Synthesis of epecatechin-4α, 8-epicatechin and -catechin dimers and derivatives thereof
AssigneeMars, Incorporated
InventorsAlan P. Kozikowski, Leo J. Romanczyk, Jr., Werner Tückmantel
Life of this patent
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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.
Claims9
A process for preparing epicatechin-(4α,8)-catechin dimer, which process comprise the steps of:
- (a) protecting the 3-hydroxyl group of 5,7,3′,4′-tetra-O-benzyl-epicatechin with a benzyl protecting group to form 3,5,7,3′,4′-penta-O-benzyl-epicarechin;
- (b) oxidizing the C-4 position of the epicarechin of step (a) to form 3,5,7,3′,4′-penta-O-benzyl-4-hydroxy-epicate;
- (c) oxidizing the C-4 hydroxyl group of the epicatechin of step (b) to form (2R,3S)-3,5,7,3′,4′-penra-O-benzyl-4-ketone-epicatechin;
- (d) adding tert-butyl lithium to 3,5,7,3′,4′-penta-O-benzyl-8-bromo-catechin to form a catechin-lithium reagent;
- (e) adding the epicatechin from step (c) to the catechin-lithium reagent from step (d) to form 3,5,7,3′,4′-penta-O-benzyl-4-hydroxy-epicatechin-(4α,8)-(3,5,7,3′,4′-penta-O-benzyl)-catechin dimer;
- (f) reducing the C-4 hydroxyl group of the dimer from step (e) to form 3,5,7,3′,4′-penta-O-benzyl-epicatechin-(4α,8)-(3,5,7,3′,4′-penta-O-benzyl)-catechin dimer;
- and
- (g) replacing the benzyl groups of the dimer of step (f) with hydrogen to form the epicatechin-(4α,8)-catechin dimer.
A process for preparing 5,7,3′,4′-tetra-O-benzyl-3-O-(tert-butyldimethylsilyl)-epicatechin-4α,8-[5,7,3′,4′-tetra-O-benzyl-3-O-(tert-O-butyldimethylsilyl]-catechin dimer comprises the steps of:
- (a) protecting the C-3 hydroxyl group of 5,7,3′,4′-tetra-O-benzylepicarechir with a tert-butyldimethylsilyl group to form 5,7,3′,4′-tetra-O-benzyl-C-3-O-(tert-butyldimethylsilyl)-epicatechin;
- (b) oxidizing the C-3 position of the epicatechin from step (a) to form 5,7,3′,4′-tetra-O-benzyl-3-O-(tert-butyldimethyisilyl)-4-hydroxy-epicatechin;
- (c) oxidizing the C-4 hydroxyl group of the epicatechin from step (b) to form (2R,3S)-5,7,3′,4′-tetra-O-benzyl-3-O-(tert-butyldimethylsilyl)-4-ketone-epicatechin;
- (d) adding tert-butyllithium to 5,7,3′,4′-tetra-O-benzyl-8-bromo-3-O-(tert-butyldimethylsilyl)-catechin to form a catechin-lithium reagent;
- (e) adding the epicatechin from step (c) to the catechin-lithium reagent from step (d) to form 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 dimer;
- (f) reducing the C-4 hydroxyl group of the dimer from step (e) to form the 5,7,3′,4′-tetra-O-benzyl-3-(tert-butyldimethylsilyl)-epicatechin-4α,8-[5,7,3′,4′-tetra-O-benzyl-3-O-(tert-butyldimethylsilyl)]-catechin dimer.
A process for preparing an epicatechin-(4α,8)-(3-O-acyl)-catechin dimer comprises the steps of:
- (a) protecting the C-3 hydroxyl group of 5,7,3′,4′-tetra-O-benzyl-epicatechin with a tert-butyldimethylsilyl group to form 5,7,3′,4′-tetra-O-benzyl-C-3-O-tert-butyldimethylsilyl)-epicatechin;
- (b) oxidizing the C-4 position of the epicatechin from step (a) to form 5,7,3′,4′-terta-O-benzyl-3-O-tetra-butyldimethylsilyl)-4-hydroxy-epicatechin;
- (c) oxidizing the C-4 hydroxyl group of the epicatechin from step (b) to form (2R,3S)- 5,7,3′,4′-tetra-O-benzyl-3-O-tert-butyldimethylsilyl-4-ketone-epicatechin;
- (d) adding tert-butyl lithium to 5,7,3′,4′-tetra-O-benzyl-8-bromo-3-O-(tert-butyldinierhylsilyl) catechin to form a catechin-lithium reagent;
- (e) adding the epicatechin from step (c) to the catechin-lithium reagent from step (d) to form 5,7,3′,4′-tetra-O-benzyl-3-(tert-butyldimethylsiyl)-4-hydroxy-epicatechin-(4α,8)-[5,7,3′,4-tetra-O-benzyl-3-O-(tert-buryldimethylsilyl)]-catechin dimer;
- (f) reducing the C-4 hydroxyl group of the dimer from step (e) to form 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 dimer;
- (g) replacing the tert-butylimethylsilyl protecting groups of the dimer of step (f) with hydrogen to form 5,7,3′,4′-tetra-O-benzyl-epicatechin-(4α,8)-(tetra-O-benzyl-catechin)-dimer;
- (h) acylating the 3-OH position of the dimer of step (g) with an activated acid or an acid chloride to form a 5,7,3′,4′-tetra-O-benzyl-epicatechin-(4α,8)-[5,7,3′,4′-tetra-O-benzyl-(3-O-acyl) catechin]-dimer, and
- (i) replacing the benzyl protecting groups of the dimer from step (h) with hydrogen to form the epicatechin (4α,8)-(3-O-acyl)-catechin dimer.
Dependencies are inferred from the claim text.