- Synthesis of procyanidin B1, B2, and B4 and their anti-inflammatory activity: The effect of 4-alkoxy group of catechin and/or epicatechin electrophiles for condensation
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Abstract: Procyanidin B1, B2, and B3 were synthesized based on a Yb(OTf)3 catalyzed equimolar condensation using methoxy and/or 4-(2-ethoxyethoxy) drivatives as electrophiles. The anti-inflammatory effect of synthetic procyanidin B1, B2, and B4 on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation of mouse ears was examined. Procyanidin B1, B2, B 4 suppressed TPA-induced inflammation of mouse ears by 48%, 34%, and 29%, respectively, at a dose of 200 μg. Their activities are stronger than those of indomethacin and glycyrrhetinic acid, the normally used antiinflammatory agent.
- Katoh,Oizumi,Mohri,Hirota,Makabe
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scheme or table
p. 233 - 238
(2012/07/28)
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- Preparation of dimeric procyanidins B1, B2, B5, and B7 from a polymeric procyanidin fraction of black chokeberry (Aronia melanocarpa)
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A semisynthetic approach has been used for the preparative formation of dimeric procyanidins B1, B2, B5, and B7. As starting material for the semisynthesis, polymeric procyanidins from black chokeberry were applied. These polymers were found to consist almost exclusively of (-)-epicatechin units. Under acidic conditions the interflavanoid linkages of the polymeric procyanidins are cleaved and the liberated (-)-epicatechin can react with nucleophiles, such as (+)-catechin or (-)-epicatechin. In this way, the polymeric procyanidins are degraded while dimeric procyanidins are formed. During this reaction only dimeric procyanidins are formed that contain (-)-epicatechin in the upper unit, that is, B1 [(-)-EC-4β→8-(+)-C)], B2 [(-)-EC-4β→8-(-)-EC], B5 [(-)-EC-4β→6-(-)-EC], and B7 [(-)-EC-4β→6-(+)-C]. The reaction mixtures of the semisynthesis can be successfully fractionated with high-speed countercurrent chromatography (HSCCC), and it is possible to isolate pure procyanidins B1, B2, B5, and B7 on a preparative scale.
- Esatbeyoglu, Tuba,Winterhalter, Peter
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experimental part
p. 5147 - 5153
(2011/07/29)
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- Total synthesis of 14C-labeled procyanidin B2
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During the last decades, many in vitro and in vivo studies have shown the beneficial effects on health of procyanidins. However, their absorption and metabolism is still not fully understood and some aspects are still controversial. In order to have a clearer picture of the metabolism of procyanidins, the use of labelled compounds is essential. In this context, the enantioselective synthesis of 14C-radiolabelled procyanidin B2 was developed in our laboratories. It was achieved in fourteen 'hot' steps, involving as key steps the Sharpless dihydroxylation of an elaborated alkene, a stereoselective intramolecular cyclization to benzylated (+)-catechin and the condensation of two (-)-epicatechin units. 11 mCi of protected procyanidin B2 were obtained from 524 mCi of potassium [14C]cyanide. Copyright
- Viton, Florian,Landreau, Cyrille,Rustidge, David,Little, Gill,Robert, Fabien,Williamson, Gary,Barron, Denis
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scheme or table
p. 371 - 374
(2011/05/05)
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- An efficient synthesis of procyanidins using equimolar condensation of catechin and/or epicatechin catalyzed by ytterbium triflate
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Stereoselective synthesis of catechin and epicatechin dimers under intermolecular condensation of equimolar amount of catechin derivatives catalyzed by Yb(OTf)3. The coupled products were successfully converted to procyanidins B1, B2, B3, and B4, respectively. Procyanidins B1, B2, B3, and B4 could be used as standard compounds for identifying the polyphenols in natural source.
- Mohri, Yoshihiro,Sagehashi, Masayoshi,Yamada, Taiji,Hattori, Yasunao,Morimura, Keiji,Hamauzu, Yasunori,Kamo, Tsunashi,Hirota, Mitsuru,Makabe, Hidefumi
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experimental part
p. 549 - 563
(2009/12/07)
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- First total synthesis of14C-labeled procyanidin B2 - A milestone toward understanding cocoa polyphenol metabolism
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The idea that foods consumed for pure pleasure could provide health benefits received much recognition in the recent years. Among these foods, cocoa and dark chocolate are particularly rich in procyanidins, one of the major dietary families of polyphenols. We developed the first asymmetric total synthesis of procyanidin B2 and applied it to the preparation of a regioselectively radiolabeled 14C-analogue, which will be used to strengthen our knowledge on the metabolism of procyanidins. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Viton, Florian,Landreau, Cyrille,Rustidge, David,Robert, Fabien,Williamson, Gary,Barron, Denis
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supporting information; experimental part
p. 6069 - 6078
(2009/05/27)
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- An efficient synthesis of procyanidins. Rare earth metal Lewis acid catalyzed equimolar condensation of catechin and epicatechin
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Stereoselective synthesis of catechin and epicatechin dimers under intermolecular condensation is achieved by an equimolar amount of coupling catalyzed by Yb(OTf)3. The coupled products were successfully converted to procyanidin B1, B2, B3, and B4.
- Mohri, Yoshihiro,Sagehashi, Masayoshi,Yamada, Taiji,Hattori, Yasunao,Morimura, Keiji,Kamo, Tsunashi,Hirota, Mitsuru,Makabe, Hidefumi
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p. 5891 - 5894
(2008/02/09)
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- An improved synthesis of procyanidin dimers: Regio- and stereocontrol of the interflavan bond
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A direct and general synthesis of procyanidin dimers B1, B2, B3 and B4 (10a-d) is presented. The approach is based on the stoichiometric coupling of two protected monomeric units (the nucleophilic 2a-b and electrophilic 4a-b partners) and deals with the regio- and stereocontrol of the C4-C8 interflavan bond as well as the control of the degree of oligomerization. The synthesis involves a five-step pathway starting from the native catechin (1a) or epicatechin (1b) to the fully deprotected dimers 10a-d. Furthermore, the process appears to be iterative as the coupling intermediates 9a-d themselves can be readily used in further selective syntheses of trimers or higher oligomers. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Tarascou, Isabelle,Barathieu, Karine,Andre, Yann,Pianet, Isabelle,Dufourc, Erick J.,Fouquet, Eric
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p. 5367 - 5377
(2007/10/03)
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- Compositions and methods of use of dimer digallates
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The invention relates to compositions, such as pharmaceuticals, foods, food additives, or dietary supplements, containing dimer digallates, and methods of use thereof, for prophylactic or therapeutic treatment of a human or a veterinary animal to treat or prevent NO-responsive health conditions, treat hypertension, cardiovascular disease, coronary artery disease, diabetes, cognitive dysfunction or disorder and/or vascular circulation disorders, prevent or reduce the risk of heart attack, stroke, congestive heart failure and/or kidney failure, or to improve blood flow, for example renal blood flow. The composition may optionally contain an additional NO modulating agent and/or a vascular-protective or therapeutic agent, or may be administered in combination with such an agent.
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Page/Page column 13
(2010/02/15)
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- Synthetic studies of proanthocyanidins. Part 5.1 Highly stereoselective synthesis and inhibitory activity of Maillard reaction of 3,4-trans catechin and epicatechin dimers, procyanidin B1, B2, B3, B4 and their acetates
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TMSOTf-catalyzed condensation of a potential electrophile with a nucleophile was achieved with a high level of 3,4-trans condensation, and we succeeded in the stereoselective synthesis of procyanidin B2 and its peracetate. Studies on the inhibitory activity of the Maillard reaction of four 3,4-trans series of catechin and epicatechin dimers, procyanidin B1, B2, B3 and B4, and their peracetates were also carried out.
- Saito, Akiko,Nakajima, Noriyuki,Matsuura, Nobuyasu,Tanaka, Akira,Ubukata, Makoto
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p. 479 - 489
(2007/10/03)
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- ISOLATION, PURIFICATION AND SYNTHESIS OF PROCYANIDIN B2 AND USES THEREOF
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Methods for the synthesis, isolation, and purification of procyanidin B2 are disclosed. The synthetic methods utilize epicatechin as a starting material and produce procyanidin BZ in high yields. The isolation methods extract procyanidin B2 from a sample of bark powder from plant matter of the genus Uncaria. The isolated and/or synthesized procyanidin B2 is used to treat amyloid disease, such as Alzheimer's disease and Parkinson's disease. Pharmaceutical compositions containing the synthesized and/or isolated procyanidin B2 are also disclosed.
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- Studies in polyphenol chemistry and bioactivity. 2. Establishment of interflavan linkage regio- and stereochemistry by oxidative degradation of an O-alkylated derivative of procyanidin B2 to (R)-(-)-2,4-diphenylbutyric acid
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The assignment of interflavan bond regio- and stereochemistry in oligomeric proanthocyanidins has in the past relied on empirical spectroscopic techniques which are influenced by the conformation of the C rings. Only recently was the 4,8-regiochemistry of procyanidin B2 (3b) firmly established by 2-dimensional NMR methods. We describe herein the proof of 4β-stereochemistry in 3b by oxidative degradation of the derivative 3d bearing differential (O-benzyl and O-methyl) protecting groups in its 'top' and 'bottom' epicatechin moieties, to (R)-(-)-2,4-diphenylbutyric acid. The key elements of the degradative process are (1) removal of the C-3 alcohol functions through a modified Barton deoxygenation employing hypophosphorous acid as the reducing agent; (2) deprotection of the 'top' unit by hydrogenolysis, followed by exhaustive aryl triflate formation with N,N-bis-(trifluoromethanesulfonyl)aniline and DBU in DMF; (3) hydrogenolytic deoxygenation of the 'top' unit over Pearlman's catalyst with concomitant scission of the O-C2 bond; (4) selective oxidation of the 'bottom' unit with NaIO4/RuCl3. The hitherto unreported absolute configuration of (-)-2,4-diphenylbutyric acid was established as R by X-ray crystal structure analysis of the (R)-(+)-α-methylbenzylamine salt. As a corollary, the selectivity of hydrogenolytic and solvolytic reactions of epicatechin-derived tetrasulfonates has been investigated.
- Kozikowski, Alan P.,Tueckmantel, Werner,George, Clifford
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p. 5371 - 5381
(2007/10/03)
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- Studies in polyphenol chemistry and bioactivity. 1. Preparation of building blocks from (+)-catechin. Procyanidin formation. Synthesis of the cancer cell growth inhibitor, 3-O-galloyl-(2R,3R)-epicatechin-4β,8-[3-O-galloyl-(2R,3R)-epicatechin]
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A project has been initiated to synthesize proanthocyanidin oligomers found in cocoa. Natural, readily available (+)-catechin was transformed into 5,7,3′,4′-tetra-O-benzyl-(-)-epicatechin (14) by (a) benzylation of the phenolic oxygens; (b) oxidation of the 3-alcohol to ketone by the Dess-Martin periodinane; and (c) reduction with lithium tri-sec-butylborohydride (L-Selectride) in the presence of LiBr. The additive diminishes the extent of ketone enolization while maintaining a stereoselectivity of ≥ 200:1. Oxidation of 14 with DDQ was performed best from the standpoint of product purification if ethylene glycol was used as the nucleophilic trapping agent. The resulting ether 19 was condensed with 14 using TiCl4 to give a good yield of benzyl-protected epicatechin-4β,8-epicatechin (octa-O-benzylprocyanidin B2, 20) as the sole dimeric product. Hydrogenolysis of 20 yielded procyanidin B2 in the first enantiospecific synthesis of this natural product which employs protected intermediates and thereby allows the necessary product separation after the condensation step to be performed on nonpolar, nonsensitive intermediates. Acylation of 20 with tri-O-benzylgalloyl chloride followed by hydrogenolysis gave access to the title bis-gallate (24). This constitutes the first synthesis of this natural product, a compound notable for its PKC-inhibitory and anticancer activity.
- Tueckmantel, Werner,Kozikowski, Alan P.,Romanczyk Jr., Leo J.
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p. 12073 - 12081
(2007/10/03)
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- Oligomeric flavanoids. Part 27. Interflavanyl bond formation in procyanidins under neutral conditions
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Dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) and silver tetrafluoroborate (AgBF4) activate the C4-S bond in the 4-thioethers of flavan-3-ols toward carbon nucleophiles to permit formation of the interflavanyl bond in procyanidins under neutral conditions.
- Steynberg, Petrus J.,Nel, Reinier J.J.,Van Rensburg, Hendrik,Bezuidenhoudt, Barend C.B.,Ferreira, Daneel
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p. 8153 - 8158
(2007/10/03)
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- PROANTHOCYANIDIN POLYMERS WITH ANTISECRETORY ACTIVITY AND PROANTHOCYANIDIN OLIGOMERS FROM GUAZUMA ULMIFOLIA BARK
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Bioassay-guided fractionation of a crude extract of Guazuma ulmifolia bark led to the isolation of polymeric proanthocyanidins which inactivated cholera toxin (CT).The average degree of polymerization (DP) of the active compounds ranged from 14.4 to 32.0.The polymers consisted mainly of (-)-epicatechin units.In polymers of a representative fraction, the flavanol units were connected by 8> bonds and, less frequently, by 6> bonds.Inhibition of CT by tannins increased with Mr and conformation flexibility of the tannin molecule.Several known procyanidin oligomers were also isolated. 1H NMR shift rules to distinguish between 8> and 6> linked proanthocyanidin peracetates, that have been proposed for dimers, were extended to trimers and a tetramer.A further diagnostic shift parameter to determine the interflavanoid bonding position is presented and the conformation of oligomeric proanthocyanidin peracetates is discussed. - Key Word Index: Guazuma ulmifolia; Sterculiaceae; bark; proanthocyanidins; tannins; polymers; gel permeation chromatography; NMR; thiolytic degradation; (-)-epicatechin; peracetates; antisecretory activity.
- Hoer, Michaela,Heinrich, Michael,Rimpler, Horst
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p. 109 - 120
(2007/10/03)
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- Tannins and Related Compounds. LIX. Aesculitannins, Novel Proanthocyanidins with Doubly-Bonded Structures from Aesculus hippocastanum L.
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A chemical examination of the seed shells of Aesculus hyppocastanum L.has led to the isolation of proanthocyanidins A-6 (10) and A-7 (11), and aesculitannins A (12), B (13), C (14), D (15), E (16), F (17) and G (18).On the basis of chemical and spectroscopic evidence, proanthocyanidins A-6 (10) and A-7 (11) have been determined to be A-type dimers each possessing a C-4, C-6 interflavanoid linkage, while aesculitannins A (12), B (13), C (14), D (15), E (16), F (17) and G (18) have been characterized as oligomeric proanthocyanidins possessing A-type unit(s) in each molecule.In addition, the presence of (-)-epicatechin (1), proanthocyanidins B-5 (3), A-2 (4), A-4 (5) and C-1 (6), epicatechin-(4β->6)-epicatechin-(4β->6)-epicatechin (7), and cinnamtannins B1 (8) and B2 (9) was also demonstrated Keywords---Aesculus hippocastanum; Hippocastanaceae; aesculitannin; doubly-bonded proanthocyanidin; procyanidin; condensed tannin; flavan-3-ol; thiolytic degradation; epimerization; hydrogen peroxide oxidation
- Morimoto, Satoshi,Nonaka, Gen-ichiro,Nishioka, Itsuo
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p. 4717 - 4729
(2007/10/02)
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- SYNTHESIS AND CHARACTERIZATION OF PROCYANIDIN DIMERS AS THEIR PERACETATES AND OCTAMETHYL ETHER DIACETATES
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Key Word Index - Biomimetic synthesis; procyanidins B1-B8; 3,4-cis-biflavanoid; all--bi--(+)-catechin; 1H NMR parameters. Condensation of (2R,3S,4R or S)-leucocyanidin or the 5,7,3',4'-tetramethyl ether of (2R,3R,4S)-leucocyanidin with flavan-3-ols yielded dimeric flavanoids which were converted to their octamethyl ether diacetates, or the deca-acetates for the 2,3-trans-procyanidin series.Comparison is made of the 1H NMR spectra of the deca-acetate and octamethyl ether diacetate derivatives which lead to useful diagnostic shift parameters characteristic of their structures.Condensation afforded a novel biflavanoid with a 3,4-cis-configuration and a triflavanoid of 'mixed' stereochemistry.
- Kolodziej, Herbert
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p. 1209 - 1216
(2007/10/02)
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- Synthesis and Conformation of Procyanidin Diastereoisomers
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The four theoretically possible diastereoisomeric 4->8 linked procyanidin dimers with two 2,3-cis-flavanoid units, epicatechin-(4β->8)-epicatechin (6), epicatechin-(4β->8)-ent-epicatechin (8), ent-epicatechin-(4α->8)-epicatechin (7), and ent-epicatechin-(4α->8)-ent-epicatechin (2), have been synthesized together with the 2,3-trans diastereoisomers catechin-(4α->8)-catechin (14) and catechin-(4α->8)-ent-catechin (15).The preferred rotamer conformations of the deca-acetate derivatives of (6), (8), (14), and (15) in chloroform were deduced from their 13C n.m.r. and high-field 1H n.m.r. spectra.The 1H n.m.r. spectra of the preferred conformers of the pairs of acetate derivatives of (6) and (15), and (8) and (14), were qualitatively similar as the relative configuration about the interflavanoid bond of one pair has a meso-relationship to the other.
- Foo, Lai Yeap,Porter, Lawrence J.
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p. 1535 - 1543
(2007/10/02)
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- HETEROGENEITY OF INTERFLAVANOID BOND LOCATION IN LOBLOLLY PINE BARK PROCYANIDINS
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Procyanidins B-1 B-3 and B-7 were obtained from Pinus taeda phloem in yields of 0.076, 0.021 and 0.034percent of unextracted dry wt.Procyanidins B-1 and B-7 were produced in relative yields of 2.4:1 by biosynthetically patterned synthesis from catechin and loblolly pine tannins.Partial acid-catalysed thiolytic cleavage of loblolly pine phloem tannins produced (2R,3S,4S)-2,3-cis-3,4-trans-3,3',4',5,7-pentahydroxy-4-phenylthioflavan and both (2R,3R,4R)-2,3-cis-3,4-trans-3,3'4',5,7-pentahydroxy-4-flavan and (2R,3R,4R)-2,3-cis-3,4-trans-3,3',4',5,7-4-flavan in ratios of 3 : 1 demonstrating regio-isomerism of the interflavanoid linkage in the polymeric procyanidins of loblolly pine bark.Key Word Index - Pinus taeda; Pinaceae; loblolly pine; bark; phloem; procyanidins; condensed tannins; interflavanoid linkage; regio-isomerism.
- Hemingway, Richard W.,Karchesy, Joseph J.,McGraw, Gerald W.,Wielesek, Richard A.
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p. 275 - 282
(2007/10/02)
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- Enantiomerism in Natural Procyanidin Polymers: Use of Epicatechin as a Chiral Resolution Reagent
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Procyanidin polymers isolated from Palmae species contain 2,3-cis 5,7,3',4'-tetrahydroxyflavan-3-ol units predominantly of the abnormal (2S,3S) configuration, but also containing about 25percent of units with a (2R,3R) configuration, the proportion of each enantiomer was determined by the stereo- and regio-specific condensation of each unit's carbocation with (2S,3S)-(+)- or (2R,3R)-(-)-epicatechin and resolution of the diastereoisomeric C(4)-C(8) linked epicatechin dimers.
- Foo, L. Yeap,Porter, Lawrence J.
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p. 241 - 242
(2007/10/02)
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- Tannins and Related Compounds. I. Rhubarb (1)
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Three new tannin-related compounds (I, II and III), along with lindleyin (IV), (+)-catechin, 3-O-galloyl-(-)-epicatechin, gallic acid, 3,5,4'-trihydroxystilbene 4'-O-β-D-(6''-O-galloyl)-glucopyranoside, 3,5,4'-trihydroxystilbene 4'-O-β-D-glucopyranoside and 4-(4'-hydroxyphenyl)-2-butanone 4'-O-β-D-glucopyranoside, have been isolated from commercial rhubarb (Rhei Rhizoma).On the basis of spectral and chemical evidence, I, II and III were characterized as 3,3'-di-O-galloylprocyanidin B-2, 3-O-galloylprocyanidin B-1 and 1,2,6-tri-O-galloylglucose, respectively.The occurence of IV in rhubarb is of great significance, since IV has been reported to have analgesic and anti-inflammatory activities almost equal to those of aspirin and phenylbutanone.Tannins in rhubarb have been partially purified (designated as rhatannin (V)).Thiolysis degradation and enzymatic hydrolysis have shown that V is mainly composed of C4 to C8 linked 3-O-galloyl-(-)-epicatechin units in the extension part (upper part) with either 3-O-galloyl-(-)-epicatechin or (+)-catechin unit in the lower terminal part.Keywords. rhubarb; polygonaceae; 3,3'-di-O-galloylprocyanidin B-2; 3-O-galloylprocyanidin B-1; 1,2,6-tri-O-galloylglucose; lindleyin; rhatannin
- Nonaka, Gen-Ichiro,Nishioka, Itsuo,Nagasawa, Tetsuro,Oura, Hikokichi
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p. 2862 - 2870
(2007/10/02)
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