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 with epoxy alcohol 49 in the presence of BF3·OEt2 gave adduct 50. After the protecting group arrangement, the resulting alcohol 51 was subjected to the pyran‐ring formation. Treatment of 51 with KH cleanly afforded the cyclized product, which was exposed to acidic conditions to give the monomer unit 52, which was employed as the nucleophilic flavan unit in the following annulation (Figure 2.24). Upon treatment of a mixture of 34 and 52 with BF3·OEt2, the corresponding annulation product 53 was obtained in excellent yield. Notably, none of other regio‐ and stereoisomers was observed. As the α‐face of the electrophilic flavan unit 34 is shielded by the C(3)‐substituent, nucleophile 52 approached from the β‐side to form the double linkages at the C(2) and C(4) positions. In addition, the nucleophile 52 selectively reacted at its C(8) position rather than the C(6) position. Finally, all protecting groups were removed to give procyanidin A2 (3).
Figure 2.21 Pettus's diinsininol aglycon synthesis.
Figure 2.22 Strategy for monomer synthesis.
Figure 2.23 De novo synthesis of the C(7)‐hydroxy monomer unit.