Synthesis of 4alpha-arylepicatechins

Abstract

Oligomeric procyanidins containing 4α-linked epicatechin units are rare in nature and have hitherto not been accessible through stereoselective synthesis. Provided herein is the preparation of the prototypical dimer, epicatechin-4α,8-epicatechin, by reaction of the protected 4-ketones with aryllithium reagents derived by halogen/metal exchange from the aryl bromides. Removal of the 4-hydroxyl group from the resulting tertiary benzylic alcohols is effected by tri-n-butyltin hydride and trifluoroacetic acid in a completely stereoselective manner, resulting in hydride delivery exclusively from the β face.

1 - 21 . (canceled)  
   
   
       22 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein R 1  is a silyl protecting group or a benzyl protecting group, wherein X and Y are independently hydrogen or hydroxy, wherein Z is a hydrogen, and wherein Bn is a benzyl group.  
   
   
       23 - 24 . (canceled)  
   
   
       25 . The compound of  claim 22 , wherein R 1  is the silyl protecting group.  
   
   
       26 . The compound of  claim 25 , wherein the silyl group is a tert-butyldimethylsilyl group.  
   
   
       27 . The compound of  claim 22 , wherein R 1  is the benzyl protecting group.  
   
   
       28 - 30 . (canceled)  
   
   
       31 . The compound of  claim 22 , which is 3,5,7,3′,4′-penta-O-benzyl-4-hydroxy-epicatechin or 5,7,3′,4′-tetra-O-benzyl-3-O-(tert-butyldimethylsilyl)-4-hydroxy-epicatechin.  
   
   
       32 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein R 1  is a silyl protecting group or a benzyl protecting group, wherein X and Y together are oxygen, wherein Z is hydrogen, and wherein Bn is a benzyl group.  
   
   
       33 . The compound of  claim 32 , wherein R 1  is the silyl protecting group.  
   
   
       34 . The compound of  claim 33 , wherein the silyl group is a tert-butyldimethylsilyl group.  
   
   
       35 . The compound of  claim 32 , wherein R 1  is the benzyl protecting group.  
   
   
       36 . The compound of  claim 32 , which is (2R,3S)-3,5,7,3′,4′-pentakis-(benzyloxy)flavan-4-one or (2R,3S)-5,7,3′,4′-tetra-O-benzyl- [(tert-butyldimethylsilyl)oxy]flavan-4-one.  
   
   
       37 - 45 . (canceled)  
   
   
       46 . A protected dimer selected from the group consisting of 5,7,3′,4′-tetra-O-benzyl-3-O-(tert-butyldimethylsilyl)-epicatechin-(4α,8)-[5,7,3′,4′- tetra-O-benzyl-3-O-(tert-butyldimethylsilyl)]-catechin; 3,5,7,3′,4′-penta-O-benzyl-epicatechin-(4α,8)-(3,5,7,3′,4′-penta-O-benzyl-catechin); and 5,7,3′,4′-tetra-O-benzyl-epicatechin-(4α,8)-(5,7,3′,4′-tetra-O-benzyl-catechin).  
   
   
       47 . A protected epicatechin-(4α,8)-catechin dimer having a 4-hydroxy group which is selected from the group consisting of 5,7,3′,4′-tetra-O-benzyl-3-O-(tert-butyldimethylsilyl)-4-hydroxy-epicatechin-(4α,8)-[5,7,3′,4′-tetra-O-benzyl-3-O-(tert-butyldimethylsilyl)catechin] and 3,5,7,3′,4′-penta-O- benzyl-4-hydroxy-epicatechin-(4α,8)-(penta-O-benzyl-catechin).  
   
   
       48 . A derivatized 5,7,3′,4′-tetra-O-benzyl-epicatechin-(4α,8)-(5,7,3′,4′-tetra-O-benzyl-catechin) dimer having at least one 3-O-acyl group.  
   
   
       49 . The dimer of  claim 48 , wherein the 3-O-acyl group is introduced using an acid selected from the group consisting of caffeic acid, coumaric acid, ferulic acid, and sinapic acid.  
   
   
       50 . The dimer of  claim 48 , which is epicatechin-(4α,8)-[(3-O-acyl)-catechin].  
   
   
       51 . The dimer of  claim 48 , wherein the 3-O-acyl group is introduced using a hydroxy-protected acid selected from the group consisting of cinnamic acid, gallic acid, and hydroxy-benzoic acid.  
   
   
       52 . The dimer of  claim 51 , wherein the 3-O- acyl group is a 3-O-(3,4,5-tri-O-benzylgalloyl) group.  
   
   
       53 . The dimer of  claim 52  which is epicatechin-(4α,8)-[(3-O-galloyl)-catechin].  
   
   
       54 . An epicatechin-(4α,8)-catechin dimer.