Synthetic methods for preparing procyanidin oligomers
AssigneeMars, Incorporated
InventorsLeo J. Romanczyk JR., Amit Basak, Craig A. Townsend
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Abstract
Processes are disclosed for the production of linear and branched procyanidin oligomers having “n” procyanidin monomeric units where n is 2 to 18. The processes include coupling protected, activated monomers with an unprotected monomer to produce a partially protected (4→8) dimer. The dimer is optionally blocked, coupled with an activated protected monomer to produce a partially protected, optionally blocked trimer, and deprotected. The steps can be repeated to produce higher oligomers. Processes are also provided for producing (8→8), (8→6), and (6→6) dimers and doubly branched oligomers. Crystalline 8-bromo tetra-O-benzyl (−)-epicatechin is produced under certain conditions.
Claims28
A process for the preparation of a procyanidin dimer, which process comprises the steps of:
- (a) protecting each phenolic hydroxyl group of a procyanidin monomer with a removable protecting group which does not deactivate the A ring of the monomer, wherein the protecting step is carried out in an aprotic solvent;
- (b) activating for coupling the C-4 position of the compound of step (a) by introducing an acyloxy group using a lead (IV) salt of an organic acid to provide an activated compound;
- and
- (c) coupling the activated compound of step (b) with an unprotected procyanidin monomer in the presence of a coupling catalyst to produce the dimer.
A process for preparing a linear procyanidin oligomer, which process comprises the steps of:
- (a) preparing a partially protected procyanidin dimer, wherein the phenolic hydroxyl groups of the top mer are protected with a removable protecting group which does not deactivate the A ring of the protected mer;
- (b) masking the unprotected phenolic hydroxyl groups of the bottom mer of step (a) and the hydroxyl groups at both C-3 positions with a removable masking group which deactivates the bottom mer of said masked, protected dimer;
- (c) deprotecting the top mer of the dimer of step (b) to provide a deprotected masked dimer thus allowing coupling to occur at the C-8 position of the deprotected top mer of the dimer;
- (d) coupling the dimer of step (c) with an unblocked or blocked, protected, activated monomer to form a trimer, wherein the top mer of the trimer is a protected blocked mer or a protected unblocked mer and is coupled at the C-8 position;
- (e) masking the blocked or unblocked trimer of step (d);
- (f) deprotecting the blocked or unblocked, protected, masked trimer of step (e) to form an blocked or unblocked trimer;
- and
- (g) optionally repeating or alternating steps (a) to (f) to prepare higher oligomers wherein the number of mers are 4 to 18.
A process for preparing a branched procyanidin oligomer, which process comprises the steps of:
- (a) preparing an unblocked or blocked, partially protected procyanidin dimer, wherein the phenolic hydroxyl groups of the top mer are protected with a removable protecting group which does not deactivate the A ring of the protected mer and while the bottom mer has free phenolic hydroxyl groups;
- (b) coupling the dimer of step (a) with a unblocked or blocked, protected, activated procyanidin monomer to form a branched trimer;
- (c) deprotecting the trimer of step (b);
- and
- (d) optionally carrying out one of the following steps in a sequential, alternating or combinational fashion to provide procyanidin oligomers having 4 to 18 mers comprising (4→8), (4→6) (6→4), and/or (8→4) linkages;
- (i) coupling the trimer of step (c) with an unblocked or blocked protected procyanidin monomer;
- or
- (ii) masking the trimer of step (b);
- deprotecting the masked trimer;
- and coupling the masked trimer with an unprotected or protected, blocked activated procyanidin monomer.
A doubly branched oligomer having the structure:
- 30
A process for producing a procyanidin dimer having a (8⇄8) linkage, said process comprising the steps:
- (a) reacting a first 8-bromo protected monomer with a hexaalkyl distannane in the presence of palladium(o) to provide a protected monomer-8-trialkyl stannane;
- (b) coupling the product of step (a) with a second 8-bromo protected monomer with tetrakis (triphenyl phosphine) palladium(o) in benzene to produce a (8⇄8) coupled dimer;
- and
- (c) deprotecting the product of step (b) to produce the (8⇄8) dimer.
A process for producing a procyanidin dimer having a (6⇄6) linkage, said process comprising the steps:
- (a) reacting a first 6-bromo protected monomer with a hexaalkyl distannane in the presence of palladium(o) to provide a protected monomer-6-trialkyl stannane;
- (b) coupling the product of step (a) with a second 6-bromo protected monomer with tetrakis (triphenyl phosphine) palladium(o) in benzene to produce a (6⇄6) coupled dimer;
- and
- (c) deprotecting the product of step (b) to produce the (6⇄6) dimer.
A process for producing a procyanidin dimer having a (6⇄8) linkage, said process comprising the steps of:
- (a) reacting a first 6-bromo protected monomer with hexaalkyl distannane in the presence of palladium(o) to provide a protected monomer-6-trialkyl stannane;
- (b) coupling the product of step (a) with a second 8-bromo protected monomer with tetrakis (triphenyl phosphine) palladium(o) in benzene to produce a (6⇄8) coupled dimer;
- and
- (c) deprotecting the product of step (b) to produce the (6⇄8) dimer.
A process for producing a procyanidin dimer having a (8⇄6) linkage, said process comprising the steps:
- (a) reacting a first 8-bromo protected monomer with a lithium trialkyl tin to provide a protected monomer-8-trialkyl stannane in the presence of palladium(o);
- (b) coupling the product of step (a) with a second 6-bromo protected monomer with tetrakis (triphenyl phosphine) palladium(o) in benzene to produce a (8⇄6) coupled dimer;
- and
- (c) deprotecting the product of step (b) to produce the (8⇄6) dimer.
A crystalline 8-bromo-tetra-O-benzyl (−) epicatechin.
Dependencies are inferred from the claim text.