Studies in Polyphenol Chemistry and Bioactivity. 3.^1,2 Stereocontrolled Synthesis of Epicatechin-4α,8-epicatechin, an Unnatural Isomer of the B-Type Procyanidins

Abstract

Oligomeric procyanidins containing 4alpha-linked epicatechin units are rare in nature and have hitherto not been accessible through stereoselective synthesis. We report herein the preparation of the prototypical dimer, epicatechin-4alpha,8-epicatechin (6), by reaction of the protected 4-ketones 11a,b with aryllithium reagents derived by halogen/metal exchange from the aryl bromides 26a,b. Removal of the 4-hydroxyl group from the resulting tertiary benzylic alcohols 27a,b was effected by tri-n-butyltin hydride and trifluoroacetic acid in a completely stereoselective manner, resulting in hydride delivery exclusively from the beta face. If benzyl was chosen for protection of the 3-hydroxyls, all protective groups could subsequently be removed in a single step by hydrogenolysis. tert-Butyldimethylsilyl groups, on the other hand, permitted selective deprotection of the 3-hydroxyls in preparation for their subsequent acylation with tri-O-benzylgalloyl chloride. Only monogalloylation at the "bottom" 3-hydroxyl took place when 28c was acylated under the previously reported conditions, reflecting the increased steric hindrance of the "top" 3-hydroxyl group in 28c compared with its 4beta,8-isomer 3. The preparation of compounds 14 and 17 containing phloroglucinol trimethyl ether in the 4alpha and 4beta linkages to epicatechin is also described. The 8-position of the bromine atom in 19, previously conjectured in analogy to the structurally characterized tetramethyl ether 20, was confirmed by transformation of both compounds into the common derivative 25.

Selective cytotoxicity of synthesized procyanidin 3-O-Galloylepicatechin-4b,8-3-O-galloylcatechin to human cancer cells

“…5 Synthetic trimeric, tetrameric, pentameric and higher oligomeric epicatechin-derived procyanidins inhibited breast cancer cell growth and induced cell death possibly through non-apoptotic mechanisms. 9,10 Pentameric procyanidin has been shown to selectively inhibit growth of human breast cancer cells through regulation of site-specific phosphorylation of several cell cycle regulatory proteins including p53 and pRb. 11 The molecular mechanisms underlying the anti-proliferative properties of the cocoa derived flavanols and procyanidins are largely unknown.…”

An efficient synthesis of procyanidins. Rare earth metal Lewis acid catalyzed equimolar condensation of catechin and epicatechin

“…Lewis acids, such as TiCl 4 and BF 3 •Et 2 O gave sluggish results. These reactions required a large excess of the nucleophile at low temperature in order to limit the reaction of the activated monomer with itself or with the dimeric product leading in both cases to oligomeric side products.…”

Synthesis and cytotoxic screening of beta-boswellic acid derivatives

“…in DCM) 32 with 1 and 3 (Scheme 8) gave derivatives 40 and 41, respectively. Hydrogenation of 40 and 41 in the presence of Pd/C (10%) for several hours furnished products 42 and 43, respectively.…”