unit F″ could achieve a stereoselective reaction, as will be discussed later (see Section 2.3.5).
2.3.3 Oxidative Conversion from B‐type PAs (Route I)
This section describes the reported reactions based on Route I in Figure 2.8. In early attempts, Nonaka et al. (1987) used the oxidative conversion of the B‐type to the A‐type structure (Figure 2.9). Upon treatment of procyanidin B1 (5) with hydrogen peroxide under basic conditions, an oxidative conversion proceeded to give procyanidin A1 (6) in 13% yield. This protocol was further applied to other B‐type structures. For example, procyanidin B5 (7) and aesculitannin A (10) were converted to the corresponding compounds having the A‐type structure, i.e. procyanidin A7 (9) and aesculitannin C (11), albeit in low yields.
As other means of converting the B‐type structure into the A‐type structure, a radical‐mediated reaction was exploited (Figure 2.10) (Kondo et al. 2000). Upon treatment of procyanidin B1 (5) with 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH), the C(2) hydrogen atom in the upper epicatechin unit was abstracted, inducing an oxidative cyclization to give procyanidin A1 (6), though the chemical yield was not reported.
2.3.4 Approaches via an Acyclic Precursor (Route II)
Weinges and Theobald (1971) reported a stepwise construction of the dioxabicyclo[3.3.1]nonane skeleton (A‐type) of PAs (Figure 2.11). The Michael addition of the o‐benzyloxyphenylmagnesium bromide to chalcone 12 gave ketone 13. After hydrogenolytic removal of the benzyl protecting groups, the resulting bisphenol was exposed to dehydrating conditions, giving bicycle 14 in 50% yield.
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
