Synthesis of Ether-Linked Proteracacinidins

Proanthocyanidins possessing ether-type interflavanyl linkages are extremely rare except for the A-type oligomers which contain the 

It was anticipated that the C(4) benzylic ether bonds in proteraca-cinidins (39)-(42) would be susceptible to solvolysis in aqueous medium. The very same conditions which are applied universally for the formation of C(sp )— C(sp ) interflavanyl linkages 40 would hence be less applicable to the generation of the ether bonds in compounds (39)-(42). We thus opted to enhance the electrophilicity at C(4) of one of the flavan-3,4-diol methyl ethers, e.g. (43) by formation of the 4-chloroflavan-3-ol derivative (44) in order to permit the formation of the crucial ether bond at near a neutral pH value. 

It was anticipated that coupling of the 4p-chloroflavan-3-ol (44) and the nForitin-4a-ol derivative (48) would also proceed via the neighboring group mechanism. The rather unexpected formation of the 4a-ether bond (F-ring) in (49), Le. with inversion of configuration at C(4) 

The co-occurrence of the ether-linked proteracacinidins (39)-(42) as well as the conventional carbon coupled analogues in Acacia galpinii (44) presumably reflects the poor nucleophilicity of the pyrogallol A-ring of the monomeric flavan-3,4-diol precursors thus permitting alternative centres to participate in interflavanyl bond forming processes. 

A similar synthetic approach was also implemented to synthesize a range of related proanthocyanidins. Notable among these are the synthesis of dimers, e.g. (55), exhibiting flavan chain extender units 

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