Proanthocyanidin Synthesis

The biosynthesis of catechin itself has recently been studied and may appropriately be mentioned here. Recent feeding experiments in the tea plant, 

in Phytochrome , ed. K. Mitrakos and W. Shropshire, Academic Press, London, 1972, 

Camellia sinensis, indicate that shikimic acid is a better precursor of the B-ring of catechins such as (42) than are phenylalanine and dihydrokaempferol. Calculations based on label dilution, following the feeding of and C precursors, showed shikimic acid to be nearly 100 times more effective a precursor than the other two intermediates. 

The degradative enzyme was found in every higher plant that was tested for it, and in the chick pea, Cicer arietinum, it was found in only those organs which are rich in flavonols. The enzyme is produced between the second and sixth day after germination and appears to parallel PAL activity in its time of synthesis. Thus, the regulation of synthesis and degradation of flavonols are interdependent and cfbsely correlated events, and active turnover must occur from the very moment of synthesis. 

The turnover of the flavanone taxifolin (46) by cultures of a Pseudomonas species grown on (-1-)-catechin has been studied by Jeffrey et al7 A flavo-protein, in the presence of NADPH and molecular oxygen, converts (46) into dihydrogossypetin (47). This intermediate is as yet unknown as a natural product, although the related flavonol is fairly widespread in plants. Compound (47) then undergoes meta-cleavage in the A-ring, to form oxalacetic acid 

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Abrahams, S. et al., The Arabidopsis TDS4 gene encodes leucoanthocyanidin dioxygenase (LDOX) and is essential for proanthocyanidin synthesis and vacuole development. Plant Cell, 35, 624, 2003. 

Damiani, F. et al., The maize transcription factor Sn alters proanthocyanidin synthesis in transgenic Lotus corniculatus plants. Aust. J. Plant Phys., 26, 159, 1999. 

Bogs J, Downey MO, Harvey JS, Ashton AR, Tanner GJ, Robinson SP. 2005 Proanthocyanidin synthesis and expression of genes encoding leucoanthocyanidin reductase and anthocyanidin reductase in developing grape berries and grapevine leaves. Plant Physiol 139 652-663. 

Bogs J, Jaffe FW, Takos AM, Walker RA, Robinson SP. 2007. The grapevine transcription factor VvMYBPAl regulates proanthocyanidin synthesis during fruit... 

Table 7.6.6. Regio- and stereo-selectivity in proanthocyanidin synthesis (from Botha et al. [28])...

Fig. 5 Scheme of the flavonoid pathway leading to synthesis of proanthocyanidins. The enzymes involved in the pathway are shown as follows CHS = chalcone synthase CHI = chalcone isomerase F3H = flavanone-3B-hydroxylase DFR = dihydroflavonol-4-reductase LDOX = leucoanthocynidin dioxygenase LAR = leucoanthocyanidin reductase ANR = anthocyanidin reductase adapted from [27] and [28]... 

Recently published literature described either the improvement of the strategies devoted to the synthesis of either catechins derivatives or oligomeric proanthocyanidins or the use of a synthetic program as a way to obtain... 

Proanthocyanidins Bacteria Ceii coat poiymers Inhibition of cell-associated proteolysis inhibition of cell wall synthesis [76]... 

Although a few mechanisms have so far been proposed to explain the antimicrobial properties exhibited by proanthocyanidins (e.g., inhibition of extracellular enzymes) [86], Jones et al. [83] postulated that their ability to bind bacterial cell coat polymers and their abihty to inhibit cell-associated proteolysis might be considered responsible for the observed activity (Table 1). Accordingly, despite the formation of complexes with cell coat polymers, proanthocyanidins penetrated to the cell wall in sufficient concentration to react with one or more ultra-structural components and to selectively inhibit cell wall synthesis. Decreased proteolysis in these strains may also reflect a reduction of the export of proteases from the cell in the presence of proanthocyanidins [83]. 

In addition to identification of flavan-3-ols and derivatives from natural sources (Table 11.3, Figure 11.3-Figure 11.5, Figure 11.7, and Figure 11.8), several synthetic studies and efforts at establishing absolute configuration have been reported. The modified Mosher method has been successfully applied to configurational definition of the flavan-3-ols and 4-arylflavan-3-ols, and the A-type proanthocyanidins. " The first stereoselective synthesis of a series of flavan-3-ol... 

In addition to the contributions dealing with the isolation and structural elucidation of procyanidins, several excellent papers describing the synthesis and chemical manipulation of the proanthocyanidins in general have been published. These may be listed as follows ... 

The probutinidins (see Section 11.2) represent a second class of proanthocyanidins with flavan chain-extension units. Only five members of this class of compounds have been identified (Table 11.14). Their structures and absolute configurations were also confirmed by synthesis via reduction of the flavanone, butin, followed by acid-catalyzed condensation with the appropriate flavan-3-ol. A notable feature of the synthetic studies was the apparent preference for (4 8) bond formation reported by both groups of authors. 

Bennie, L. et al.. Oligomeric flavanoids. Part 32. Structure and synthesis of ether-linked proter-acacinidin and promelacacinidin proanthocyanidins from Acacia caffra. Phytochemistry, 53, 785, 2000. 

Saito, A. et al.. Synthetic studies of proanthocyanidins. Highly stereoselective synthesis of the catechin dimer, procyanidin B-3, Biosci. Biotechnol. Biochem., 66, 1764, 2002. 

Proanthocyanidins and Procyanidins - In a classical study Bate-Smith ( ) used the patterns of distribution of the three principal classes of phenolic metabolites, which are found in the leaves of plants, as a basis for classification. The biosynthesis of these phenols - (i) proanthocyanidins (ii) glycosylated flavonols and (iii) hydroxycinnamoyl esters - is believed to be associated with the development in plants of the capacity to synthesise the structural polymer lignin by the diversion from protein synthesis of the amino-acids L-phenylalanine and L-tyro-sine. Vascular plants thus employ one or more of the p-hydroxy-cinnarayl alcohols (2,3, and 4), which are derived by enzymic reduction (NADH) of the coenzyme A esters of the corresponding hydroxycinnamic acids, as precursors to lignin. The same coenzyme A esters also form the points of biosynthetic departure for the three groups of phenolic metabolites (i, ii, iii), Figure 1. 

The two principal classes of proanthocyanidins found (10) in plant tissues are the procyanidins (1, R e H) and the prodeTphin-idins (1, R s OH). Proanthocyanidins of mixed anthocyanidin character (1, R = H or OH) have been noted. In any tissue where proanthocyan din synthesis occurs there is invariably found a range of molecular species - from the monomeric flavan-3-ols (catechins, gallocatechins) to the polymeric forms (1) and biosynthetic work (11) suggests a very close relationship between the metabolism of the parent f1avan-3-o1 and the synthesis of proanthocyanidins, Figure 4. 

The branch pathway for anthocyanin biosynthesis starts with the enzymatic reduction of dihydrofiavonols to their corresponding flavan 3,4-diols (leucoanthocyanidins) by substrate-specific dihydroflavonol 4-reductases (DFR). Flavan 3,4-diols are the immediate precursors for the synthesis of catechins and proanthocyanidins. Catechins are formed by enzymatic reduction of the flavan 3,4-diols in the presence of NADPH to leucoanthocyanidins, which are subsequently converted to anthocyanidins by the 2-oxoglutarate-dependant dioxygenase, anthocyanidin synthase. Further glycosylation, methylation, and/or acylation of the latter lead to the formation of the more stable, colored anthocyanins (Scheme 1.1). The details of the individual steps involved in flavonoid and isoflavonoid biosynthesis, including the biochemistry and molecular biology of the enzymes involved, have recently appeared in two excellent reviews.7,8... 

Keywords Adsorption Anthocyanins Flavonoid Synthesis Mutagenicity Proanthocyanidins... 

If, as supposed, epicatechin synthesis starts from cyanidin, then the production of proanthocyanidins in the skins and seeds does not occur... 

Two additional developments that impacted the elaboration of synthesis protocols of proanthocyanidins via catechin (2) and epicatechin (3) derivatives and/or analogues, involved the transformation of readily available and inexpensive catechin (2) into the considerably more expensive epicatechin (3), and the design of experimental conditions permitting 0-benzylation of the phenolic hydroxy groups of flavan-3-ols in high yield. The transformation of catechin (2) into tetra-0-benzylepicatechin (52) (Scheme 7) involved the per-0-benzylation of the phenolic hydroxy groups of catechin (2) to afford tetra-0-benzylcatechin (50) in approximately 20% yield. Inversion of the configuration at C-3 was accomplished by oxidation to the... 

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