Synthesis of ellagic acid and its 4,4'-di-Ο-alkyl derivatives from gallic acid is described. Ellagic acid is prepared by oxidative coupling of gallic acid with ο-chloranil. Functionalized methyl bormogallate underwent Ullmann coupling to give the biphenyl that upon lactonization resulted in the ellagic acid and its alkoxy derivatives

Alam, Ashraful

Takaguchi, Yutaka

Tsuboi, Sadao

Okayama University Digital Information Repository

Synthesis of ellagic acid and its 4,4'-di-Ο-alky derivatives from gallic acid

Okayama University Scientific Achievement Repository

Journal of the Faculty of Environmental Science and Technology,Okayama UniversityVoLlO, No.1, pp.l11-117, February 2005Synthesis of ellagic acid and its 4,4'-di-O-alky derivatives from gallic acidAshraful Alam,a,b Yutaka Takaguchia and Sadao Tsuboia,*(Received November 29, 2004)Synthesis ofellagic acid and its 4,4'-di-O-alkyl derivatives from gallic acid is described.Ellagic acid is prepared by oxidative coupling of gallic acid with o-chloranil.Functionalized methyl bormogallate underwent Ullmann coupling to give the biphenylthat upon lactonization resulted in the ellagic acid and its alkoxy derivatives.Keywords: ellagic acid, 4,4'-di-O-alkylellagic acid, Ullmann coupling, oxidativecouplingIntroductionEllagic acid and its derivatives are very potent fortheir various biological activities such asanti-tumor, I anti-HIV,2 anti-cancer,3 anti-hepa-titis,4 anti-oxidant5 and anti-microbial6 effects.Interestingly ellagic acid and its derivativesexhibit free radical scavenging activity and thusused in anti-aging supplements.7 Takasaki8 hasreported the isolation of variety of ellagic acidderivatives and their inhibitory effects onEpstein-Barr virus action. They found theenhanced inhibitory activity of some ellagic acidderivatives than the parent compound ellagic acid.Other di- or trialkoxy derivatives (Fig. 1) alsofound to be much more active than the ellagicacid itself. Besides the wide biological activity ofellagic acid and its derivatives, these are used as*Corresponding author, Phone/Fax: 81-86-251-8898;E-mail: stsuboi6@cc.okayama-u.ac.jp"Department of Environmental Chemistry andMaterials, Faculty of Environmental Sciences andTechnology, Okayama University, Okayama, Japan.bOn study leave from Dept. of Chern., Shahjalal Uni.of Sci. and Tee., Sylhet-3114, Bangladesh.111important ingredients for some supliments suchas anti-aging, skin lightening and other skin carecosmetics.9 Recent study revealed that the ellagicacid prevent the breast cancer and base on this,some oral medicines or medicated creamscontaining ellagic acid are commerciallyavailable. 10Fig. 1 Ellagic acid and its 4,4'-di-O- derivatives.R1=R3=H, R2=R4= OMe;4,4'-di-0-methylellagic, 12aR1=R3=H, R2=~= 08n;4,4'-di-O-benzylellagic, 12bHigh concentration of Ellagic acid occurs inraspberries, strawberries, cranberries, grapes,berries, nuts such as walnuts, pecans, etc andthese are good sources for the dietaryrequirements of ellagic acid. In plants, it ispresent in the form of esters of glucose withhexahydroxydiphenic acid, called ellagitannin.When hydrolyzed, ellagitannin yields ellagic acid,and this method of hydrolysis is one of the majorsources of ellagic acid. On the other hand all the112 J. Fac. Environ. Sci. and Tech., Okayama Univ.l0 (1) 2005ellagic acid derivatives investigated so far eitherhas been isolated from the plants materials orderivatized from ellagic acid.4(b),8,1l Commercialellagic acid is provided by hydrolysis of naturalellagitannins. However, recently the synthesis ofellagic acid has been reported. 1ZHere we wish to report a simple method for thesystematic synthesis of ellagic acid, 4,4'-di-O-methylellagic acid 12a and 4,4'-di-O-benzyl-ellagic acid 12b from the cheap andcommercially available gallic acid. This methodcan also be applied for the synthesis of other4,4'-di-O-derivative as well as other tri-O-derivatives of ellagic acid.Results and discussionCommercially available gallic acid 1 wasesterified to methyl gallate 2 by treating it withmethanol in the presence of HzS04. Methylgallate 2 was treated with oxidizing agento-chloranil at -40°C to room temperaturefollowed by the reduction with NaZSZ04 gave thehexahydroxy diphenyl 4. 13 Compound 4 wasrefluxed with MeOHlHzO (l :I) resulted inlactonization13 and gave the desired ellagic acid 5in high yield (Scheme I).Unlike most of the reported methods mentionedbefore, we started the synthesis of4,4'-di-O-alkylellagic acid from gallic acid 1(Scheme 2). For this purpose methyl gallate 2was converted to methyl 3-methoxy-4,5-dihydroxybenzoate 7a via acetal 6 in 99% yieldover 2 steps. Similarly, methyl 3-benzyloxy-4,5-dihydroxybenzoate 7b was also prepared inalmost 100% yield from 6. Regioselectivebromination of 7a and 7b at 6-position was doneby our DBDMH method,14 which gave thecorresponding bromides 8a and 8b respectively.The hydroxy groups of 8a and 8b were protectedas acetals 9a and 9b respectively. Then, the fullyhydroxy protected methyl bromogallate 9a and9b underwent the Ullmann coupling reaction togive the desired key intermediate lOa and lOb in40 and 70% yield respectively. Deprotection oflOa and lOb gave the tetrahydroxybiphenyl llaand llb in 98% ofyield.Scheme 1. Preparation ofellagic acid by oxidative coupling of gallic acidreflux, 8h, Quant.ii. Na2S204, rt.,30 mini. -40·C- rt., 3h..OHOH~o OMe ~OOMe'7' I~ '7'~ Io OH 0 OHo 03HO 0OH5, ellagic acido-chloranil,..MeOH:H20 (1:1),..OHoHO OHOH4,48% from 2~o OH 0 OMe'-'::: MeOH, H2S04, qI .. IHO .0 OHre~~~o6h, HO ~ OHOH OH1, gallic acid 2, methyl gallateOHAlam et al. / Synthesis of ellagic acid 113Lactonization of compounds lla and llb byrefluxing with MeOH/H20 (I: I) gave thequantitative yield of desired ellagic acidderivatives 4,4'-di-O-methylellagic acid 12a and4,4'-di-O-benzylellagic acid 12b respectively.Scheme 2. Preparation of4,4'-di-O-alkylellagic acid from gallic acid by Ullmann couplingo OMe ~OOMe~ (EtObCH,I ~ Amberlyst 15E. I ":::HO .0 OH benzene, O.b- OHOH reflux, 18h EtO~O2 6,99%~o OMei. Mel (or BnCI), DBDMHK2C03 ,DMF, ~ (0.51eq),70·C, 12h; ii. Hel, HO I .b- OR CHCI3, rt,MeOH, rt., 2h OH 24h7a, R= Me, 99%7b, R= Bn, -100%~o OMeSr ~.. IHO .b- OROHsa, R= Me, 98%8b, R= Bn, 95%~o OMe(EtObCH, Sr ~Amberlyst 15E, I.. 0 .0benzene ORreflux, 171, EtO>-O9a, R= Me, 69%9b, R= Bn, 66%Cu, DMF, 110·C,3h then 180·C 18h10a, R= Me, 40%10b, R= Bn, 70%2N HCI, MeOH,..rt., 4h, 98%oRoxt$&0HO I ~ 9' I OHo :::,... ORo12a, R= Me, 4,4'-di-o-methylellagic acid12b, R= Bn, 4,4'-di-o-benzylellagic acidOMeMeOH:H20 (1:1),..reflux, 8h, quant.OROH11a, R= Me11b, R= BnROExperimentalGeneral: All moisture-sensitive reactions werecarried out under nitrogen atmosphere usingoven-dried glassware. Solvents were dried overstandard drying agents. Reactions weremonitored on TLC on silica gel 60 F254 andvisualized under UV light and/or 5% ethanolicsolution of phosphomolybdic acid. Flashchromatography was performed on silica gel(Merck, 60N, spherical, neutral, 40-50 mash).Melting points were determined with aMel-TEMP apparatus. IR was recorded on aThermo Nicolet Avatar 360T2 instrument usingATR. 'H NMR (300 MHz) and BC NMR (75MHz) were recorded by JEOL AL 300 instrument.GC-MS was studied with a SHIMADZU GCMS-QP5000 instrument.Methyl gallate (2): To a 200 ml round bottomflask fitted with a condenser was added gallicacid 1 (6.00 g, 10.8 mmol), dry MeOH (120 ml)and cone. H2S04 (1.20 g), and then the mixturewas heated at retluxing temperature for 6-8 h.After completion of the reaction, the solvent was114 J. Fac. Environ. Sci. and Tech.. Okayama Univ.10 (1) 2005removed in vacou and extracted with EtOAcfollowed by washing with sufficient amount ofwater. The organic layer was concentrated invacou giving the crude methyl gallate 2.Recrystallization from hot water gave 6.36 g ofpure methyl gallate (99%).Dimethyl 4,4',5,5',6,6'-hexahydroxybiphenyl-2,2'-dicarboylate (4): Solution of 2 (1.70 g, 9.24mmol) in Et20 (90ml) was added dropwise underargon to a stirred cooled solution of o-chloranil(2.49 g, 10.1 mmol) in Et20 (20ml) at -40°c.After completion of the addition, the reactionmixture was allowed to warm slowly to rt. over 2hour and an additional 1h and was stirred at rt.The yellow solid was appeared at the bottom ofthe flask and separated by filtration. The solidwas washed extensively with cooled Et20 to givea yellow solid (1.28 g). The yellow solid wasdissolved in THF and solution was cooled to O°Cand Na2S204 (1.22 g) was added. The solutionwas stirred at rt for 30 min, poured in ice-cooledwater and the organic layer was extracted withEt20. Removal of the solvent gave the crudehexahydroxydiphenyl 4: mp 240-245°C(decomp.).IH NMR (CDCh- CD30D) 8 3.46 (s, 6H), 7.12 (s,2H), 7.66 (bs, 6H); 13C NMR (CDCh-CD30D) 851.33, 110.70, 118.73, 122.55, 137.53, 144.52,144.65.Ellagic acid (5): Compound 4 (260 mg) wasrefluxed in MeOH:H20 (1: 1, 5ml) for 18 hresulted in lactonization. Complete removal ofthe solvent yielded the crude ellagic acid 5 (218mg, 100%) which was recrystallized fromDMSO/CHCh (1: 1) to give a light brown solid:mp 350"C; IR: 3572, 3066, 1690, 1616, 1581,1446, 1396, 1326, 1195, III 0, 1053, 922, 882,756 cm,l (identical with the authentic ellagicacid). Anal. Calcd for CI4H60: C, 55.64; H, 2.00;Found: C, 55.52; H, 2.11.Methyl-3-hydroxy-4,5-(ethoxymethylenedioxy)benzoate (6): A mixture of compound 2 (2.50 g,13.6 mmol), (EtO)3CH (6.03 g, 40.7 mmol) andAmberlyst 15E (62 mg) in benzene (140 ml) wasrefluxed for 18 h with azeotropic removal of theEtOH:benzene mixture by using the Dean Starktrap. After completion, the reaction mixture wasfiltered over celite and the solvent was removedand directly put on a silica gel column eluted with10-15% EtOAc in hexane yielded 3.21 g of 6(99%) as a white solid: mp 91-92°C; IR: 3351,1709, 1618, 1438, 1316, 1254, 1081, 1038, 765cm,l; IH NMR (CDCh) 8 1.28 (t, 3H, J= 7.1 Hz),3.75 (q, 2H, J= 7.1 Hz), 3.88 (s, 3H), 5.56 (bs,IH),6.96(s, IH), 7.19 (d, IH, J= 1.5 Hz), 7.39 (d,IH, J= 1.8 Hz); l3C NMR (CDCh) 8 14.68,52.38,59.71, 102.71, 113.96, 120.04, 124.03, 137.08,138.68, 147.14, 166.95.Methyl 3-methoxy-4,5-dihydroxybenzoate(7a):Compound 6a was treated with Mel (1.2 eq),K2C03 (2.0 eq.) in DMF at 55-60"C for 12 h.Then the crude was extracted with Et20, washedwith brine, dried over MgS04and concentrated.The crude was treated with 2N aq.HCI at rt. for 2h in MeOH gave 7a (99% yield over 2 steps) as acolorless crystal: mp 115-119°C; IR: 3382, 1708,1593, 1506, 1436, 1243, 1161, 1058, 1000,964,726 cm'l; IH NMR (CDCh) 8 3.88 (s, 3H), 3.92(s, 3H), 5.49 (s, IH), 5.86 (s, 1H), 7.21 (d, IH, J=1.8 Hz), 7.34 (d, IH, J= 1.8 Hz); l3C NMR(CDCh- CD30D) 8 51.85, 55.96, 104.94, 110.78,120.38,138.51, 144.21, 147.18, 167.56.Alam et a1. / Synthesis of ellagic acid 115Methyl 3-benzyloxy-4,5-dihydroxybenzoate(7b): Using a similar procedure of 7a withBnCI instead of Mel compound 7b was obtainedin ~100% yield as a colorless solid: mp142-145°C; lR: 3412, 3342, 1686, 1434, 1326,1239, 1055,744 em-I; IH NMR (CDCh) 8 3.87 (s,3H), 5.14 (s, 2H), 5.36 (s, IH), 5.84 (s, IH), 7.31(d, lH, J= 1.8 Hz), 7.35 (d, IH, J= 1.8 Hz),7.39-7.43 (m, 5H); l3C NMR (CDCh-CD30D) 851.76, 71.03, 106.36, 110.92, 120.36, 127.71,128.06, 128.38, 136.08, 138.62, 144.33, 167.33Methyl 2-bromo-3,4-dihydroxy-5-methoxyben-zoate (8a): Using the procedure of ref. 14, 8awas prepared form 7a in 98% yield as a slightyellow crystal: mp 140-142°C; lR: 3461, 3341,1717, 1601, 1429, 1292, 1210, 1101, 1018,923,776 em-I; IH NMR (CDCh) 8 3.91 (s, 3H), 3.94(s, 3H), 5.84 (s, IH), 5.92 (s, lH), 7.18 (s, IH);l3C NMR (CDCh) 8 52.30,56.42, 103.26, 107.06,121.81, 136.68, 141.36, 145.67, 165.94.Methyl 2-bromo-3,4-dihydroxy-5-benzoxyben-zoate (8b): Using the same procedure of 8a, 8bwas prepared from 7b in 95% yield as a lightyellow crystal: mp 116-118"C; lR : 3370, 1712,1342, 1222, 1000 em-I; IH NMR (CDCh) 8 3.90(s, 3H), 5.14 (s, 2H), 5.91 (s, IH), 5.92 (s, IH),7.27 (s, 1H), 7.38-7.52 (m, 5H); l3C NMR(CDCh- CD30D) 8 52.14, 71.34,103.24, 108.31,121.44, 127.96, 128.45, 128.62, 133.74, 137.64,142.61, 144.93, 167.37.Methyl 2-bromo-3,4-(ethoxymethylenedioxy)-5-methoxybenzoate (9a): Using the similarprocedure as compound 6, compound 9a wasprepared in 69% yield from 8a as a white solid:mp 80-81°C; lR: 1722, 1432, 1318, 1171, 1081,1035, 938, 752, 700 em-I; 'H NMR (CDCh) 81.28 (t, 3H, J= 7.1 Hz), 3.73 (q, 2H, J= 7.1 Hz),3.91 (s, 3H), 3.94 (s, 3H), 7.01 (s, IH); 13C NMR(CDCh) 8 14.68, 52.28, 59.85, 71.79, 94.16,114.41,119.91, 124.17, 127.65, 128.32, 128.59,135.90, 137.24, 140.43, 146.57, 165.41.Methyl 2-bromo-3,4-(ethoxymethylenedioxy)-5-benzoxybenzoate (9b): Using the similarprocedure of 9a, 9b was prepared in 66% yieldfrom 8b as a light yellow crystal: mp 116-118°C;lR: 3370, 1712, 1342, 1222, 1000 cm-\ IH NMR(CDCh) 8 3.90 (s, 3H), 5.14 (s, 2H), 5.91 (s, IH),5.92 (s, IH), 7.27 (s, 1H), 7.38-7.52 (m, 5H); 13CNMR (CDCh-CD30D) 8 52.14, 71.34, 103.24,108.31, 121.44, 127.96, 128.45, 128.62, 133.74,137.64, 142.61, 144.93, 167.37.Dimethyl 4,4'-dimethoxy-5,6,5',6'-bis(ethoxymethlenedioxy)biphenyl-2,2'-dicarboxylate (lOa): Amixture of compound 9a (655 mg), Cu powder(655 mg) and DMF (1.5 ml) was stirred at 110°Cfor 3h. Then another 10 ml of DMF was addedand the reaction mixture was stirred at 180°C for18 h. After completion, crashed ice was addedand extracted with CHCh. The organic layer waswashed with water and then brine, dried overMgS04 and concentrated in vacou. Purificationby silica gel column chromatography (eluted with20% EtOAc in hexane and then 100% CHCh)gave 155 mg of lOa (40%). White solid, IH NMR(CDCh) 8 1.28 (1, 6H, J= 7.1 Hz), 3.73 (q, 4H, J=7.1 Hz), 3.84 (s, 6H), 4.00 (s, 3H), 4.03 (s, 3H),6.89 (s, 2H).Dimethtl 4,4'-dibenzoxy-5,6,5',6'-bis(ethoxymethylenedioxy)biphenyl-2,2'-dicarboxylate (lOb):Using the same procedure as lOa, lOb was116 1. Fac. Environ. Sci. and Tech., Okayama Univ.lO (1) 2005obtained in 70% from 9b as gummy solid. IR:2979, 1724, 1638, 1589, 1433, 1348, 1314, 1243,1171, 1091, 1036, 906, 746, 698. IH NMR(CDCh) 01.28 (t, 6H, J= 7.1 Hz), 3.73 (q, 4H, J=7.1 Hz), 3.60 (s, 6H), 5.24 (s, 4H), 7.34--7.49 (m,12H); l3C NMR (CDCh) 0 14.13, 14.56, 14.65,14.68, 51.76, 51.85, 58.27, 58.66, 58.72, 58.93,71.48, 111.29, 111.61, 111.87, 112.59, 112.66,112.71, 112.76, 119.63, 119.70, 119.73, 119.87,123.05, 123.21, 123.41, 123.63, 127.73, 128.18,128.54, 128.66, 128.68, 136.27, 136.97, 137.09,137.14, 140.58, 140.69, 140.75, 140.82, 145.70,145.75, 166.21, 166.23, 166.25.Dimethyl 5,5',6,6'-tetrahydroxy-4,4'-dimethoxybiphenyl-2,2'-dicarboxylate (11a): Treatment oflOa with 2N HCI in MeOH at room temperaturefor 4 h gave the hexahydroxy biphenyl 11a in98% yield. White solid, IH NMR(CDCh-CD30D) 0 3.63 (s, 6H), 3.75 (s, 6H),5.30 (s, 2H), 5.89 (s, 2H), 7.42 (s, 2H).Dimethyl 5,5',6,6'-tetrahydroxy-4,4'-dibenzoxybiphenyl-2,2'-dicarboxylate (11b):Using thesame procedure as 11a, 11b was also prepared in98% yield from lOb. IR: 3232, 1701, 1617, 1572,1497, 1444, 1371, 1338, 1255, 1186, 1126, 1089,810, 757, 740, 695. IH NMR (CDCh) 0 3.63 (s,6H), 5.18 (s, 4H), 5.30 (s, 2H), 5.89 (s, 2H),7.40~7.46 (s, 1H), 7.38-7.52 (m, 12H); l3C NMR(CDCh) 8 51.86, 71.26, 107.00, 1l9.09, 121.30,128.22, 128.53, 128.74, 133.95, 136.58, 141.72,144.97, 166.74.4,4'-Di-O-methylellagic acid (12a): Compound11a was dissolved in MeOWH20 (1:1) and wasrefluxing at 1100e for 8 h gave the final product12a in almost quantitative yield. Light brownsolid: mp 358-361°C(decomp) (lit. IS 360-363); IHNMR (CDCh- DMSO-D6) 0 4.00 (s, 6H), 7.57 (s,2H), 7.85 (s, 2H).4,4'-Di-O-benzylellagic acid (12b): Using thesimilar procedure as 12a, 12b was prepared inquantitative yield. Light yellow solid, mp280-285 "C (decomp); IH NMR (CDCh-DMSO-D6) 0 5.31 (s, 4H), 7.35~7.45 (m, 6H),7.51-7.55 (m, 4H), 7.66 (s, 2H), 7.92 (s, 2H).AcknowledgementWe would like to thank Miss. RozanaBorhannoddin for doing some related preliminaryexperiments.References1. 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Synthesis of ellagic acid and its 4,4'-di-Ο-alky derivatives from gallic acid

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