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Planta Med 2011; 77(11): 1071-1085
DOI: 10.1055/s-0030-1270908
7th Tannin Conference Award Lecture
Reviews
© Georg Thieme Verlag KG Stuttgart · New York

Towards the Synthesis of Proanthocyanidins: Half a Century of Innovation

Daneel Ferreira1 , 2 , Christina M. Coleman1
  • 1Department of Pharmacognosy, School of Pharmacy, University of Mississippi, University, MS, USA
  • 2Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS, USA
Weitere Informationen

Publikationsverlauf

received Dec. 22, 2010 revised February 11, 2011

accepted February 14, 2011

Publikationsdatum:
16. März 2011 (online)

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Abstract

Results emanating from the synthesis of proanthocyanidins played a crucial role in defining the constitution, regiochemistry, and absolute configuration of this complex but fascinating group of plant secondary metabolites. The initial efforts, commencing in 1966, were focused on structure elucidation of, especially, the procyanidins, profisetinidins, and prorobinetinidins. However, over the past 12 years the emphasis has shifted to the synthesis of the bioactive procyanidins and some of their derivatives at a scale that would permit assessment of their pharmacological properties. With a few exceptions, the vast majority of these synthetic protocols involve the formation of the interflavanyl bond by acid/Lewis acid activation at C-4 of a flavan-3,4-diol or its equivalent, and subsequent trapping of the incipient C-4 carbocation by the nucleophilic centers of a flavan-3-ol (catechin). This review represents the first comprehensive chronicle depicting the development of the subject of proanthocyanidin synthesis.

Key words

synthesis - proanthocyanidins - procyanidins - profisetinidins - flavan‐3,4‐diols - catechins - condensed tannins

References

  • 1 Roux D G. Recent advances in the chemistry and chemical utilization of the natural condensed tannins.  Phytochemistry. 1972;  11 1219-1230
    CrossrefPubMedGoogle Scholar
  • 2 Geissman T A, Yoshimura N N. Synthetic proanthocyanidin.  Tetrahedron Lett. 1966;  24 2669-2673
    PubMedGoogle Scholar
  • 3 Drewes S E, Roux D G. Condensed tannins 18. Stereochemistry of flavan-3,4-diol tannin precursors: (+)-mollisacacidin, (−)-leucofisetinidin and (+)-leucorobinetinidin.  Biochem J. 1964;  90 343-350
    PubMedGoogle Scholar
  • 4 Creasy L L, Swain T. Structure of condensed tannins.  Nature (London). 1965;  208 151-153
    CrossrefPubMedGoogle Scholar
  • 5 Weinges K, Perner J. The structure of a C30H26O12 procyanidin from cola nuts.  Chem Commun. 1967;  7 351-352
    PubMedGoogle Scholar
  • 6 Weinges K, Perner J, Marx H D. Proanthocyanidins, XVI. Synthesis of the octamethyldiacetyl procyanidin B-3.  Chem Ber. 1970;  103 2344-2349
    CrossrefPubMedGoogle Scholar
  • 7 Haslam E. Biogenetically patterned synthesis of procyanidins.  J Chem Soc Chem Commun. 1974;  594-595
    PubMedGoogle Scholar
  • 8 Fletcher A C, Porter L J, Haslam E, Gupta R K. Plant proanthocyanidins. Part 3. Conformational and configurational studies of natural procyanidins.  J Chem Soc [Perkin I]. 1977;  1628-1637
    PubMedGoogle Scholar
  • 9 Thompson R S, Jacques D, Haslam E, Tanner R J N. Plant proanthocyanidins. Part 1. Introduction; the isolation, structure, and distribution in nature of plant procyanidins.  J Chem Soc [Perkin I]. 1972;  1387-1399
    PubMedGoogle Scholar
  • 10 Roux D G, Du Preez I C, Rowan A C, Feeney J. Hindered rotation about the sp2-sp3 hybridized carbon-carbon bond between flavonoid units in condensed tannins.  J Chem Soc Chem Commun. 1971;  315-316
    PubMedGoogle Scholar
  • 11 Ferreira D, Hundt H K L, Roux D G. Stereochemistry of a tetraflavanoid condensed tannin from Rhus lancea.  J Chem Soc Chem Commun. 1971;  1257-1259
    PubMedGoogle Scholar
  • 12 Botha J J, Ferreira D, Roux D G. Condensed tannins. Circular dichroism method of assessing the absolute configuration at C-4 of 4-arylflavan-3-ols, and stereochemistry of their formation from flavan-3,4-diols.  J Chem Soc Chem Commun. 1978;  698-700
    PubMedGoogle Scholar
  • 13 Botha J J, Young D A, Ferreira D, Roux D G. Synthesis of condensed tannins. Part 1. Stereoselective and stereospecific synthesis of optically pure 4-arylflavan-3-ols, and assessment of their absolute stereochemistry at C-4 by means of circular dichroism.  J Chem Soc [Perkin I]. 1981;  1213-1219
    PubMedGoogle Scholar
  • 14 Botha J J, Ferreira D, Roux D G. Condensed tannins: direct synthesis, structure and absolute configuration of four biflavonoids from Black Wattle Bark (“Mimosa”) extract.  J Chem Soc Chem Commun. 1978;  700-702
    PubMedGoogle Scholar
  • 15 Botha J J, Ferreira D, Roux D G. Synthesis of condensed tannins. Part 4. A direct biomimetic approach to [4,6]- and [4,8]-biflavonoids.  J Chem Soc [Perkin I]. 1981;  1235-1245
    PubMedGoogle Scholar
  • 16 Young D A, Cronjé A, Botes A L, Ferreira D, Roux D G. Synthesis of condensed tannins. Part 14. Biflavonoid profisetinidins as synthons. The acid-induced “phlobaphene” reaction.  J Chem Soc [Perkin I]. 1985;  2521-2527
    PubMedGoogle Scholar
  • 17 Viviers P M, Kolodziej H, Young D A, Ferreira D, Roux D G. Synthesis of condensed tannins. Part 11. Intramolecular enantiomerism of the constituent units of tannins from the Anacardiaceae: stoicheiometric control in direct synthesis: derivation of 1H NMR parameters applicable to higher oligomers.  J Chem Soc [Perkin I]. 1983;  2555-2562
    PubMedGoogle Scholar
  • 18 Malan J C S, Young D A, Steynberg J P, Ferreira D. Oligomeric flavanoids. Part 9. The first flavanoids based on mopanol and peltogynol as inceptive electrophiles.  J Chem Soc [Perkin I]. 1990;  219-225
    PubMedGoogle Scholar
  • 19 Malan J C S, Steynberg P J, Steynberg J P, Young D A, Bezuidenhoudt B C B, Ferreira D. Oligomeric flavanoids. Part 14. Proguibourtinidins based on (−)-fisetinidol and (+)-epifisetinidol units.  Tetrahedron. 1990;  46 2883-2890
    CrossrefPubMedGoogle Scholar
  • 20 Coetzee J, Mciteka L, Malan E, Ferreira D. Oligomeric flavanoids. Part 30. Structure and synthesis of butiniflavan-epicatechin and -epigallocatechin probutinidins.  Phytochemistry. 1999;  52 737-743
    CrossrefPubMedGoogle Scholar
  • 21 Coetzee J, Mciteka L, Malan E, Ferreira D. Structure and synthesis of the first procacinidin dimers based on epicatechin, and gallo- and epigallocatechin.  Phytochemistry. 2000;  53 795-804
    CrossrefPubMedGoogle Scholar
  • 22 Bennie L, Malan E, Coetzee J, Ferreira D. Structure and synthesis of ether-linked proteracacinidin and promelacacinidin proanthocyanidins from Acacia caffra.  Phytochemistry. 2000;  53 785-793
    CrossrefPubMedGoogle Scholar
  • 23 Van der Westhuizen J H, Ferreira D, Roux D G. Synthesis of condensed tannins. Part 2. Synthesis by photolytic rearrangement, stereochemistry, and circular dichroism of the first 2,3-cis-3,4-cis-4-arylflavan-3-ols.  J Chem Soc [Perkin I]. 1981;  1220-1226
    PubMedGoogle Scholar
  • 24 Ding Y, Li X-C, Ferreira D. 4-Arylflavan-3-ols as proanthocyanidin models: absolute configuration via density functional calculations of electronic circular dichroism.  J Nat Prod. 2010;  73 435-440
    CrossrefPubMedGoogle Scholar
  • 25 Botha J J, Ferreira D, Roux D G, Hull W E. Condensed tannins: Condensation mode and sequence during formation of synthetic and natural triflavonoids.  J Chem Soc Chem Commun. 1979;  510-512
    PubMedGoogle Scholar
  • 26 Botha J J, Viviers P M, Young D A, Du Preez I C, Ferreira D, Roux D G, Hull W E. Synthesis of condensed tannins. Part 5. The first angular [4,6 : 4,8]-triflavonoids and their natural counterparts.  J Chem Soc [Perkin I]. 1982;  527-533
    PubMedGoogle Scholar
  • 27 Viviers P M, Young D A, Botha J J, Ferreira D, Roux D G, Hull W E. Synthesis of condensed tannins. Part 6. The sequence of units, coupling position and absolute configuration of the first linear [4,6 : 4,6]-triflavanoid with terminal 3,4-diol function.  J Chem Soc [Perkin I]. 1982;  535-540
    PubMedGoogle Scholar
  • 28 Young D A, Ferreira D, Roux D G, Hull W E. Synthesis of condensed tannins. Part 15. Structure of natural “angular” profisetinidin tetraflavanoids: asymmetric induction during oligomeric synthesis.  J Chem Soc [Perkin I]. 1985;  2529-2535
    PubMedGoogle Scholar
  • 29 Young D A, Kolodziej H, Ferreira D, Roux D G. Synthesis of condensed tannins. Part 16. Stereochemical differentiation of the first “angular” (2S, 3R)-profisetinidin tetraflavanoids from Rhus lancea (Karee) and the varying dynamic behaviour of their derivatives.  J Chem Soc [Perkin I]. 1985;  2537-2544
    PubMedGoogle Scholar
  • 30 Delcour J A, Ferreira D, Roux D G. Synthesis of condensed tannins. Part 9. The condensation sequence of leucocyanidin with (+)-catechin and with the resultant procyanidins.  J Chem Soc [Perkin I]. 1983;  1711-1717
    PubMedGoogle Scholar
  • 31 Delcour J A, Serneels E J, Ferreira D, Roux D G. Synthesis of condensed tannins. Part 13. The first 2,3-trans-3,4-cis-procyanidins: sequence of units in a “trimer” of mixed stereochemistry.  J Chem Soc [Perkin I]. 1985;  669-673
    PubMedGoogle Scholar
  • 32 Steenkamp J A, Ferreira D, Roux D G. Sterospecific functionalization of the heterocyclic ring systems of flavan-3-ol and [4, 8]-biflavan-3-ol derivatives with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).  Tetrahedron Lett. 1985;  26 3045-3048
    CrossrefPubMedGoogle Scholar
  • 33 Kozikowski A P, Tueckmantel W, George C. Studies in polyphenol chemistry and bioactivity 2. Establishment of interflavan linkage regio- and stereochemistry by oxidative degradation of an O-alkylated derivative of procyanidin B-2 to (R)-(−)-2,4-diphenylbutyric acid.  J Org Chem. 2000;  65 5371-5381
    CrossrefPubMedGoogle Scholar
  • 34 Tueckmantel W, Kozikowski P, Romanczyk L J. 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].  J Am Chem Soc. 1999;  121 12073-12081
    CrossrefPubMedGoogle Scholar
  • 35 Steynberg P J, Nel R J J, Van Reusburg H, Bezuidenhoudt B C B, Ferreira D. Oligomeric flavanoids. Part 27. Interflavanyl bond formation in procyanidins under neutral conditions.  Tetrahedron. 1998;  54 8153-8158
    CrossrefPubMedGoogle Scholar
  • 36 Mustafa J, Khan R, Khan I A, Ferreira D. Benzylation of flavan-3-ols (catechins).  Org Prep Proced Int. 2004;  36 61-68
    CrossrefPubMedGoogle Scholar
  • 37 Kozikowski A P, Tueckmantel W, Bottcher G, Romanczyk L J. Studies in polyphenol chemistry and bioactivity 4. Synthesis of trimeric, tetrameric, pentameric, and higher oligomeric epicatechin-derived procyanidins having all-(4β → 8)-interflavan connectivity and their inhibition of cancer cell growth through cell cycle arrest.  J Org Chem. 2003;  68 1641-1658
    CrossrefPubMedGoogle Scholar
  • 38 Tueckmantel W, Kozikowski A P, Romanczyk L J. Methods for the preparation of catechin and epicatechin dimers. US Patent 2000061547. 2000
    Google Scholar
  • 39 Romanczyk L J, Kozikowski A P, Tueckmantel W, Lippman M E. Preparation of polyphenols for use as anticancer agents. US Patent 6207842. 2002
    Google Scholar
  • 40 Kozikowski A P, Tueckmantel W, Romanczyk L J, Ma X. Synthesis of oligomeric epicatechin and catechin-derived procyanidins as anticancer agents. US Patent 415616. 2005
    Google Scholar
  • 41 Sharma P K, Kolchinski A P, Shea H A, Nair J J, Gou Y, Romanczyk L J, Schmitz H H. Scale-up syntheses of two naturally occurring procyanidins: (−)-epicatechin-(4β → 8)-(+)-catechin and (−)-epicatechin-3-O-galloyl-(4β → 8)-(−)epicatechin-3-O-gallate.  Org Process Res Dev. 2007;  11 422-430
    CrossrefPubMedGoogle Scholar
  • 42 Ohmori K, Ushimaru N, Suzuki K. Oligomeric catechins: an enabling synthetic strategy by orthogonal activation and C(8) protection.  Proc Natl Acad Sci USA. 2004;  101 12002-12007
    CrossrefPubMedGoogle Scholar
  • 43 Deprez S, Mila I, Scalbert A. Carbon-14 biolabeling of (+)-catechin and proanthocyanidin oligomers in willow tree cuttings.  J Agric Food Chem. 1999;  47 4219-4230
    CrossrefPubMedGoogle Scholar
  • 44 Krisa S, Teguo P W, Decendit A, Deffieux G, Vercauteren J, Merillon J-M. Production of 13C-labelled anthocyanins by Vitis vinifera cell suspension cultures.  Phytochemistry. 1999;  51 651-656
    CrossrefPubMedGoogle Scholar
  • 45 Nay B, Arnaudinaud V, Peyrat J-F, Nuhrich A, Deffieux G, Merillon J-M, Vercauteren J. Total synthesis of labeled flavanoids. 2. 13C-labeled (±) -catechin from potassium [13C]cyanide.  Eur J Org Chem. 2000;  7 1279-1283
    PubMedGoogle Scholar
  • 46 Nay B, Monti J-P, Nuhrich A, Deffieux G, Merillon J-M, Vercauteren J. Methods in synthesis of flavonoids. Part 2: 1 High yield access to both enantiomers of catechin.  Tetrahedron Lett. 2000;  41 9049-9051
    CrossrefPubMedGoogle Scholar
  • 47 Arnaudinaud V, Nay B, Vercauteren J. Gram-scale production and applications of optically pure [13C]-labeled (+)-catechin and (−)-epicatechin.  Eur J Org Chem. 2001;  12 2379-2384
    PubMedGoogle Scholar
  • 48 Arnaudinaud V, Nay B, Verge S, Nuhrich A, Deffieux G, Merillon J-M, Monti J-P, Vercauteren J. Total synthesis of isotopically labeled flavonoids. Part 5: Gram-scale production of 13C-labeled (−)-procyanidin B3.  Tetrahedron Lett. 2001;  42 5669-5671
    CrossrefPubMedGoogle Scholar
  • 49 Arnaudinaud V, Nay B, Nuhrich A, Deffieux G, Merillon J M, Monti J-P, Vercauteren J. Total synthesis of isotopically labeled flavonoids. Part 3: 13C-labeled (−)-procyanidin B3 from 1[13C]-acetic acid.  Tetrahedron Lett. 2001;  42 1279-1281
    CrossrefPubMedGoogle Scholar
  • 50 Saito A, Nakajima N, Tanaka A, Ubukata M. Synthetic studies of proanthocyanidins. Highly stereoselective synthesis of the catechin dimer, procyanidin-B3.  Biosci Biotechnol Biochem. 2002;  66 1764-1767
    CrossrefPubMedGoogle Scholar
  • 51 Saito A, Nakajima N, Tanaka A, Ubukata M. Synthetic studies of proanthocyanidins. Part 3. Stereoselective 3,4-cis-catechin and catechin condensation by TMSOTf-catalyzed intramolecular coupling method.  Tetrahedron Lett. 2003;  44 5449-5452
    CrossrefPubMedGoogle Scholar
  • 52 Saito A, Nakajima N, Tanaka A, Ubukata M. Synthetic studies of proanthocyanidins. Part 4. The synthesis of procyanidin B1 and B4: TMSOTf-catalyzed cyclization of catechin and epicatechin condensation.  Heterocycles. 2003;  61 287-298
    CrossrefPubMedGoogle Scholar
  • 53 Saito A, Nakajima N, Matsuura N, Tanaka A, Ubukata M. Synthetic studies of proanthocyanidins. Part 5. 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.  Heterocycles. 2004;  62 479-489
    CrossrefPubMedGoogle Scholar
  • 54 Saito A, Tanaka A, Ubukata M. Nakajima N. Stereoselection of 3,4-cis- and 3,4-trans-catechin and catechin condensation under intramolecular coupling method.  Synlett. 2004;  11 2040-2042
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 55 Saito A, Emoto M, Tanaka A, Doi Y, Shoji K, Mizushina Y, Ikawa H, Yoshida H, Matsuura N, Nakajima N. Stereoselective synthesis of procyanidin B3-3-O-gallate and 3,3′′-di-O-gallate, and their abilities as antioxidant and DNA polymerase inhibitor.  Tetrahedron. 2004;  60 12043-12049
    CrossrefPubMedGoogle Scholar
  • 56 Saito A, Tanaka A, Ubukata M. Nakajima N. Efficient stereoselective synthesis of proanthocyanidin trimers with TMSOTf-catalyzed intermolecular condensation.  Synlett. 2004;  6 1069-1073
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 57 Tarascou I, Barathieu K, Andre Y, Pianet I, Dufourc E, Fouquet E. An improved synthesis of procyanidin dimers: regio- and stereocontrol of the interflavan bond.  Eur J Org Chem. 2006;  23 5367-5377
    PubMedGoogle Scholar
  • 58 Sajiki H, Kume A, Hattori K, Hirota K. Mild and general procedure for Pd/C-catalyzed hydrodechlorination of aromatic chlorides.  Tetrahedron Lett. 2002;  43 7247-7250
    CrossrefPubMedGoogle Scholar
  • 59 Sajiki H, Kume A, Hattori K, Hirota K, Nagase H, Hirota K. Complete and truly catalytic degradation method of PCBs using Pd/C-Et3N system under ambient pressure and temperature.  Tetrahedron Lett. 2002;  43 7251-7254
    CrossrefPubMedGoogle Scholar
  • 60 Mohri Y, Sagehashi M, Yamada T, Hattori Y, Morimura K, Kamo T, Hirota M, Makabe H. An efficient synthesis of procyanidins. Rare earth metal Lewis acid catalyzed equimolar condensation of catechin and epicatechin.  Tetrahedron Lett. 2007;  48 5891-5894
    CrossrefPubMedGoogle Scholar
  • 61 Mohri Y, Sagehashi M, Yamada T, Hattori Y, Morimura K, Hamauzu Y, Kamo T, Hirota M, Makabe H. An efficient synthesis of procyanidins using equimolar condensation of catechin and/or epicatechin catalyzed by ytterbium triflate.  Heterocycles. 2009;  79 549-563
    CrossrefPubMedGoogle Scholar
  • 62 Oyama K-I, Kuwano M, Ito M, Yoshida K, Kondo T. Synthesis of procyanidins by stepwise- and self-condensation using 3,4-cis-4-acetoxy-3-O-acetyl-4-dehydro-5,7,3′,4′-tetra-O-benzyl-(+)-catechin and (−)-epicatechin as a key building monomer.  Tetrahedron Lett. 2008;  49 3176-3180
    CrossrefPubMedGoogle Scholar
  • 63 Achilonu M C, Bonnet S L, Van der Westhuizen J H. Synthesis of proanthocyanidins. Part 1. The first oxidative formation of the interflavanyl bond in procyanidins.  Org Lett. 2008;  10 3865-3868
    CrossrefPubMedGoogle Scholar

Dr. Daneel Ferreira

Department of Pharmacognosy
School of Pharmacy
University of Mississippi

P. O. Box 1848

University, MS 38677

USA

Telefon: +1 66 29 15 70 26

Fax: +1 66 29 15 69 75

eMail: dferreir@olemiss.edu