Studies in polyphenol chemistry and bioactivity. 1. Preparation of building blocks from (+)-catechin. Procyanidin formation. Synthesis of the cancer cell growth inhibitor, 3-O-galloyl-(2R,3R)-epicatechin-4β,8-[3-O- galloyl-(2R,3R)-epicatechin]

Werner Tückmantel, Alan P. Kozikowski, Leo J. Romanczyk

Research output: Contribution to journalArticle

Abstract

A project has been initiated to synthesize proanthocyanidin oligomers found in cocoa. Natural, readily available (+)-catechin was transformed into 5,7,3',4'-tetra-O-benzyl-(-)-epicatechin (14) by (a) benzylation of the phenolic oxygens; (b) oxidation of the 3-alcohol to ketone by the Dess-Martin periodinane; and (c) reduction with lithium tri-sec-butylborohydride (L- Selectride) in the presence of LiBr. The additive diminishes the extent of ketone enolization while maintaining a stereoselectivity of ≥200:1. Oxidation of 14 with DDQ was performed best from the standpoint of product purification if ethylene glycol was used as the nucleophilic trapping agent. The resulting ether 19 was condensed with 14 using TiCl4 to give a good yield of benzylprotected epicatechin-4β,8-epicatechin (octa-O- benzylprocyanidin B2, 20) as the sole dimeric product. Hydrogenolysis of 20 yielded procyanidin B2 in the first enantiospecific synthesis of this natural product which employs protected intermediates and thereby allows the necessary product separation after the condensation step to be performed on nonpolar, nonsensitive intermediates. Acylation of 20 with tri-O- benzylgalloyl chloride followed by hydrogenolysis gave access to the title bis-gallate (24). This constitutes the first synthesis of this natural product, a compound notable for its PKC-inhibitory and anticancer activity.

Original languageEnglish (US)
Pages (from-to)12073-12081
Number of pages9
JournalJournal of the American Chemical Society
Volume121
Issue number51
DOIs
StatePublished - Dec 29 1999
Externally publishedYes

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Growth Inhibitors
Hydrogenolysis
Catechin
Cell growth
Polyphenols
Bioactivity
Ketones
Cocoa
Stereoselectivity
Acylation
Oxidation
Ethylene glycol
Biological Products
Oligomers
Purification
Condensation
Ethers
Neoplasms
Lithium
Alcohols

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

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title = "Studies in polyphenol chemistry and bioactivity. 1. Preparation of building blocks from (+)-catechin. Procyanidin formation. Synthesis of the cancer cell growth inhibitor, 3-O-galloyl-(2R,3R)-epicatechin-4β,8-[3-O- galloyl-(2R,3R)-epicatechin]",
abstract = "A project has been initiated to synthesize proanthocyanidin oligomers found in cocoa. Natural, readily available (+)-catechin was transformed into 5,7,3',4'-tetra-O-benzyl-(-)-epicatechin (14) by (a) benzylation of the phenolic oxygens; (b) oxidation of the 3-alcohol to ketone by the Dess-Martin periodinane; and (c) reduction with lithium tri-sec-butylborohydride (L- Selectride) in the presence of LiBr. The additive diminishes the extent of ketone enolization while maintaining a stereoselectivity of ≥200:1. Oxidation of 14 with DDQ was performed best from the standpoint of product purification if ethylene glycol was used as the nucleophilic trapping agent. The resulting ether 19 was condensed with 14 using TiCl4 to give a good yield of benzylprotected epicatechin-4β,8-epicatechin (octa-O- benzylprocyanidin B2, 20) as the sole dimeric product. Hydrogenolysis of 20 yielded procyanidin B2 in the first enantiospecific synthesis of this natural product which employs protected intermediates and thereby allows the necessary product separation after the condensation step to be performed on nonpolar, nonsensitive intermediates. Acylation of 20 with tri-O- benzylgalloyl chloride followed by hydrogenolysis gave access to the title bis-gallate (24). This constitutes the first synthesis of this natural product, a compound notable for its PKC-inhibitory and anticancer activity.",
author = "Werner T{\"u}ckmantel and Kozikowski, {Alan P.} and Romanczyk, {Leo J.}",
year = "1999",
month = "12",
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AU - Tückmantel, Werner

AU - Kozikowski, Alan P.

AU - Romanczyk, Leo J.

PY - 1999/12/29

Y1 - 1999/12/29

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