256236-25-6Relevant academic research and scientific papers
Processes for the preparation of protected-(+)-catechin and (-)-epicatechin monomers, for coupling the protected monomers with an activated, protected epicatechin monomer, and for the preparation of epicatechin-(4B,8)-epicatechin or -catechin dimers and their digallates
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Page/Page column 6, (2010/11/25)
Improved processes for the preparation of tetra-O-benzyl protected catechin, for the coupling of the tetra-O-benzyl protected catechin or epicatechin with a C-4 activated, tetra-O-benzyl protected epicatechin for the galloylation of the epicatechin-(4β,8)-catechin or -epicatechin dimer-the dimer digallates, and for the deprotection (i.e., debenzylation) of the protected epicatechin dimers and protected epicatechin dimer digallates are disclosed.
Scale-Up Syntheses of Two Naturally Occurring Procyanidins: (-)-Epicatechin-(4β,8)-(+)-catechin and (-)-Epicatechin-3-0-galloyl- (4β, 8)-(-)-epicatechin-3-0-gallate
Sharma, Pradeep K.,Kolchinski, Alexander,Shea, Helene A.,Nair, Jayesh J.,Gou, Yanni,Romanczyk Jr., Leo J.,Schmitz, Harold H.
, p. 422 - 430 (2012/12/31)
A scaleable process for the synthesis of two naturally occurring procyanidins, namely (-)-epicatechin-(4β,8)-(+)-catechin (1) and(-)-epiratechin-3-O-galloyl-(4β,8)-(-)-epicatechin-3-O-gallate (2), is described. The key steps were highlighted by improvements for the benzylation of (+)-catechin (3), stereo-selective reduction of the C-3 keto group of (2A)-5,7,3′,4′-tetrakis(benzyloxy)flavan-3-one (10), and coupling between 4-hydroxyethoxy-5,7,3′,4′-tetra-O-benzyl-(-)-epicatechin (11) and 5,7,3′,4′-tetra-O-benzyl-(+)-catechin (4) or 5,7,3′,4′-tetra-O-benzyl-(-)-epicatechin (6), respectively. The debenzylation performed in a biphasic system resulted in an improved yield and purity of the target compounds. The chemistry was scaled-up to produce multigram quantities of the title compounds (1 and 2) for various in vitro, ex vivo, and in vivo studies. Moreover, the scale-up process provided a detailed description for the preparation of multihundred to kilogram scale quantities of intermediates used in the synthesis of these two titled procyanidins.
Synthesis of dimeric, trimeric, tetrameric pentameric, and higher oligomeric epicatechin-derived procyanidins having 4beta,8-interflavan linkages and their use to inhibit cancer cell growth through cell cycle arrest
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Page 6, (2008/06/13)
Various processes are disclosed for preparing protected epicatechin oligomers having (4β,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 (4β,8)4-pentamers to treat cancer is also disclosed.
Studies in polyphenol chemistry and bioactivity. 4. Synthesis of trimeric, tetrameric, pentameric, and higher oligomeric epicatechin-derived procyanidins having all-4β,8-interflavan connectivity and their inhibition of cancer cell growth through cell cycle arrest
Kozikowski, Alan P.,Tueckmantel, Werner,Boettcher, Gesine,Romanczyk Jr., Leo J.
, p. 1641 - 1658 (2007/10/03)
We report an improved synthesis of bis(5,7,3′,4′-tetra-O-benzyl)epicatechin 4β,8-dimer (3) from 5,7,3′,4′-tetra-O-benzylepicatechin (1) and 5,7,3′,4′-tetra-O-benzyl-4-(2-hydroxyethoxy)epicatechin (2) by replacing the previously employed Lewis acid, titanium tetrachloride, with the clay mineral Bentonite K-10. Under the same conditions, the benzyl-protected all-4β,8-trimer, -tetramer, and -pentamer were obtained regioselectively from their lower homologues, albeit in rapidly decreasing yields. Reaction of 2 with an organoaluminum thiolate generated from 2-mercaptobenzothiazole and trimethylaluminum followed by acetylation produced 3-O-acetyl -4-[(2-benzothiazolyl)thio]5,7,3′,4′-tetra-O-benzylepicatechin (12). Medium-sized protected oligomers with 4β,8-interflavan linkages are obtained in improved yields by using this compound as the electrophile and silver tetrafluoroborate as activator and are isolated by reversed-phase HPLC. Their deprotection by ester saponification followed by hydrogenolysis yielded the free procyanidins, which were characterized as their peracetates. The synthetic procyanidins are identical by normal-phase HPLC with fractions isolated from cocoa. The principle of chain extension by two members was demonstrated using a dimeric electrophile obtained by self-condensation of compound 12. Both the synthetic and natural pentamer 32 inhibit the growth of several breast cancer cell lines. Using the MDA MB 231 line, it was established that this outcome is based on the induction of cell cycle arrest in the G0/G1 phase. Subsequent cell death is more likely necrotic rather than apoptotic. Control experiments demonstrate that the polyphenol itself, rather than hydrogen peroxide potentially formed by its autoxidation, is the causative agent.
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]
Tueckmantel, Werner,Kozikowski, Alan P.,Romanczyk Jr., Leo J.
, p. 12073 - 12081 (2007/10/03)
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 benzyl-protected 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.
