Synthesis of dimeric, trimeric, tetrameric pentameric, and higher oligomeric epicatechin-derived procyanidins having 4,8-interflavan linkages and their use to inhibit cancer cell growth through cell cycle arrest
Various processes are disclosed for preparing protected epicatechin oligomers having (4.beta.,8)-interflavan linkages. In one process, a tetra-O-protected epicatechin monomer or oligomer is coupled with a protected, C-4 activated epicatechin monomer in the presence of an acidic clay such as a mortmorillonite clay. In another process, a 5,7,3',4'-benzyl protected or a 3-acetyl-, 5,7,3',4'-benzyl protected epicatechin or catechin monomer or oligomer is reacted with 3-O-acetyl-4-[(2-benzothiazolyl)thio]-5,7,3',4'-tetra-O-benzylepicatechin in the presence of silver tetrafluoroborate. In another process, two 5,7,3',4'-benzyl protected epicatechin monomers activated with 2-(benzothiazolyl)thio groups at the C-4 positions are cross-coupled in the presence of silver tetrofluoroborate. A process is also disclosed for reacting an unprotected epicatechin or catechin monomer with 4-(benzylthio)epicatechin or catechin. The use of naturally-derived and synthetically-prepared procyanidin (4.beta.,8).sub.4-pentamers to treat cancer is also disclosed.
CROSS REFERENCE TO RELATED APPLICATION
This application claims the benefit of filing date of U.S. provisional application Ser. No. 60/415,616 entitled SYNTHESIS OF TRIMERIC, TETRMERIC, PENTAMERIC, AND HIGHER OLIGOMERIC EPICATECHIN-DERIVED PROCYANIDINS HAVING 4.beta.,8-INTERFLAVAN LINKAGES AND THEIR USE TO INHIBIT CANCER CELL GROWTH THROUGH CELL CYCLE ARREST which was filed on Oct. 2, 2002.
Processes are disclosed for the production of linear and branched procyanidin oligomers having "n" procyanidin monomeric units where n is 2 to 18. The processes include coupling protected, activated monomers with an unprotected monomer to produce a partially protected (4.fwdarw.8) dimer. The dimer is optionally blocked, coupled with an activated protected monomer to produce a partially protected, optionally blocked trimer, and deprotected. The steps can be repeated to produce higher oligomers. Processes are also provided for producing (8.fwdarw.8), (8.fwdarw.6), and (6.fwdarw.6) dimers and doubly branched oligomers. Crystalline 8-bromo tetra-O-benzyl (-)-epicatechin is produced under certain conditions.
