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.
Figure 2.24 Total synthesis of procyanidin A2 via flavan annulation.
More recently, it was found that the annulation could work even with a non‐protected flavan unit, e.g. catechin or epicatechin, as a nucleophile (Figure 2.25) (Betkekar et al. 2019). In a solvent mixture of ethanol and 1,4‐dioxane, (–)‐epicatechin was allowed to react with electrophilic flavan unit 54 in the presence of camphor sulfonic acid, affording annulation product 55 along with minute amounts of its regioisomers 56 and 57. After chromatographic separation (silica gel) and deprotection, all products were converted to their free‐forms, i.e. procyanidin A2 (3), proanthocyanidin A6, and proanthocyanidin A7.
Figure 2.25 Annulation with a free flavan unit and syntheses of procyanidin A2, and proanthocyanidin A6 and A7.
These results indicate that the free flavan unit preferentially reacted at its C(8) position rather than the C(6) position. To address the origin of this C8/C6‐regioselectivity, a DFT calculation was conducted on the putative Wheland intermediates II and III, generated by the reaction on the model substrate I with CH3+ (Figure 2.26). The result suggested that the C8‐methyl intermediate II is energetically more stable over the C6‐counterpart III.
Figure 2.26 DFT calculations of the Wheland intermediates, II and III, derived from model compound I.
2.3.6.3 Synthesis of (+)‐Cinnamtannin B1 (62)
This annulation method was also applied to the synthesis of a trimeric natural product, (+)‐cinnamtannin B1 (62) (Figure 2.27) (Ito et al. 2014), which is known as a rare sweet polyphenol. To realize the convergent assembly of the trimeric scaffold, the orthogonal coupling strategy was adapted by employing monomers 34, 58, and 52. Annulation of dioxy electrophilic unit 34 with sulfide 58 was carried out by using BF3·OEt2 to give the coupling product 59 in 91% yield. The arylthio group remained intact under the hard Lewis acidic conditions. Next, the soft activation of dimeric sulfide 59 was conducted by using I2 and Ag2O, enabling the reaction with the nucleophilic epicatechin unit 52 to give trimer 60 in 96% yield. After two‐step deprotection via 61, (+)‐cinnamtannin B1 (62) was obtained in 70% overall yield.
2.3.6.4 Synthesis of Selligueain A (63)
The coupling protocols were applied to the synthesis of selligueain A (63), isolated from the rhizomes of Selliguea feei (Figure 2.28) (Noguchi et al. 2018). Although this compound is interesting because of the pronounced sweetness, 35 times sweeter than sucrose, it had been obtained in only minute amounts from nature. A serious issue was that the trimers are comprised of two rare flavan monomer units, i.e. (–)‐epiafzelechin (EZ) and (+)‐afzelechin (AZ), which manifests a general bottleneck in the chemical synthesis of flavan oligomers – that is, the limited availability of their monomeric constituents. Note that commercially available flavan‐3‐ol is basically limited to (+)‐catechin, and other congeners are scarce and could not be used as the starting materials.
The initial step in the assembly of these monomer units was the annulation of the top unit 64 and the middle unit 65 by using BF3·OEt2 to give 66 as a sole product in 86% yield (Figure 2.29). Importantly, no formation of the C(4)→C(6)‐linked products was observed, and the sulfide moiety remained intact under these hard Lewis acidic conditions. After detachment of the silyl group in 66, the arylthio group in the resulting alcohol 67 was activated under soft Lewis acidic conditions to react with the bottom unit 68. The annulation reaction proceeded the annulation, giving trimer 69 in 93% yield. It should be noted that the seemingly labile benzylic acetal moiety at the C(2) position of the top unit remained untouched. Finally, all benzyl groups and the bromine atom were removed by hydrogenolysis to give pure 63 in 85% yield.
2.3.6.5 Synthesis of Procyanidin A2 (3)
As another synthetic approach, Sharma et al. (2015) reported the de novo synthesis of a series of the dimeric PAs having an A‐type structure, which relied on the Friedel–Crafts reaction of two monomeric units followed by internal acetalization (
