Epicatechin synthesis

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

The various chemical processes influencing the colour formation in tea have been vigorously investigated. The self-association of black tea polyphenol theaflavin and its com-plexation with caffeine [175], and the role of epicatechin quinone in the synthesis and degradation of theaflavin [176] have been studied in detail. 

T. Tanaka, C.mine, K. Inoue, M. Matsuda and I. Kouno, Synthesis of theaflavin from epicate-chin and epigallocatechin by plant homogenates and role of epicatechin quinone in the synthesis and degradation of theaflavin. J. Agr. Food Chem. 50 (2002) 2142-2148. 

The synthetic protocol (Scheme 11.2) toward the flavan-3-ol permethylaryl ethers is based upon the transformation of rc7ro-chalcones into 1,3-diarylpropenes. These compounds are then subjected to asymmetric dihydroxylation to give diarylpropan-l,2-diols that are used as chirons for essentially enantiopure flavan-3-ols. The protocol is demonstrated in Scheme 11.2 for the synthesis of the tetra-(9-methyl-3-(9-acetyl derivatives 61a, 61b, 62a, and 62b of (-l-)-catechin (2), (—)-e 7-catechin, (—)-epicatechin (3), and (+)-e 7-epicatechin (4). ... 

Tuckmantel, W., Kozikowski, A.P., and Romanczyk, L.J. Jr., Studies in polyphenol chemistry and bioactivity. 1. Preparation of building blocks from (+)-catechin. Procyanidin formation. Synthesis of the cancer cell growth inhibitor, 3-0-galloyl-(2R,3R)-epicatechin-4(3,8-[3,0-galloyl-(2R,3R)-epicatechin], J. Am. Chem. Soc., 121, 12073, 1999. 

Bonnet, S.L. et al., Structure and synthesis of phlobatannins related to bis-fisetinidol-epicatechin profisetinidin trifiavanoids. Phytochemistry, 43, 253, 1996. 

Coetzee, J. et al., Oligomeric flavanoids. Part 31. Structure and synthesis of the first procassinidin dimers based on epicatechin, and gallo- and epigallocatechin. Phytochemistry, 53, 795, 2000. Hatano, T. et al., Flavan dimers with lipase inhibitory activity from Cassia nomame. Phytochemistry, 46, 893, 1997. 

Earlier proposals (12, 13, U) and the results of biosynthetic experiments (18) have been adumbrated into a scheme of biosynthesis for the procyanidins (Figure k) in which it is suggested that they are formed as byproducts during the final stage of the synthesis of the parent flavan-3-ol structures, (+)-catechin and (-)-epicatechin (11, 18). A two step reduction of the f1av-3-en-3-ol... 

Resveratrol has also been reported to offer protection against cardiovascular disease, such as coronary heart disease. The effects of resveratrol on factors implicated in the development of coronary heart disease - human platelet aggregation and the synthesis of eicosanoids (lipids) from arachidonate by platelets - were investigated and compared with the actions of other wine phenolics - catechin (1.39), epicatechin (7.18a), and quercetin (1.43) - and the antioxidants a-tocopherol (7.10a), hydroquinone and butylated hydroxytoluene. Resveratrol and quercetin demonstrated a dose-dependent inhibition of platelet aggregation, whereas the other compounds tested were inactive. Resveratrol also inhibited the synthesis of the eicosanoids in a dose-dependent manner, whereas the other phenolics were less effective of not effective at all. Removal of the alcohol from the wine did not diminish the effect on platelet aggregation (Pace-Asciak et al., 1995 Goldberg et al., 1995). 

Inflammation is now recognized as a key process in atherogenesis [Libby, 2002]. The potential for dietary flavonoids to inhibit inflammatory activities is of particular interest. A potential anti-inflammatory feature of the flavonoids is the ability to inhibit the biosynthesis of eicosanoids. Selected phenolic acids and some flavonoids have been shown to inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5-LO) pathways [Nijveldt et al., 2001 Takano-Ishikawa et al., 2006], Epicatechin and related flavonoids have been shown to inhibit the synthesis of pro-inflammatory cytokines in vitro [Sanbongi et al., 1997], and plasma metabolites of catechin and quercetin inhibit the adhesion of monocytes to cultured endothelial cells [Koga and Meydani, 2001]. Silymarin has been shown to inhibit the production of inflammatory cytokines, such as interleukin-1, interferon-, and tumor necrosis factor-a (TNFa), from macrophages and T-cells [Matsuda et al., 2005], Some flavonoids can inhibit neutrophil... 

By reduction of dihydroquercetin and dihydromyricetin, operated by the enzyme dihydroflavonol-4-reductase (DFR) (in vine the reduction of dihydrokaempferol does not occur), 2,3-trans leucocyanidin and leucodelphinidin form. Successive synthesis of (+)-catechin and (+)-gallocatechin (2,3-trans isomers) is mediated by the enzyme leucoan-thocyanidin reductase (LAR). On the other hand, the synthesis of (—)-epicatechin and (—)-epigallocatechin (2,3-cis isomers) proceeds via oxidation of 2,3-trans leucoanthocyanins into cyanidin and delphinidin (accompanied with chirality loss) mediated by the enzyme leucoan-thocyanidin dioxygenase (LDOX), which is followed by the reduction catalyzed by the enzyme anthocyanidin reductase (ANR) with reacquisition of chrality (Fujita et al., 2005). 

Blount JW, Ferruzzi M, Raftery D, Pasinetti GM, Dixon RA (2012) Enzymatic synthesis of substituted epicatechins for bioactivity studies in neurological disorders. Biochem Biophys Res Commun 417 457-461... 

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... 

A highly stereoselective synthesis of the unnatural procyanidin diastereoisomer epicatechin-(4o —> 8)-epicatechin (114) has been reported (Scheme 17). " The selectively protected 8-lithio epicatechin derivative... 

Scheme 17 Synthesis of epicatechin-(4a 8)-epicatechin (114) and its mono-O-gaiiate (115). Reagents and conditions (a)dry THF, -78 °C (b) n-BusSnH, CF3CO2H (c)48% HF, CH3CN (d) 20% Pd(OH)2/C, H2, EtOAc/MeOH (e) galloylation.

Scheme 19 Synthesis of procyanidin tri- through undeca-mers [(123)-(131)] with epicatechin constituent units.

A considerable effort has also been devoted to the synthesis of C- and, to a lesser extent, " C-labeled catechins and procyanidins. Administration of [U- " C]phenylalanine or [1- " C]acetate to willow tree shoots, led to the isolation of labeled procyanidins B-3 (93), procyanidin B-6 [catechin-(4Q —> 6)-catechin], procyanidin C-2 bis-[catechin-(4Q 8)]-catechin, and a related polymer of high radio-purity. The C-labeled anthocyanins, cyanidin- 3 - 0-/3-D-glucopyranoside, peonidin- 3-0-/3-D-glycopyranoside, and malvidin- 3- 0-/3-D-glucopyranoside, were similarly produced by incorporation of [l- C]phenylalanine into cell suspension cultures of Vitis vinifera Vercauteren and his coworkers made significant contributions by synthesizing r r-4-[ C]catechin, and enantiopure 4-[ C]catechin, 4-[ C]epicatechin, and gram quantities of 4-[ C]procyanidin B-3. ... 

Water stress may upregulate the phenyl propanoid synthesis pathway and hence enhance the level of anthocyanin and hydroxycinnamic acids contributing to elevated levels of antioxidants in sweet potato roots (Philpott et al. 2003). Drought and cold stresses elevated (-)-epicatechin and some flavonoid levels in hawthorn... 

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