MXPA00003249A - Synthetic methods for polyphenols - Google Patents

Abstract

A process is disclosed for the production of polyphenol oligomers having n polyphenol monomeric units, n being an integer from 2-18. The process includes coupling of a protected polyphenol, having protected phenolic hydroxyl groups, which a C-4 functionalized polyphenol monomer. The protected polyphenol may be a protected polyphenol monomer or a protected polyphenol oligomer having 2-17 monomeric units. Advantageously, polyphenol monomeric units forming the polyphenol oligomers may be the same or different flavanoid compounds.

Description

"SYNTHETIC METHODS FOR POLYPHENOLES" BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention relates to synthetic polyphenol monomers and oligomers, derivatives thereof and methods for making and using the same.

BACKGROUND OF THE RELATED ART Polyphenols are a highly diverse group of compounds (D. Ferreira, JP Steynberg, DG Roux, and EV, Brandt, Tetrahedron, 48, (10), 1743-1803 (1992)) which occurs widely in a variety of plants, some of which enter the food chain. In many cases, they represent an important class of compounds present in the human diet. Even though some of the polyphenols are considered as being non-nutritive, interest in these compounds has been raised due to their possible beneficial effects on health. For example, the corcetin (a flavonoid) has been shown to possess anticarcinogenic activity in studies of experimental animals E.E. Deschner, J. Ruperto, G. Wong, and H.L. Newmark, Carcinogenesis, 1, 1193-1196 (1991) and R. Kato, T. Nakadate, S. Yamamoto and T. Sugimura, Carcinogenesis, 4, 1301-1305 (1983)). It has been shown that (+) - Catechin and (-) - epicatechin (flavan-3-oles) inhibit the reverse transcriptase activity of the Leukemia virus (Chu S.-C, Hsieh, Y.-S. and Lim, J .-Y., J. of Naural Products, 55, (2), 179-183 (1992)). Nobotanine (an oligomeric hydrolysable tannin) has also been shown to possess activity against CT tumors. Okuda, T. Yoshida, and T. Hatano, Molecular Structures and Pharmacological Activities of Polyphenols - Oligomeric Hydrolyzable Tannins and Others - Presented at the XVIth International Conference of the Groupe Polyphenols, Lisbon, Portugal, July 13 to 16, 1992 ). Statistical reports have also shown that mortality from stomach cancer is significantly lower in the tea-producing districts of Japan. Epigallocatechin gallate has been reported to be a pharmacologically active material in green tea that inhibits mouse skin tumors (Okuda et al., Ibid.). Ellagic acid has also been shown to possess anticarcinogenic activity in several animal tumor models (M. Boukharta, G. Jalbert and A. Castonguay, Efficacy of Elagititanins and Ellagic Acid as Chemopreventive Agents of Cancer - Presented at the XVIth International Conference of the Groupe Polyphenols, Lisbon, - Portugal, from July 13 to 16, 1992). Proanthocyanidin oligomers have been disclosed (JP 4-190774) by the Kikkoman Corporation for use as antimutagens. The use of phenolic compounds in foods and their modulation of tumor development in experimental animal models has recently been presented at the 202nd National Meeting of the American Chemical Society (Phenolic Compounds in Foods and Their Effects on Health I. Analysis, Occurrence &; Chemistry, Ho, C.-T., CY Lee, and Huang, M.-T editors, ACS Symposium Series 506, American Chemical Society, Washington, DC (1992), Phenolic Compounds in Foods and Their Effects on Health II. Antioxidants &Cancer Prevention, Huang, M.-T, Ho, C.-T., and CY Lee, editors, ACS Symposium Series 507, American Chemical Society, Washington, DC (1992); Procyanidin polyphenols, and particularly the higher oligomers thereof have recently been found to possess a broad spectrum of biological activity, reference is made to co-pending US Patent Application Number 08 / 831,245, and the corresponding International Application Number PCT / US97 / 05693 , filed on April 2, 1997, North American Patent Application Number 08 / 709,406, filed September 6, 1996, Number 08 / 631,661, and corresponding International Patent Application Number - - PCT / US96 / 04497, filed April 2, 1996, now abandoned, and US Patent Application Number 08 / 317,226, filed October 3, 1994, now U.S. Patent Number 5,554,645, each of which is incorporated herein by reference, which disclose the variety of health benefits provided by procyanidin polyphenols as well as a means to increase the concentration of these beneficial polyphenols. in extracts, foods, pharmaceutical preparations, and chocolate compositions. Reference is also made to the original application, US Patent Application Number 08 / 948,226, filed on October 9, 1997, which discloses the methods for preparing polyphenol oligomers, and specifically procyanidin polyphenols, the exposure of which also it is incorporated herein by reference. Isolation, separation, purification and identification methods have been established for recovery of a scale of procyanidin oligomers for in vi tro and in vivo valuation of comparison of biological activities. For example, activity against cancer is allowed by pentameric procyanidins through decamerics, but not by monomers through tetrameric compounds. Currently, the quantities - - of grams of pure pentamer (> 95 percent) are obtained by time-consuming methods that are not satisfactory to obtain a sufficient quantity of the pentamer for pharmacological and large-scale bioavailability studies. An even greater effort is required to obtain gram quantities of higher oligomers, hexamers through dodecamers, for similar studies since they are present in the natural product in concentrations much lower than the pentamer. In addition, increasing the oligomeric size increases the structural complexity. Factors such as differences in the chirality of the monomer units comprising the oligomer, different binding sites of interflavan, differences in the chirality of the interflavan binding, dynamical rotation isomerization and the interflavan links, and the multiple points of binding in nucleophilic centers impose efficiency constraints on current analytical methods of separation and purification for subsequent identification. These collective factors point to a need for synthesis methods to allow unambiguous testing of both the structure configuration and absolute of higher oligomers to provide large amounts of structurally defined oligomers for in vi tro and in vivo valuation and to provide novel structural derivatives of the procyanidins that occur naturally to establish the structure-activity relationships of these materials. Accordingly, it would be advantageous to develop a versatile synthetic process capable of providing large quantities of any desired polyphenol oligomer.

COMPENDIUM OF THE INVENTION _ This invention is directed to a process for preparing a polyphenol oligomer comprising coupled units of monomeric polyphenol, or flavannoid. The process of this invention comprises: (a) forming at least one protected polyphenol monomer by protecting each phenolic hydroxyl group of a polyphenol monomer with a protecting group having the formula: c is an integer from 1 to 3 d is an integer from 1 to 4 e is an integer from 0 to 2 f is an integer from 0 to 2; 3 Rl is H, OH or OR; R and R3 are independently protective groups; and R ^ is halo; (b) functionalizing the 4-position of at least one protected polyphenol monomer to produce a functionalized protected polyphenol monomer having the formula: where c is an integer from 1 to 3; d is an integer from 1 to 4; e is an integer from 0 to 2; f is an integer from 0 to 2; and is an integer from 2 to 6; R1 is H, OH or OR3; 5 R4 is H or R; R, R3 and R5 are independently protecting groups; and R2 is halo; (c) coupling the protected polyphenol monomer with the protected polyphenol monomer functionalized to produce a protected polyphenol dimer such as the polyphenol oligomer, wherein the monomeric polyphenol units of the protected polyphenol monomer and the functionalized polyphenol monomer comprising the oligomer are the same or different; and (d) optionally repeating the functionalization and coupling steps to form a polyphenol oligomer having n monomer units, where n is 2 an integer from 3 to 18. _ The halo group (s) of R, when e + f it is at least 2, it can be the same or different, that is, they are selected from the group consisting of chlorine, fluorine, bromine, iodine. The process of this invention also provides means for the preparation of novel derivatives of the polyphenol oligomer. Halogenation of the functionalized protected polyphenol monomer provides a halogenated functionalized polyphenol monomer having the formula: where, c is an integer from 1 to 3, d is an integer from 1 to 4, e is an integer from 0 to 2, f is an integer from 0 to 2, and is an integer from 2 to 6, R1 is H, OH or OR3, R4 is H or R5, R, R3 and R5 are independently protective groups, and R2 is halo, where if e + f is at least 2, the halo substituent can be the same or different. This halogenated functionalized monomer can be used for the production of a halogenated polyphenol oligomer by coupling the monomer with either a protected polyphenol monomer or a protected polyphenol oligomer. Alternatively, the halogenated polyphenol oligomers can be prepared by the direct halogenation of the polyphenol oligomer. Other novel derivatives can be prepared by esterifying or glycosylating the polyphenol oligomer to produce a derived polyphenol oligomer. The formation of the derived oligomers can be carried out either before or subsequent to the removal of the protecting groups of the phenolic hydroxyl groups of the polyphenol oligomer. Accordingly, this invention is also directed to novel polyphenol monomers, novel polyphenol oligomers and novel polyphenol monomer and oligomer derivatives.

BRIEF DESCRIPTION OF THE DRAWINGS (solvent carrier), monomer (epicatechin), pentamer (purified by preparative HPLC), ED "synthetic epicatechin dimer (EC- (4β-8) -EC)), and EDDG (epicatechin dimer bisgalate synthesized (EC -3-O-galoyl- (4β-8) -EC-3-O-gallate) against the human breast cancer cell line MDA MB 231 at various concentrations of μg / milliliter.Figure 1 (b) is a bar graph showing the ratio of the dose response between the control monomer (solvent vehicle), (epicatechin), pentamer (purified by preparative HPLC), ED (synthetic epicatechin dimer) (EC- (4ß- »8) -EC)), and EDDG (epicatechin dimer bisgalate synthesized (EC-3-O-galoyl- (4ß-» 8) -EC-3-0-gallate)) against MDA MB 435 human breast cancer cell line at various concentrations of μg / milliliter. Figure 1 (c) is a bar graph showing the ratio of the dose response between control (solvent vehicle), monomer (epicatechin), EGCG (epigallocatechin gallate from Sigma), ED (synthesized epicatechin dimer ( EC- (4ß-8) -EC)), EDDG (epicatechin dimer bisgalate synthesized (EC-3 -O-galoyl- (4ß-8) -EC-3-O-gallate)) ECDD (repeated synthesis of bisgalate of epicatechin dimer (EC-3-O-galoyl- (4ß-8) -EC-3-O-gallate), and ECTT (trimeric trimer - Synthetic epicatechin ([EC-3-O-galoyl- (4β-8)] 2-EC-3-0-gallate)) against the human breast cancer cell line MDA 231 at various concentrations of μg / milliliter. Figure 1 (d) is a bar graph showing the dose response relationship between the control (solvent vehicle), monomer (epicatechin), EGCG (epigallocatechin gallate from Sigma), ED (synthesized epicatechin dimer (EC- (4ß-8) -EC)), EDDG (synthesized epicatechin dimer bisgalate (EC-3-O-galoyl- (4β? 8) - EC-3-O-gallate)) ECDD (repeated synthesis of epicatechin dimer bisgalate (EC-3-O-galoyl- (4ß-> 8) - EC-3-O-gallate), and ECTT (trisgalate of synthesized epicatechin trimer ([EC-3-O-galoyl- (4ß-> 8)] 2 ~ EC-3-O-gallate) against the MCF-7 human breast cancer cell line at various concentrations of μg / milliliter.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for synthesizing polyphenol oligomers and derivatives thereof. The present compounds of the invention have the same uses, and are formulated, purified and administered in the same manner as described in the North American Patent Application Number 08 / 831,245, filed on April 2, 1997. Accordingly, the compounds this US Patent Number 08 / 831,245, filed April 2, 1997. Accordingly, the compounds of this invention can be used, for example, as antineoplastic agents, antioxidants, DNA topoisomerase enzyme inhibitors, cyclo-oxygenase modulators and / or lipoxygenase, nitric oxide nitric oxide-synthase modulators, such as non-steroidal anti-inflammatory agents, antimicrobial agents, apoptosis modulators, platelet aggregation modularers, glucose modulators, and oxidative DNA damage inhibitors. As used herein, the term "polyphenol monomer" means a polyhydroxy substituted compound having the following flavanoid base structure: where c is an integer from 1 to 3; d is an integer from 1 to 4; Rl is H or OH. The polyphenol monomer may contain additional substituents, or derivatives of the hydroxyl substituents, as will be described continuation. The term "polyphenol oligomer" means a polymer composed of a series of polyphenol monomer units which may possess the same or different flavanoid structures. The polyphenol monomer units are the polyphenol monomers that have been coupled or ligated together to form an oligomer. The term polyphenol (s) includes proanthocyanidins, and derivatives thereof, and specifically includes procyanidins, such as those that can be extracted from cocoa beans, and derivatives thereof, as well as structurally similar synthetic materials. Representative proanthocyanidins include: Substitution Pattern Class Monomer 3 5 7 8 3 '41 5' Proapigeninidine Apigeniflavan H OH OH H OH OH Prolteolinidine Luteoliflavan H OH OH H OH OH H Proticetinidine Tricetiflavan H OH OH H OK OH OH Propelargonidin Afzelechin OH OH OH H OH OH Procyanidin Catechin OH OH OH OH OH OH Prodelfinidine Galocatechin OH OH OH OH OH OH Proguibourtinidine Guibourtinidol OH H OH H OH OH Profisetinidine Fisetinidol OH OH OH OH OH OH Prolbine inidine Robinetinidol OH OH OH OH OH OH Proteinacacinidine Oritin OH OH OH OH OH OH Promelacacinidine Prosopin OH OH OH OH OH OH H The present invention provides a process for preparing essentially pure polyphenol oligomers and derivatives thereof.

In a preferred embodiment, the present invention provides a process for synthesizing the polyphenol oligomers of the formula where x is an integer from 0 to 16 a is an integer from 1 to 15 20 b is an integer from 1 to 15 the sum of a + b is an integer from 2 to 17; c is independently an integer from 1 to 3 d is independently an integer from 1 to 4 e is independently an integer from 0 to 2 f is independently an integer from 0 to 2 R is independently hydrogen, alkyl 1 to 4 carbon atoms, benzyl, substituted benzyl, or a silyl residue containing alkyl or aryl substituents of 1 to 6 carbon atoms or, when cod is 2 and adjacent, methylene, diphenylmethylene or substituted diphenylmethylene, where the substituted benzyl or each substituted phenyl may contain substituents which are selected from the group consisting of halo, nitro, cyano, aryl, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkoxy of 3 to 8 carbon atoms; and R is hydrogen, hydroxy, an.-O-glycoside, an -O-substituted glycoside, -OC- (O) -aryl, aryl-OC (O) -substituted aryl, -OC (O) -styryl, or styryl -0C (0) -substituted; wherein the substituted glycoside is substituted by -C (O) -aryl, -C (O) -substituted aryl, -C (O) -styryl or -C (O) -substituted styryl; wherein the substituted aryl or the substituted styryl can contain the substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, aryl, amino, methylenedioxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 atoms of carbon, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, and cycloalkoxy of 3 to 8 carbon atoms; 2 R2 is halo; and R is halo, wherein if e + f is at least 2 the halo substituent may be the same or different; and wherein the process comprises the steps of subjecting a first polyphenol monomer to conditions sufficient to produce a polyphenol monomer functionalized at C-4 and coupling that the C-4 monomer functionalized with a second polyphenol monomer or an oligomer having up to 17 monomer units that are the same or different. The first and second polyphenol monomers may be the same or different. The process of the present invention can be used to prepare essentially pure polyphenol oligomers, and derivatives thereof. Oligomeric compounds consisting of polyphenol monomer units n, wherein n is an integer from 2 to 18, preferably from 2 to 5, or from 4 to 12, most preferably n is from 3 to 12, and especially preferred n is 5 to 12, and that has links of 4- > 6 and 4- > 8 The polyphenol oligomers prepared by the processes of this invention may be represented by the aforementioned formula, wherein x is 0 to 16 and above. When x is 0, the oligomer is called a "dimer", - when x is 1, the oligomer is called a "trimer"; when x is 2, the oligomer is called a "tetrameter"; when x is 3, the oligomer is called a "pentamer"; and similar names can be designated for oligomers having up to and including 16 and more, such as when x is 16, the oligomer is called an "octadecamer". The linear and branched polyphenol oligomers can be prepared by the process of the present invention using a sequence comprising protection, functionalization, coupling and deprotection reactions. In this reaction sequence, any polyphenol monomer, as exemplified above, can be used to prepare linear or branched oligomers containing monomer units of the same polyphenol monomer or different polyphenol monomers. Higher oligomers can be prepared by repeating the coupling step by coupling a dimer, trimer or higher oligomer with an additional monomer. Generally the process of producing polyphenol oligomers comprises the steps of: (a) protecting each phenolic hydroxyl group of at least the first and second polyphenol monomers using an appropriate phenol protecting group to provide at least one first and second protected polyphenol monomers, wherein the first and second Polyphenol monomers can be the same or different flavanoid compounds; (b) functionalizing the 4-position of the first protected polyphenol monomer to produce a functionalized polyphenol monomer; (c) coupling the functionalized polyphenol monomer with the second protected polyphenol monomer to produce the polyphenol oligomer, wherein the oligomer is a protected polyphenol dimer. The polyphenol dimer produced in this way is composed of the first and second coupled monomers, such as the first and second monomer units. The functionalization and coupling steps can be repeated to form polyphenol oligomers, wherein the oligomers can consist of n monomers, and n is an integer from 3 to 18. Preferably, n is an integer from 5 to 12. Accordingly, the process described above may be continued by: (a) functionalizing the 4-position of a protected third polyphenol monomer to produce a third functionalized polyphenol monomer. (b) coupling the third functionalized polyphenol monomer with the protected polyphenol dimer to produce a protected polyphenol trimer; 1 (c) optionally repeating the steps of functionalization and coupling to form a polyphenol oligomer consisting of n monomers, wherein n is an integer from 4 to 18. The first, second and third polyphenol monomers may possess the same flavanoid structures or different Suitable protecting groups used in the process of this invention include those protecting groups which can be introduced and removed from the polyphenol monomers and oligomers without racemization or degradation of the monomers or oligomers and which are stable for the conditions used for the functionalization reactions. and coupling. Methods for protecting and deprotecting the hydroxyl groups are well known to those skilled in the art and are described in "Protective Groups in Organic Synthesis" of T.W. Greene, John Wiley & Sons. Preferably, the protecting groups used in the process of this invention to protect the phenolic hydroxyl groups from the polyphenol monomers include benzyl, alkyl of 1 to 4 carbon atoms, substituted benzyl, alkyl, silyl, arylsilyl, or substituted arylsilyl which contains alkyl of 1 to 6 carbon atoms, aryl or substituted aryl substituents, wherein the substituted benzyl or substituted aryl protecting group may contain substituents which are selected from the group consisting of halo, nitro, cyano, aryl, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, and cycloalkoxy of 3 to 8 carbon atoms. When the polyphenol monomer contains two phenolic hydroxyl groups that are adjacent, the protecting group may be methylene, diphenylmethylene or substituted diphenylmethylene, wherein each of the substituted phenyl groups of the diphenylmethylene protecting group may contain substituents that are selected from the group consisting of halo, nitro, cyano, aryl, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms and cycloalkoxy of 3 to 8 carbon atoms. As used herein, "aryl" means an aromatic hydrocarbon compound that is selected from the group consisting of phenyl, substituted phenyl, naphthyl or substituted naphthyl, wherein the substituted phenyl or the substituted naphthyl may contain substituents that are selected from the group consists of halo, nitro, cyano, aryl, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, and cycloalkoxy of 3 to 8 carbon atoms. The protecting group can be removed from the phenolic hydroxyl groups of the polyphenol oligomer to produce an unprotected polyphenol oligomer. further, the protected or unprotected polyphenol oligomer can be derivatized to produce derived polyphenol oligomers. Preferably, the process of the present invention comprises: (a) protecting each phenolic hydroxyl group from a first and second polyphenol monomer using an appropriate phenol protecting group to provide a first and a second protected polyphenol monomer, wherein the First and second polyphenol monomers can be the same or different flavanoid compounds; (b) oxidatively functionalizing the 4-position of the first protected polyphenol monomer using an oxidation binder to provide a 4-functionalized protected polyphenol monomer. (c) coupling the second protected polyphenol monomer and the functionalized polyphenol monomer using a catalyst to provide a polyphenol oligomer; Y (d) optionally deprotecting the polyphenol oligomer to provide an unprotected polyphenol oligomer. The oxidative functionalization of the 4-position of a protected polyphenol monomer produces a functionalized protected polyphenol monomer having the formula: where c is an integer from 1 to 3 d is an integer from 1 to 4 _ e is an integer from 0 to 2, f is an integer from 0 to 2 and is an integer from 2 to 6, Rl is H, OH OR OR3; R4 is H or R5; R, R3 and R5 are independently protecting groups; and R2 is halo; When e or f are 1 or 2, the functionalization of the monomer preferably precedes the introduction of the halo substituent.

An important transformation in the process of the present invention is the formation of the oxidatively functionalized protected polyphenol monomer used in the oligomer-forming coupling reaction. It has been determined that the high purity of this monomer is important to obtain oligomeric products of good purity. Advantageously, it has been found that the formation of the polyphenol monomer of 4-alkoxy using ethylene glycol, instead of lower alkyl alcohols, provides a functionalized polyphenol monomer which can be easily purified by chromatography. The use of methanol, ethanol or even isopropyl alcohol provides 4-alkoxy polyphenol monomers which are neither separable nor difficult to chromatographically separate from the non-oxidized phenol and the by-products and can not be used satisfactorily in the forming coupling reaction. of the oligomer. Accordingly, another aspect of the present invention comprises providing an essentially pure functionalized polyphenol monomer of 4- (2-hydroxyethyl) to form the polyphenol oligomers. A preferred quinone type oxidation agent is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Another important transformation in the process of this invention is the coupling of the oxidatively functionalized polyphenol monomer to a polyphenol monomer protected or a protected polyphenol oligomer. The coupling reaction is carried out using a protic acid catalyst or a Lewis acid catalyst. Hydrochloric acid (HCl) is an exemplary protic acid that can be used as a catalyst in the process of this invention. A particularly useful form of hydrochloric acid is an anhydrous solution in dioxane. Exemplary Lewis acid catalysts which are useful in the present invention include titanium tetrahalides (eg, titanium tetrachloride), aluminum trihalides (eg, aluminum trichloride), boron trihalides (eg, boron trifluoride etherate), triallyl or triarylsilyl compounds, (eg, trimethylsilyl triflate) and the like. Exemplary oxidizing agents useful in the process of this invention include quinone type oxidation agents and metal acetate oxidation agents (e.g., lead tetraacetate). Preferably, the process of the present invention comprises: (a) protecting each phenolic hydroxyl group from a first and a second polyphenol monomer using a benzyl ether protecting group to produce a first and a second protected polyphenol monomer, in where he first and second polyphenol monomers may be the same or different and are flavanoid compounds; (b) oxidatively functionalizing the 4-position of the first protected polyphenol monomer using a quinone oxidation agent in the presence of an alcohol, preferably a diol, to provide a protected polyphenol monomer functionalized with 4-alkoxy having the formula: where c is an integer from 1 to 3; d is an integer from 1 to 4; and is an integer from 2 to 6; R is a protecting group; and Rl is H or OH. (c) coupling the second protected polyphenol monomer and the functionalized -polyphenol monomer using a protic acid catalyst or a Lewis acid catalyst to provide a polyphenol oligomer; and (d) deprotecting the polyphenol oligomer to provide an unprotected polyphenol oligomer.

Preferably, the process of the present invention comprises: (a) protecting each phenolic hydraxyl group from the first and second polyphenol monomers using a benzyl ether protecting group to produce a first and a second protected polyphenol monomer; (b) oxidatively functionalizing the 4-position of the second protected polyphenol monomer using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in the presence of ethylene glycol to provide a 4-functionalized protected polyphenol monomer having the formula : where is an integer from 1 to 3; d is an integer from 1 to 4; R1 is H or OH; and Bz represents a benzyl residue (c) coupling the first protected polyphenol monomer and the second protected polyphenol monomer functionalized using titanium tetrachloride to provide a polyphenol oligomer; Y (d) deprotecting the polyphenol oligomer to provide an unprotected polyphenol oligomer. The processes of this invention also provide for the preparation of novel derived oligomers, wherein at least one unprotected hydroxyl group of the polyphenol oligomer is derived using normal esterification or glycosylation techniques to form an ester or a glycosyl ether derivative, respectively. Accordingly, this invention is directed to a process for the production of a derived polyphenol oligomer, which comprises esterifying a protected polyphenol oligomer, wherein each phenolic hydroxyl group of the polyphenol oligomer is protected, to produce an esterified polyphenol oligomer protected, and with a process comprising esterifying an unprotected polyphenol oligomer to produce an esterified polyphenol oligomer. Optionally, protecting groups of the protected esterified polyphenol oligomer can be removed to provide an esterified polyphenol oligomer. This invention is also directed to a process for the production of a derived polyphenol oligomer, which comprises glycosylating the polyphenol oligomer, which is forming a glycosyl ether derivative of the oligomer, wherein each phenolic hydroxyl group of the polyphenol oligomer is protect, for producing a protected glycosylated polyphenol oligomer, and with a process comprising glycosylating an unprotected polyphenol oligomer to produce a glycosylated polyphenol oligomer. Optionally, the protected glycosylated polyphenol oligomer protecting groups can be removed to provide a glycosylated polyphenol oligomer. In addition, the ester derivatives of the glycosyl ethers can be prepared by esterifying at least one hydroxyl group of the glycosyl residue. The ester derivatives of the polyphenol oligomer can be prepared by treating the oligomer having a hydroxyl residue reactive with an activated acid. As used herein, an activated acid is an organic acid having a carboxyl residue that is activated toward the reaction with a hydroxyl moiety. The activated acid can be a compound that can be isolated, such as an acid chloride, an acid anhydride, a mixed acid anhydride and the like or can be formed in itself, for example, by treatment of an acid with dicyclohexyl carbodiimide ( DCC), carbonyl di-imidazole and the like. The polyphenol oligomer glycosides can be prepared by the methods described in K. Toshima; K. Tatsuta, Chem Rev., 93, 1503-1531 (1993), K. Igarashi Adv. Carbobydr. Chem. Biochem. , 34, 243 (1977) and D. Kahne and others, J. Am. Chem. Soc. , 11, 6881 (1989) or by treatment of a monomer using cyclodextrin glucanotransferase (EC 2.4.1.19 CGTase) according to the procedures described by Funayama and others to produce a monomer glycoside (M. Funayama, H. Arakawa, R Yamamoto, T. Nishino, T. Shin and S. Murao, Biosci, Biotech, Biochem., 58 (5), 817-821 (1994) In accordance with the process of this invention, the polyphenol oligomers, consisting of from 2 to 18 monomer units, they can be esterified to provide an esterified polyphenol oligomer, while the 3-hydroxyl group in at least one monomeric unit of the oligomer is converted to an ester, where half of the ester can be -OC (O) aryl, aryl-OC (O) -substituted, -OC (O) -styryl, styryl-OC (0) -substituted; wherein the substituted aryl or the substituted styryl contains at least one substituent selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, thiol, methylenedioxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms and cycloalkoxy of 3 to 8 carbon atoms. Preferably, the ester moiety, the C (O) -substituted aryl and the C (O) -substituted styryl are derived from an acid that is selected of the group consisting of caffeic, cinnamic, coumaric, ferulic, gallic, hydrobenzoic and sinapic acids. In addition, the polyphenol oligomers cising from 2 to 18 monomer units can be glycosylated to provide glycosylated polyphenol oligomers, wherein the 3-hydroxyl group in at least one monomeric unit of the oligomer is converted to a glycosyl ether, wherein the glycosyl residue may be an -O-glycoside or an O-substituted glycoside, wherein the substituted glycoside is substituted by -C (0) -aryl, aryl -C (0) -substituted, -C (0) -styryl or styryl -C (0) -substituted; wherein the substituted aryl or the substituted styryl can contain the substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, thiol, methylenedioxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 atoms of carbon, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms and cycloalkoxy of 3 to 8 carbon atoms. Preferably, the glycoside moiety is derived from a sugar that is selected from the group consisting of glucose, galactose, xylose, rhamnose and arabinose. Another embodiment of this invention provides a process for halogenating the protected polyphenol monomers, the protected polyphenol monomers functionalized and the polyphenol oligomers prepared according to the process of this invention. A halogenated polyphenol monomer having the formula where c is an integer from 1 to 3; d is an integer from 1 to 4 e is an integer from 0 to 2 f is an integer from 0 to 2 1 R and R are independently a protecting group; 1 3 R is H, OH or OR; and 1 R is halo; they can be prepared by the process of treating a polyphenol monomer, wherein e and f are 0, with a halogenating agent for a time and at a temperature sufficient to effect the halogenation of the monomer. The halo group can be chlorine, bromine, fluorine, iodine or a mixture thereof. The bromine group is especially preferred. Exemplary halogenation agents which may be useful in the process of this invention include N-bromosuccinimide, acetyl hypofluorite, cesium fluoroxysulfate, trifluoromethyl hypofluorite, salts of N-fluoropyridinium, bis (tetrafluoroborate) of 1- chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane, sulfuryl chloride / diphenylsulfide (in the presence of a Lewis acid), sodium, calcium or tertiary butyl hypochlorite, trimethyl (phenyl) ammonium tetrachloroiodate ( III), tetraethylammonium trichloride, iodine / periodic acid, iodo / bis (trifluoroacetoxy) iodobenzene, iodine / copper acetate (II), iodine / silver sulfate, dichloroiodate (I) of trimethyl ammonium -benzyl and the like. Other catechin brominating agents are described in the European Patent of Ballenegger et al., (Zytna SA) Number 0096 007, the disclosure of which is incorporated herein by reference. In yet another embodiment of this invention, a halogenated functionalized polyphenol monomer having the formula: where c is an integer from 1 to 3 d is an integer from 1 to 4 e is an integer from 0 to 2 f is an integer from 0 to 2 and is an integer from 2 to 6 1 3 R is H, OH or OR; 4 5 R is H is H or R; 3 5 R, R and R are independently protective groups; and 2 R is halo; they can be prepared by the process of treating a functionalized polyphenol monomer, wherein e and f are 0, with a halogenating agent for a time and at a temperature sufficient to effect the halogenation of the monomer. The halo group (s) of R, where e + f is at least 2, may be the same or different, that is, it is selected from the group consisting of chlorine, fluorine, bromine, iodine. Advantageously, different halogen substituents can be introduced into the polyphenol monomer. For example, a polyphenol monomer can be subjected to a first halogenation to introduce a 2-halogen substituent, so that for (R) e, e is a 1 and R2 is bromine. This halogenated monomer can then be subjected to a second halogenation to introduce a different 2-halogen substituent so that for (R) e, e is 2 and R2 is bromine and fluorine. Similarly, the halogenation can be carried out to introduce different halogen substituents 2 into (R) f. Alternatively, one or both of the alkoxy-hydroxyl groups of the polyphenol monomer functionalized can be protected with protective groups, 3 R or R, before halogenization, to provide a monomer having the following formula: Exemplary alcohol-hydroxyl protecting groups are the same protecting groups (R) described above which are useful for protecting the phenolic hydroxyl moieties. The protective group that can be used to protect the alcohol-hydroxyl moieties (R or R) may be the same as or different from the protecting group used to protect the phenolic hydroxyl moieties (R) preferably the alcohol-hydroxyl moiety in the position 3 of the polyphenol monomer can be protected using an alkyl silyl protecting group, preferably a tertiary butyl-dimethylsilyl protecting group.

Optionally, the alcohol-hydroxyl protecting groups can be removed from the functionalized polyphenol monomer after halogenation or removed after coupling to another monomer or oligomer. More preferably, the alcohol-hydroxyl protecting group is selected such that the removal of the protecting group can be achieved without the removal of the substituent. of halogen. For example, hydrogenolysis, used to remove the benzyl protecting groups, of a benzylated-brominated monomer would both de-benzylate and de-brominate a monomer or an oligomer. The skilled artisan will recognize that the protecting group (s) and the substituent (s) and halogen can be selected such that these groups can be removed or retained during the steps of protection, halogenation, coupling and deprotection. Limiting the amount of the halogenation agent used during the halogenation reaction will provide for the selective formation of mono-, di-, tri- or tetra-halogenated polyphenol monomers. In accordance with the process of this invention, the use of about one equivalent of the halogenating agent provides for the formation of mono-halogenated monomers, while the use of three equivalents of the halogenating agent provides for the preparation of polyphenol monomers protected from triazole. bromine and functionalized protected polyphenol monomers of tri-bromine. The regiochemistry of the halogenation depends on the substitution pattern of the starting polyphenol monomer, specifically, the flavannoid compound initiator of the hydroxyl substitution pattern. For example, the mono-bromination of the protected polyphenol monomers (+) - catechin or (-) - epicatechin, provides the preparation of the 8-bromine derivatives of these flavanoids. The di-bromination of protected (+) - catechin or (-) - epicatechin provides the preparation of 6,8-dibromo products. Tri-bromination of protected (+) - catechin or (-) - epicatechin provides preparation of 6, 8, 6 '-tribromo products. Accordingly, the process of this invention provides that any and all polyphenol monomers or oligomers disclosed herein, may optionally be halogenated to form novel halogenated polyphenol monomers or oligomers. A mono-, di- or tri-halogenated functionalized polyphenol monomer can be coupled with a protected polyphenol monomer or with a protected polyphenol oligomer to produce a novel halogenated polyphenol oligomer using any of the methods described above. The coupling of the halogenated functionalized protected polyphenol monomer with a halogenated protected polyphenol monomer or with a halogenated protected polyphenol oligomer produces other halogenated polyphenol oligomers. The coupling of the halogenated functionalized monomer with a protected, 8-halogenated polyphenol monomer or oligomer produces coupled or branched oligomers (4a-> 6) or (4β-> 6). The formation of these branched compounds can be achieved only when the protecting groups in the phenolic hydroxyl groups of the halogenated protected monomer or the halogenated protected oligomer do not prevent the reaction due to spherical hindrance. For example, when sterically large protecting groups such as benzyl are present in the halogenated protected polyphenol monomer, coupling will not occur. While the coupling of unprotected polyphenols will provide branched compounds. Preferably, the halogenated polyphenol compounds produced herein are brominated polyphenol compounds. Alternatively, the halogenated polyphenol oligomers can also be prepared by the direct halogenation of a selected polyphenol oligomer. A further embodiment of this invention are the halogenated polyphenol monomers derived or non-derived having the formula: where c is an integer from 1 to 3 d is an integer from 1 to 4 e is an integer from 0 to 2 f is an integer from 0 to 2; Y where c is an integer from 1 to 3. d is an integer from 1 to 4 e is an integer from 0 to 2, f is an integer from 0 to 2, and is an integer from 2 to 6, and for each of the aforementioned, R is alkyl of 1 to 4 carbon atoms, benzyl, substituted benzyl, alkyl of 1 to 4 carbon atoms and one silyl moiety containing alkyl of 1 to 6 carbon atoms or aryl substituents, or when cod is 2 and are adjacent, methylene, diphenylmethylene or substituted diphenylmethylene, wherein the substituted benzyl or each substituted phenyl may contain substituents which are selected from the group consisting of halo, nitro, cyano, aryl, alkyl of 1 to 6 carbon atoms, carbon, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkoxy of 3 to 8 carbon atoms; R is hydrogen, hydroxy, an -O-glycoside, an -O-substituted glycoside, -OC (O) -aryl, aryl-OC (O) -substituted, -OC (O) -styryl, styryl-OC (O) -substituted; wherein the substituted glycoside is substituted by -CÍO) -aryl, aryl-C (O) -substituted, -C (O) -styryl, styryl-C (O) -substituted; and 2 R is halo; wherein the substituted aryl or the substituted styryl can contain the substituents that are selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, thiol, methylenedioxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 atoms of carbon, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms and cycloalkoxy of 3 to 8 carbon atoms. Accordingly, yet another embodiment of the invention is directed to a process for the production of a polyphenol oligomer by coupling the polyphenol monomers, wherein each phenolic hydroxyl group of the polyphenol monomer is protected, comprising the steps of: (a) functionalizing the 4-position of the first protected polyphenol monomer to produce a functionalized polyphenol monomer; (b) replacing position 6 or position 8 of a protected polyphenol, wherein the polyphenol is a protected monomer or a protected oligomer to produce a blocked polyphenol; and (c) coupling the polyphenol monomer functionalized with the blocked polyphenol to form the polyphenol oligomer. Advantageously, the position 8 of the blocked polyphenol is replaced in such a way that the position 4 of the functionalized polyphenol monomer is coupled to the 6 position of the blocked polyphenol. The compounds prepared by the processes of this invention can be purified e.g. compounds or combinations thereof may be essentially pure; for example, purify itself to apparent homogeneity. Purity is a relative concept and the numerous examples demonstrate the isolation of the compounds or combinations thereof as well as the purification thereof in such a way that by means of exemplified methods of a skilled artisan an essentially pure compound or a combination thereof can be obtained. the same or purify them to the apparent homogeneity (eg purity by HPLC: observation of a single chromatographic crest). As defined herein, an essentially pure compound or a combination of compounds is at least about 40 percent pure e.g. at least about 50 percent pure, advantageously at least about 60 percent pure e.g. at least about 70 percent pure, more advantageously at least about 75 to 80 percent pure, preferably at least about 90 percent pure; more preferably more than 90 percent pure, e.g. at least 90 percent to 95 percent pure or even purer, such as more than 95 percent pure, e.g. from 95 percent to 98 percent pure. further, the stereoisomers of the oligomers are encompassed within the scope of the invention. The stereochemistry of the substituents in a monomeric polyphenol unit of the oligomer can be described in terms of their relative stereochemistry, "alpha-beta" or "cis / trans", or in terms of absolute stereochemistry, "R / S". The term "alpha" () indicates that the substituent is oriented below the plane of the flavan ring, while "beta" (ß) indicates that the substituent is oriented above the plane of the ring. The term "cis" indicates that two substituents are oriented on the same face of the ring, while "trans" indicates that two substituents are oriented on opposite faces of the ring. The terms R and S are used to represent the disposition of the substituents around a stereogenic center, based on the rank of the groups according to the atomic number of the atoms directly attached to the stereogenic center. For example, the flavanoid compound (+) - catechin, can be defined as (2R, trans) -2- (3 ', 4'-dihydroxyphenyl) -3,4-dihydro-2H-l-benzopyran-3, 5,7 -triol, or as (2R, 3S) -flavan-3, 3 ', 4', 5, 7-pentaol. Interflavan binding (monomeric polyphenol unit-polyphenol monomer unit) is often characterized using the terms relative to / ß or cis / trans; a / ß is used herein to designate the relative stereochemistry of the interflavan binding. The linear and branched polyphenol oligomers can be prepared by the process of this invention. Any polyphenol monomer can be used to prepare linear or branched oligomers containing monomeric units having the same or different flavanoid structures. The possible links between the monomer units comprising the oligomers are distinguished by the links Superior (T), Intermediate (M), Board (J), Bottom (B). Representative examples for a linear pan-screen and a branched pan-screen are shown below.

M M B M M M M B B Pentamer linear branched pentamer There are multiple stereochemical links or binding orientation between the 4 position of a monomer unit and the 6 and 8 position of the adjacent monomer unit; the stereochemical bonds between the monomeric units are designated herein as Í4a-6) or (4ß-> 6) or (4a-8) or (4ß- »8) for the linear oligomers. In addition to the stereochemical differences in the binding of interflavan to the carbon 4 position, a bond to the carbon 2-position can have alpha or beta stereochemistry and a bond to the carbon 3-position can have alpha or beta stereochemistry (eg (- ) -epicatechin or (+) -catechin). For links to a branched or joint monomer unit, the stereochemical bonds are (6-4a) or (6-4ß) or (8-> 4a) or (8- »4ß). When a monomeric polyphenol unit (e.g., C or EC) is linked to another monomer unit of polyphenol (e.g. EC or C), the bonds are advantageously (4a-> 6) or (4a-8). In addition, the regioisomers of the polyphenol oligomers are encompassed within the scope of this invention. A person skilled in the art will appreciate that the rotation of a number of bonds within the oligomer can be restricted due to spherical hindrance, particularly if the oligomer is replaced such as with benzyl groups. Accordingly, all possible regioisomers and stereoisomers of the compounds of the invention are encompassed within the scope of the invention. In still another embodiment, the invention is directed to a process for the production of a desired stereoisomer or region of a polyphenol oligomer of the formula: (RO) c where x is an integer from 0 to 16; c is independently an integer from 1 to 3; d is independently an integer of 1 a; R is independently alkyl of 1 to 4 carbon atoms, benzyl, substituted benzyl, and a silyl moiety containing alkyl or aryl substituents of 1 to 6 carbon atoms, or, when cod is 2 and remain adjacent, diphenylmethylene or diphenylmethylene substituted, wherein the substituted benzyl or each substituted phenyl may contain substituents which are selected from the group consisting of halo, nitro, cyano, aryl, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkoxy of 3 to 8 carbon atoms; and 1 R is an -O-glycoside, a glycoside -O-substituted, -OC (O) aryl, aryl-OC (O) -substituted, -OC (O) -styryril, styryl -OC (O) -substituted; wherein the substituted glycoside is substituted by -C (O) -aryl, -C (O) -substituted aryl, -C (0) styryl; -C (0) substituted styryl; wherein the substituted aryl or the substituted styryl can contain the substituents that are selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, thiol, methylenedioxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms and cycloalkoxy of 3 to 8 carbon atoms; and wherein each phenolic hydroxyl group of a polyphenol monomer is protected, comprising the steps of: (a) functionalizing the 4-position of the first polyphenol monomer having a selected stereochemistry; (b) coupling the functionalized polyphenol monomer with a second polyphenol monomer having a selected stereochemistry to form a dimer having a selected regiochemistry; (c) purifying the dimer; (d) if x equals 1, functionalize the position 4 of a third polyphenol monomer having a selected stereochemistry; (e) coupling the third functionalized polyphenol monomer having a selected stereochemistry with the dimer to form a trimer having selected regiochemistry; (f) purifying the trimer; and (g) if x is greater than 1, sequentially add the functionalized polyphenol monomer to the trimer and to the successively higher oligomers by the steps mentioned above. The invention is also directed to a process for producing a polyphenol oligomer of the formula: wherein a bond to position 2 of the carbon has alpha or beta stearochemistry; a link to position 3 of the carbon has alpha or beta stereos; a link to position 4 of the carbon has alpha or beta stearochemistry; wherein: c is independently an integer from 1 to 3; d is independently an integer of 1 a; x is 0 to 16; R is independently hydrogen, alkyl of 1 to 4 carbon atoms, benzyl, substituted benzyl and a silyl residue containing alkyl or aryl substituents of 1 to 6 carbon atoms or, when co ~ d is 2 and remain adjacent, diphenylmethylene or substituted diphenylmethylene, wherein the substituted benzyl or each substituted phenyl may contain substituents which are selected from the group consisting of halo, nitro, cyano, aryl, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, C 1-6 alkoxy, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkoxy of 3 to 8 carbon atoms; and 1 R is hydroxy or an -O-glycoside, an -O-substituted glycoside, -OC (O) aryl, aryl-OC (O) -substituted, -OC (O) -styryril or styryl-OC (0) - replaced; wherein the substituted glycoside is substituted by -C (O) -aryl, aryl-C (O) -substituted, -C (O) styryl or styryl-C (O) -substituted; wherein the substituted aryl or the substituted styryl can contain the substituents that are selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, thiol, methylenedioxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 atoms carbon haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms and cycloalkoxy of 3 to 8 carbon atoms; comprising: (a) reacting a compound of the formula: where m is an integer from 1 to 3; n is an integer from 1 to 4; and R is alkyl of 1 to 4 carbon atoms, benzyl, substituted benzyl and a silyl moiety containing alkyl or aryl substituents of 1 to 6 carbon atoms or when cod is 2 and adjacent, diphenylmethylene or substituted diphenylmethylene, in wherein the substituted benzyl or each substituted phenyl may contain substituents which are selected from the group consisting of halo, nitro, cyano, aryl, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkoxy of 3 to 8 carbon atoms; Ri is H or OH; with a compound of the formula: where m is an integer from 1 to 3; n is an integer from 1 to 4; and is an integer from 2 to 6; and R is independently alkyl of 1 to 4 carbon atoms, benzyl, substituted benzyl and a silyl moiety containing alkyl or aryl substituents of 1 to 6 carbon atoms, or, when cod is 2 and adjacent, diphenylmethylene or substituted diphenylmethylene, wherein the substituted benzyl or each substituted phenyl may be substituted. contain substituents which are selected from the group consisting of halo, nitro, cyano, aryl, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkoxy of 3 to 8 carbon atoms; and R1 is H or OH; to form a protected polyphenol oligomer having protected phenolic hydroxyl groups; and (b) deprotecting the phenolic hydroxyl groups of the protected polyphenol oligomer. In a further embodiment, the invention is directed to a process for the production of a procyanidin polyphenol oligomer, comprising: (a) protecting each phenolic hydroxyl group from a (+) - catechin or from a (-) -epicatechin with a protective group to produce a protected (+) - (-) -protected epicatechin; (b) functionalizing the 4-position of the protected (+) -catecholine or the protected (-) -epicatechin to produce a functionalized (+) - protected -catenquina or a functionalized protected (-) -epicatequina having the formula: where y is an integer from 2 to 6; R is a protecting group; and R1 is hydrogen; Y (c) coupling the protected (+) -canthine or the protected (-) -epicatechin with the functionalized protected (+) -canthine or the protected functionalized (-) -epicatechin to produce the polyphenol oligomer. In another embodiment, the invention is directed to a process for preparing a procyanidin polyphenol oligomer consisting of n monomeric units of (+) -catechin or (-) -epicatechin where n is an integer of 2 to 18, which comprises: (a) protecting each phenolic hydroxyl group from a (+) - catechin or a (-) - epicatechin with an appropriate protecting group to produce a protected (+) - cataquine or a (-) - Protected epicatechin; (b) functionalize position 4 of the protected (+) -canthine or the protected (-) -epicatechin to produce a functionalized (+) - protected -catenquina or a (-) -protected functionalized epicatechin that has the formula: where y is an integer from 2 to 6; R is a protecting group; and R1 is hydrogen; and (c) coupling the protected (+) -canthine or protected (-) -epicatechin with the protected functionalized (+) -cancechin or the protected functionalized (-) -epicatechin to produce a protected polyphenol oligomer, wherein n is equal to 2; (d) removing the protecting group of each phenolic hydroxyl group from the protected polyphenol oligomer to produce the polyphenol oligomer, wherein n is equal to 2, (e) coupling the protected polyphenol oligomer where n is equal to 2, and the protected (+) - functionalized guar or protected (-) - epicatechin functionalized to produce a protected polyphenol oligomer where n equals 3, (f) removing the protecting group of each phenolic hydroxyl group from the polyphenol oligomer protected to produce the polyphenol oligomer, where n is equal to 3. (g) optionally repeating the process of coupling a protected polyphenol oligomer, where n is equal to 3 or more, with the functionalized (+) - protected -catecholine wave (-) -protected epicatechin functionalized to produce the protected polyphenol oligomers, wherein n equals 4 to 18, (h) removing the protecting group from each phenolic hydroxyl group of protected polyphenol oligomer to produce the polyphenol oligomer, wherein n equals 4 to 18. Advantageously, each phenolic hydroxyl group is protected using a benzyl ether protecting group, and is 2. In a further embodiment, the invention is directed to a process for producing a procyanidin polyphenol oligomer of the formula: where a link to position 2 of coal has alpha or beta stereochemistry; a bond to position 3 of carbon has alpha or beta stereochemistry; a bond to position 4 of carbon has stereochemistry of alpha or beta; m is from 0 to 16; R is hydrogen; and R1 is hydrogen; which comprises: ía) reacting a compound that is selected from the group consisting of "_.

Y or a mixture thereof, with a compound selected from the group consisting of or a mixture thereof, where y is an integer from 2 to 6; to form a protected polyphenol oligomer having benzylated phenolic hydroxyl groups; and (b) deprotecting the benzylated phenolic hydroxyl groups of the protected polyphenol oligomer. Still in a further embodiment, the invention is directed to a process for producing a polyphenol oligomer of the formula: wherein a bond to position 2 of carbon has alpha or beta stereochemistry; a bond to position 3 of carbon has alpha or beta stereochemistry; a bond to position 4 of carbon has alpha or beta stereochemistry; m is from 1 to 16; R is hydrogen; and R is hydrogen; comprising: (a) reacting a compound of the formula: wherein a bond to position 2 of carbon has alpha or beta stereochemistry; a bond to position 3 of carbon has alpha or beta stereochemistry; a bond to position 4 of carbon has alpha or beta stereochemistry; p is from 0 to 15; R is independently alkyl of 1 to 4 carbon atoms, benzyl, substituted benzyl, and a silyl moiety containing alkyl or aryl substituents containing from 1 to 6 carbon atoms, or, when cod is 2 and remain adjacent, _ Diphenylmethylene or substituted diphenylmethylene wherein the substituted benzyl or each substituted phenyl may contain substituents which are selected from the group consisting of halo, nitro, cyano, aryl, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms , cycloalkyl of 3 to 8 carbon atoms, cycloalkoxy of 3 to 8 carbon atoms; and R _ is hydrogen, a glycoside, substituted glycoside, -CÍO) aryl, aryl -C (O) -substituted, -C (0) -styryl, styryl -C (0) -substituted; wherein the substituted glycoside is substituted by -C (0) aryl, aryl -C (0) -substituted, -C (O) styryl, C (0) -substituted styryl; wherein the substituted aryl or the substituted styryl can contain the substituents which are selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, thiol, methylenedioxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, and cycloalkoxy of 3 to 8 carbon atoms; with a compound that is selected from the group consisting of is selected from the group consisting of Y or a mixture thereof, wherein m = p + 1. The flavanoid compounds, (+) - catechin and (-) -epicatechin are used herein to exemplify the types of polyphenol oligomers that can be prepared by the process of this invention. The links between the adjacent (+) -catechin and (-) -epicatechin monomeric polyphenol units that are abbreviated C and EC, "respectively, they are from position 4 to position 6 or position 4 to position 8, and this link between position 4 of a monomer and position 6 and 8 of the adjacent monomer units are designated here as (4? 6) or (4-? 8). Examples of the compounds within the scope of this invention include dimers, EC- (4β-> 8) -EC and EC- (4β? -6) -EC, wherein EC- (4β-> 8), -EC is prefers; trimers [EC- (4ß-8)] 2-EC, [EC- (4ß- 8)] 2-C and [EC- (4ß-> 6)] 2-C and [EC- (4ß? 6) ] 2-EC, where [EC- (4β? 8)] 2-EC is preferred; the tetramers [EC- (4β? 8)] .3-EC, [EC- (4β-8)] 3 -C and [EC- (4β? 8)] 2-EC (4β-> 6) -C , where you prefer - - [EC- (4ß-8)] 3-EC and the pentamers [EC- (4ß- »8)] 4-EC, [EC- (4ß? 8)] 3-EC- (4ß- 6) -EC, [EC- (4β-> 8)] 3-EC (4β-8) -C and [EC- (4β? 8)] 3-EC- (4β- 8) -EC, where [EC- (4β - > 8)] 4-EC is preferred. An example of a branched trimer is EC- (4ß-> 8) -EC L (6? 4ß) -EC examples of a branched tetramer include [EC- (4β-8)] 2-EC; and L (6- »4ß) -EC [EC- (4β? 8)] -EC- (6-4β) -EC; L (4ß? 8) -EC an example of a pentamer is [EC- (4ß? 8)] 3-EC L (6- »4ß) -EC In addition, the compounds that approve the aforementioned activities also include hexamers to dodecamers, examples of which are mentioned below: A hexamer, wherein a monomer (C or EC) is bonded to a pentamer compound mentioned above, eg, [EC- (4β-> 8)] 5-EC, [EC- (4β- 8) ] 4-EC- (4β- 6)] -EC, [EC- (4β? 8)] 4-EC- (4β- 8) -C and [EC- (4β? 8)] 4-EC- (4β ?6C; wherein [EC- (4β-> 8)] 5-EC is preferred; an example of a branched hexamer is L (6? 4ß) -EC A heptamer, wherein any combination of two monomer units (C and / or EC) are linked to a pentamer compound listed above, e.g., [EC- (4ß? 8)] 6-EC, [EC- (4ß- 8)] 5-EC- (4ß- »6)] -EC, [EC- (4β? 8)] 5-EC- (4β-> 8) -C and [EC- (4β- 8)] 5-EC- (4β? 6) -C; in a preferred embodiment, the heptamer is [EC- (4β- 8)] g-EC; an example of a branched heptamer is [EC- (4ß? 8)] 5-EC, L (6- »4ß) -EC An octamer, wherein any combination of three monomer units (C and / or EC) are linked to a pentamer compound listed above, e.g., [EC- (4ß-> 8)] 7-EC, [EC- (4β? 8)] g-EC- (4β? 6)] -EC, [EC- (4β? 8)] g-EC- (4β? 8) -C and [EC- (4β? 8)] g-EC- (4β? 6) -C; in a preferred embodiment, the octamer is [EC- (4β-> 8)] 7-EC; an example of a branched octamer is [EC- (4ß-8)] 6-EC, L (6? -4ß) -EC A nonamer, wherein any combination of four monomer units (C and / or EC) are linked to a pentamer compound listed above, eg, [EC- (4β-> 8)] g-EC, [EC - (4ß- 8)] 7-EC- (4ß- 6)] -EC, [EC- (4ß? 8)] 7-EC- (4ß- »8) -C and [EC- (4ß? 8) ] 7-EC- (4β- »6) -C; in a preferred embodiment, the nonamer is [EC- (4β-8)] g-EC; an example of a branched nonamer is [EC- (4β? 8)] 7-EC, L (6- > 4β) -EC A decamer, wherein any combination of five monomer units (C and / or EC) are linked to a pentamer compound listed above, eg, [EC- (4β? 8)] 9-EC, [EC- ( 4ß? 8)] 8-EC- (4ß- 6)] -EC, [EC- (4ß-8)] 8 -EC- (4ß- »8) -C and [EC- (4ß-8)] g -EC- (4β-6) -C; in a preferred embodiment, the decamer is [EC- (4β-> 8)] 9-EC; an example of a branched decamer is [EC- (4ß- »8)] -EC, L (6-» 4ß) -EC An undecamer wherein any combination of six monomer units (C and / or EC) are linked to a pentamer compound listed above, e.g., [EC- (4ß? 8)] 10-EC, [EC- (4ß-> 8)] g-EC- (4ß- »6)] -EC, [EC- (4ß-» 8)] 9- EC- (4β? 8) -C and [EC- (4β- »8)] g-EC- (4β? 6) -C; in a preferred embodiment, the undecamer is [EC- (4ß- »8)] 10" EC, an example of a branched undecamer is [EC- (4β? 8)] g-EC, L (6- * 4β) - EC A dodecamer, wherein any combination of seven monomer units (C and / or EC) are linked to a pentamer compound listed above, eg, [EC- (4β? 8)] ii-EC, [EC- ( 4β- 8)] 10-EC- (4β-6)] -EC, [EC- (4β? 8)] io-EC- (4β? 8) -C and [EC- (4β-> 8)] 10-EC- (4β? -6) -C; in a preferred embodiment, the dodecamer is [EC- (4β-8)] n-EC; an example of a branched dodecamer is [EC- (4ß? -8)] lo-EC, L (6- »4ß) -EC It will be understood from the detailed description that the aforementioned list is exemplary and is provided to illustrate the types of compounds that can be prepared by the processes of this invention and is not intended as an exhaustive list of the compounds encompassed by this invention. The skilled artisan will recognize that the reaction sequence discussed above can be modified in the final steps to yield oligomers having x = 2-16, without undue experimentation. Higher oligomers, i.e., x = 2-16, can be isolated using the dimer and / or the trimer as the starting material for the coupling reaction, and products derived therefrom can subsequently be used as a starting material for coupling reactions in order to produce even higher oligomers. In addition, the skilled artisan will recognize that various reagents may be employed to carry out the processes of this invention without undue experimentation, and without deviating from the spirit or scope thereof. Skilled artisans will be able to visualize additional synthesis pathways, based on this exposure and knowledge of the technique; without undue experimentation, e.g., based on careful retrospective analysis of the polymeric compounds, as well as the monomers. For example, the coupling of polyphenol monomers through an organometallic intermediate has been disclosed by K. einges et al., Chem. Ber. 103, 2344-2349 (1970).

In addition, the linear and branched polyphenol oligomers can be prepared by direct acid catalyzed coupling of the monomeric polyphenol units using the conditions described by L. Y. Foo and R.

Hemingway, J. Chem. Soc. , Chem. Commun. , 85-86 (1984), - J. J. Botha, et al., J. Chem. Soc. , Perkin I. 1235-1245 (1981); J. J. Botha et al .; J7 Chem. Soc. , Perkin I. 527-533 (1982), and H. Kolodziej, Phytoche is try 25, 1209-1215 (1986). Accordingly, still another embodiment of this invention is directed to a process for the production of a desired stereoisomer or region of a polymeric compound of the formula An, wherein A is a monomer of the formula: wherein n is an integer from 3 to 18, such that there is at least one terminal monomeric unit A, and a plurality of additional monomer units; R is 3- (a) -0H, 3- (ß) -0H, 3- (a) -O-sugar, or 3- (ß) -O-sugar; the bonding of the adjacent monomers is carried out between position 4 and positions 6 or 8; a link for the additional monomer unit in position 4 has alpha or beta stereochemistry; X, Y and Z are selected from the group consisting of the monomeric unit A, hydrogen, and a sugar, with the stipulations that at least as regards a terminal monomeric unit, the bonding of the additional monomer unit to it is in a position 4 and optionally Y = Z = hydrogen; the sugar is optionally substituted with a phenolic moiety, and the pharmaceutically acceptable salts, the derivatives thereof, and the oxidation products thereof; whose process comprises the steps of: (a) functionalizing the position 4 of a first polyphenol monomer; (b) reacting the functionalized polyphenol monomer with a second polyphenol monomer to form a dimer; (c) purifying the dimer; (d) functionalizing position 4 of a third polyphenol monomer; (e) reacting the third functionalized polyphenol monomer with a dimer to form a trimer; (f) purifying the trimer; (g) sequentially adding the functionalized polyphenol monomer to the trimer and the successively higher oligomers by the above-mentioned steps; and (h) optionally deriving the protected or unprotected polyphenyl oligomer to produce a derivatized polyphenol oligomer. Preferably, n is 5, the sugar is selected from the group consisting of glucose, galactose, xylose, rhamnose and arabinose, and the phenolic moiety is selected from the group consisting of caffeic, cinnamic, coumaric, ferulic, gallic, hydroxybenzoic and sinapic The invention is also directed to a process for the production of a polymeric compound of the formula An, wherein A is a monomer of the formula: wherein n is an integer from 3 to 18, such that at least there is a terminal monomeric unit A, and a plurality of additional monomer units; R is 3- (a) -0H, 3- (ß) -0H, 3 - (a) -O-sugar, or 3- (β) -O-sugar; the bonding of the adjacent monomers is carried out between position 4 and positions 6 or 8; a link for the additional monomer unit in position 4 has alpha or beta stereochemistry; X, Y and Z are selected from the group consisting of the monomeric unit A, hydrogen, and a sugar, with the stipulations that as regards the last terminal monomeric unit, the binding of the additional monomer unit to it is in the position 4 and optionally Y = Z = hydrogen. the sugar is optionally substituted with a phenolic moiety, and pharmaceutically acceptable salts, derivatives thereof, and oxidation products thereof; which process comprises: (a) protecting each phenolic hydroxyl group from a (+) - catechin or from a (-) - epicatechin with a protecting group to produce a protected (+) - catechin or a protected (-) -epicatechin; (b) functionalizing the 4-position of the protected (+) - protected or the protected (-) - epicatechin or of a mixture thereof to produce a functionalized (+) - protected bisquinake, a functionalized protected (-) -epicatechin or a protected functionalized mixture thereof; (c) combining the (+) - catechin or the protected (-) -epicatechin with the functionalized (+) - protected -catenquina or the functionalized protected (-) -epicatequina or mixtures thereof to produce a protected polyphenol oligomer; (d) removing the protecting group of the phenolic hydroxyl groups from the polyphenol oligomer to produce an unprotected polyphenol oligomer; and (e) optionally deriving the protected or unprotected polyphenol oligomer to produce a derivatized polyphenol oligomer. In still another embodiment, the invention is directed to a polymeric compound of the formula An wherein - is a monomer of the formula: - wherein n is an integer from 3 to 18, such that at least there is a terminal monomeric unit A, and a plurality of additional monomer units; R is 3- (a) -0H, 3- (ß) -0H, 3 - (a) -O-sugar, or 3- (β) -O-sugar; the bonding of the adjacent monomers is carried out between position 4 and positions 6 or 8; a link for the additional monomer unit in position 4 has alpha or beta stereochemistry; X, Y and Z are selected from the group consisting of the monomeric unit A, hydrogen, and a sugar, with the stipulations that as regards the last terminal monomeric unit, the bonding of the additional monomer unit to it is in the position 4 and optionally Y = Z = hydrogen. the sugar is optionally substituted with a phenolic moiety, and pharmaceutically acceptable salts, derived therefrom, and oxidation products thereof. Preferably, n is 5, the sugar is selected from the group consisting of glucose, galactose, xylose, rhamnose and arabinose, and the phenolic moiety is selected from the group consisting of caffeic, cinnamic, coumaric, ferulic, gallic, hydroxybenzoic and sinapic From Preferably the compound is essentially pure, preferably purified to apparent homogeneity. Derivatives of the compound wherein one or more of the phenolic hydroxyl groups are benzylated are also encompassed within the scope of the invention. Adjacent monomers can be linked in the 4-position by (4-6) or (4-8); and each of X, Y and Z is H, a sugar or an adjacent monomer, with the stipulations that if X and Y are adjacent monomers, Z is H or sugar, and if X and Z are adjacent monomers, Y is H or sugar, and that as to at least one of the two terminal monomers, the bonding of the adjacent monomer is in a 4 position and optionally, Y = Z = hydrogen. One or more of the monomer units can be derived with a gallate or β-D-glucose, including the 3-position of a terminal monomer unit. These processes can be used to prepare linear or branched oligomers containing repeating monomer units of a single polyphenol monomer or different polyphenol monomers. In addition, given the phenolic character of the present compounds, the skilled artisan can use various methods of phenolic coupling, selective protection / deprotection, organometallic additions and photochemical reactions, e.g., in a convergent, linear or biomimetic approach, or combinations thereof, together with normal reactions known to those skilled in the art of synthetic organic chemistry, as additional synthetic methods for preparing the polyphenol oligomers. In this respect reference is made to. Carruthers, Some Modern Methods of Organic Synthesis, Third Edition, Cambridge University Press, 1986, and J. March, Advanced Organic Chemistry, Third Edition, John Wiley & Sons, 1985, van Rensburg et al., J. Chem. Soc. Chem. Commun. 24: 2705-2706 (December 21, 1996), the European Patent of Ballenegger et al., (Zyma SA) Number 0096 007 Bl, all of which are incorporated herein by reference. The process of this invention also provides a means for incorporating an isotope tag, e.g., deuterium and tritium, into the polyphenol oligomers. For example, a polyphenol monomer or oligomer can be dissolved in D2O and CD3CN, and gently heated in order to initiate H-D exchange (this reaction can also be carried out using T2O and CH3CN in order to incorporate a tritium in the molecule). Alternatively, deuterium or tritium can be incorporated using the methods of M. C. Pierre et al., Tetrahedron Letters 38, (32), 5639-5642 (1997) or E. Keihlmann et al., Can. J. Chem., 26, 2431-2439 (1988). The incorporation of a deuterium or tritium atom in the polyphenol oligomer facilitates the determination of the manner in which polyphenol compounds can be metabolized after ingestion. - The polyphenol oligomers, and derivatives thereof, prepared by the process of this invention have the same uses, and are formulated, purified and administered in the same manner as described in the North American Patent Application Number 08 / 831,245 filed. on April 2, 1997. This invention is also directed to a pharmaceutical composition comprising a compound of the formula: and a pharmaceutically acceptable carrier or excipient and with a method for treating a subject and need for treatment with an anti-cancer agent comprising administering to the subject an effective amount of the composition. Cancer includes breast cancer. In still another embodiment, the invention is directed to a pharmaceutical composition comprising a compound of the formula: and a pharmaceutically acceptable carrier or excipient, and a method for treating a subject and need for treatment with an anti-cancer agent comprising administering to the subject an effective amount of the composition. Cancer includes breast cancer. Examples 8 and 10 describe the preparation of a trimer dimer and trisgalate bisgalate, respectively. Their ip-vitro titration (Example 25 against several human breast cancer cell lines showed activity equivalent to the pentamer.) These results were surprising since the previously inactive procyanidin dimer score and the trimer significantly increased the antineoplastic activity of these oligomers. this way, the oligomers' classification produces compounds that are useful for the uses described in the North American Application Serial Number 08 / 831,245, filed on April 2, 1997. In addition, the following table lists the exemplary examples of the oligomers subjected to useful for the uses described in the North American Patent Application Number 08 / 831,245, filed on April 2, 1997.

Table: Gallated Procyanidin Oligomers EC-3-O-galoyl- (4β8) -EC-3-O-gallate C-3-O-galoyl- (4 -8) -EC-3-O-gallate C- 3-O-galoyl- (4a- »8) -C EC- (4β-> 8) -EC-3-O-gallate C- (4a-8) -EC-3-O-gallate EC-3-O-galoyl- (4β-8) -C EC (4β 8) -EC-3-0-β-D-glucose-4,6-bisgalate [EC-3-O-galoyl- (4β -8)] 2-EC-3-0-gallate [EC-3-O-galoyl- (4β? 8)] 3 -EC-3 -O-gallate [EC-4β? -8)] 4-EC- 3-0-gallate [EC-4β-8)] 5-EC-3-0-gallate [EC-4β-8]] g-EC-3-O-gallate [EC-4β? 8]] 7-EC -3-0-gallate [EC-4β? 8]] 8-EC-3-0-gallate [EC-4β? 8]] g-EC-3-O-gallate [EC-4β? 8]] 10- EC-3-O-gallate [EC-4β-8]] 11-EC-3-0-gallate The examples given below are intended as an illustration of certain preferred embodiments of the invention, and no limitation is implied of the invention. The skilled artisan will recognize many variations in these examples to cover a wide range of formulas and processes in order to rationally adjust the compounds of the invention for a variety of applications without deviating from the spirit or scope of the invention. In the following examples, the (+) - catechin and (-) -epicatechin are exemplary polyphenol monomers used to demonstrate the processes of the present invention and no limitation of the invention is implied. The (-) -epicatechin as used herein, can be obtained from commercial sources, or the protected epicatechin can be prepared from protected (+) -catecholine (Example 3).

EXAMPLE 1 Preparation of (2R, 3S, trans) - 5,7,3 ', 4'-Tetra-O-benzylcatecholine A solution of (+) - catechin (65.8 grams, 226.7 millimoles, anhydrous), dissolved in anhydrous dimethylformamide (DMF, 720 milliliters), was added dropwise, at room temperature over a period of 80 minutes, to a stirred suspension of sodium hydride, 60 percent in oil, (39 grams, 975 millimoles, 4.3 equivalents) in DMF (180 milliliters). (S. Miura, and others, Radioisotopes, 32, 225-230 (1983)). After stirring for 50 minutes, the flask was placed in an ice bath / -10 ° C NaCl. The benzyl bromide (121 milliliters, 1.02 moles, 4.5 equivalents) was added dropwise within 80 minutes and the brown reaction mixture was warmed to room temperature, with stirring overnight. The resulting reaction mixture was evaporated and the resulting sweet-like solid dissolved, with heating and stirring in two portions of the solvent each consisting of 200 - milliliters of chloroform (CHCl3) and 100 milliliters of water.

The phases were separated, the aqueous phase was extracted with CHCl3 (20 milliliters), and the combined organic phases were washed with water (100 milliliters), dried through magnesium sulfate (MgSO4) and evaporated. The residue was purified by chromatography on silica gel (42 x 10 centimeters; ethyl acetate / chloroform / hexane 1: 12: 7) to provide, after evaporation and vacuum drying, 85 grams of the crude product which was recrystallized from trichlorethylene (1.3 liters) to provide 35.1 grams (24 percent) of a whitish powder. Resonance 1 Nuclear Magnetic H (CDCI3) d 7.47-7.25 (m, 20 H), 7.03 (s, 1 H), 6.95 (s, 2 H), 6.27, 6.21 (ABc, 2H, J = 2? z), 5.18 (s, 2 H), 5.17 (narrow ABc, 2H), 5.03 (s, 2 H), 4.99 (s, 2 H), 4.63 (d, 1 H, J = 8.5 Hz), 4.00 (m, 1 H) ), 3.11, 2.65 (ABc, 2 H, J = 16.5 Hz, both parts d with J = 5.5 and 9 Hz, respectively), 1.59 (d, 1 H, J = 3.5 Hz); IR (film) 344.0 (br), 1618, 1593, 1513, 1499, 1144, 1116, 733, 696 c "1; MS m / z 650 (M +, 0.5 percent), 319, 181, 91. Alternatively , the (+) - tetra-0-benzyl catechin can be prepared using the method described by H. Kawamoto et al., Mokazai Gakkaishi, 37, (5) 488-493 (1991), using potassium carbonate and benzyl bromide in DMF. The partial racemization of catechin, both in the - 2- positions as 3-, was observed by M.-C. Pierre et al., Tetrahedron Letters, 38, (32) 5639-5642 (1997).

EXAMPLE 2 Preparation of (2R) -5, 7, 3 ', 4' Tetrakis (benzyloxy) flavan-3-one The freshly prepared Dess-Martin periodinane (39.0 grams, 92 millimoles, prepared by the method of D. B. Dess and J.C. Martin, J. Am. Chem. Soc. 113, 7277-7287 (1991) and R. E. Ireland and L. Liu, J. Org. Chem. 58, 2899 (1993)), was added at room temperature, all at once, to a stirred solution of tetra-O-benzylcatechine according to Example 1 (54.4 grams, 83.8 mmol) in methylene chloride (420 milliliters). Within about 1.5 hours, 30 milliliters of methylene chloride saturated with water was added dropwise to the reaction mixture to form a cloudy amber solution (SD Meyer and SL Schreiber, J. Org. Chem., 59, 7549- 7552 (1994)). Twenty minutes later, the reaction mixture was diluted with a saturated solution of sodium carbonate (NaHC 3, 500 milliliters) and a 10 percent aqueous solution of Na 2 S 2 · 3.5H 20 (200 milliliters). The phases were separated and the aqueous phase was extracted with 50 milliliters of methylene chloride. The combined organic phases are - filtered through silica gel (24 x 9 cm, chloroform / ethyl acetate 9: 1). The eluate was evaporated and dried under vacuum to obtain 50.1 grams (92 percent) of the ketone, which was purified by recrystallization from chloroform / ether: melting temperature from 144 ° C to 144.5 ° C; [a] D + 38.5 °, [a] 546 + 48.7 ° (chloroform, c 20.8 grams / 1 liter); Nuclear Magnetic Resonance of H (CDCI3) 6 7.45- 7.26 (m, 20 H), 6.96 (s, 1 H), 6.88, 6.86 (ABc, 2 H, J = 8 Hz, part B, d with J = 1.5 Hz ), 6.35 (narrow ABc, 2 H), 5.24 (s, 1 H), 5.14 (s, 2 H), 5.10 (narrow ABc, 2 H), 5.02 (s, 2 H), 5.01 (s, 2 H) ), 3.61, 3.45 (ABc, 2 H, J = 21.5 Hz).

EXAMPLE 3 Preparation of 5, 7, 3 ', 4' -Tetra-O-benzylpenechtechin A solution of 1 M lithium tri-sec-butylborohydride in tetrahydrofuran, mentioned below after THF, (100 milliliters, L-Selectride®, sold by Aldrich Chemical Co., Inc., of Milwaukee, Wl) was added, under an argon atmosphere, to a stirred 0 ° C solution of anhydrous lithium bromide, LiBr, (34.9 grams, 402 mmol) in 100 milliliters of anhydrous THF. The resulting mixture was cooled to -78 ° C, using an acetone / C02 bath, followed by the dropwise addition of a flavanone solution according to Example 2 (50.1 grams, 77.2 millimoles) in 400 milliliters of anhydrous THF, over a period of 50 minutes. The stirring was continued at -78 ° C for .135 minutes. The cooling bath was removed and 360 milliliters of 2.5 M aqueous sodium hydroxide (NaOH) was added to the reaction mixture. The reaction flask was placed in a water bath at room temperature and a mixture of 35 percent aqueous H 2 O 2 (90 milliliters) and ethanol (270 milliliters) was added over a period of 130 minutes. The agitation was continued during the night. Chloroform (700 milliliters) was added to dissolve the crystallized productThe phases were separated, the aqueous phase was extracted with CHCl3 (50 milliliters), the combined organic phases were dried through MgSO4, evaporated and dried in vacuo to give 56.6 grams of the crude product. This material was dissolved in 600 milliliters of a boiling mixture of ethyl acetate (EtOAc) and ethanol (EtOH), (2: 3), and allowed to crystallize at room temperature, and then in the refrigerator. The product was isolated by suction filtration, washed with 2 x 50 milliliters of cold EtOAc / EtOH (-20 ° C) (1: 3) and dried under vacuum first at room temperature and then at 80 ° C to obtain 35.4 grams (70 percent) of a light yellow solid. Evaporated mother liquor was filtered through silica gel, SIO2, (14 x 6.5 cm, CHCl3, and then - CHCl3 / EtOAc 12: 1), the eluate was concentrated to 40 milliliters, and the residue was diluted with 60 milliliters of ethanol, to obtain an additional 5.5 grams (11 percent) of the O-benzylpepickechin as a yellowish solid melting temperature of 129.5 at 130 ° C (EtOAc / EtOH) [a] D -27.7 °, [a] 546 -33.4 ° (EtOAc, c 21.6 grams per liter) 1 Nuclear Magnetic Resonance of H (CDCI3) d 7.48-7.25 (m, 20 H), 7.14 (s, 1 H), 7.00, 6.97 (ABc, 2 H, J = 8.5 Hz, part A, d with J = 1.5 Hz), 6.27 (s, 2 H), 5.19 (s, 2 H), 5.18 (s, 2 H), 5.02 (s, 2 H), 5.01 (s, 2 H), 4.91 (s, 1 H), 4.21 (br s, 1 H), 3.00, 2.92 (ABc, 2 H, J = 17.5 Hz, both parts d with J = 1.5 and 4 Hz, respectively), 1.66 (d, 1 H, J = 5.5 Hz); Analysis Calculated for C43H38O6: C, 79.36; H, 5.89. Found C, 79.12; H, 5.99 EXAMPLE 4 Preparation of (2R, 3S, 4S) -5, 7, 3 ',' -Tetra 0-benzyl-4- (2-hydroxyethoxy) epicatechin Ethylene glycol (6.4 milliliters, 115 millimoles, 5.8 equivalents) was added, at room temperature with stirring, to a solution of tetra-O-benzyl capetinquina according to Example 3 (12.75 grams, 19.6 millimoles) in 130 milliliters of anhydrous methylene chloride. , followed by the addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone - (DDQ, 8.9 grams, 39.2 millimoles, 2.0 equivalents), all at once, with vigorous agitation. (J: A. Steenkamp, et al.), Te trahedron Let ters, 26, (25) 3045-3048 (1985)). After about 2 hours, the reaction mixture-dimethylaminopyridine (DMAP, 4.8 grams, 39.2 mmol) was added resulting in the formation of a dark green precipitated material. After being stirred for an additional 5 minutes, 100 grams of silica gel was added, and the mixture was concentrated under reduced pressure. The residue was placed on top of a column of silica gel (11 x 6.5 centimeters) which was eluted with EtOAc / hexane (1: 1), and the eluate was concentrated under reduced pressure. The resulting crude material was re-purified by chromatography on silica gel (39 x 10 cm, EtOAc / hexane (1: 2), followed by EtOAc / hexane (2: 3)) to provide, after evaporation and drying, at vacuum, 7.3 grams (52 percent) of benzyl-4- (2-hydroxyethoxy) epicatechin, as a foam or solid, which was recrystallized from acetonitrile: melting temperature of 120 ° C-121 ° C; Nuclear Magnetic Resonance of XH (CDC13) d 7.48-7.26 (m, 20 H), 7.14 (d, J = 1.5 Hz), 7.02, 6.97 (ABc, 2 H, J = 8 Hz, part A, d with J = 1.5 Hz), 6.29, 6.26 (ABc, 2 H, J = 2 Hz), 5.19 (s, 2 H), 5.17 (s, 2 H), 5.10 (s, 1 H), 5.08, 5.02 (ABc, 2 H) , partially hidden), 5.00 (s, 2 H), 4.59 (d, 1 H, J = 2.5 Hz), 3.95 (br 1 H), 3.82-3.74 (m, 1 H), 3.72-3.57 (m, 3 H), 2.17 (br 1 H), 1.64 (d, 1 H, J = 5.5 Hz); IR (film) 3450 (br), 1616, 1592, 1512, 1152, 1114, 735, 697 cm "1. Analysis Calculated for C45H42O8: C, 76.04; H, 5.96 Found: C, 76.57; H, 6.02.

EXAMPLE 5 Preparation of the Oligomers of O-Benzylkenetophequina (4β? 8) To a cold stirred (0 ° C) solution of benzyl-4- (2-hydroxyethoxy) epicatechin according to Example 4 (3.28 grams, 4.6 mmol) and tetra-O-benzyl-epicatechin according to Example 3 (12.0 grams, 18.4 mmol, 4 equivalents) in anhydrous THF (40 milliliters) and anhydrous methylene chloride (50 milliliters), added by drops, in 10 minutes, titanium tetrachloride (4.6 milliliters of 1 M of TÍCI4 in methylene chloride). (H.

Kawamoto et al., Mokazai Gakkaishi, 37, (5) 448-493 (1991)). The resulting amber solution was stirred in an ice bath for 5 minutes, then at room temperature for 90 minutes. The reaction was terminated by the addition of 30 milliliters of saturated aqueous NaHCO 3 and 100 milliliters of water (resulting pH: 8). The resulting mixture was extracted with methylene chloride (2 times 20 milliliters). The organic layers - 8) The combined extracts were washed with 50 milliliters of water, dried over MgSO 4, evaporated and dried in vacuo. The resulting glass deposited a pink solid during the dissolution of methylene chloride (CH2Cl2) and allowed to stand at room temperature. The solid was filtered, washed with 3 x 15 milliliters of CH2Cl2 / hexane (1: 1), and dried under vacuum to obtain 6.1 grams of recovered tetra-O-benzylpene tequinate. From the evaporated mother liquor, the oligomers were isolated by column chromatography on silica gel (45 x 5.2 cm). Elution with CH2Cl2 / hexane / EtOAc (13: 13: 1) yielded an additional 4.9 grams of the recovered tetra-O-benzylepsytechin, followed by 2.17 grams of the crude O-benzyl dimer. Elution of the dimer was completed using methylene chloride / hexane / EtOAc (10: 10: 1). Elution of 0.98 gram of the crude O-benzyl trimer and 0.59 gram of higher oligomers was obtained using methylene chloride / hexane / EtOAc (8: 8: 1 to 6: 6: 1). The dimer and trimer were further purified by preparative HPLC on a silica gel column, using ethyl acetate / hexane or ethyl acetate / isooctane as the eluent. The maximum detection was carried out using a ultraviolet light detector at 265 to 280 nanometers. Trimer: MS (MALDI- + TOF, DHBA matrix) m / z (M + H) 1949.4; calculated for + C129H110O18; 1947.8; (M + Na) 1971.2; calculated for (9 - + Ci29HnoOi8Na: 1969.8; (M + K) 1988.3; calculated for C129H110O18K: 1985.7.

EXAMPLE 6 Preparation of Epicatechin Dimer To a solution of the O-benzyl-dimer according to Example 5 (22.3 milligrams, 17.2 micromoles) in 0.5 milliliter of ethyl acetate were added in sequence, 2 milliliters of methanol and 7.2 milligrams of 10 percent Pd / C. The mixture was stirred under 1 bar of H2 for 3 hours and filtered through cotton. The filter residue was washed with methanol and the combined filtrates were evaporated. A Nuclear Magnetic Resonance spectrum of the crude product indicated the presence of a benzylated material. The procedure was therefore repeated, with the amount of catalyst increased to 17.5 milligrams and the time prolonged to 3.7 hours. The crude polyphenol dimer (9.6 milligrams) was purified by preparative HPLC (CIS / methanol reverse phase column water (85:15) with the addition of 0.5 percent acetic acid, detection at 265 nanometers) to provide 4.5 milligrams (45 percent) of polyphenol dimer as a 1 amorphous film. Nuclear Magnetic Resonance of H (300 MHz, acetone-d6 / D2? 3: 1 (in volume / volume), TMSl d 7.19 (br, 1 H), 7.01 (overlapping s + br, 2 H), 6.86-6.65 (m, 4 H), 6.03 (br, 3 H), 5.10 (br, 1 H), 5.00 (br, 1 H) ), 4.69 (br, 1 H), 3.97 (s, 1 H), 2.92, 2.76 (br ABc, 2 H, 17 Hz); MS (MALDI-TOF, DHBA matrix) m / z (M + K) 616.8; + calculated for C30H26O12K: 617.1; (M + Na) 600.8; calculated for C3? H26? i2Na: 601.1.

EXAMPLE 7 Preparation of O-Benzyl Cappingyl Dimer Bisgalate To a solution of gallic acid of tri-O-benzyl (38 milligrams, 87 micromoles, 5 equivalents), DMF (1 microliter) in methylene chloride (0.6 milliliter), oxalyl chloride (15 microliters, 172 micromoles, 10 mmol) was added. equivalents). The resulting reaction mixture was stirred at room temperature for about 1 hour, evaporated and dried in vacuo to give tri-O-benzyl galoyl chloride. A solution of the O-benzyl-dimer according to Example 5 (22.5 milligrams, 17.3 micromoles) in anhydrous pyridine (0.5 milliliter) was added to crude galloyl chloride at room temperature, and the resulting mixture was stirred for 44.5 hours. After the addition of 20 microliters of water, stirring was continued for 2.5 hours, followed by the addition of 10 milliliters of 5 HCl. percent. The resulting mixture was extracted with methylene chloride (3 times 5 milliliters), the combined organic phases were dried through MgSO 4, evaporated and purified by filtration through silica gel using with EtOAc / CHCl 3 (1: 19). The concentration of the eluted material and vacuum drying yielded 36.0 milligrams (97 percent) of the dimer bisgalate.

O-benzyl as a colorless film: [a] D -53.3O, [a] 546 -65.6 ° (CH2Cl2, c 15.7 grams / liter); IR (film) 1720, -1 1591, 1498, 1428, 1196, 1112, 736, 696 cm "; MS (MALDI-TOF, + DHBA matrix) m / z (M + K) 2181.8; calculated for + C142H118O20K: 2181-8; (M + Na) 2165.9; calculated for Ci42H? I8? 2? Na: 2165.8.

EXAMPLE 8 Preparation of Epicatechin Dimer Bisgalate To a solution of the O-benzyl dimer bisgalate according to Example 7 (33.8 milligrams, 15.8 micromoles) in 4 milliliters of THF were added in sequence 4 milliliters of methanol, 0.2 milliliter of water, and 42 milligrams of 20 percent. of Pd (OH) 2 / C. The mixture was stirred under 1 bar of H2 for 75 minutes and filtered through cotton. The filter residue was washed with 2.2 milliliters of methanol / H2? (10: 1) and the filtered material combined was concentrated under reduced pressure to provide 14.2 milligrams of a yellow amorphous crude product. A 7.2 milligram aliquot was purified by preparative HPLC (silica gel, ethyl acetate / hexane, detection at 280 nanometers) to yield 5.0 milligrams (71 percent) of the polyphenol dimer bisgalate as a cloudy pink glass of which no small amounts of ethanol and acetic acid could be removed: 1 Nuclear Magnetic Resonance of H (acetone-of / D2? 3: 1 in volume / volume, TMS, most of the broad signals) d 7.08 (s, 2 H, sharp) , 7.1-6.7 (m, 7 H), 6.66 (d, 1 H, sharp, J = 8 Hz), 6.17 (s, 1 H), 5.94 (s, 2 H), 5.70 (s, 1 H), 5.49 (s, 1 H), 5.44 (s, 1 H), 4.9 (very br, 1 H), 4.80 (s, 1 H), 3.08, 2.88 (ABc, 2 H, J = 17 Hz, "Part A , d, J = 4Hz); MS (MALDI-TOF, DHBA matrix) m / z (M + Na) 904.9, calculated for C44H34? 2oNa: 905.2.

EXAMPLE 9 Preparation of O-Benzylkenetechin Trimer Trisgalate Using the procedure described in Example 7, O-benzyl trimer trisgalate was obtained from the O-benzyl trimer according to Example 5 in 78 percent yield after purification by HPLC. (conditions: silica gel, ethyl acetate / hexane, 280 1 nanometer); Nuclear Magnetic Resonance of H: extremely complicated; IR (film) 3031, 1719, 1594, -1 1498, 1428, 1116, 735, 696 cm.

EXAMPLE 10 Preparation of Epicatechin Trimer Trisgalate Using the procedure described in Example 8, the polyphenol trimer trisgalate of the O-benzyl trimer trisgalate was obtained according to Example 9 in 60 percent yield after purification by HPLC. (reverse phase gradient Cía from 15 percent to 25 percent of B in A, where A is 0.5 percent by volume of acetic acid (AcOH) in water and B is 0.5 percent of AcOH in ethanol, 280 nanometers); Nuclear Magnetic Resonance of 1H (300 MHz, D2? / Acetone-ds 1: 3 (in volume / volume) d 7.10 (s, 2 H), 7.1-6.88 (m, 7 H), 6.82-6.70 (m, 3 H), 6.68-6.60.

EXAMPLE 11 Preparation of 8-Bromo-5, 7, 3 ', 4' -tetra-O-benzyl-epitopequina Method A: To a solution of 116 milligrams (178 micromoles) of tetra-O-benzyl-epitopequina in 4 milliliters of anhydrous CH 2 Cl 2 were added with ice cooling and stirring 32 milligrams (180 micromoles) of N-bromosuccinimide (NBS). Stirring at 0 ° C was continued for 100 minutes, the solution was concentrated, and the residue was purified by chromatography on silica gel (15 x 1.8 cm) with CHCl 3 / EtOAc (25: 1). Crystallization of CHCl3 / ethanol yielded 110 milligrams (85 percent) of a colorless cotton-like solid. Melting temperature of 137.5 ° C; [a] D-50.4 °, [a] 546 -60.7 ° (c 17.3 grams / liter, EtOAc); Nuclear Magnetic Resonance of 1H (300 MHz, CDC13, TMS) d 7.5-7.25 (m, 20 H), 7.23 (d, 1 H, J = 1.5 Hz), 7.03, 6.98 (ABc, 2 H, J = 8.5 Hz , part A, d with J = 1 Hz), 6.25 (s, 1 H), 5.22 (s, 2 H), 5.19 (s, 2 H), 5.11 (s, 2 H), 5.02, 4.96 (ABc, 2 H, J = 9 Hz), 4.98 (s, 1 H), 4.27 (br s, 1 H), 3.04, 2.90 (ABC, 2 H, J = 17.5 Hz, both parts d with J = 1.5 and 4 Hz , respectively), 1.58 13 (d, 1 H, J = 4.5 Hz); Nuclear Magnetic Resonance of C (75 MHz, CDCI3) d 156.86, 154.79, 151.65, 149.09, 148.73, 137. 31, 137.15, 136.77, 136.72, 130.82, 128.67, 128.65, 128.58, 128.56, 128.09, 127.98, 127.87, 127.50, 127.31, 127. 25, 127.13, 118.91, 115.17, 113.07, 102.85, 93.07, 78. 62, 71.35, 71.20, 70.31, 65.92, 28.00; TR (suspension in mineral oil) 3571, 1606, 1581, 1518, 1184, 1119, 771, -1 732, 694 cm; MS m / z 399/397 (l / l percent), 332 (1 percent 0), 181 (8 percent), 91 (100 percent).

Analysis calculated for C43H37? EBr: C, 70.78; H, 5.11. Found: C, 70.47; H, 5.10. Method B: At 563 milligrams (771 micrqmoles) of 5, 7, 3 ', 4-tetra-8-bromocatechin, prepared by the method described in Example 1, in 5 milliliters of CH2CL2 was added at room temperature all at once 425 milligrams (1.00 millimol) of Dess-Martin periodinane. CH2Cl2 saturated with water was added dropwise within 40 minutes to produce a slight turbidity. After another 20 minutes, 20 milliliters of each of the saturated NaHC? 3 solution and a 10 percent aqueous solution of Na2S2? 3.5H2O were added. The phases were separated and the aqueous phase was extracted with 3 x 15 milliliters of ether. The combined organic phases were concentrated and the residue was filtered through silica gel (20 x 2.5 cm, ether / hexane 1: 1). The eluted material was evaporated and dried under vacuum to obtain 522 milligrams (93 percent) of the ketone as 1 a colorless foam: Nuclear Magnetic Resonance of H (CDC13 d 7.47-7.25 (m, 20 H), 7.04 (d, 1 H, J = 1 Hz), 6.85, 6.81 (ABc, 2 H, J = 8.5 Hz, part B, d with = 8.5 Hz), 3. 52, 3.48 (ABc, 2 H, J = 21.5 Hz); Magnetic Resonance 13 Nuclear of C (CDCI3 d 203.99, 155.55, 155.40, 150.68, 148. 98, 137.06, 136.90, 136.28, 136.04, 128.64, 128.62, 128. 46, 128.41, 128.22, 128.05 ^ 127.78, 127.76, 127.35, 127.17, 127.13, 127.08, 126.99, 118.86, 114.59, 112.43, 103. 54, 93.96, 93.87, 82.91, 71.25. 71.04, 70.98, 70.38. -1 33.30; IR (film) 1734, 1605, 1513, 1099, 737 696 cm. To 598 milligrams (822 micromoles) of the aforementioned crude ketone in 8.2 milliliters of anhydrous THF were added dropwise within 10 minutes 1.23 milliliters of a 1M solution of lithium tri-sec-butylborohydride (L-Selectride®). After being stirred at -78 ° C for 3 hours, the starting material was still detectable in the reaction mixture by thin layer chromatography, "TLC," (Si? 2, EtOAc / hexane 1: 3), and added 1.23 milliliters of the reducing agent. Stirring was continued for another 4 hours while the temperature was allowed to rise gradually to -4 ° C. Aqueous NaOH (2.5 M, 6 milliliters) and 4 milliliters of 35% aqueous H2O2 were added with continuous cooling; the resulting exothermic reaction raised the bath temperature to +12 ° C. The stirring in the water bath was continued overnight, and then the mixture was partially evaporated, and 20 milliliters of ether and 10 milliliters of EtOAc were added. The phases were separated, and the aqueous phase was extracted with 50 milliliters of EtOAc. The combined organic phases were evaporated, and the residue was purified by chromatography on silica gel (23 x 2.5 cm) with EtOAc / hexane 1: 3 to obtain 327 milligrams (55 percent) of the product as a light yellow foam.

EXAMPLE 12 Preparation of O-Methylene Catechin Tetramer The trimer of O-methylepickechin (prepared according to Examples 1 to 5, except that in Example 1 dimethyl sulfate and potassium carbonate are used in acetone to prepare the protected monomer, tetra-o-methylcatechol) joke in position 8 of the epicatechin half using any of the procedures of Example 11. The resulting bromine derivative is reacted with 5, 7, 3 ', 4' -tetra-0-methyl-4- (2-hydroxyethoxy) epicatechin according to with Example 5 to yield a mixture of tetramers having a fourth half of epicatechin bound to the positions 6 predominantly of the lower and middle epicatechin halves, as well as the higher oligomers. The desired intermediate, O-methyl-8-bromo-EC- (4β8) -EC- (6- »4β) -EC L (4β-8) -EC is isolated by preparative HPLC as in Example 11. The purified intermediate is cleaved by treatment of its THF solution at a low temperature, preferably at -78 ° C, with an excess of alkyl lithium, preferably n- or tert-butyl-lithium, and protonation of the solution or suspension resulting from the branched tetramer protected with lithium by the addition of a weak proton acid such as water or an alcohol.

EXAMPLE 13 Preparation of O-Benzylkene Tetramer Tetramer Tetramer Using the procedure described in Example 7, the tetramerite tetramerite of O-benzyleptoptechin is obtained from the tetramer of O-benzylpepickechin according to Example 12.

EXAMPLE 14 Preparation of Epicatechin Tetramer Tetramer Using the procedure described in Example 8, the epicatechin tetramer tetra tetralate is obtained from the tetramer of tetramer of O-benzylepickechin according to Example 13.

EXAMPLE 15 3,5,7,3 ', 4-Penta-0-benzyl-8-bromoepicatechin At 53 milligrams (1.3 millimoles) (of suspension at 60 percent in mineral oil) was added with agitation to 0 ° C under N2, 738 milligrams (1.01 millimole) of 5, 7.3 ', 4-tetra-O-benzyl-8-bromoepicatechin in 2 milliliters of anhydrous DMF. After 10 minutes, 0.18 milliliter (1.5 millimoles) of benzyl bromide net was added. The mixture was stirred at 0 ° C for 145 minutes and at room temperature for 5.5 hours, and then 0.1 milliliter of water was added. Chromatography on Si 2 (27 x 2.6 cm) with EtOAc / hexane 1: 4 and drying in vacuo (room temperature, and then 80 ° C) yielded 650 milligrams (78 percent) of the product as a yellowish glass: ] D -1 -52.6 °, [a] 546-63.4 ° (EtOAc, c 17.9 g L); Resonance 1 Magnetic Nuclear of H (CDCls) d 7.50-7.14 (m, 23 H), 6.99 (m, 2 H), 6.94, 6.91 (ABc, 2 H, J = 8.5 Hz, part A, d with J = 1.5 Hz), 6.23 (s, 1 H), 5.19 (s, 2 H), 5.11 (s, 5 H), 4.97 (S, 2 H), 4.38, 4.30 (ABc, 2 H, J = 12.5 Hz), 3.97 (m critical, 1 H), 2.95, 2.80 (ABc, 2 H, J = 17 Hz, both parts d with J = 3.5 and 4.5 Hz, respectively); Resonance 13 Nuclear Magnetic of C (CDCI3) d 156.44, 154.62, 151.94, 148. 65, 137.92, 137.41, 137.26, 136.75, 136.71, 131.68, 128.56, 128.53, 128.38, 128.12, 128.00, 127.85, 127.70, 127.62, 127.43, 127.33, 127.25, 127.19, 127.02, 119.15, 114.74, 113.29, 103.40, 93.11, 92.76, 78.06, 72.13, 71.32, 71.26, 71.21, 70.83, 70.22, 24.73; IR (film) 1605, 1580, 1513, 1454, 1346, 1265, 1125, 1095, 735, 697; IR (film) 1605, 1580, 1513, 1454, 1346, 1265, 1125, 1095, 1 -1 735, 697 cm. Analysis Calculated for CsoH43? 5Br: C, 73.26; H, 5.29. Found C, 72.81; H, 5.12 EXAMPLE 16 5,7,3 ', 4 -Tetra-O-benzyl-6,8-dibromoepicatechin To a solution of 334 milligrams (914 micromoles) of 5, 7, 3 ', 4-tetra-O-benzyl-epitopequina in 10 milliliters of anhydrous CH 2 Cl 2, 192 milligrams (1.08 millimoles) of N- was added in a single time to ice cooling. recrystallized bromosuccinimide (NBS). The reaction mixture was stirred at 0 ° C for 45 minutes and at room temperature for 17 hours. A solution of 200 milligrams of a2S2? 3.5H2O in 5 milliliters of water was added. After brief stirring, the phases were separated, the aqueous phase was extracted with 5 milliliters of CH2Cl2, and the combined organic phases were dried through MgSO4 and evaporated. Chromatography on silica gel (30 x 2.6 cm) with EtOAc / CHCl2 / hexane 1: 12: 7 (to remove the trace byproduct) then 3: 12: 7, was followed by evaporation and vacuum drying to provide 362 milligrams (87 percent) of dibromide in a colorless foam: [a] 546 -58.2 °, (EtOAc, c 13.5 gL ~ l); Resonance 1 Magnetic Nuclear of H (CDCI3) d 7.64 (d, 2 H, J = 7 Hz), 7.52-7.26 (m, 18 H), 7.17 (s, 1 H), 7.03, 6.97 (s, 2H), . 20 (s, 2 H), 5.17 (s, 2 H), 5.03 (s, 2 H), 5.01, 4.97 (ABc, 2 H, J = 11 Hz), 4.99 (s, 1 h), 4.19 (m critical, 1 H), 3.04, 2.87 (ABc, J = 17.5 Hz, both parts d with J = 1. 5 and 3.5 Hz, respectively), 1.55 (d, 1 H, J = 3.5 Hz); 13 Nuclear Magnetic Resonance of C (CDCI3) d 154.43, 152.57, 151.09, 149.03, 148.82, 137.10, 136.94, 136.50, 136.37, 130.13, 128.52, 128.50, 128.48, 128.47, 128.43, 128.35, 128.32, 128.16, 127.82, 127.81, 127.36, 127.20, 118.81, 115.06, 112.91, 112.30, 105.23, 103.25, 78.80, 74.61, 74.55, 71.24, 71.14, 65.33, 28.75; IR (film) 1734, 1606, 1513, 1369, 1266, 1184, 1113, 1083, 735, 697 -1 cm, Calculated Analysis for C43H36? 6Br2: C, 63. 88; H, 4 49 Found: C, 64.17; H, 4.45.

EXAMPLE 17 5,7,3 ', 4' -Tetra-O-Benzyl-6,8,6'-tribromoepicatechin To a solution of 1.72 grams (2.65 millimoles) of 5, 7, 3 ', 4-tetra-0-benzyl capetinquina in 26 milliliters of anhydrous CH2CI2 were added with ice cooling at the same time 1.89 grams (10.6 millimoles) of the N- recrystallized bromosuccinimide. The reaction mixture was stirred at 0 ° C for 1 hour at room temperature for 20 hours. A solution of 3 grams of Na2S2 • 3 • 5H2O in 25 milliliters of water was added. The partial phase separation occurred only after the addition of 30 milliliters of brine, 230 milliliters of water, and 130 milliliters of CH2Cl2. The residual emulsion was separated to one side, the aqueous phase was extracted with 100 milliliters of CH 2 Cl 2, and this organic phase and 200 milliliters of water were stirred in a separating funnel with the emulsion. The phase separation again was incomplete, and the remaining emulsion was extracted one last time with 100 milliliters of CH2Cl2. The combined organic phases were dried through MgSO 4 and concentrated. Chromatography on silica gel (17 x 4.5 cm) with EtOAc / CHCl3 / hexane 1: 12: 7, then 1: 15: 4 was followed by evaporation and vacuum drying to provide 2.01 grams (85 percent) of the tribromide as a light tan solid. The analytical sample was obtained by crystallization of CHCl3 / EtOH: melting temperature of 154 ° C to 156 ° C; [a] ü- 112 °, [a] 546-135 ° (EtOAc, c -1 1 9.7 gL); Nuclear Magnetic Resonance of H (CDCI3 d 7.66 (d, 2 H, 6.5 Hz), 7.52 (d, 2 H, J = 6.5 Hz), 7.48-7.26 (m, 17 H), 7.14 (s, 1 H), 5.28 (s, 1 H), 5.23 (s, 2 H), 5.17 (s, 2 H), 5.06 (s, 2 H), 5.02 (s, 2 H), 4.44 (critical m, 1 H), 3.10, 2.95 (ABc, J = 17 Hz , part A br, part B, d with J = 4 Hz), 1.35 (d, 1 H, J = 4 Hz); Magnetic Resonance 13 Nuclear of C (CDCI3 d 154.54, 152.53, 151.09, 149.15, 148. 32, 136.49, 136.44, 136.40, 136.31, 128.72, 128.54, 128.52, 128.48, 128.42, 128.36, 128.33, 128.16, 128.02, 127. 89, 127.41, 127.27, 118.84, 114.58, 112.30, 111.42, 105.38, 103.14, 78.61, 74.62, 74.58, 71.46, 70.96, 62.66, 28. 99; IR (film) 1499, 1385, 1367, 1266, 1182, 1109, -1 1083, 734, 695 cm. Analysis Calculated for C43H35? EBr3: C, 58. twenty; H, 3.98. Found: C, 58.52; H, 3.80.

EXAMPLE 18 (2R, 3S, 4S) -5,7,3 ', 4'-Tetra-0-benzyl-8-bromo-4- (2-hydroxyethoxy) epicatechin Method A: To a solution of 202 milligrams (284 micromoles) of (2R, 3S, 4S) -5, 7, 3 ', 4'-tetra-O-benzyl-4- (2-hydroxyethoxy) epicatechin in 4 milliliters of CH2CL2 were added at a temperature of -78 ° C all at once 51 milligrams (286 micromoles) of the recrystallized N-bromosuccinimide. The reaction mixture was stirred in the cold thawing bath, which after 65 minutes had reached 0 ° C. A solution of 50 milligrams of Na2S2? 3.5H20 in 1 milliliter of water was added, the cold bath was stirred and the mixture was stirred for 15 minutes at room temperature. The phases were separated and the organic phase was extracted with 5 milliliters of CH2Cl2. The combined organic phases were dried through MgSO 4, concentrated and purified by chromatography on silica gel (33 x 1.6 cm) with EtOAc / hexane 1: 1 (Note 1) . After the starting material and the mixed fractions containing comparable concentrations of both components were eluted, fractions consisting mostly of the desired product were collected. These fractions were further purified by preparative HPLC (Whatman Partisil 10,500 x 9.4 mm, EtOAc / hexane 1: 1, 5 milliliters per minute, detection 280 nanometers).

The main maximum with tR of 14.4 minutes was isolated: 1 Nuclear Magnetic Resonance of H (CDCI3) d 7.49-7.25 (m, 20 H), 7.23 (d, 1 H, J = 1 Hz), 7.05, 6.98 (ABc, 2 H, J = 8 Hz, part A, d with J = 1.5 Hz), 6.28 (s, 1 H), 5.23 (s, 3 H), 5.19 (s, 2 H), 5.12 (s, 2 H) , 5.05, 4.99 (ABc, 2 H, J = 11.5 Hz), 4.63 (d, 1 H, J = 3 Hz), 4.03 (br. 1H), 3.83-3.76 (m, 1 H), 3.74-3.56 (m, 3 H), 2.11 (br, 1 H), 1.57 (br, 13 1 H); Nuclear Magnetic Resonance of C (CDCI3) 5 158.30, 156. 61, 152.17, 149.09, 148.73, 137.18, 137.07, 136.39, 136.02, 130.04, 128.68, 128.61, 128.49, 128.46, 128.33, 127.98, 127.79, 127.60, 127.45, 127.23, 126.93, 118.95, 115.16, 113.24, 103.36, 92.78, 75.05, 71.30, 71.21, 71.09, 70.83, 70.70, 70.23, 67.90. 61.89; IR (film) 3380 (br), 1603, 1577, 1514, 1187, 1130, 1111, 733, 696 cm'1. Method B: At 44.1 milligrams (43.3 micromoles) of the bis (TBDMS) ether of Example 19, dissolved in 0.4 milliliter of anhydrous THF, 0.19 milliliter of a solution of tetrabutylammonium fluoride (1M in THF) was added. The mixture stirred in a closed flask for 4 hours, and then evaporated and the residue was purified by chromatography on silica gel (15 x 1.8 centimeters) with EtOAc / CHCl3 / hexane 1: 12: 7 (to remove a precursor), and then 1: 19: 0). The eluted material was evaporated and dried under vacuum to yield 32.7 milligrams (96 percent) of the product as a colorless film.

EXAMPLE 19 (2R, 3S, 4S) -5,7,3 ', 4'-Tetra-O-benzyl-3-o- (tert-butyldimethylsilyl) -4- [2- [(tert-butyldimethylsilyl) oxy] ethoxy ] epicatechin To the solution of 2.18 grams (3.07 millimoles) of (2R, 3S, 4S) -5,7,3 '-4' -tetra-O-benzyl-4- (2-hydroxyethoxy) epicatechin and 0.63 gram (9.2 millimoles) of imidazole in 5 milliliters of anhydrous DMF were added, at room temperature, all at once, 1.30 grams (8.6 millimoles, 2.8 ex.) of tertiary butyldimethylsilyl chloride. The mixture was stirred at room temperature in a capped flask for 24 hours and then filtered directly through silica gel (33 x 3.7 cm) with EtOAc / hexane 1: 6 to provide, after evaporation and vacuum drying, 2. 63 grams (91 percent) of the product as a glass -1 colorless [a] D + 3.9 °, [a] 546 + 4.7 ° (EtOAc, c 9.0 gL); Nuclear Magnetic Resonance of H (CDC13) d 7.51-7.28 (m, 20 H), 7.12 (d, 1 H, J = 1 Hz), 6.98, 6.93"(ABc, 2 H, J = 8 Hz," part A , d with J = 1 Hz), 6.24, 6.22 (ABc, 2 H, J = 2 Hz), 5.19, 5.14 (ABc, 2H, partially hidden), 5.17 (s, 2 H), "5.09-4.96 (2 overlapping ABc, 4 H), 4.50 (d, 1 H, J = 3 Hz), 3.89 (br d, 1 H, J = 2.5 Hz), 3.69 (m, 4 H), 0.88 (s, 9 H), 0.67 (s, 9 H), 0.04 (s, 3 H), 0.03 (s, 3 H), -0.21 (s, 3 H), -0.48 (s, 3H); Nuclear Magnetic Resonance of 13"C (CDCI3) d 160.12, 159.39, 156.63, 148.88, 148.30, 137. 37, 137.02, 136.83, 132.65, 128.53, 128.49, 128.42, 128. 38, 127.94, 127.82, 127.75, 127.67, 127.62, 127.51, 127.33, 127.26, 120.14, 115.28, 114.29, 102.23, 94.28, 93.17, 75.22, 71.5, 71.40, 70.63, 70.32, 70.11, 69.98, 69.61, 62.71, 25.95, 25.59, 18.38, 1790, -5.10, -5.18, -5.25, -5.40; IR (film) 2952, 2928, 2855, 1616, 1593, 1257, 1153, 1136, 1108, 835, 777, 735, 696 cm "1. Analysis Calculated for C57H70O8SÍ2: C, 72.88; H, 7.51 Found: C 73.35; H, 7.04.

EXAMPLE 20 (2R, 3S, 4S) -5,7,3 ', 4'-Tetra-O-benzyl-8-bromo-3-O- (tert-butyldimethylsilyl) -4- [2- [tert-butyldimethylsilyl]) oxy] ethoxy] epicatechin - 1 7 - To a solution of 2.61 grams (2.78 millimoles) of (2R, 3S, 4S) -5,7,3 ', 4'-tetra-O-benzyl-3-0- (tert-butyldimethylsilyl) -4- [2- [(tert-butyldimethylsilyl) oxy] ethoxy] epicatechin, in 35 milliliters of CH 2 Cl 2 were added at -78 ° C, all at the same time, 500 milligrams (2.81 mmol) of recrystallized N-bromosuccinimide. The reaction mixture was stirred in a cold thawing bath, which after 6 hours had reached +20 ° C. A solution of 0.5 gram of a2S2? 3.5H2O in 10 milliliters of water was added, the cold bath was stirred and the mixture was stirred for 10 minutes at room temperature. The phases were separated, and the organic phase was extracted with 5 milliliters of CH2Cl2. The combined organic phases were concentrated and filtered through silica gel with EtOAc / hexane 1: 4. Evaporation and vacuum drying resulted in 2.72 grams (96 percent) of the product as a colorless glass: [α] D -1 - 25.8 °, [α] 546 - 31.6 ° (EtOAc, c 20.2 gL); Resonance 1 Magnetic Nuclear of H (CDCI3) d 7.51-7.25 (m, 20 H), 7.22 (s, 1 H), 6.98, 6.94 (ABc, 2 H, J = 8 Hz, Part A br), 6.22 (s, 1 H), 5.30 (s, 1 H), 5.19 (s, 2 H), 5.17 (s, 2 H), 5.11 (s, 2 H), 5.06, 4.98 (ABc, 2 H, J = 12 Hz), 4.54 (d, 1 H, J = 3 Hz), 3.94 (br d, 1 H, J = 2.5 Hz), 3.73-3.60 (m, 4 H), 0.88 (s, 9 H), 0.60 (s, 9 H), 0.04 (s, 3 H), 0.03 (s, 3 H), -0.24 (s, 3 H), -0.56 (s, 3H); Nuclear Magnetic Resonance of 13C (CDCI3) d 158.04, 156.11, 152.88, 148.92, 148.05, 137. 42, 137.31, 136.62, 136.59, 132.24, 128.59, 128.52, 128. 41, 128.37, 128.01, 127.85, 127.69, 127.63, 127.45, 127. 31, 127.19, 126.99, 119.46, 115.41, 113.76, 103.75, 92. 61, 91.79, 75.78, 71.60, 71.05, 71.03, 70.61, 70.47, 70. 14, 69.30, 62.65, 25.94, 25.47, 18.39, 17.90. -5.10, -5.19, -5.50; IR (film) 2952, 2928, 285, 1605, 1578, -1 1257, 1186, 1135, 1114, 835, 777, 735, 696 cm. Analysis Calculated for C57H69? SBrSÍ2: C, 67.24; H, 6.83. Found: C, 67.35; H, 6.57.

EXAMPLE 21 (2R, 3S, 4S) -5,7,3 ', 4'-Tetra-O-benzyl-6,8,6'-tribromo-3-O- (tert-butyldimethylsilyl) -4- [2- [(tert-butyldimethylsilyl) oxy] ethoxy] epicatechin To a solution of 96.0 milligrams (94.3 micromoles) of (2R, 3S, 4S) -5, 7, 3 ', 4' -tetra-O-benzyl-8-bromo-3-0- (tert-butyldimethylsilyl) -4 - [2- [(tert-butyldimethylsilyl) oxy] ethoxy] epicatechin in 1.2 milliliters of CH2Cl2, were added at room temperature, all of them at once (65 milligrams, 365 micromoles, 3.87 equivalents) of the recrystallized N-bromosuccinimide. The reaction mixture was kept at room temperature for 20.5 hours and then a 0.5 gram solution of Na2S2? 3.5H2? in 5 milliliters of water and the mixture was stirred for 10 minutes at room temperature. The phases were separated and the organic phase was extracted with 2 x 5 milliliters of CH2Cl2. The combined organic phases were concentrated and filtered through silica gel (34 x 1.1 cm) with 1:12 EtOAc / hexane. Evaporation and vacuum drying resulted in 90. 3 milligrams (81 percent) of the product as a colorless -1 glass [a] 546 -74.1 ° (EtOAc, c 9.0 gL); Resonance 1 Magnetic Nuclear of H (CDCI3) d 7.64 (d, 2H, J = 7Hz), 7. 60 (d, 2H, J = 7 Hz), 7.49-7.28 (m, 17H), 7.13 (s, 1 H), 5.62 (s, 1 H), 5.24, 4.97 (ABc, 2 H. J = 11 Hz ), 5.16 (s, 4) H), 5.09 (s, 2 H), 4.53, 4.43 (ABc), 2 H. J = 2.5 Hz, B beyond br), 3.09-3.81 (m, 1 H), 3.80-3.71 (m, 3 H), 0.84 (s, 9 H), 0.65 (s, 9 H), -0.02 (s, 3 H), -0.16 (s, 3 H), -0.57 (s, 3 H) (a signal of YES-CH3 supposedly 13 coinciding with TMS); Nuclear Magnetic Resonance of C (CDC13) d 156.15, 154.11, 153.92, 148.72, 148.65, 136.90, 136. 69, 136.58, 136.38, 129.61, 128.52, 128.50, 128.45, 128. 43, 128.32, 128.16, 127.94, 127.91, 127.64, 127.44, 127. 33, 119.23, 115.83, 113.33, 110.94, 104.76, 103.01, 75.85, 75.64, 74.56, 71.75, 71.50, 70.89, 70.79, 64.27, 62. 55, 25.97, 25.58, 18.44, 17.73, -5.24, -5.30, -5.80; IR -1 (film) 2927, 2856, 1499, 1360, 1259, 1106, 836 cm EXAMPLE 22 (2R, 3S, 4S) -5,7,3 ', 4'-Tetra-O-benzyl-6,8, 6'-tribromo-4- (2-hydroxyethoxy) epicatechin To 73.4 milligrams (62.4 micromoles) of the bis (TBDMS) ether in 0.4 milliliter of anhydrous THF was added 0.25 milliliter of a solution of tetrabutylammonium fluoride (1M in THF). The mixture was stirred in a closed flask for 2.5 hours, and then evaporated, and the residue was purified through silica gel chromatography (15 x 1 cm) with EtOAc / hexane 1: 2 (to remove a precursor) and then 1: 1. The evaporated eluate material was further purified by preparative thin layer chromatography (Si 2, 200 x 200 x 2 mm, EtOAc / hexane 1: 1) to yield 44.8 milligrams (76 percent) of the product as a colorless film: [α] D-81.6 °, [α] 546 -98.3 ° (EtOAc, c -1 1 10.1 gL); Nuclear Magnetic Resonance of H (CDCI3) d 7. 65 (d, 2 H. J = 6.5 Hz), 7.54 (d, 2 H. J = 6.5 Hz), 7.48-7.24 (m, 17 H), 7.13 (s, 1 H), 5.57 (s, 1 H) ), 5.24, 5.08 (ABc, 2 H. J = 11 Hz), 5.22, 5.18 (ABc, 2 H. J = 11.5 Hz), . 13 (s, 2 H), 5.06 (s, 2 H), 4.45 (d, 1 H, J = HZ), 4.25 (br, 1 H), 3.84-3.76 (m, 1 H), 3.72-3.58 (m, 3 H), 2.11 (br, 1 H), 1.48 (br, 1 H); Nuclear Magnetic Resonance of 13 C (CDCI3) 156.24, 154.70, 151.52, 149.24, 148.39, 136.50, 136. 38, 136.18, 128.60, 128.58, 128.52, 128.51, 128.49, 128.44, 128.09, 128.06, 128.03, 127.94, 127.46, 127.27, 118.92, 115.03, 112.99, 111.33, 105.40, 103.41, 76.04, 75.08, 74.66, 71.50, 71.08, 71.03, 70.96, 64.12, 61.95; GO (film) 3500 (br), 1580, 1500, 1365, 1262, 1193, 1121, -1 1097, 736, 696 cm.

EXAMPLE 23 [5,7,3,4'-Tetra-0-benzyl-8-bromo-3-0- (tert-butyldimethylsilyl) epicatechin] - (4,8) (5, 7, 3 ', 4' - tetra-O-benzylpentaxin) To a solution of 97.3 milligrams (95.6 micromoles) of (2R, 3S, 4S) -5, 7, 3 ', 4' -tetra-O-benzyl-8-bromo-3-O- (tert-butyldimethylsilyl) -4 - [2- [(tert-butyldimethylsilyl) oxy] ethoxy] epicatechin and 311 milligrams (478 micromoles, 5 equivalents) of 5, 7, 3 ', 4' -tetra-O-benzyl-epitopequina in 0.85 milliliter of anhydrous THF and 1.1 milliliters of anhydrous CH2CI2 was added with stirring and exclusion of moisture at 0 ° C, 0.10 milliliter (0.10 millimole) of a solution of 1 M of TÍCI4 in CH2CI2. After 140 minutes at room temperature, 5 milliliters of saturated aqueous NaHC 3 and 10 milliliters of CH 2 Cl 2 were added, the phases were separated and the aqueous phase was extracted with 2 x 10 milliliters of CH 2 Cl 2. The combined organic phases were dried through MgSO 4 and evaporated, and the residue was filtered through silica gel with EtOAc / toluene 1:19. Evaporation and vacuum drying provided 239 milligrams of a foam, the components of which could Separate only by HPLC preparation (Whatman Partisil 10, 500 x 9.4 mm, EtOAc / toluene 1:24, 5 milliliters per minute, detection at 290 nanometers). Of 234 milligrams of this mixture, 34.8 milligrams of the desired product was obtained at RT, 10.3 minutes. The remaining small impurities were removed by HPLC of additional preparation (Whatman Partisil 10,500 x 9.4 mm, EtOAc / hexane at 1: 4, 5 milliliters per minute, detection at 280 nanometers, tR 16.1 min) to yield 30.3 milligrams (21 percent) of the header compound as a glass: [a] D + 16.2 °, -1 [a] 546 + 19.4 ° (EtOAc, c 12.3 gL); Magnetic resonance 1 Nuclear of H (CDCI3) (two rotamers) d 7.5-6.7 (m), 6.26 (s), 6.22 (s), 6.14 (s), 6.09 (s), 5.99 (s), 5.52 (s), 5.44 (s), 5.20-4.71 (m), 4.56, 4.37 (ABc, J = 12.5 Hz), 4.12 (br), 3.90 (br s), 3.74 (br), 3.03, 2.95 (ABc, minor rotamer, J = 17 Hz, both "parts d with J = 2.5 and 3.5 Hz, respectively), 2.92, 2.81 (ABc, main rotamer, J = 18 Hz, part B, d with J = 4.5 Hz), 1.35 (s), 0.54 (s), 0.50 (s), -0.31 (s), -0.54 (s); IR (film) 2927, 1603, 1512, -1 1267, 1111, 734, 696 cm; MS (ES) m / z 1512.8, 1511.9, + 1510.8, 1509.8, 1508.8 (M + NH4; calculated for l3cl2Cg1H 18lBrN012Si / l2Cg2Hg18lBrN012Si / 13Cl2Cg1H9179BrN012Si / l2Cg2Hg179BrN012Si: 1511.5 / 1510.5 / 1509.5 / 1508.5).

EXAMPLE 24 (5,7,3 ', 4' -Tetra-O-benzyl-8-bromoepicatequin) (4, 8) - (5, 7, 3 ', 4' -tetra-O-benzyl-epitopequina) Method A: To a solution of 78.6 milligrams (99.5 micromoles) of (2R, 3S, 4S) -5, 7, 3 ',' -tetra-0-benzyl-8-bromo-4- (2-hydroxyethoxy) epicatechin and 324 milligrams (498 micromoles, 5 equivalents) of 5, 7, 3 ', 4' -tetra-O-benzyl capsyquina in 0.85 milliliter of anhydrous THF and 1.1 milliliter of anhydrous CH2CI2 was added with stirring and exclusion of moisture at 0 ° C, 0.10 milliliter (0.10 millimole) of a 1M solution of TIC4 in CH2Cl2. After 3.5 hours at room temperature, 3 milliliters of an aqueous solution of saturated NaHCO 3 was added and 10 milliliters of CH 2 Cl 2 were added, the phases were separated and the organic phase was dried through MgSO 4 and evaporated. The residue was filtered through SiO2, eluting in sequence with EtOAc / CHCl3 / hexane of 1: 12: 7 (to remove most of the unreacted tetra-O-benzyleptoptechin), and then 1: 19: 0. The desired product was isolated from the evaporated crude product by HPLC preparation (Whatman Partisil 10,500 x 9.4 mm, EtOAc / hexane 1: 4, 5 milliliters per minute, detection at 280 nm, tR 27.5 mm) to obtain 36.3 milligrams (26 percent) ) of a glass.

- Method B: To a solution of 60.4 milligrams (46.5 micromoles) of 0-4.8-dimer of benzylated epicatechin in 0.9 milliliter of anhydrous CH2Cl2 was added at -78 ° C all at once 8.3 milligrams (47 micromoles) of N - recrystallized bromosuccinimide. The reaction mixture was stirred and allowed to thaw at 0 ° C for 1.5 hours, and then stirred at 0 ° C for 40 minutes. Thin Layer chromatography of the mixture (SIO2, EtOAc / toluene 1: 9) showed that a certain amount of the material with the same mobility as the starting material (Rf 0.49) was present in addition to a product (Rf 0.43). The mixture was re-cooled to -40 ° C, and an additional 2.2 milligrams (12 micromoles) of NBS was added. After the mixture had thawed at 0 ° C within 70 minutes, the thin layer chromatogram of the mixture remained unchanged, and the reaction was terminated by stirring briefly at room temperature with a 0.1 gram solution of Na2S2 3.5. H2O in 2 milliliters of water. The phases were separated, and the aqueous phase was extracted with 5 milliliters of CH2Cl2. Evaporation, filtration through silica gel (10 x 1.1 cm) with EtOAc / CH2Cl2 / hexane of 1: 6: 3, and again evaporation gave 65 milligrams of a crude mixture that was separated by TLC preparation (SIO2). , 200 x 200 x 2 mm, EtOAc / toluene 1:15, 2 runs) and further purified by preparative HPLC (Whatman Partisil 10, 500 x 9. 4 nm, EtOAc / hexane 1: 4, 5 milliliters / minute, detection at 280 nm). The main product obtained in this way was identical by Nuclear Magnetic Resonance with one obtained previously: [a] D, [a] 546 + 0.6 ° (EtOAc, c 8.4 -1 1 gL); Nuclear Magnetic Resonance of H (CDC13 (two rotamers) d 7.5-6.8 (m), 6.78 (d, J = 8 Hz), 6.74 (d, J = 1 Hz), 6.34 (s), 6.27 (dd, J = 1, 8 Hz), 6.19 (s), 6.16 (s), 6.02 (s), 5.56 (s), 5.36 (s), 5.2-4.95 (m), 4.9-4.7 (m), 4.60, 4.36 (ABc , J = 12 Hz), 4.33 (br), 4.11 (br), 3.99 (s), 3.80 (br), 3.08-2.80 (2 ABc, minor rotamer part A to 3.04, J = 17.5 Hz, part B not discernible; main rotamer at 2.96, 2.85, J = 18 Hz, part B d with J = 4.5 Hz), 1.66 (d, J = 5 Hz), 1.58 (d, J = 5 Hz) 1.40 (d, J = 3. 5 Hz), 1.28 (partially overlapped with an impurity derived from the solvent); IR (film) 1604, 1512, 1266, -1 1117, 735, 696 cm, MS (ES) m / z 1398.6, 1397.6, 1396.6, + 1395.6, 1394.6 (M + NH4; calculated for 13C12C85H7781BrNOi2 / 12C86H77aiBrNOi2 / 13 - 12, i CJ "" C85H7779BrNOi2 / 12C86H7779BrNOi2: 1397. 5/1396, 5/1395.5 / 1394.5).

EXAMPLE 25 Cytotoxic Activity - The epicatechin dimer bisgalate (abbreviated ECDG) and epicatechin trimer trisgalate (abbreviated ECTG) were screened for activity against certain breast cancer cell lines, and the results are presented graphically in Figure 1 (a) - (d). All human tumor cell lines were obtained from the American Type Culture Collection. The cells were grown as monolayers in IMEM containing 10 percent fetal bovine serum without antibiotics. The cells were kept in a humidified atmosphere of 5 percent CO2 at 37 ° C. After trypsinization, the cells were counted and adjusted to a concentration of 1,000 to 2,000 cells per 100 milliliters. The proliferation of the cell was determined by plating the cells (1,000-2,000 cells / well) in a 96-well microtiter plate. After the addition of 100 microliters of cells per well, the cells were allowed to settle for 24 hours. At the end of the 24 hour period, various polyphenol derivatives were added at different concentrations to obtain dose response results. The polyphenols were dissolved in media at a concentration of 2 times and 100 microliters of each solution was added in triplicate wells. On consecutive days, the plates were stained with 50 microliters of crystal violet (2.5 grams of crystal violet dissolved in 125 milliliters of methanol, 375 milliliters of water), for 15 minutes. The stain was removed and the plate was gently submerged in cold water to remove the excessive stain. The washings were repeated twice more, and the plates were allowed to dry. The remaining spot was solubilized by adding 100 microliters of 0.1 M sodium citrate / 50 percent ethanol to each well. After solubilization, the number of cells was quantified in an ELISA plate reading apparatus at 540 nanometers (reference filter at 410 nanometers). The growth of the cancer cell line at the end of four days was plotted as the percent growth of the control and is shown in Figure 1 (a) - (d) as bar graphs. The error bars represent +/- the normal deviation of three duplicate measurements. The data indicated that the monomer (epicatechin) and the synthetic epicatechin dimer did not show cytotoxicity against the breast cancer cell lines investigated. However, the synthetic epicatechin dimer bisgalate and the synthetic epicatechin trimer trisgalate produced a cytotoxic effect equivalent to the pentamer gallate and / or epigallocatechin gallate, especially at higher dosages. It was surprisingly found that the dimer bisgalate and the trimer trisgalate exhibited higher - antineoplastic activity when compared with the non-derived dimer and trimer. These results indicate that the comparison of the previously inactive cocoa procyanidin oligomers considerably increases the antineoplastic activity of the compounds. Therefore, the dimer score provides a compound that is useful for use as described in US Patent Application Number 08 / 831,245 filed on April 2, 1997.

Claims (41)

R E I V I ND I C A C O N E S:

1. A process for the production of a polyphenol oligomer, wherein the oligomer consists of monomer units, each unit consisting of a coupled polyphenol monomer, the process comprising the steps of: (a) protecting each phenolic hydroxyl group from a first and second polyphenol monomer, with a protecting group for producing first and second protected polyphenol monomers independently selected from monomers represented by the formula: c is an integer from 1 to 3 d is an integer from 1 to 4 e is an integer from 0 to 2. f is an integer from 0 to 2, Rl is H, OH or OR3; R and R3 are independently protective groups; and R2 is halo; (b) functionalizing the 4-position of the first protected polyphenol monomer to produce a monomer of protected and functionalized polyphenol having the formula: where c is an integer from 1 to 3; d is an integer from 1 to 4 e is an integer from 0 to 2, f is an integer from 0 to 2 and is an integer from 2 to 6 R1 is H, OH or OR3; R4 is H or R5; R, R3 and R5 are independently protecting groups; and R2 is halo; (c) coupling the second protected polyphenol monomer with a functionalized protected polyphenol monomer to produce a protected polyphenol dimer such as the polyphenol oligomer; and (d) optionally repeating the functionalization and coupling steps to form the polyphenol oligomer having n monomer units, wherein n is an integer from 3 to 18.

2. The process according to claim 1, wherein at least one R 2 is halo, and at least one of the protected polyphenol monomers.

3. The process according to claim 1, wherein at least one R2 is halo for the second protected polyphenol monomer.

4. The process according to claim 1, wherein R1 is OR3 or R4 and R3 is the functionalized protected polyphenol monomer.

5. The process according to claim 4, wherein R3 is an alkylsilyl protecting group.

6. The process according to claim 2, wherein halo is bromine.

The process according to claim 6, wherein the protected polyphenol monomer is a brominated protected epicatechin or brominated protected catechin.

8. The process according to claim 7, wherein the epicatechin is an 8-bromoepicatechin or an 8-bromocatechin.

9. The process according to claim 7, wherein the epicatechin is 6,8,6'-tribromo-epicatechin or a 6, 8, 6 '-tribromo-catechin.

10. The process according to claim 2, wherein at least one R2 is halo for the functionalized protected polyphenol monomer.

The process according to claim 10, wherein the functionalization and coupling steps are repeated to form a halogenated polyphenol oligomer having from 3 to 18 monomer units.

12. The process according to claim 10, wherein halo is bromine.

The process according to claim 12, wherein the brominated functionalized polyphenol monomer is a brominated functionalized epicatechin or a brominated functionalized catechin.

The process according to claim 13, wherein the epicatechin is an 8-bromoepicatechin or an 8-bromocatechin.

15. The process according to claim 13, wherein the epicatechin is a 6,8,6'-tribromo-epicatechin or a 6, 8,6 '-tribromocatechin.

16. The process according to claim 1, wherein n is an integer from 5 to 12.

17. The process according to claim 1, further comprising halogenating the polyphenol oligomer.

18. The process according to claim 1, wherein the step of functionalizing the 4-position of the protected polyphenol monomer comprises oxidatively functionalizing the 4-position of the protected polyphenol monomer using a quinone oxidation agent in the presence of a diol.

19. The process according to claim 18, wherein the diol is ethylene glycol and y is

20. The process according to claim 1, wherein R is independently alkyl of 1 to 4 carbon atoms, benzyl, substituted benzyl,. a silyl moiety containing alkyl of 1 to 6 carbon atoms or aryl substituents, and when cod is 2 and adjacent are, methylene, diphenylmethylene or substituted diphenylmethylene, wherein the substituted benzyl or each substituted phenyl may contain substituents which are selected from the group consisting of halo, nitro, cyano, aryl, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkoxy of 3 to 8 carbon atoms.

21. The process according to claim 1, which further comprises removing the group protecting the phenolic hydroxyl groups of the polyphenol oligomer to produce an unprotected polyphenol oligomer.

22. The process according to claim 1, wherein R is benzyl.

23. The process according to any of claims 1 to 21, further comprising the step of forming a derivative of the polyphenol oligomer by esterifying the polyphenol oligomer in the 3-position and at least one monomeric unit, to produce an oligomer of esterified polyphenol.

24. The process according to any of claims 1 to 21, further comprising the step of forming a polyphenol oligomer derivative by glycosylating the polyphenol oligomer in the 3-position of at least one monomer unit, to produce an oligomer of glycosylated polyphenol.

25. The process according to claim 23, wherein the 3-position of at least one monomeric unit is converted to a derivative group which is selected from the group consisting of -OC (O) aryl, aryl of -OC (O ) -substituted, -OC (O) -styryl and styryl of -OC (0) -substituted; wherein the substituted aryl or the substituted styryl contains at least one substituent selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, thiol, methyolenedioxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms and cycloalkoxy of 3 to 8 carbon atoms.

26. The process according to claim 23, wherein the 3-position of at least one monomeric unit is converted to a derivative group which is derived from an acid selected from the group consisting of caffeic, synnamic, coumaric acids, ferulic, gallic, hydroxybenzoic and sinapic.

27. The process according to claim 24, wherein the 3-position of at least one monomeric unit is converted to a derivative group which is selected from the group consisting of -O-glycoside or an -O-substituted glycoside, wherein the substituted glycoside is substituted by -C (O) aryl, -C (0) -substituted aryl, -C (O) -styryl or -C (O) -substituted styryl, wherein the substiuted aryl or the styryl substituted may contain substituents that are selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, thiol, methylenedioxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy from 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms and cycloalkoxy of 3 to 8 carbon atoms.

28. The conformance process "with claim 27, wherein the glycoside is selected from the group consisting of glucose, galactose, xylose, rhamnose and arabinose

29. The process according to any of claims 1 to 21, provided that when the polyphenol oligomer has the formula: where . x is an integer from 0 to 16; c is independently an integer from 1 to 3; d is independently an integer from 1 to 4. e is independently an integer from 0 to 2 f is independently an integer from 0 to 2 R is independently selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, benzyl, substituted benzyl, a silyl moiety containing alkyl of 1 to 6 carbon atoms or aryl substituents and when cod is 2 and adjacent, methylene, diphenylmethylene or substituted diphenylmethylene, wherein the substituted benzyl or each substituted phenyl may contain substituents which are selected from the group consisting of halo, nitro, cyano, aryl, alkyl of 1 to 6 carbon atoms, haloalkyl of Ccg, alkoxy of 1 to 6 carbon atoms-haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms and cycloalkoxy of 3 to 8 carbon atoms; and R is selected from the group consisting of hydrogen, an O-glycoside, an -O-substituted glycoside, -C (O) aryl, aryl -C (O) -substituted, -C (0) -styryl and a styryl of -C (O) -substituted, wherein the substituted glycoside is substituted by -C (O) aryl, aryl -C (O) -substituted, -C (O) -styryl, styryl-C (O) -substituted, in wherein the substituted aryl or substituted styryl may contain the substituents that are selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, thiol, methylenedioxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms and cycloalkoxy of 3 to 8 carbon atoms; and R2 is halo.

30. A compound of the formula: where c is an integer from 1 to 3 d is an integer from 1 to 4. e is an integer from 0 to 2, f is an integer from 0 to 2 R is selected from the groups consisting of hydrogen, alkyl of 1 to 4 carbon atoms, benzyl, substituted benzyl, a silyl residue containing alkyl of 1 to 6 carbon atoms or aryl substituents, when cod is 2 and adjacent, methylene, diphenylmethylene or substituted diphenylmethylene, where the substituted benzyl is or each substituted phenyl may contain substituents which are selected from the group consisting of halo, nitro, cyano, aryl, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkoxy of 3 to 8 carbon atoms; ~ R1 is selected from the group consisting of hydrogen, hydroxy, an -O-glycosides, an -O-substituted glycoside, -OC (O) -aryl, aryl-OC (O) -substituted, wherein the substituted glycoside is substituted by -C (O) -aryl, aryl-C (O) -substituted, -C (O) -styryl or styryl -C (O) -substituted; and R2 is halo; wherein the substituted aryl or the substituted styryl can contain the substituents that are selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, thiol, methylenedioxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 atoms of carbon, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms and cycloalkoxy of 3 to 8 carbon atoms.

31. A compound of the formula: where c is an integer from 1 to 3, d is an integer from 1 to 4. e is an integer from 0 to 2, f is an integer from 0 to 2, and is an integer from 2 to 6, R is selected of the group consisting of hydrogen, alkoyl of 1 to 4 carbon atoms, benzyl, substituted benzyl, a silyl moiety containing aryl of 1 to 6 carbon atoms or aryl substituents and when cod is 2 and remain adjacent, methylene, diphenylmethylene or substiumed diphenylmethylene, wherein the substituted benzyl or each substituted phenyl may contain substituents selected from the group consisting of halo, nitro, cyano, aryl, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms and cycloalkoxy of 3 to 8 carbon atoms; R is selected from the group consisting of hydrogen, hydroxy, an -O-glycoside, an -O-substituted glycoside, -OC (O) -aryl, aryl-OC (O) -substituted, -OC (0) - styryl, and styryl -OC (O) -substituted; wherein the substituted glycoside is substituted by -C (O) -aryl, aryl-C (O) -substituted, -C (O) -styryl, styryl-C (O) -substituted; and R2 is halo; wherein the substituted aryl or the substituted styryl can contain the substituents which are selected from the group consisting of halo, hydroxyl, anhydro, cyano, amino, thiol, methylenedioxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 atoms of carbon, haloalkyl of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms and cycloalkoxy of 3 to 8 carbon atoms.-

32. A process for the production of a compound polymeric of the formula An, wherein A is a monomer of the formula: wherein n is integer from 3 to 18, such that there is at least one terminal monomer unit A, and a plurality of additional monomer units; R is 3- (a) -0H, 3- (β) -0H, 3 - (a) -O-sugar or 3- (β) -O-sugar; the bonding of the adjacent monomers is carried out between position 4 and positions 6 or 8; a link for the additional monomer unit in position 4 has alpha or beta stereochemistry; X, Y and Z, are selected from the group consisting of the monomeric unit A, hydrogen and a sugar, with the stipulations that as regards at least one terminal monomeric unit, the bonding of the additional monomer unit to it is in a-4 position and optionally Y = Z = hydrogen; the sugar is optionally substituted with a phenolic half; and pharmaceutically acceptable salts, derivatives thereof and oxidation products thereof; whose process comprises: (a) protecting each phenolic hydroxyl group from a (+) - catechin or a (-) - epicatechin with a protecting group to produce a protected (+) - cataquine or a (-) -protected epicatechin; (b) functionalizing the 4-position of the protected (+) -cantucine or the protected (-) -epicatechin or a mixture thereof to produce a functionalized (+) - protected -catenquina, a functionalized protected (-) -epicatequina or a functionalized protected mixture thereof; (c) coupling the protected (+) - protected (or) protected (-) - epicatechin with the functionalized (+) - protected -catenquina or the functionalized protected (-) -epicatequina or mixtures thereof to produce a protected polyphenol oligomer; (d) removing the protecting group from the phenolic hydroxyl groups, the polyphenol oligomer to produce an unprotected polyphenol oligomer; and (e) optionally forming the protected or unprotected polyphenol oligomer derivative to produce a derivatized polyphenol oligomer.

33. The process according to claim 32, wherein n is 5.

34. The process according to claim 32, wherein the sugar is selected from the group consisting of glucose, galactose, xylose, rhamnose or arabinose.

35. The process according to claim 32, wherein the phenolic moiety is selected from the group consisting of caffeic, cinnamic, coumaric, ferulic, gallic, hydroxybenzoic and sinapic acids.

36. A pharmaceutical composition comprising a compound of the formula: and a pharmaceutically acceptable carrier or excipient.

37. A method for treating a subject in need of treatment with an anti-cancer agent, comprising administering an effective amount to the subject of a composition according to claim 36.

38. The method of claim 37, wherein the cancer is breast cancer

39. A pharmaceutical composition comprising a compound of the formula:

40. A method for treating a subject in need of treatment with an anticancer agent comprising administering an effective amount to the subject of a composition according to claim 39.

41. The method of claim 40, wherein the cancer is cancer. chest.