Synthesis of Oligomeric Epicatechin- and Catechin-Derived Procyanidins

Abstract

Various processes are disclosed for preparing procyanidin oligomers having (4,8)-interflavan linkages. In an improved process, a tetra-O-protected-epicatechin or -catechin monomer or oligomer is coupled with a protected, C-4 alkoxy-activated-epicatechin or -catechin monomer in the presence of an acidic clay instead of a Lewis acid. In a second process, a 5,7,3′,4′-tetra-O-protected or preferably penta-O-protected-epicatechin or -catechin monomer or oligomer is reacted with a tetra-O-protected or preferably penta-O-protected-epicatechin or -catechin monomer having a thio activating group at the C-4 position; the coupling is carried out in the presence of silver tetrafluoroborate. In third process, two molecules of a penta-O-protected-epicatechin or -catechin monomer activated with a 2-(benzothiazolyl)thio group at the C-4 position are self-condensed in the presence of silver tetrafluoroborate. An improved two-step process for preparing a C-4 alkoxy activated tetra-O-benzyl-protected, 8-bromo-blocked-epicatechin or -catechin monomer is also provided. The use of naturally-derived and synthetically-prepared procyanidin (4β,8) 4 -pentamers to treat cancer is also disclosed.

1 - 38 . (canceled)  
   
   
       39 . An improved process for preparing 5,7,3′,4′-tetra-O-benzyl-4-(2-hydroxyethoxy)-8-bromo-epicatechin or -catechin comprises the steps of: 
 (a) reacting 5,7,3′,4′-tetra-O-benzyl-epicatechin or -catechin with ethylene glycol in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to form 5,7,3′,4′-tetra-O-benzyl-4-(2-hydroxyethoxy)-epicatechin or -catechin; and    (b) brominating the 5,7,3′,4′-tetra-O-benzyl-4-(2-hydroxyethoxy)-epicatechin or -catechin with N-bromosuccinimide to form the 5,7,3′,4′-tetra-O-benzyl-4-(2-hydroxyethoxy)-8-bromo-epicatechin or -catechin.    
   
   
       40 . The process of  claim 39 , wherein the monomer of step (a) is 5,7,3′,4′-tetra-O-benzyl-epicatechin.  
   
   
       41 . An improved process for preparing 5,7,3′,4′-tetra-O-benzyl-4-(2-hydroxyethoxy)-8-bromo-epicatechin or -catechin comprises the steps of: 
 (a) brominating 5,7,3′,4′-tetra-O-benzyl-epicatechin or -catechin with N-bromosuccinimide to form 5,7,3′,4′-tetra-O-benzyl-8-bromo-epicatechin or -catechin, and    (b) reacting the 5,7,3′,4′-tetra-O-benzyl-8-bromo-epicatechin or -catechin with ethylene glycol in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to form the 5,7,3′,4′-tetra-O-benzyl-4-(2-hydroxyethoxy)-8-bromo-epicatechin or -catechin.    
   
   
       42 . The process of  claim 41 , wherein the monomer of step (a) is 5,7,3′,4′-tetra-O-benzyl-epicatechin and wherein the yield of the 5,7,3′,4′-tetra-O-benzyl-4-(2-hydroxyethoxy)-8-bromo-epicatechin is about 67%.  
   
   
       43 . (canceled)  
   
   
       44 . The process of  claim 39 , wherein tle yield of the 5,7,3′,4′-tetra-O-benzyl-4-(2-hydroxyethoxy)-g-bromo-epicatechin is about 63%.  
   
   
       45 . The process of  claim 41 , wherein the yield of the 5,7,3′,4′-tetra-O-benzyl-4-(2-hydroxyethoxy)-8-bromo-epicatechin is about 67%.