideau definition of polyphenol includes plant-derived dimer and trimer types of phenolic classes—e.g., lignans and flavanoids—that occupy the structure and property "space" between simple and WBSSH polyphenols.[citation needed] For instance, the gallic acid dimer, ellagic acid (M.W. 302, right) is an example of a dimeric Quideau polyphenol that is at the core of various naturally occurring phenols. The example raspberry ellagitannin (M.W. ~2450),[8] on the other hand, with its 6 ellagic acid-type components and two additional monomeric phenolics, for a total of 14 gallic acid units (and all of their substituent phenolic hydroxyl groups), meets the criteria of both definitions of polyphenol.

      Defining chemistry of the polyphenol class

      Individual polyphenols engage in reactions related to their core structure—standard phenolic reactions (e.g., ionization, oxidations to ortho- and para-quinones, and other underlying aromatic transformations related to the presence of the phenolic hydroxyl, etc.; see phenol image above)—as well as reactions related to their peripheral structures (e.g., nucleophilic additions, oxidative and hydrolytic bond cleavages, etc.).[9] Per the WBSSH definition, the larger subclass of polyphenols display more specific further chemical behaviors—formation of particular metal complexes (e.g., intense blue-black iron(III) complexes), and precipitation of proteins and particular amine-containing organics (e.g., particular alkaloid natural products).[5]

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      Chemical structure and synthesis

      Structural features

      As opposed to smaller phenols, polyphenol are large molecules (macromolecules). The upper molecular weight limit for small molecules is approximately 800 Daltons, which allows for the possibility to rapidly diffuse across cell membranes so that they can reach intracellular sites of action.[citation needed]

      As the earlier images suggest, polyphenol compositions are normally limited to carbon, hydrogen and oxygen in undefined proportion, with the preeminent substructure being the phenol unit.[citation needed] In common with simple and mid-molecular weight phenolic dimers and trimers, the phenol substructures of polyphenols have various further nomenclatures depending on the number of phenolic hydroxyl groups.[citation needed]

      Phenol
      Pyrocatechol
      Resorcinol
      Pyrogallol
      phloroglucinol
      Phenol
      Pyrocatechol
      Resorcinol
      Pyrogallol
      Phloroglucinol

      "Phenol", per se, is the term for a substructure with one phenolic hydroxyl group, catechol- and resorcinol-types (benzenediols) have two, and pyrogallol- and phloroglucinol-types (benzenetriols) have three.[citation needed] Polyphenols may have heteroatom substituents other than hydroxyl groups, and ether and ester linkages are common, as are various carboxylic acid derivatives (see theaflavin gallate image).[citation needed]

      The biphenyl/biaryl substructure of polyphenols, here as prepared by synthetic chemists using the copper-mediated Ullmann reaction. This substructure can be observed in the structure of ellagic acid above. The carbon-carbon bond in biaryls in nature is also synthesized though a metal-mediated coupling reaction, often involving iron.
      A C-glucoside substructure in the phenol-saccharide conjugate structure of puerarin, a mid-molecular weight plant natural product (though not a polyphenol)—where the attachment of the phenol to the saccharide is via a carbon-carbon bond, as in polyphenols with this substructure. Also a part of the structure is an isoflavone, which contains the 10-atom benzopyran "fused ring" system seen in polyphenols.
      An example of the spiro-type substructure found in polyphenols—where two rings are joined at a single shared point—with illustration of the two stereoisomers that can arise because of such junctures, labeled R and S (from the CIP system, for rectus/right/clockwise and sinister/left/counterclockwise, respectively).

      Apart from the phenol units, the carbon frameworks can be complex, arising from various biosynthetic pathways, especially phenylpropanoid and polyketide branches aimed at plant and related secondary metabolites.[citation needed] Diverse biosynthetic steps abound: the 7-atom ring (7-membered ring) appearing in theaflavin structure above is an example of a "carbocycle" that is of a nonbenzenoid aromatic tropolone type.[citation needed] In addition, there are periodic occurrences of:[citation needed]

      Because of the preponderance of saccharide-derived core structures (e.g., see tannic acid image above), as well as spiro- and other structure types, natural chiral (stereo) centers abound.[citation needed]

      Chemical synthesis

      [icon] This section requires expansion with: secondary and tertiary sources to support the history and milestones. WIthout such sourcing, this section violates WP:OR. (March 2013)
      En example of a synthetically achieved small ellagitannin, tellimagrandin II, derived biosynthetically and sometimes synthetically by oxidative dimerization of two of the galloyl moieties of 1,2,3,4,6-pentagalloyl-glucose.

      True polyphenols from the tannin and other WBSSH types are routinely biosynthesized in the natural sources from which they derive (see below); their chemical syntheses using standard organic chemical methods have been accomplished, but were somewhat limited until the first decade of the new millennium because they involve challenging regioselectivity and stereoselectivity issues.[citation needed] Early work focused on the achiral synthesis of phenolic-related components of polyphenols,[citation needed] such as the Nelson and Meyers synthesis of the permethyled derivative of the ubiquitous diphenic acid core of ellagitannins in 1994[10] and in synthesis of more complex permethylated structures such as a (+)-tellimagrandin II derivative by Lipshutz and coworkers in the same year,[11] and Itoh and coworker's synthesis of a permethylated pedunculagin with particular attention to axial symmetry issues in 1996.[12] The first[citation needed]total synthesis of a fully unmasked polyphenol, that of the ellagitannin tellimagrandin I, was a diastereoselective sequence reported in 1994 by Feldman, Ensel and Minard.[13]

      Further total syntheses of deprotected polyphenols that followed were led by the Feldman group, for instance in Feldman and Lawlor's synthesis of the ellagitannin, coriariin A and other tannin relatives.[14] Khanbabaee and Grosser accomplished a relatively efficient total synthesis of pedunculagin in 2003.[15][16]

      Work proceeded with focus on enantioselective total syntheses, e.g., on atroposelective syntheses of axially chiral biaryl polyphenols,[17][18] with recent further important work including controlled assembly of a variety of polyphenols according to integrated strategies, such as in syntheses of extended series of procyanidins (oligomeric catechins) by various groups[19] and of resveratrol polyphenols by the Snyder group at Columbia that included the diverse carasiphenols B and C, ampelopsins G and H, and nepalensinol B.[20][21] The novel strategies and methods referred to in these recent examples helped to open the field of polyphenol chemical synthesis to an unprecedented degree.[21]

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      Chemical properties and uses

      Functional classifications

      In terms of functional and operational classification, polyphenols can be divided into hydrolyzable tannins (gallic acid esters of glucose and other sugars or cyclitols) and phenylpropanoids, such as lignans, flavonoids, and condensed tannins.[citation needed]Tannin chemistry originated in the importance of tannic acid to the tanning industry; lignans to the chemistry of soil and plant structure; and flavonoids to the chemistry of plant secondary metabolites for plant defense, and flower color (e.g. from anthocyanins).[citation needed]

      Chemical properties

      Polyphenols are molecules producing autofluorescence, especially lignin and the phenolic part of suberin.[citation needed]

      Polyphenols are reactive species toward oxidation.[22]ABTS may be used to characterise polyphenol oxidation products.[23]

      Polyphenols can interact with proteins (case of tannins) and other food matrices.

      		 This article has multiple issues. Please help improve it or discuss these issues on the talk page.

      Chemical uses

      Some polyphenols are traditionally used as dyes. For instance, in the Indian subcontinent, the pomegranate peel, high in tannins and other polyphenols, or its juice, is employed in the dyeing of non-synthetic fabrics.[24]

      Polyphenols, especially, tannins, can be used as precursors in green chemistry[25] notably to produce plastics or resins by polymerisation with[26] or without the use of formaldehyde[27] or adhesives for particleboards.[28] The aims are generally to make use of plant residues from grape, olive (called pomaces) or pecan shells left after processing.[citation needed]

      Polyphenols are also used for the production of creosote to treat wood.[citation needed]

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      Biology

      Occurrence in nature

      The most abundant polyphenols are the condensed tannins, found in virtually all families of plants, and comprising up to 50% of the dry weight of leaves.[citation needed]

      Some polyphenols produced by plants in case of pathogens attacks are called phytoalexins.[citation needed] High levels of polyphenols in some woods can explain their natural preservation against rot.[29]

      Flax and Myriophyllum spicatum (an submerged aquatic plant) secrete polyphenols that are involved in allelopathic interactions.[30][31]

      Polyphenols are also found in animals. In arthropods such as insects[32] and crustaceans[33] polyphenols play a role in epicuticle hardening (sclerotization). The hardening of the cuticle is due to the presence of a polyphenol oxidase.[34] In crustaceans, there is a second oxidase activity leading to cuticle pigmentation.[35] There is apparently no polyphenol tanning occurring in arachnids cuticle.[36]

      Metabolism

      Biosynthesis and metabolism

      Polyphenol oxidase (PPO) is an enzyme that catalyses the oxidation of o-diphenols to produce o-quinones. It is the rapid polymerisation of o-quinones to produce black, brown or red polyphenolic pigments that is the cause of fruit browning. In insects, PPO serves for the cuticle hardening.[37]

      Laccase is a major enzyme that initiates the cleavage of hydrocarbon rings, which catalyzes the addition of a hydroxyl group to phenolic compounds. This enzyme can be found in fungi like Panellus stipticus, organisms able to break down lignin, a complex aromatic polymer in wood that is highly resistant to degradation by conventional enzyme systems.

      Anthracyclines or hypericin[38] are derived from polyketides cyclisation.[39]

      The glycosylated form increases the solubility of polyphenols.[40]

      Content in food

      See also: List of phytochemicals in food
      Main articles: Natural phenols and polyphenols in wine and Natural phenols and polyphenols in tea
      Unseasoned dotorimuk, a Korean dish made of acorn flour.

      Generally foods contain complex mixtures of polyphenols.[41] According to a 2005 review on polyphenols: "The most important food sources are commodities widely consumed in large quantities such as fruit and vegetables, green tea, black tea, red wine, coffee, chocolate, olives, and extra virgin olive oil. Herbs and spices, nuts and algae are also potentially significant for supplying certain polyphenols. Some polyphenols are specific to particular food (flavanones in citrus fruit, isoflavones in soya, phloridzin in apples); whereas others, such as quercetin, are found in all plant products such as fruit, vegetables, cereals, leguminous plants, tea, and wine."[41]

      Some polyphenols are considered antinutrients, compounds that interfere with the absorption of nutrients as a mechanism of plant defense against herbivores.[citation needed]

      Phenolic and carotenoid compounds with antioxidant properties in vegetables have been found to be retained significantly better through steaming than through frying.[42]

      Polyphenols in wine, beer and various nonalcoholic juice beverages can be removed using finings, substances that are usually added at or near the completion of the processing of brewing.

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      Marketing argument

      The presence of polyphenols has been used by some companies to sell functional foods, dietary supplements or anti-aging creams.[citation needed]

      Functional foods may contain polyphenols. For superfruit beverages, which may include extracts from fruits such as açai or pomegranate, the detailed composition of polyphenols is usually not revealed on the nutrition label.[citation needed] Instead, there may be an ORAC value given for the in vitro antioxidant capacity of the product.[citation needed] Polyphenol-enriched drinks may actually deliver the intended blend of bioavailable polyphenols, which would normally require consumption of several different plant-derived foods.[43]

      Health benefits from using these products have not been scientifically confirmed or approved by regulatory authorities and may only be supported by preliminary research.[citation needed] Accordingly, there are no recommended Dietary Reference Intake levels established for polyphenols as exist for essential nutrients.[citation needed]

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      Potential health effects

      Main article: Health effects of polyphenols

      The diverse structures of phenolic compounds prohibits broad statements about their health effects. Further, the possible health effects of specific phenolic compounds remain mostly unproved.[44] Natural phenols have been investigated in organic products as a source of additional health benefit, but no conclusion is supported by existing research.[45]

      Compared with the effects of polyphenols in vitro, the effects in vivo, although the subject of ongoing research, are limited and vague. The reasons for this are 1) the absence of validated in vivo biomarkers, especially for inflammation or carcinogenesis; 2) long-term studies failing to demonstrate effects with a mechanism of action, specificity or efficacy; and 3) invalid applications of high, unphysiological test concentrations in the in vitro studies, which are subsequently irrelevant for the design of in vivo experiments.[46] In rats, polyphenols absorbed in the small intestine[47] may be bound in protein-polyphenol complexes modified by intestinal microflora enzymes,[48] allowing derivative compounds formed by ring-fission to be better absorbed.[49][50]

      A review of studies on the bioavailability of polyphenols published in 2010 found that "definitive conclusions on bioavailability of most polyphenols are difficult to obtain and further studies are necessary."[41]

      Traditional medicine

      In the Indian subcontinent's ancient Ayurveda system of medicine, the pomegranate has extensively been used as a source of traditional remedies for thousands of years.[24]

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      Research techniques

      Sensory and potential biological properties

      With respect to food and beverages, astringency is primarily a tactile sensation rather than a taste; the cause of astringency is not fully understood, but it is measured chemically as the ability of a substance to precipitate proteins.[51]

      A review published in 2005 found that astringency increases and bitterness decreases with the mean degree of polymerization. For water-soluble polyphenols, molecular weights between 500 and 3000 were reported to be required for protein precipitation. However, smaller molecules might still have astringent qualities likely due to the formation of unprecipitated complexes with proteins or cross-linking of proteins with simple phenols that have 1,2-dihydroxy or 1,2,3-trihydroxy groups.[52] Flavonoid configurations can also cause significant differences in sensory properties, e.g. epicatechin is more bitter and astringent than its chiral isomer catechin. In contrast, other polyphenols, such as hydroxycinnamic acids, do not have astringent qualities, but are bitter.[53]

      Analysis

      The analysis techniques are those of phytochemistry: extraction, isolation, structural elucidation,[54] then quantification.

      Extraction

      Extraction of polyphenols[55] can be performed using a solvent like water, hot water, methanol, methanol/formic acid, methanol/water/acetic or formic acid etc. Liquid liquid extraction can be also performed or countercurrent chromatography. Solid phase extraction can also be made on C18 sorbent cartridges. Other techniques are ultrasonic extraction, heat reflux extraction, microwave-assisted extraction,[56]critical carbon dioxide,[57]pressurized liquid extraction[58] or use of ethanol in an immersion extractor.[59] The extraction conditions (temperature, extraction time, ratio of solvent to raw material, solvent and concentrations) have to be optimized.

      Mainly found in the fruit skins and seeds, high levels of polyphenols may reflect only the measured extractable polyphenol (EPP) content of a fruit which may also contain non-extractable polyphenols. Black tea contains high amounts of polyphenol and makes up for 20% of its weight.[60]

      Concentration can be made by ultrafiltration.[61] Purification can be achieved by preparative chromatography.

      Analysis techniques

      Reversed-phase HPLC plot of separation of phenolic compounds. Smaller natural phenols formed individual peaks while tannins form a hump.

      Phosphomolybdic acid is used as a reagent for staining phenolics in thin layer chromatography. Polyphenols can be studied by spectroscopy, especially in the ultraviolet domain, by fractionation or paper chromatography. They can also be analysed by chemical characterisation.

      Instrumental chemistry analyses include separation by high performance liquid chromatography (HPLC), and especially by reversed-phase liquid chromatography (RPLC), can be coupled to mass spectrometry. Purified compounds can be identified by the mean of nuclear magnetic resonance.

      Microscopy analysis

      The DMACA reagent is an histological dye specific to polyphenols used in microscopy analyses. The autofluorescence of polyphenols can also be used, especially for localisation of lignin and suberin.

      Quantification

      A method for polyphenolic content quantification is volumetric titration. An oxidizing agent, permanganate, is used to oxidize known concentrations of a standard tannin solution, producing a standard curve. The tannin content of the unknown is then expressed as equivalents of the appropriate hydrolyzable or condensed tannin.[62]

      Some methods for quantification of total polyphenol content are based on colorimetric measurements. Some tests are relatively specific to polyphenols (for instance the Porter's assay). Total phenols (or antioxidant effect) can be measured using the Folin-Ciocalteu reaction. Results are typically expressed as gallic acid equivalents. Polyphenols are seldom evaluated by antibody technologies.[63]

      Other tests measure the antioxidant capacity of a fraction. Some make use of the ABTS radical cation which is reactive towards most antioxidants including phenolics, thiols and vitamin C.[64] During this reaction, the blue ABTS radical cation is converted back to its colorless neutral form. The reaction may be monitored spectrophotometrically. This assay is often referred to as the Trolox equivalent antioxidant capacity (TEAC) assay. The reactivity of the various antioxidants tested are compared to that of Trolox, which is a vitamin E analog.

      Other antioxidant capacity assays which use Trolox as a standard include the diphenylpicrylhydrazyl (DPPH), oxygen radical absorbance capacity (ORAC),[65]ferric reducing ability of plasma (FRAP)[66] assays or inhibition of copper-catalyzed in vitro human low-density lipoprotein oxidation.[67]

      New methods including the use of biosensors can help monitor the content of polyphenols in food.[68]

      Quantitation results produced by the mean of diode array detector-coupled HPLC are generally given as relative rather than absolute values as there is a lack of commercially available standards for all polyphenolic molecules.

      Other techniques

      Chemometrics analyses on acquired data can be performed to compare samples from different origins.

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      See also

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      References

      1. ^ a b c Quideau, S. P.; Deffieux, D.; Douat-Casassus, C. L.; Pouységu, L. (2011). "Plant Polyphenols: Chemical Properties, Biological Activities, and Synthesis". Angewandte Chemie International Edition 50 (3): 586. doi:10.1002/anie.201000044.  edit
      2. ^ Quideau S (2011). "Why bother with polyphenols?". Groupe Polyphenols. Retrieved 15 February 2011. 
      3. ^ a b Polyphenol on www.merriam-webster.com online dictionary
      4. ^ Manach, Scalbert, Morand, et all. (2004) "Polyphenols: food sources and bioavailability". Am J Clin Nutr; 79: 727–47.
      5. ^ a b c Haslam, E.; Cai, Y. (1994). "Plant polyphenols (vegetable tannins): Gallic acid metabolism". Natural Product Reports 11 (1): 41–66. doi:10.1039/NP9941100041. PMID 15206456.  edit
      6. ^ Quideau S (2011). "Why bother with polyphenols?". Groupe Polyphenols. Retrieved 16 une 2012. 
      7. ^ a b Isolation and structure elucidation of tannins. G. Nonaka, Pure & Appl. Chem.,Vol. 61, No. 3, pp. 357–360, 1989.
      8. ^ Cardiovascular disease and phytochemicals. Anonymous. C. Hamilton et al.
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      10. ^ TD Nelson & AI Meyers (1994) A Rapid Total Synthesis of an Ellagitannin [sic], J. Org. Chem. 59(9): 2577-2580
      11. ^ BH Lipshutz, ZP Liu & F Kayser (1994) Cyanocuprate-Mediated Intramolecular Biaryl Couplings Applied to an Ellagitannin - Synthesis of (+)-O-Permethyltellimagrandin II, Tet. Lett. 35(31):5567-5570
      12. ^ T Itoh, J Chika, S Shirakami S, et al. (1996) Synthesis of trideca-O-methyl-alpha-pedunculagin. Diastereo-favoritism studies on intramolecular ester-cyclization of axially chiral diphenic acids with carbohydrate core, J. Org. Chem. 61(11): 3700-3705
      13. ^ KS Feldman & SM Ensel (1994), Ellagitannin chemistry. Preparative and mechanistic studies of the biomimetic oxidative coupling of galloyl esters, J. Amer. Chem. Soc. 116(8):3357-3366 (and references therein)
      14. ^ KS Feldman, MD Lawlor & K Sahasrabudhe (2000), Ellagitannin chemistry. Evolution of a three-component coupling strategy for the synthesis of the dimeric ellagitannin coriariin A and a dimeric gallotannin analogue, J. Org. Chem. 65(23):8011-8019 (and references therein)
      15. ^ K Khanbabaee & M Grosser (2003), An efficient total synthesis of pedunculagin by using a twofold intramolecular double esterification strategy, Eur. J. Org. Chem. (11):2128-2131
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      17. ^ G Bringmann, T Gulder, TAM Gulder, et al. (2011) Total Synthesis of Axially Chiral Biaryl Natural Products, Chem. Revs. 111(2):563-639.
      18. ^ L. Pouysegu, D. Deffieux, G. Malik Gaelle, et al. (2011) Synthesis of ellagitannin natural products, Nat. Prod. Reports 28(5):853-874
      19. ^ AP Kozikowski, W Tückmantel, G Boettcher, LJ Romanczyk Jr (2003) J. Org. Chem. 68: 1641–1658; K Ohmori, T Shono, Y Hatakoshi, T Yano, T. and K Suzuki (2011), Integrated Synthetic Strategy for Higher Catechin Oligomers. Angew. Chemie Int. Ed. 50:4862–4867.
      20. ^ S.A. Snyder, A. Gollner & M.I. Chiriac, 2011, Regioselective reactions for programmable resveratrol oligomer synthesis, Nature 474, 461–466 (23 June 2011) doi:10.1038/nature10197
      21. ^ a b S. Quideau, 2011, Organic chemistry: Triumph for unnatural synthesis, Nature 474, 459–460 (23 June 2011) doi:10.1038/474459a
      22. ^ Estimating the selectivity of ozone in the removal of polyphenols from vinasse. Santos M.A, Bonilla Venceslada J.L, Martin Martin A and Garcia Garcia I, Journal of chemical technology and biotechnology, 2005, volume 80, number 4, pages 433–438, INIST:16622840
      23. ^ Osman, A. M.; Wong, K. K. Y.; Fernyhough, A. (2006). "ABTS radical-driven oxidation of polyphenols: Isolation and structural elucidation of covalent adducts". Biochemical and Biophysical Research Communications 346 (1): 321–329. doi:10.1016/j.bbrc.2006.05.118. PMID 16756947.  edit
      24. ^ a b K. K. Jindal, R. C. Sharma (2004). Recent trends in horticulture in the Himalayas. Indus Publishing. ISBN 81-7387-162-0. "... bark of tree and rind of fruit is commonly used in ayurveda ... also used for dyeing ..." 
      25. ^ Polshettiwar, Vivek; Varma, Rajender S. (2008). "Greener and expeditious synthesis of bioactive heterocycles using microwave irradiation". Pure and Applied Chemistry 80 (4): 777–90. doi:10.1351/pac200880040777. 
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      28. ^ Pizzi, A.; Valenezuela, J.; Westermeyer, C. (1994). "Low formaldehyde emission, fast pressing, pine and pecan tannin adhesives for exterior particleboard". Holz als Roh- und Werkstoff 52 (5): 311–5. doi:10.1007/BF02621421. 
      29. ^ Hart, John H.; Hillis, W. E. (1974). "Inhibition of wood-rotting fungi by stilbenes and other polyphenols in Eucalyptus sideroxylon". Phytopathology 64 (7): 939–48. doi:10.1094/Phyto-64-939. 
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      Last modified on 28 May 2013, at 21:48