Synthesis of 4α-arylepicatechins
AssigneeMars, Incorporated
InventorsAlan P. Kozikowski, Leo J. Romanczyk, Jr., Werner Tückmantel
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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 an epicatechin -4α,8-epicatechin dimer which 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-epicatechin;
- (b) oxidizing the C-4 position of the epicatechin of step (a) to form 3,5,7,3′,4′-penta-O-benzyl-4-hydroxy-epicatechin;
- (c) oxidizing the C-4 hydroxy group of the epicatechin of step (b) to form a (2R,3S)-3,5,7,3′,4′-penta-O-benzyl-4-ketone-epicatechin;
- (d) adding tert-butyllithium to 3,5,7,3′,4′-penta-O-benzyl-8-bromo-epicatechin to form a protected epicatechin lithium reagent;
- (e) adding the epicatechin from step (c) to the epicatechin 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)-epicatechin dimer;
- (f) reducing the C-4 hydroxyl group of the dimer of step (e) to form 3,5,7,3′,4′-penta-O-benzyl-epicatechin-4α, 8-(3,5,7,3′,4′-penta-O-benzyl)-epicatechin dimer;
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- (g) replacing the benzyl groups of the dimer of step (f) with hydrogen to form the epicatechin 4α, 8-epicatechin dimer.
A process for preparign a 5,7,3′,4′-tetra-O-benzyl-3-O-(tert-butlydimethylsilyl)-epicatechin-4α,8-[5,7,3′,4′-tetra-O-benzyl-3-O-(tert-butyldimethylsilyl)-epicatechin] dimer comprises the steps of:
- (a) protecting the C-3 hydroxyl group of 5,7,3′,4′-tetra-O-benzylepicaechin 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 (b) to form 5,7,3′,4′-tetra-O-benzyl-3-O-(tert-butyldimethylsilyl)-4-hydroxy-epicatechin;
- (c) oxidizing the C-4 hydrozyl group of the epicatechin from step (c) to form 5,7,3′,4′-tetra-O-benzyl-3-O-(tert butyldimethysilyl)-4-ketone-epicatchin;
- (d) adding tert-butyllithium to 5,7,3′,4′-tetra-O-benzyl-8-bromo-3-O-(tert-butyldimethylsilyl)-epicatechin to form an epicatechin lithium reagent;
- (e) adding the epicatechin from step (c) to the lithium epicatechin reagent from step (d) to form 5,7,3′,4′-tetra-O-benzyl-3-O-(tert-butyldimethysilyl)-4-hydroxy-epicatechin-4α,8-[5,7,3′,4′-tetra-O-benzyl-3-O-(tert-bityldimethysilyl)-epicatechin] dimer;
- (f) reducing the C-4 hydroxyl group of the dimer form step (e) to form the 5,7,3′,4′-tetra-O-benzyl-3-O-(tert-bityldimethylsilyl)-epicatechin-4α, 8-[5,7,3′,4′-tetra-O-benzyl-3-O-(tert bityldimethysilyl)-epicatechin] dimer.
A process for preparing an epicatechin-4α,8-(3-O-acyl)-epicatechin dimer comprises the steps of:
- (a) protecting the C-3 hydroxyl group of 5,7,3′,4′-tetra-O-benzylepicatechin with a tert-butyldimethylsilyl group to form 5,7,3′,4′-tetra-O-benzyl-C-3-O-(tert-butyldimethysilyl)-epicatechin;
- (b) oxidizing the C-4 position of the epicatechin form step (b) to form 5,7,3′,4′-tetra-O-benzyl-3-O-(tert-butyldimethylsilyl)-4-hydroxy-epicatechin;
- (c) oxidizing the C-4 hydroxyl group of the epicatechin from step (c) to form 5,7,3′,4′-tetra-O-benzyl-3-O-tert-butyldimethysilyl-4-ketone-epicatchin;
- (d) adding tert-butyllithium to 5,7,3′,4′-tetra-O-benzyl-8-bromo-3-O-(tert-butyldimethysilyl)-epicatechin to form an epicatechin lithium reagent;
- (e) adding the epicatechin from step (c) to the lithium epicatechin reagent from step (d) to form 5,7,3′,4′-tetra-O-benzyl-3-O-(tert-butyldimethysilyl)-4-hydroxy-epicatechin-4α, 8-[5,7,3′,4′-tetra-O-benzyl-3-O-(tert-butyldimethysilyl)-epicatechin] 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-butyldimethysilyl)-epicatechin-4α, 8-[5,7,3′,4′-tetra-O-benzyl-3-O-(tert butyldimethysilyl)-epicatechin] dimer;
- (g) replacing the tert-butyldimethylsilyl protecting groups of the dimer from step (f) with hydrogen to form 5,7,3′,4′-tetra-O-benzyl-epicatechin-4α, 8-(tetra-O-benzyl-epicatechin) dimer;
- (h) acylating at the 3-OH position of the bottom mer of the dimer of step (g) by reaction with an activated acid or acid chloride acid to form a 5,7,3′,4′-tetra-O-benzylepicatechin-4α, 8-[5,7,3′,4′-tetra-O-benzyl-(3-O-acyl)-epicatechin] dimer;
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- (i) replacing the benzyl protecting groups of the dimer from step (h) with hydrogen to form the epicatechin -4α, 8-(3-O-acyl)-epicatechin) dimer.
Dependencies are inferred from the claim text.