compounds having the A-type connectivity."/>
Figure 2.3 Origin of the structural diversity in oligomeric PAs: compounds having the A‐type connectivity.
Figure 2.4 Acid hydrolysates of the dimeric proanthocyanidin isolated from Aesculus hippocastanum, and three possible dimeric structures proposed by Mayer.
Later, Weinges and coworkers extracted several related compounds from cranberries (Vaccinium vitis‐idaea), which included the “Mayer's dimer” mentioned above (Weinges et al. 1968). They arbitrarily classified those compounds into two categories by the number of hydrogen atoms (Figure 2.5): the dimeric proanthocyanidin compounds with molecular formula C30H24O12 as the A‐type, and those with C30H26O12 as the B‐type. Thus, the above‐stated Mayer's compound, i.e. procyanidino‐(–)‐epicatechin, was renamed procyanidin A2.
Haslam and coworkers later proposed the currently accepted structure 3 (Figure 2.5a) with a characteristic bicyclic skeleton formed by two interflavan bonds {C(4)–C(8) and C(2)–O[C(7)]} based on the 1H‐ and 13C‐NMR data and some chemical evidences (Jacques et al. 1973, 1974). A decade later, the structure was unequivocally verified by X‐ray crystallography (Van Rooyen and Redelinghuys 1983).
With advances in the separation and analytical methods, the more complicated oligomeric PAs having A‐type linkages have been identified from various plant sources. Figure 2.6 shows some of the tetramers with A‐type structure, which are homo‐ or hetero‐oligomers (Nonaka et al. 1983; Morimoto et al. 1985; Morimoto et al. 1987; Balde et al. 1995; Nam et al. 2017). It should be noted that the molecular diversity arises not only from the elements stated before, but also from the inclusion of the enantiomeric flavan‐3‐ols (e.g. ent‐AZ, ent‐EC, ent‐CA in pavetannin C5) as constituent monomers. The diversity will increase in the future, and some of these compounds may show potentially significant biological activities.
2.3 Synthetic Studies
2.3.1 Hypothetical Biosynthetic Routes
On the biogenesis of the characteristic double linkages (A‐type), two putative pathways have been proposed (Paths I and II, Figure 2.7) (Selenski and Pettus 2006). Different consequences would be expected on the reactivity and the stereochemistry in the formation of the [3.3.1]bicyclo skeleton D. Path I entails the addition of the flavan nucleophile B to the electrophilic partner A, producing the singly linked dimer C (the B‐type structure). Oxidation at the C(2) position of the upper flavan unit in C allows the formation of a doubly linked derivative D (the A‐type structure). From the stereochemical standpoint, if the initial C–C bond is formed in a stereoselective manner, the stereochemistry generated by the subsequent C–O bond formation would be settled spontaneously, due to the steric constraints in the bicyclic skeleton. On the other hand, Path II is based on a formal [3+3]‐cycloaddition of the flavylium E with the flavan unit B. Since the flavylium E lacking any stereogenic centers is achiral (prochiral), the [3+3]‐cycloaddition reaction needs to proceed with enantiofacial selectivity, which may be regulated by enzymes in the biogenesis. These putative biosynthetic pathways would give hints to chemical synthesis.
Figure 2.5 Mayer's PA (procyanidin A2): the terminological origin of A/B‐type structures.
Figure 2.6 Structures of the tetramers with A‐type linkages.
Figure 2.7 Two plausible biosynthetic pathways forming the A‐type structure.
2.3.2 Retrosynthesis
Figure 2.8 illustrates a synthetic analysis en route to the A‐type structure, focusing on the key dioxabicyclic skeleton. Three potential pathways are shown.
Route I is relevant to the Path I biosynthesis discussed in Section 2.3.1 (see Figure 2.7), disconnecting the C–O bond i in A to B with a single connection and the C(2) cation center, which could be traced back to a B‐type structure B' as a precursor. In executing the synthesis, this approach has an advantage, that the corresponding B‐type structures are synthetically well accessible (Ohmori et al. 2004, 2011; Oyama et al. 2008; Kozikowski and Tückmantel 2009; Saito et al. 2009; Yano et al. 2012; Makabe 2013). However, a concern is that the site‐specific oxidation at the C(2) benzylic center on the upper flavan unit may be challenging.
Figure 2.8 Retrosynthetic analyses of the A‐type structure.
Route II relies on the retrosynthetic hydrolysis of the acetal moiety in A. Dissection of the bonds i and ii suggests ketone C as the precursor. Assuming the Michael addition, ketone C is accessible by combining an electrophilic chalcone unit E and a nucleophilic flavan unit D. In this approach, rigorous stereocontrol at the Michael addition stage is necessary.
Route III corresponds to another biomimetic pathway (Path II, Figure 2.7), based on the two‐bond disconnection at bonds i and iii in A, assuming a formal [3+3]‐cycloaddition of a dicationic species F and a nucleophilic partner G. As the possible synthetic equivalents to the key dicationic species F, one could conceive flavylium salt F' or flavan unit F″ with two leaving groups at the C(2) and C(4) positions. This approach would realize direct conversion to the key bicyclic skeleton. If flavylium salt F' were used, the enantiocontrol would
