Interflavanoid bond

On the other hand, the flavan-3-ol units can also be doubly linked by an additional ether bond between C2 07 (A-type). Structural variations occurring in proanthocyanidin oligomers may also occur with the formation of a second interflavanoid bond by C-0 oxidative coupling to form A-type oligomers (Fig. 3) [17,20]. Due to the complexity of this conversion, A-type proanthocyanidins are not as frequently encountered in nature compared to the B-type oligomers. 

Hermingway RW (1989) Reactions at the interflavanoid bond of proanthocyanidins. In Hermingway RW, Karchesy JJ (eds) Chemistry and significance of condensed tannins. Plenum Press, New York, NY... 

The structural diversity of procyanidins is based on the two possible monomer units (+)-catechin and (-)-epicatechin, on the different types of interflavanoid bonds and on the different lengths of chains which are possible. Besides the most common C4—>C8 and C4—>C6 linkages doubly linked flavan-3-ol structures exist, too. In addition to a C4- C8 bond they are linked by an ether bond between 07—>C2 [1] (see Fig. (3)). Cyclic structures have been proposed for procyanidins from kaki (Diospyros kaki) [12] and cherry (Primus avium) [13]. Higher molecular weight procyanidins are usually of moderate size (up to 3 000 daltons) [14], but also polymers with very high molecular weights (20 000 to ISO OOO... 

Procyanidins are quite reactive and are therefore considered as some of the most unstable natural phenolic compounds [19-20]. They are subject to enzymatic oxidation by polyphenol oxidases as well as to spontaneous oxidation [21], Coupled oxidation reactions involving o-quinones of phenolic acids have been reported [22-24], Procyanidins are thermally labile [25] and can easily undergo molecular rearrangements in acidic or basic media [26]. In model solutions interflavanoid bonds of procyanidins were found to be unstable, but also new carbon-carbon bonds were formed... 

Kiehne et al. [282] who analyzed green tea using a thermospray interface in the positive ionization mode could distinguish fragments originating form upper (T) and lower (B) units of dimeric procyanidins. Cleavage of the interflavanoid bond resulted in a carbenium-ion (T-l) and a neutral fragment from the lower unit which could be protonated under the experimental conditions to form a pseudo molecular ion (B + H+). 

There are some limitations to MS detection. On one hand, it is impossible to differentiate between the stereoisomers (+)-catechin and (-)-epicatechin and on the other hand the configuration of the interflavanoid bond can not be determined [171,269]. However, results from off-line FAB-MS suggest that additional structural information, which up to now is not accessible with any other detection mode, might be obtained. Karchesy et al. [285-286] could distinguish between linear and branched trimers from the different ion species that were produced. Furthermore, slight differences in abundance of characteristic ions for 4(3— 8-linked and... 

The situation is more complex in defining the regioselectivity of procyanidin synthesis. Here differences between kinetic control and thermodynamic equilibrium ratios become particularly important because of the lability of the in-terflavanoid bond in these compounds and because of differences in both the relative rate of acid-catalyzed cleavage and rate of condensation for the C-6 and C-8 substituted isomers (148). Work of Haslam s group indicated that the C-8 substituted procyanidins predominated over their C-6 linked pairs by a factor of 8 to 9 to 1 (177, 352). However, Botha et al. (28) obtained catechin-(4a- 8)-catechin and catechin-(4a- 6)-catechin in relative yields of 3.2 to 1 from a 2-hour bio-mimetic synthesis with 0.1 M HCl at ambient temperature. Similarly, Hemingway et al. (143) obtained epicatechin-(4)ff- 8)-catechin and epicatechin-(4)ff- 6)-cate-chin in relative yields of about 2.5 to 1 through synthesis by reaction of Pinus taeda proanthocyanidins with excess catechin for 48 hours at 25 °C using HCl as a catalyst. This ratio was similar to the yield of the two isomers isolated from the phloem of Pinus taeda. The extreme lability of the interflavanoid bond in the procyanidins causes one to wonder if true kinetic control ratios can be obtained from acid-catalyzed reactions of the procyanidins. 

Refers to absolute configuration of the parent flavan-3,4-diol and flavan 3-ol Tentative assignment of interflavanoid bond location and location of carboxyl substitution... 

The procyanidins are broadly distributed in the leaves, fruit, bark, and less commonly the wood of a wide spectrum of plants (Sect. 7.7). About 50 procyanidins ranging from dimers to pentamers have now been isolated and their structures defined. The 2/ ,3/ -(2,3-c/5 )-procyanidins linked by (4)8- 8)- and/or (4)8- 6)-inter-flavanoid bonds occur most frequently. Many plants contain mixtures of 2R,3R-(2,3-cis) and 2R,3S-(2,3-trans) procyanidins but the compounds of the former stereochemistry normally predominate. The distribution of these compounds in commercially important woody plants has been extended continually from the early work of Porter (300) on Pinus radiata bark through the survey of Pinaceae by Samejima (329) to the recent isolation of dimers from the bark of Juniperus communis (94). The plants that contain predominantly 2R,3S- 2,3-trans) compounds are, so far, restricted to few plant genera, including fruits of Ribes species or the catechins of Salix species. All 2,3-cis procyanidins have [4-)8]-interflavanoid bonds (i.e., 3,4-/wa25 configuration). Most natural 2y3-trans procyanidins isolated to date have [4-a]-interflavanoid bonds (i.e. also 3 A-trans but opposite configuration). However, Delcour et al. (68) and Kolodziej (210, 211) have recently ob-... 

Jacques et al. (176) isolated two trimeric procyanidins that contained both (4yff 8)- and (4)ff- 8 2)ff- 0->7)-interflavanoid bonds, and partially defined their structures. Nonaka et al. (275) have now unequivocally established the locations of interflavanoid bonds in a series of these compounds from Cinnamomum zeylanicum (cinnamon), including a trimer, two tetramers (59), and a pentamer. The cinchonains such as 60 and 61, cinnamate derivatives of procyanidins are among the more unusual structural variations that have been found in the procyanidins (273). These compounds emphasize the high degree of nucleophilicity of the phloroglucinol ring in procyanidins. These no doubt are examples of a vari-... 

H-NMR spectra of the procyanidins, like most other proanthocyanidins, show restricted rotation about the interflavanoid bond under normal temperature conditions (91, 98, 352, 382). The phenolic forms of procyanidins with a 2,3-cis-3A-trans upper unit give broadened but first order spectra until the temperature is reduced to 0 C where two rotational isomers become apparent (98). It is very important to establish the presence and relative proportions of rotational isomers in the free phenols at physiological temperature conditions. It is not possible to resolve these rotamers by NMR because of the comparatively slow time scale. The presence of two rotamers of the dimeric procyanidins as free phenols, and in proportions similar to those found for the locked methyl ether or acetate derivatives, has recently been shown by time-resolved fluorescence decay methods... 

In the methyl ether or acetate derivatives, the rotational isomers are locked at ambient temperature and second order NMR spectra are clearly seen for dimeric procyanidin derivatives (98). Probe temperatures must be increased to 160° to 180°C in nitrobenzene before the spectra collapse to first order. The (4 ff- >8)-linked isomers exhibit one preferred rotational isomer whereas two rotational isomers are evident in nearly equal proportions in the (4 S- 6)-linked compounds. In these 2, i-cis- iA trans procyanidins, the lower flavan unit is in a quasi-2iX dX position. Here the restricted rotation is due to interaction of the A-ring substituent(s) ortho to the interflavanoid bond and the C-2 hydrogen together with the n system of the A-ring of the upper unit (98). 

The discussions of the reactions of flavan-3-ols (Sect. 7.6.3.1.3) and of the flavan-3,4-diols (Sect. 7.6.3.2.3) are, for the most part, directly applicable to those of the oligomeric proanthocyanidins and condensed tannins, the critical difference, of course, being reactions at the interflavanoid bond. Although this difference is obvious, the interflavanoid bond, particularly its lability to either acid- or base-catalyzed solvolysis (107, 144, 148, 152, 225), has not been given adequate consideration in many instances. Reactions of condensed tannins are sometimes incorrectly postulated to parallel those of the flavan-3-ols. It seems far more appropriate now to use dimeric proanthocyanidins as model compounds for study of the reactions of condensed tannins, because these compounds are easily synthesized and their spectral properties are well known. 

Foo L Y, McGraw G W, Hemingway R W 1983 Condensed tannins Preferential substitution at the interflavanoid bond by sulfite ion. J Chem Soc Chem Commun 672-673... 

Laks P E, Hemingway R W 1987 Condensed tannins Base-catalysed reactions of polymeric procyanidins with phenyl-methanethiol. Lability of the interflavanoid bond and pyran ring. J Chem Soc Perkin Trans I 465-470... 

The NMR spectra of profisetinidin polymers are quite distinct from pro-cyanidin polymers in several respects (34). In particular, C-4 for a fisetinidol-4 unit occurs at J 130 and J 110 respectively, well upfield and downfield respectively from the corresponding resonances, J 155 and d 97, in catechin-4 units (34). NMR is, however, less useful for assigning relative stereochemistry than for Type 1 polymers. Type 2 oligomers have a low degree of interflavanoid bond stereospecificity (15, 119), in contrast to Type 1 polymers (i.e. 4a or 4)8), and this leads to extra spectral complexities. In addition, the B units of quebracho and wattle tannins have a phloroglucinol A-ring oxidation pattern, whereas the T and M units are of the resorcinol A-ring pattern (15). 

A further feature that makes Type 2 polymers harder to characterize is the relatively high stability of the interflavanoid bond to acid cleavage compared with C-ring opening reactions (Sect. 7.6.3.3.2). Thus anthocyanidins or benzylsulfide derivatives are formed with difficulty and lower yield than occurs for the Type 1... 

Current evidence also supports the view that proanthocyanidin homopolymers do not possess such regiospecificity of interflavanoid bonds, and maintain a similar ratio of 4- 8/4- 6 units to that observed in naturally occurring trimers, approximately 3 to 4 1. Moreover, a proportion of chains will be branched (Sect. 7.7.2.1). 

It must also be noted that at the natural pH of proanthocyanidin solutions (pH 4.5), the interflavanoid bond of Type 1 proanthocyanidins is sufficiently labile to undergo acid-catalyzed cleavage at ambient temperatures (11, 63). Solutions of proanthocyanidins will, therefore, gradually undergo disproportionation. This stresses the need for proanthocyanidins to be isolated at relatively low temperatures and with reasonable speed for the final preparation to reflect accurately the composition in the original plant cells. 

More recently, Roux and co-workers (149) have isolated a complex array of oligomeric polyphenols based on (2jR,3S)-3,3, 4, 7,8-pentahydroxyflavan from the heartwood of mesquite (Prosopis glandulosa). These include some oligomers linked by normal proanthocyanidin interflavanoid linkages (i.e. 4- 6), but predominantly the form of linkage has arisen from oxidative coupling to form biphenyl and m-terphenyl interflavanoid bonds. These are just the sort of bonds expected to be formed in secondary processes in any proanthocyanidin polymer, and it is still an open question as to the extent of these processes in outer bark and heartwood. 

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