(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 of 33 was masked by a bromine atom, affording bromide 34 in excellent yield.
As a model study using the dication precursor 34, the reaction with phloroglucinol derivative 35 was examined in the presence of BF3·OEt2 (Figure 2.20). Upon the reaction started at –78 °C followed by gradual warming, the starting material 34 was consumed at –40 °C, and two products were produced (run 1, Table 2.1). The major product was single‐linked compound 36 with the C(4)–C(2) bond, whereas the minor product 37 had the desired dioxabicyclic structure. Importantly, these products, 36 and 37, were the single stereoisomers, respectively. Re‐exposure of 36 to the same conditions led to a smooth conversion into 37. Thus, the annulation proceeded in a stepwise manner, starting with the formation of the C(4)–C(2) bond from the β‐side to form 36 followed by the C(2)–O bond formation to give 37. Indeed, by extending the reaction time and raising the temperature, the annulation of 34 and 35 went to completion, giving 37 in excellent yield (run two).
Figure 2.19 Synthesis of a 2,4‐dioxy flavan derivative.
Figure 2.20 Model study for stereoselective flavan annulation.
Table 2.1 Results of flavan annulation.
| run | time / h a) | temperature / °C | product (yield) |
|---|---|---|---|
| 1 | 2 | −78 → −40 | 36 (66%), 37 (20%) |
| 2 | 3 | −78 → −20 | 37 (93%) |
a) Duration of the gradual warming.
2.3.6 Total Synthesis
This section describes several completed syntheses of the oligomeric PAs with A‐type linkages.
2.3.6.1 Synthesis of Diinsininol Aglycon (45)
Selenski and Pettus (2006) developed an efficient synthetic approach to bicycle 45, corresponding to the aglycon of diinsininol (46), by exploiting the [3+3] annulation approach (Figure 2.21). As an electrophilic unit, flavylium 40 was prepared by the condensation of 2,4,6‐triacetoxybenzaldehyde (38) and 3,4‐dihydroxyacetophenone (39). On the other hand, the nucleophilic partner 44 was synthesized from styrene 41 and benzaldehyde 42. Treatment of 42 with LiAlH4 in the presence of MgBr2 generated o‐quinonemethide A, which underwent a [4+2]‐cycloaddition with styrene 41, giving the corresponding flavan 43 in 45% yield. DDQ‐oxidation in the presence of H2O followed by removal of the protecting groups afforded free flavanone 44 in 72% yield (two steps). The reaction of flavylium salt 40 with nucleophile 44 (6 equiv) proceeded under microwave irradiation at 120 °C, giving the annulated product 45 in 32% yield. The product was obtained as a single diastereomer, albeit in a racemic form.
2.3.6.2 Synthesis of Procyanidin A2 (3)
The protocol described earlier (Figure 2.20) was applied to the synthesis of procyanidin A2 (3) (see Figure 2.5), in which a nucleophilic monomer unit needed to be selectively protected (vide infra). The present authors have developed a de novo synthetic approach to the epi‐type catechins (Figure 2.22) (Stadlbauer et al. 2012), relying on the ortho‐metalation of aryl fluoride I (#1) and reaction with epoxy alcohol II, followed by an SNAr oxycyclization of adduct III to give flavan IV (#2). This protocol enabled access to monomer unit 52 with a free hydroxy group at C(7) (Figure 2.23) (Ito et al. 2014). Starting from 1,3,5‐trifluorobenzene (47), sequential substitutions with t‐BuOK and BnOK gave mono‐fluoride 48. Regioselective lithiation of 48 followed by the reaction
