Flavonols synthesis

Stracke R, De Vos RC, Bartelniewoehner L, Ishihara H, Sagasser M, Martens S, Weisshaar B (2009) Metabolomic and genetic analyses of flavonol synthesis in Arabidopsis thaliana support the in vivo involvement of leucoanthocyanidin dioxygenase. Planta 229(2) 427-445... 

Flavonol synthesis occurs in two main periods the first one around flowering and the second after the main period of anthocyanin biosynthesis. In the latter phase, flavonol accumulation is highly dependent on environmental factors and, in particular, much increased by sun exposure of the berries. ... 

This enzyme catalyzes the stereospecific conversion of the (2R, JR)-dihydroflavonols, DHK and DHQ, to the corresponding flavonols, by introducing a double bond between C-2 and C-3. The enzyme was first reported in parsley cell cultures,58 and later shown to occur in several plant species.7 A cDNA clone encoding FLS was isolated from Petunia hybridal and its antisense expression strongly reduced flavonol synthesis in flower petals, thus allowing a higher flux of dihydroflavonols to be channeled towards anthocyanin synthesis.59... 

Luo, J., ButeUi, E., HiU, L. et al. (2008). AtMYB12 regulates caffeoyl quinic acid and flavonol synthesis in tomato expression in fruit results in very high levels of both types of polyphenol. The Plant Journal, 56, 316 326. 

Ibrahim R K, De Luca V, Jay M, Voirin B 1982 Polymethylated flavonol synthesis is catalyzed by distinct O-methyltransferases. Naturwissenschaften 69 41-42... 

The Auwers flavone synthesis consists of treatment of dibromo-coumarones 1 with alcoholic alkali to give the flavonols 2. It can also be described as the three-step sequence of 3 — 6. 

There is no published mechanistic study on the Auwers flavone synthesis. The mechanism may involve the nucleophilic addition of oxonium 7, derived from 1, with hydroxide to give 8. Base-promoted ring opening of 8 could provide the putative intermediate 9, which then could undergo an intramolecular Michael addition to form 10. Expulsion of bromide ion from 10 would then give flavonol 2. 

Despite the formation of several products, the AFO reaction has remained a popular method for the synthesis of flavonols. 

As described earlier one of the possible products from the AFO reaction is dihydroxyflavonols. Simpson and coworkers took advantage of this outcome in their synthesis of the flavonol rhamnocitrin (23). Chalcone 24 was subjected to the typical AFO conditions to deliver dihydroxyflavonol 25. The isolated product was further subjected to hydrogen peroxide to afford flavonol 25a in 30% yield. However, treatment of 25 with bismuth acetate, generated in situ from bismuth carbonate and acetic acid, gave 25a in 77% yield for a respectable 52% overall yield over two steps. 25a was then selectively demethylated with anilinium chloride to deliver rhamnocitrin (23). 

Hundreds of flavonols have been isolated and characterized many of them are biologically active. Hence a great synthetic interest has arisen. Some of the efforts have concentrated on the synthesis of naturally oecurring flavonols while others have focused on the synthesis of flavonol derivatives for structure activity relationships. ... 

Rhodophyta, Rhodophyceae, Ceramales, Rhodomelaceae). Aust. J. Chem. 42 1591-1603. Collins, F. W., De Luca, V., Ibrahim, R. K., Voirin, B. and Jay, M. 1981. Polymethylated flavonols of Chrysosplenium americanum. I. Identification and enzymic synthesis. Zeit. Naturforsch. 36c 730-736. 

De Luca, V. and Ibrahim, R. K. 1985a. Enzymatic synthesis of polymethylated flavonols of Chrys-osplenium americarmm. I. Partial purification and some properties of S-adenosyl-L-methionine flavonol 3-, 6-, 7-, and 4 -0-methyltransferases. Arch. Biochem. Biophys. 238 596-605. 

Figure 1. Postulated pathway for the enzymatic synthesis of polymethylated flavonol glucosides in Chrysosplenium americanum GT, O-glucosyl-transferase OH, hydroxylase OMT, O-methyl transferase.

Regulation of Flavonoid Synthesis in C. americanum. Biosynthesis of methylated flavonol glucosides seems to be under tight regulation, not only by the substrate specificity of the enzymes involved, but also by other factors, among which are (a) the strict position specificity of these enzymes towards their hydroxylated or partially methylated substrates (b) the apparent difference in microenvironment of the different methyl-transferases, whereby those earlier in the pathway utilized aglycones whereas later enzymes accepted only glucosides as substrates (c) the subtle characteristic differences in methyl-transferases with respect to their pH optima, pi values and requirement for Mg ions, despite their similar molecular size ... 

Downey, M., Harvey, J., and Robinson, S., Synthesis of flavonols and expression of flavonol synthase genes in the developing grape berries of Shiraz and Chardonnay (Vitis vinifera L.). Aust. Grape Wine Res. 9, 110, 2003. 

It has been suggested that the synthesis of flavones, flavanones, and flavonols could have evolved primarily as chemical messengers, such as defense molecules. Indeed, flavonoids have recently been described as a novel class of hormones. Interestingly, in this regard, the... 

Since the early contributions of Willstatter and Robinson, several alternative approaches following mainly two routes have been considered for synthesis of anthocyanins.One of the routes includes condensation reactions of 2-hydroxybenzaldehydes with acetophenones, while the other uses transformations of anthocyanidin-related compounds like flavonols, flavanones, and dihydroflavonols to yield flavylium salts. The urge for plausible sequences of biosynthetic significance has sometimes motivated this latter approach. In the period of this review, new synthetically approaches in the field have also predominantly been following the same general routes however, some new features have been shown in synthesis of pyranoanthocyanidins. 

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. 

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