Recent Advances in Polyphenol Research. Группа авторов
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Xia et al. (2014) reported a cascade reaction of 2‐hydroxychalcones with phloroglucinol derivatives by using a catalytic amount of ethylenediammonium diacetate (EDDA, 10 mol%), constructing the dioxabicyclo[3.3.1]nonane skeleton (Figure 2.12). The reaction of 15 with 16 proceeded in refluxing toluene via the Michael reaction followed by an internal acetal formation, giving the condensation product 17 in 87% yield.
Kraus and Geraskin (2017) reported a facile one‐pot formation of the A‐type structure (Figure 2.13). Under acidic conditions, twofold nucleophilic reactions of phloroglucinol to acetylenic aldehyde 18 generated bis‐arylated 19 as an intermediate, which underwent acid‐catalyzed acetal formation to give bicycle 20. After acetylation, tetraacetate 21 was obtained in high yield.
Figure 2.9 Oxidative conversion of the B‐type to the A‐type structure.
Figure 2.10 Radical‐mediated oxidative conversion.
Figure 2.11 Stepwise construction of the A‐type structure.
Figure 2.12 Cascade reaction of 2‐hydroxychalcones with a phloroglucinol derivative
Figure 2.13 One‐pot formation of the A‐type structure.
2.3.5 Annulation Approach (Route III)
For the direct construction of the characteristic dioxabicyclo[3.3.1]nonane skeleton, a pioneering approach was reported by the annulation of flavylium ion 22 with phloroglucinol as a nucleophilic unit to form 23 (Figure 2.14) (Jurd and Waiss 1965). Treatment of flavylium salt 22 with phloroglucinol in aqueous MeOH under weakly acidic conditions (pH 5.8, 60 °C, 15 minutes) gave, after acetylation, the annulation product 23 as colorless prisms (23% yield). The stereochemistry was not clarified.
A similar reaction was reported by Pomilio et al. (1977) (Figure 2.15), carrying out the annulation of flavylium 24 and (+)‐catechin under mild acidic conditions (pH 5.8). The reaction was sluggish, and isolation of the product after thorough protection of hydroxy groups resulted in a poor yield of annulation product 25.
Kraus et al. (2009) improved this reaction (Figure 2.16). Treatment of flavylium salt 24 with phloroglucinol followed by treatment with silica gel gave the annulation product 26 in good yield. Moreover, use of (+)‐catechin as a nucleophile gave a diastereomer mixture of two annulation products 27a and 27b in 89% combined yield. Recently, another research group reported a similar protocol (Alejo‐Armijo et al. 2018).
Figure 2.14 Direct annulation approach to the A‐type structure.
Figure 2.15 Early studies on annulation reaction of flavylium 24 with (+)‐catechin.
Figure 2.16 Annulation reaction by Kraus.
An asymmetric version of this approach appeared recently by using a salt of binaphthol‐derived chiral phosphoric acid as a chiral phase transfer catalyst (Figure 2.17) (Yang et al. 2016). Reaction of flavylium salt 28 with phloroglucinol derivative 29 in the presence of A as a catalyst (10 mol%) allowed the enantioselective nucleophilic attack of 29 to the C(4) position of 28 to give adduct 30, which was treated with p‐toluenesulfonic acid to give bicycle 31 in 56% yield with a high enantioselectivity (94% ee).
Figure 2.17 Asymmetric annulation approach.
Figure 2.18 Strategy for stereoselective annulation.
The present authors' group recently developed a novel concept in a flavan annulation (Figure 2.18) (Ito et al. 2014). Two requirements en route to the requisite dioxabicyclic skeleton include (i) design of a suitable precursor I to generate the dicationic species II, and (ii) regioselective dual bond formation with III via mode A, not vice versa (mode B). An additional requirement was the stereoselectivity. Thanks to the C(3) stereocenter in II, the annulation would proceed in a stereoselective manner.
As a dication equivalent, two oxygen‐based leaving groups X at the C(2) and C(4) positions were envisioned, and the precursor I could be available by oxidation of flavan derivatives. Thus, the oxidation of epicatechin derivative 32 with DDQ in the presence of ethylene glycol gave 2,4‐ethylenedioxy derivative 33 in 69% yield (Figure 2.19). The C(8) position