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 inevitably pose a serious problem. In contrast, use of the flavan 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