Oxidative Synthesis of Bioactive B-3 Analogue of Procyanidin with 3,4-cis Stereochemistry

Procyanidins are polyphenols naturally ubiquitous in fruits, grains, seeds, nuts, plant barks and vegetables. However, isolating the natural bioactive compounds from plant materials produces mixtures of proanthocyanidins that are difficult to separate, thus compromising the yield of the desired pure-form procyanidins. Therefore, there is a need to synthesise high-yield homogeneous procyanidin compounds with well-defined stereo- and regiochemistry. This study describes a method for synthesising the free phenolic procyanidin B-3 analogue. Treatment of a solution of tetra-O-benzyl-3-oxocatechin 3 b (1 equiv.) and penta-O-benzylcatechin 2 c (3 equiv.) with silver tetrafluoroborate (AgBF4) readily afford the per-O-benzyl ethers of 3-oxo-catechin-(4 -> 8)-catechin 18 exclusively. Subsequent sodium borohydride reduction followed by catalytic hydrogenation afforded the free phenolic B-3 procyanidin (catechin-(4 beta -> 8)-catechin) 20 with 3,4-cis Stereochemistry in a good percentage yield of 86 %. This paper describes the synthesis of a free phenolic procyanidin B-3 analogue, which excludes the pre-functionalisation of flavan-3-ol and derivatives ' C-4 positions that cause competing polymerisation. Treating Tetra-O-benzyl-3-oxocatechin and penta-O-benzylcatechin with AgBF4 yielded 5,7,3 ' 4 '-Tetra-O-benzyl-3-oxo-catechin-4 beta -> 8-3,5,7,3 ',4 '-penta-O-benzyl-catechin exclusively. Reduction of the 3-oxo-catechin-(4 -> 8)-catechin and hydrogenating the product yields free phenolic B-3 procyanidin catechin-(4 beta -> 8)-catechin with 3,4-cis stereochemistry, characterised using NMR, FTIR, MS, and CD. image