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(12) United States Patent (10) Patent No.: US 7,126,014 B2 Kozikowski Et Al

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(12) United States Patent (10) Patent No.: US 7,126,014 B2 Kozikowski Et Al USOO7126014B2 (12) United States Patent (10) Patent No.: US 7,126,014 B2 Kozikowski et al. (45) Date of Patent: Oct. 24, 2006 (54) SYNTHESIS OF EPECATECHIN-4C, Pierre et al., “Deuterium Labeled Procyanidin Syntheses'. Tetra 8-EPICATECHN AND -CATECHN DIMERS hedron Letters, 1997, 38(32), p. 5639-5642. AND DERVATIVES THEREOF Kiehlmann, et al., “Iodination and deuteration of catechin deriva tives”, Can. J. Chem., 1988, 66, p. 2431-2439. (75) Inventors: Alan P. Kozikowski, Princeton, NJ Botha et al., “Synthesis of Condensed Tannins. Part 5. The First (US); Leo J. Romanczyk, Jr., Angular 4.6:4,8-Triflavanoids and Their Natural Counterparts”. Hackettstown, NJ (US); Werner Journal of the Chemical Society, 1982, 527-533. Tickmantel, Washington, DC (US) Foo, et al., “Condensed Tannins: Synthesis of the First Branched Procyanidin Trimer'. J. Chem., Soc., Chem. Commun., 1984, 85-86. (73) Assignee: Mars, Inc. Weinges et al., “Synthese des Octamethyl-diacetyl-procyanidins B3', Chem. Ber:, 1970, 103, 2344-2344. (*) Notice: Subject to any disclaimer, the term of this Delcour et al., “Synthesis of Condensed Tannins. Part 9.+ The patent is extended or adjusted under 35 Condensation Sequence of Leucocyanidin with (+)-Catechin and U.S.C. 154(b) by 359 days. with the Resultant Procyanidins”. J. Chem. Soc. Perkin Trans., 1983, 1711-1717. (21) Appl. No.: 10/783,801 Keogh et al., “A new synthesis of flavans', Chem. Ind., 1961, 3398. Kim et al., “(-)-Epicatechin Content in Fermented and Unfermented (22) Filed: Feb. 20, 2004 Cocoa Beans”, Journal of Food Science, 1984. 49(4), 1090-1092. Balas et al., “2D NMR Structure Elucidation of Proanthocyanidins: (65) Prior Publication Data the Special Case of the Catechin-(4C-8)-catechin-(4C-8)-catechin Trimer'. Magnetic Resonance in Chemistry, 1995, 33, N2, p. 85-94. US 2005/OO14958 A1 Jan. 20, 2005 Saito, Akiko et al., “Synthetic Studies of Proanthocyanidins. Highly Stereoselective Synthesis of the Catechin Dimer, Procyanidin-B3”. Related U.S. Application Data Biosci. Biotechnol. Biochem., 66(8), 1764-1767, 2002. (62) Division of application No. 10/214,830, filed on Aug. Kozikowski, et al., “Studies in Polyphenol Chemistry and Bioactiv 8, 2002, now Pat. No. 6,720,432, which is a division ity”. J. Org. Chem. 2001, 66, 1287-1296. of application No. 09/655,360, filed on Sep. 5, 2001, Tickmantel "Studies in Polyphenol Chemistry and Bioactivity”. J. now Pat. No. 6,476,241. Am. Chem. Soc. 1999, 121, 12073-12081. Kozikowski et al. “Studies in Polyphenol Chemistry and Bioactiv (51) Int. Cl. ity”. J. Org. Chem. 2000, 66, 5371-5381. C07C3II/76 (2006.01) Delcour, J. et al., “Direct Synthesis of the Barley Proanthocyanidins Prodelphindin B3, Prodelphinidin 2 and Two Trimeric (52) U.S. Cl. ...................................................... 549/4O6 Proanthocyanidins with a Mixed Prodelphinidin-Procyanidin (58) Field of Classification Search ................. 54974O6 Stereochemistry”. J. Inst. Brew, 1986, vol. 92, pp. 244-249. See application file for complete search history. Ishimaru et al., Phytochemistry, 1987, vol. 26, No. 4, pp. 1160-1170. (56) References Cited Kozikowski et al. “Studies in Polyphenol Chemistry and Bioactiv ity”. J. Org. Chem. 2000, 65, 5371-5381. U.S. PATENT DOCUMENTS Primary Examiner Taofiq Solola 4,644,011 A 2, 1987 Ballenegger et al. ....... 514,456 5,554,645 A 9/1996 Romanczyk, Jr. et al. .. 514/453 (74) Attorney, Agent, or Firm Margaret B. Kelley; 6,156,912 A 12/2000 Tickmantel et al. ........ 549,399 Gibbons, Del Deo, Dolan 6,207,842 B1 3/2001 Romanczyk, Jr. et al. .. 549/399 6.420,972 B1 7/2002 Loose ..................... 340,545.1 (57) ABSTRACT FOREIGN PATENT DOCUMENTS DE 1518003 1, 1969 Oligomeric procyanidins containing 4C-linked epicatechin EP OO39 844 11, 1981 units are rare in nature and have hitherto not been accessible EP 1 O26 164 A1 8, 2000 through stereoselective synthesis. Provided herein is the WO WO 90,13304 11, 1990 preparation of the prototypical dimer, epicatechin-4C.8- WO WO99, 19319 4f1999 epicatechin, by reaction of the protected 4-ketones with aryllithium reagents derived by halogen/metal exchange OTHER PUBLICATIONS from the aryl bromides. Removal of the 4-hydroxyl group Kawamoto et al., “Synthesis of Condensed Tannin Derivatives from the resulting tertiary benzylic alcohols is effected by Regiospecifically Linked through a Single Interflavanoid-Linkage tri-n-butyltin hydride and trifluoroacetic acid in a completely and Their Protein-Precipitating Capacities'. Mokuzai Gakkaishi, Stereoselective manner, resulting in hydride delivery exclu 1991 37(8), p. 741-747. sively from the B face. Ferreira et al., “Diversity of Structure and Function in Oligomeric Flavanoids”, Tetrahedron Report No. 308, 1992, 48(10), p. 1743 1803. 9 Claims, No Drawings US 7,126,014 B2 1. 2 SYNTHESIS OF EPECATECHIN-4o, The stereochemistry of the substituents on a polyphenol 8-EPICATECHIN AND -CATECHN DIMERS monomeric unit of a proanthocyanidin may be described in AND DERVATIVES THEREOF terms of their relative stereochemistry, “alpha/beta’ or “cis/ trans’. The term “alpha” (C) indicates that the substituent is This application is a divisional application of prior appli oriented below the plane of the flavan ring, whereas, “beta' cation Ser. No. 10/214,830 filed Aug. 8, 2002, now U.S. Pat. (B) indicates that the substituent is oriented above the plane No. 6,720,432 issued Apr. 13, 2004, which is a divisional of the ring. The term “cis' indicates that two substituents are application of prior application Ser. No. 09/655,360 filed oriented on the same face of the ring, whereas “trans' Sep. 5, 2001, now U.S. Pat. No. 6,476,241 issued Nov. 5, 10 indicates that two Substituents are oriented on opposite faces 2002. of the ring. The isolation of pure proanthocyanidins from natural FIELD OF THE INVENTION Sources becomes increasingly difficult with increasing degree of oligomerization. Degradation by thiolysis permits This invention, in general, relates to polyphenolic prod 15 identification of the underlying monomeric units but the ucts, particularly proanthocyanidins. The invention further tasks of elucidating the position and stereochemistry of the relates to synthetic processes for preparing polyphenolic interflavan linkages is nontrivial. Both of these factors have natural products and other related compounds. resulted in few defined oligomers above the tetramer being described in the prior art. Proanthocyanidins and their parent BACKGROUND OF THE INVENTION monomers also occur naturally in the form of a variety of derivatives, for example, glycosides or esters with hydroxy Proanthocyanidins (nonhydrolyzable tannins) are a group lated aromatic carboxylic acids, Such as gallic or hexahy of polyphenolic natural products, of current interest because droxydiphenic acid. of their numerous biological activities, their widespread Among the proanthocyanidins, two Subtypes, the procya occurrence in foodstuffs, and their resulting relevance for 25 nidins (5.7.3',4'-hydroxylation) and prodelphinidins (5.7.3", human health. 4',5'-hydroxylation), are widespread in human foodstuffs, Proanthocyanidins are dimeric or oligomeric flavanoids e.g., cocoa. Cocoa procyanidins consist predominantly of which have one or several hydroxyl groups on their aromatic epicatechin (the C-3 epimer of catechin) building blocks. rings and often an additional hydroxyl group in the 3 Oligomers up to the size of the decamer have been identi position. Eleven different hydroxylation patterns of the A 30 fied. From the pentamer on, these oligomers exhibit growth and B rings have been found in nature. Representative inhibitory activity against various cancer cell lines. (Ro proanthocyanidins include: manczk, L. J. Jr.; Hammerstone, J. F., Jr.; Buck, M. M. U.S. Pat. No. 5,554,645, Sep. 10, 1996.) Flavan-3-ols are bio synthetically derived from (2S)-phenylalanine via flavan-3, 35 4-diols. These latter intermediates readily form a highly stabilized carbenium ion (or quinone methide) in position C-4 which attacks the A ring of a flavan-3-ol in what is essentially a Friedel–Crafts alkylation process forming an interfiavan bond. This process can be repeated once or 40 several times, resulting in chain-type oligomers which together with the dimers are known as non-hydrolyzable 5 4 tannins, condensed tannins, or proanthocyanidins. As one skilled in the art will realize, the structural complexity of Substitution Pattern these compounds rapidly increases with their chain length as 45 a consequence of different hydroxylation patterns and C-3 Class Monomer 3 5 7 8 3' 4' 5 Stereochemistry in the monomer units and different regio Proapi- Apigeni- H OH OH H OH and stereochemistries of the interflavan linkages, as well as geninidin flavan Proluteo- Luteoli- H OH OH OH OH additional structural modifications. In addition, chain inidin flavan 50 branching may occur by alkylation of a monomer unit in Protri- Triceti- H OH OH OH OH OH both its 6- and 8-positions. cetinidin flavan To prove definitively the structures assigned to the com Propelar- Afzelechin OH OH OH H OH gonidin pounds purified from cocoa, comparisons must be made to Procya Catechin OH OH OH OH OH epicatechin dimers and oligomers of defined structure pre nidin 55 pared synthetically. Synthetic monomers, dimers and oligo Prodel Gallo- OH OH OH OH OH OH phinidin catechin mers are useful to develop structure-activity relationships in Progui- Guibour- OH H OH H OH various in vitro and ultimately in vivo models of anticancer Ol- tinidol activity. inidin The synthetic challenge posed by procyanidins is related Prof- Fisetinidol OH H OH OH OH Setinidin 60 to the difficulty in controlling the interfiavan regio- and Prorobi- Robine- OH H OH OH OH OH Stereochemistry, as well as the sensitivity of the non-pro netinidin tinidol tected compounds to acids, bases, and oxidizing agents. The Proteraca- Oritin OH H OH OH H OH cinidin condensation between flavan-3-ols and 4-substituted, elec Promelac- Prosopin OH H OH OH OH OH trophilic flavans has traditionally been performed without acinidin 65 the use of phenol protecting groups in a mildly acidic medium or recently with AgBF for benzylthio as the 4-sub stituent.
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