Flavan-3,4-diol

The significance of flavan-3,4-diols in plants rests primarily on their probable role as precursors of the polymeric proanthocyanidins. Co-occurrence of the 5-deoxy compounds - i.e., quibourtacacidins, mollisacacidins, and robinetinidins - with the related proanthocyanidins in Acacia species and the ready synthesis of naturally occurring proanthocyanidins from reactions of these flavan-3,4-diols with catechin under mild acidic conditions constitutes heavy but not definitive evidence for this thesis (31, 315-317). 

Some inconsistencies occur in the distribution of dihydroflavonols, flavan-3,4-diols, and proanthocyanidins in plants outside the Leguminosae that have caused doubts about the central role of flavan-3,4-diols in proanthocyanidin metabolism (134-136). One concern is the fact that no 5,7-dihydroxy-substituted 

Another concern has been that the hydroxylation patterns of the dihydro-flavonols and flavonols are often not reflected in the co-occurring proanthocyanidins. In the barks of southern pines for example, dihydromyricetin and myricetin are prominent constituents of the outer bark (151). However, the proanthocyanidins and condensed tannins have only very small proportions of prodelphinidin units (146). It is probable that the pool of dihydro flavonols used in reduction to flavan-3,4-diols and flavan-3-ols occurs prior to the hydroxylation at C-5.  

The most important concern is lack of an accounting for the preponderance of 2,3-cis procyanidin units in the proanthocyanidins of conifers (see Sect. 7.7). Stafford s (338, 339) proposal of a C-3 epimerase that provides a 2,3-cis dihydroflavonol that is held on an enzyme surface and is immediately reduced to the flavan-3,4-diol in one pool or that is reduced through two stages to the flavan-3-ol in another pool is certainly an attractive explanation. However, enzymes from cell suspension cultures of Pseudotsuga menziesii (Douglas-fir) or Ginkgo biloba gave only a 2,3-trans flavan-3,4-diol (338-342), and it is known that the 2,3-cis procyanidin units predominate over the 2,3-trans isomers by a factor of 3 1 in the phloem (189). Thus such an epimerase was not present in these enzyme preparations. 

An explanation for the formation of 2jR,3jR-(2,3-c/5)-proanthocyanidins from the 2i ,3S-(2,3-/ra/Z5 )-flavan-3,4-diols could lie in a tautomeric rearrangement of quinone methide intermediates to flav-3-en-3-ols, which could then be stereospecifically converted back to either 2,3-trans or 2,3-cis quinone methides (145). Chemical evidence supporting this thesis has been obtained by the formation of diarylprqpanone derivatives from the reaction of polymeric procyanidins with phenylmethanethiol under alkaline conditions (223). Enzymes controlling the quinone methide to flav-3-en-3-ol rearrangements rather than C-3 inversion of dihydroflavonols may be involved. In either case, evidence continues to mount that the flavan-3,4-diols are indeed central intermediates in the biogenesis of proanthocyanidins and that this conversion is under enzymic (genetic) control (219, 341, 342). 

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In a few cases, the synthesis was directed towards well-defined oligomers (dimers, trimers, etc.). The synthesis of bis(5,7,3, 4 -tetra-0-benzyl)-EC 4/1,8-dimer from 5,7,3, 4 -tetra-0-benzyl-EC and 5,7,3, 4 -tetra-0-benzyl-4-(2-hydroxyethoxy)-EC was described by Kozikowski et al. [41]. This compound exhibited the ability to inhibit the growth of several breast cancer cell fines through the induction of cell cycle arrest in the Gq/Gi phase. Analogously, procyanidin-B3, a condensed catechin dimer, has been obtained through condensation of benzylated catechin with various 4-0-alkylated flavan-3,4-diol derivatives in the presence of a Lewis acid. This reaction led to protected procyanidin-B3 and its diastereomer. In particular, octa-O-benzylated procyanidin-B3 has been produced with high levels of stereoselectivity and in excellent isolation yields [42]. 

Flavanols and procyanidins Flavanols, or flavan-3-ols, are synthesized via two routes, with (+) catechins formed from flavan-3,4-diols via leucoanthocyanidin reductase (LAR), and (—) epicatechins from anthocyanidins via anthocyanidin reductase (ANR) (see Fig. 5.4). These flavan-3-ol molecules are then polymerized to condensed tannins (proanthocyanidins or procyanidins), widely varying in the number and nature of their component monomers and linkages (Aron and Kennedy 2008 Deluc and others 2008). It is still not known whether these polymerization reactions happen spontaneously, are enzyme catalyzed, or result from a mixture of both. 

Flavan-3,4-diols FIavan-3,4-diols, also known as leucoanthocyanidins, are not particularly prevalent in the plant kingdom, instead being themselves precursors of flavan-3-ols (catechins), anthocyanidins, and condensed tannins (proanthocyanidins) (see Fig. 5.4). Flavan-3,4-diols are synthesized from dihydroflavonol precursors by the enzyme dihydroflavonol 4-reductase (DFR), through an NADPH-dependent reaction (Anderson and Markham 2006). The substrate binding affinity of DFR is paramount in determining which types of downstream anthocyanins are synthesized, with many fruits and flowers unable to synthesize pelargonidin type anthocyanins, because their particular DFR enzymes cannot accept dihydrokaempferol as a substrate (Anderson and Markham 2006). 

The stereoselective epoxidation of chalcones, followed by acid-catalysed ring closure and concomitant cleavage of the epoxide ring, provides a very efficient route to chiral flavon-3-ols and, subsequently, by borohydride reduction to produce flavan-3,4-diols [13, 14], It has been shown that diastereoselective reduction of the chiral flavon-3-ols by sodium borohydride in methanol yields the trans-2,3-dihydroxy compounds, whereas borohydride reduction in dioxan produces the cis-isomers [14] the synthetic procedure confirms the cis configuration of the 2,3-hydroxy groups of naturally occurring leucodelphinidins [14]. 

The second mechanism is based on nucleophilic addition onto the carbonium ion formed in acid solutions from flavan 3,4-diols or by cleavage of procyanidins. A condensation... 

The naturally occurring compounds in the flavan, flavan-3-ol, flavan-4-ol, flavan-3,4-diol, and proanthocyanidin classes, together with their plant sources, are listed in Table 11.2-Table 11.17. The lists are confined to new compounds reported in the post-1992 period or those that have been overlooked in the 1994 review, and therefore must be considered in conjunction with the corresponding tables of the Porter reviews to be comprehensive. Since many of the monomeric analogs have been published under trivial names these will be retained to facilitate electronic literature searches. Unfortunately, a considerable number of these potentially chiral compounds have been reported without assignment of absolute configuration, and are hence presented as such. 

Owing to the purported role of the flavans and flavan-3-ols as nucleophilic chain-terminating units, and of the flavan-4-ols and flavan-3,4-diols (leucoanthocyanidins) as electrophilic chain-extension units in the biosynthesis of the proanthocyanidins," the chemistry of these four classes of compounds is intimately linked to that of the proanthocyanidins. 

In contrast to the ubiquitous distribution of flavonoids hydroxylated at C-3 or C-4 of their heterocyclic rings, the unsubstituted flavans (2-phenylchromans) are more rarely found. The flavans co-occur with chalcones, flavanones, flavan-3,4-diols, flavonols, and 1,3-diphenyl-propanes. 

NMR data of the per-O-acetyl derivatives. However, the proposed 2,3-cis-3,4-trans configuration of the 0-acetyl derivatives of 110 and 113 did not appear to be supported by coupling constants ( /2,3 = 2.5, 73,4= 10.5 Hz and 72,3 = 3.5, V3 4 = 9.5 Hz, respectively) and suggests that a reinterpretation of data is now required. A further feature that casts doubt on the validity of the structural claims is the apparent stability of leucopelargonidin (113) in contrast to the well-established reactivity of flavan-3,4-diols with 5,7-dihydroxy A-rings. °... 

The 8-0-methylepioritin-4a-ol (114) complements the rare series of flavan-3,4-diols where 0-methylation had occurred at one of the phenolic hydroxyl functions (Figure 11.10). Compounds 115-122 were obtained from various Lonchocarpus species. 

For additional information regarding the chemistry of the flavans, flavan-3-ols, flavan-4-ols, and flavan-3,4-diols the reader is referred to Refs. 7-12. 

Notable from Table 11.10 and Table 11.11 is the considerable number of proteracacini-dins and promelacacinidins at both the di- and trimeric levels possessing 2,3-cis-3,A-cis-flavan-3,4-diol terminating moieties. It has been demonstrated that melacacidin (158) is basically inert toward solvolysis or epimerization at This was recently confirmed... 

Ali, M. and Bhutan , K., Flavan-3,4-diols from Musa sapientum seeds, Pharmazie, 48, 455, 1993. Malan, E., A (4(3 5)-linked proteracacinidin dimer from the heartwood of Acacia caffra. 

Stich, K. et al., Enzymatic conversion of dihydroflavonols to flavan-3,4-diols using extracts of Dianthus caryophyllus L. (carnation), Planta, 187, 103, 1992. 

Ferreira, D. et al.. Circular dichroic properties of flavan-3,4-diols, J. Nat. Prod., 67, 174, 2004. Cai, Y. et al.. Biological and chemical investigation of dragon s blood from croton species of South America. Part 1. Polyphenolic compounds from Croton lechleri. Phytochemistry, 30, 2033, 1991. Cui, C.B., Davallin, a new tetrameric proanthocyanidin from the rhizomes of Davallia mariesii Moore, Chem. Pharm. Bull, 39, 2179, 1991. 

Clark-Lewis, J.W. and Williams, L.R., Flavan derivatives. XVII. Epimerization of the benzylic 4-hydroxyl group in flavan-3,4-diols and the formation of 4-alkyl ethers by solvolysis, Aust. J. Chem., 20, 2152, 1967. 

Flavonoids can be classified according to their biosynthetic origins. Some flavonoids are both intermediates in biosynthesis and end-products, e.g. chalcones, flavanones, flavanon-3-ols and flavan-3,4-diols. Other classes are only known as the end-products of biosynthesis, e.g. anthocyanins, flavones and flavonols. Two further classes of flavonoids are those in which the 2-phenyl side-chain of flavonoid isomerizes to the 3-position (giving rise to isoflavones and related isoflavonoids) and then to the 4-position (giving rise to the neoflavonoids). The major classes of flavonoids, with specific examples, are summarized helow. 

The Atlas of Stereochemistry includes material on isochromans, flavanoids and rotenoids (B-78MI22202) and an extensive discussion of the stereochemistry of flavan-3,4-diols is available . 

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