A New and Convenient One-StepSynthesis of the Natural 3-Deoxyantho­cyanidins Apigeninidinand Luteolinidin Chlorides from 2,4,6-Triacetoxy­benzaldehyde

Abstract

The total synthesis of apigeninidin (1), luteolinidin (2) and 5,7-dihydroxyflavylium (5) chlorides is performed through a one step reaction from an acetylated derivative of a commercial reagent. Condensation reaction between 2,4,6-triacetoxybenzaldehyde and an acetophenone derivative in anhyd methanolic hydrogen chloride provides the 3-deoxyanthocyanidins in high yields.Apigeninidin (1) and luteolinidin (2) chlorides ( Figure 1) are the most common of the natural 3-deoxyanthocyanidins, a group of yellow-orange flavylium pigments. 2 These 5,7-dihydroxyflavylium salts, possessing at least one additional hydroxyl group in the 4¢ position, are contained in food plants such as corn and sorghum. 3 Apigeninidin has been earlier investigated as a food colorant, 4 and hair dye preparations containing this substance have more recently been patented, 5 which underlines the possible industrial use of these colored derivatives.In previous studies, 6-8 we have shown that natural 3-Oglucosylated flavylium salts (the monoglucosylated anthocyanins from Vitis vinifera grapes) possess DNA triplex stabilizing properties. Such properties are useful in the antigene strategy, a potential therapeutic approach consisting in the regulation of gene expression by nucleic acids, since one of its limitations pertains to the weak stability of the triplex formed between a target duplex and a synthetic oligonucleotide. 6,7,9 Concerning the stabilizing properties of the monoglucosylated flavylium salts previously studied, we have demonstrated that the sugar moiety at their 3 position could preclude efficient interaction with the triplex and so limit the activity. 6 Thus, we decided to study non-glucosylated derivatives such as 1 and 2, 6,7 that we have chosen to obtain by total synthesis, since their extraction is greatly time-consuming and leads generally to only small amounts of substances. In the present work, we report a new and convenient synthesis of these cationic derivatives.The synthesis of apigeninidin and luteolinidin chlorides were firstly realized by Robinson et al. in the thirties by condensation between an acetophenone and a protected phloroglucinaldehyde. 10 The products were however generally obtained as crude mixtures after three or four steps and in 30% yields in the best cases. More recently, in the eighties, Sweeny and Iacobucci carried out a method in which these natural derivatives were synthesized through an oxidative decarboxylation of the corresponding 4-carboxy-2-flavenes obtained from Bülow's intermediates. 11 This synthesis proceeds in four steps and in overall yields of around 40% from phloroglucinol dimethyl ether. Another method consists in the chemical conversion of flavonoid precursors: Sweeny and Iacobucci thus obtained apigeninidin chloride in two steps from 4¢,5,7-triacetoxyflavan in 21% yield. 12 All these reactions, though leading to the desired compounds, proceed in several steps and in limited yields. Moreover, mixtures of organic salts are often formed during these syntheses, which can greatly complicate ...

Rapid Preparation of 3‐Deoxyanthocyanidins and Novel Dicationic Derivatives: New Insight into an Old Procedure

“…[18] [b] Studied conditions: HPF 6 (50 % in water)/AcOH/room temp./24 to 48 h. vered in pure form. In addition, whereas flavylium chlorides, [16] tetrafluoroborates, [15,21] or triflates [21] have already been described, flavylium hexafluorophosphates had never previously been disclosed in the literature.…”

“…[14] However, two alternatives, circumventing this structural restriction, have recently been proposed: Kuhnert et al developed an efficient BF 3 ·Et 2 O-mediated version, [15] while T. Mas optimized the condensation by using the peracetylated derivative of phloroglucinaldehyde as reagent and by performing the reaction in acidic methanol. [16] Another classic route to 3-deoxyanthocyanidins 3 is based on the chemical modification of a flavonoid precursor already possessing the appropriate carbon skeleton. Sweeny and Iacobucci, for example, described two reduction/oxidation sequences that, when applied to 2Ј-hydroxychalcones and flavanones, allowed access to phloroglucinol-type 3-deoxyanthocyanidins (Scheme 2).…”

Straightforward Synthesis of Highly Hydroxylated Phloroglucinol-Type 3-Deoxyanthocyanidins

“…Nevertheless, two successful alternatives were recently published. 10,11 Scheme 1 Retrosynthetic analyses of the 3-deoxyanthocyanidin skeleton: a = classical disconnection 10 and b = investigated disconnection In the present work, we report an efficient and straightforward procedure for the preparation of phloroglucinol-type 3-deoxyanthocyanidins via an acid-mediated condensation between phenolic derivatives and arylethynylketones (Scheme 1:…”

“…We actually noticed upon a counteranion screening that flavylium hexafluorophosphates exhibit the lowest solubility in acetic acid among Cl -, Br -, HSO 4 -, and BF 4 -, highlighting probably the formation of the most intimate ion pair in the case of the interaction between a flavylium cation and a hexafluorophosphate anion. 13 Moreover, it should be noted that whereas flavylium chlorides, 11 tetrafluoroborates, 10,14 or triflates 14 have been already described, no report of flavylium hexafluorophosphates was so far mentioned. At first, since permethylated 3-deoxyanthocyanidins are generally regarded as the more convenient synthetic precursors of their phenolic analogues, we precisely checked our conditions for the access to such permethylated salts.…”

Straightforward Synthesis of Highly Hydroxylated Phloroglucinol-Type 3-Deoxyanthocyanidins

“…Nevertheless, two successful alternatives were recently published. 10,11 In the present work, we report an efficient and straightforward procedure for the preparation of phloroglucinol-type 3-deoxyanthocyanidins via an acid-mediated condensation between phenolic derivatives and arylethynylketones (Scheme 1: disconnection b).…”