Subscribe to RSS
DOI: 10.1055/s-0030-1270908
© Georg Thieme Verlag KG Stuttgart · New York
Towards the Synthesis of Proanthocyanidins: Half a Century of Innovation
Publication History
received Dec. 22, 2010
revised February 11, 2011
accepted February 14, 2011
Publication Date:
16 March 2011 (online)
![](https://www.thieme-connect.de/media/plantamedica/201111/lookinside/thumbnails/10.1055-s-0030-1270908-1.jpg)
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
- 2 Geissman T A, Yoshimura N N. Synthetic proanthocyanidin. Tetrahedron Lett. 1966; 24 2669-2673
- 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
- 4 Creasy L L, Swain T. Structure of condensed tannins. Nature (London). 1965; 208 151-153
- 5 Weinges K, Perner J. The structure of a C30H26O12 procyanidin from cola nuts. Chem Commun. 1967; 7 351-352
- 6 Weinges K, Perner J, Marx H D. Proanthocyanidins, XVI. Synthesis of the octamethyldiacetyl procyanidin B-3. Chem Ber. 1970; 103 2344-2349
- 7 Haslam E. Biogenetically patterned synthesis of procyanidins. J Chem Soc Chem Commun. 1974; 594-595
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 36 Mustafa J, Khan R, Khan I A, Ferreira D. Benzylation of flavan-3-ols (catechins). Org Prep Proced Int. 2004; 36 61-68
- 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
- 38 Tueckmantel W, Kozikowski A P, Romanczyk L J. Methods for the preparation of catechin and epicatechin dimers. US Patent 2000061547. 2000
- 39 Romanczyk L J, Kozikowski A P, Tueckmantel W, Lippman M E. Preparation of polyphenols for use as anticancer agents. US Patent 6207842. 2002
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
Dr. Daneel Ferreira
Department of Pharmacognosy
School of Pharmacy
University of Mississippi
P. O. Box 1848
University, MS 38677
USA
Phone: +1 66 29 15 70 26
Fax: +1 66 29 15 69 75
Email: dferreir@olemiss.edu