Indian Journ al or Chcmistry Vol. 418, Novcmber 2002, pp . 239S-2398

Note

A practical synthesis of lra ns-resveratro l HO

Zhen Shen . Guang & Xua n Zhen ang* Department of Chcmistry. Z hejiang University, :lI1 Campus, OH Hangzhou, Zhcjiang. 3 10027 , P.R.China

Receil'ed II Jalluary 2002; accepfed ( revised) 14 JUlie 2002 1

Thc to tal sy nthcs is of biological ly ac ti vc substance frallS­ 3,5-Dihyd roxybenzo ic ac id on treatment with al ka­ re svcratro l 1 has bce n dcscri bed wi th modcrate ovcrall y ield (3S.7 %). Starti ng frolll 3,S-d ihydroxybenzoic ac id, 3,S­ e dimeth yl sul fa te afforded meth yl 3,5-dimethoxy­ dimcthoxybcnzo nat c mcth y l cster is prcpared. The react ion of the benzoate 2 in good yield in one step. The un es teri fied estcr with hydrnine hydrate fol lowcd by oxidation with prod uct 3 obtained from thi s reacti on was esteri fied K, fFe(C )61 givcs the key intermediate 3,S-dilllethoxy­ by meth anol to provide more of compo un d 2. Subse­ benzaldehyde, which is condcnsed with diethyl(4-lllct hoxy­ benzy l)phosphonate to yield only fralls-3,S,4'-t rilllct hylstilbe ne. quent treatment of th e ester 2 with hydraz in e hydrate T hc sy nthe sis of fralls-rcsvera trol is complcted by the dcprotec­ afforded benzo hydraz ide 4. Oxid ati on of 4 wi th ti on reaction with BBr,ICH2C1 2. K3[Fe(CN)6] gave the key interm edi ate 3,5- dimethoxybenzaldehyde 5. The yield of the ox idati on trans-Resveratrol ((£)-3,5,4'-trihydroxystilbene) 1 has reacti on was improved in th e presence of catalyti c bee n identified as a constituent of many pl ant species. amount of PEG-400, which served as a ph ase-transfe r It has potent anti fun ga l properti es and appears to be catalys t. Foll ow in g th e Wittig-Honer reacti on, the t sy nthesized by vines in res ponse to fun gal infection -] compo un d 5 condensed with dieth yl (4- methoxy­ Biological interest in lralls- resveratrol 1 is sti mul ated benzy l) phosphonate 7 in DMFI aOCH} to give only by reports of its presence in Japanese herbal medi ca­ trans-3,5,4'-tri me th ylstilbene 8. Thi s was more kely ti ons used for the treatment of fun gal, in fa mm atory, due to th e tri eth yl ph osphite ester to be used, all owing 4 and lipid di so rders . In fac t, hydroxylated stilbenes iso meri zati on of th e double bond to th e th ermody­ have been in vesti gated both fo r th eir ological ro le in nami call y favo ured trans-i somer. The yield was al so pl ant defence again st path ogens and fo r th eir phanna­ improved by the addition of small amount of phase­ s cological propeni es . Because of its remarkabl e transfer catalyst tetrabutylammonium iodi de. The in­ ph ys iological activity, we were in terested in th e total termedi ate diethyl(4 -methoxybenzy l)phosphonate 7 sy nthesis of thi s natural prod uct. was prepared by sequential brom in ati on and ph os­ Currentl y, ve ry few stu dies have concerned th e to­ phonati on of 4- meth oxy lbenzyl alcohol (see 6 1I tal sy nth esis of hyd roxylated stilbenes - . Attempts to Scheme II). We tri ed to carry out the Witti g reaction prepare trans-resveratro l by cond ensati on of by condensing 5 with dimeth yl(4-meth oxybenzyl)­ triphenylbenzy lphosph onium bromide with methoxy­ ph osph onate or diphenyl(4-meth oxybenzy l)ph os­ benza ldehyde were not very successful because of its ph onate. The results were undesirabl e i.e. relati ve low yield . Moreover, cis-i so mer product was also lower yield of trans-i so mer; fa irl y large amoun t of fo rmed, whi ch was difficult to be separated. We, cis-i somer (ca.30%) whi ch resul ted in th e di fficulty of therefore, turned to modify Wittig reacti on usin g the seperati on. In order to deprotect th ree meth yl groups, ph osphonate intermedi ate and th e trans-i somer was several deprotecti g agents, such as A IC I)/CH 3CN, exclu sively ac hi eved. In the case of the presence of A lh/CH3CN , A II 3/CS4, BBr)CH2Ci2 and BBr3/(CH)]S, ph ase transfer agent, th e Wittig reacti on proceeded were used '2 . The res ults ex hi bited that BBr3/CH]Ci 2 with improved yield. In thi s note we descri be th e sy n­ was the bes t one. The hi gh yield (90%) was reached th es is of trans-resveratrol 1 (see Scheme I). The pre­ and onl y trans-resveratroll was obtained. sent route is suitable for large-scale producti on of lrans-resveratro l 1 with th e adva ntages of hi gh overall Experimental Section yield, mild reacti on conditi ons and use of in ex pensive All bps are uncorrected. Melting po int was meas­ materi als. ured usin g XT-4 mi cromeltor. IR spec tra were 2396 I DIAN J. CIIEM .. SEC B. OVEMBER 2002

2 4

CH30H K3[ Fe(CN)6] PEG-400 'f

3

CH3 OCH3

CH3

H OH

H

Scheme I

20H 2PO H three-necked flask with 50 mL of distil led water and 92Br 9 (OC2 S)2 30% NaOH aqueous solution with stirring until the ":: PB ri CH2CI2 ":: P(OC2Hs)3 ":: pH of 13.0 was achieved . The mixture was stirred for I ,/ » I , I // .& .& anoth er L hr. T hen (CH3hS0 4 (80 mL) and 30% 9 NaOH were added dropwise simultaneously at 40°C OCH OCH OCH 3 3 3 until the fina l pH of solution was 8.5-9. (CH3h S04 6 7 ( 10 mL) was added slowly at temperature 80-90°C and th e mixture stirred further fo r 2 hI'. The product Scheme II obtai ned was poured into 500 mL water and left 'over­ recorded on a icolet 5DX FT-IR spectrometer ght at room temperature. It was filtered, washed and (cnf\ IHNMR spectra o n a Bruker AVANCE dried to give browni sh soli d 2 in 82.5% yield . The DMX500 NMR using TMS as internal standard fi ltered li q uo r was neutralized wi th 10% HC I until the (chemical shi fts in (5, ppm); and mass spectra on a p H 4-5 reached. The white fine powder 3 was ob­ HP5890GC/MS spectrometer. Column chromatogra­ tained after fil tering and washing in 12.7% yield. phy was carri ed out over Ii ca-gel (80- 100 mesh). Then 3 was esterified with methanol by well estab­ A ll material s used were of anal yti cal g rade. li shed method to give ester 2 (8 1.8(}f, yield ). Thus, Synthesis of methyl 3,S-dimethoxybenzoate 2 th e overall yield of 2 was 92.9%, mp 38-42°C; IR from 3,S-dimethoxybenzoic acid. 3,5-Dih ydroxy­ (KBr; cm' I): 2959, 1717, 1598, 1457. 1352, 1300, benzoic acid (20.0 g) was charged into a 250 mL 1242, 1158, 1065,887, 762, 675; MS (1I1I z): M+ 196 NOTES 2397

( 100%), 165 (60%), 13 8 (20%), 137 (20%), 135 962, 852, 567; MS (m/z): M+ 258 (51 %), 230 (8%), ( 12%), 122 ( 18%), 107 ( 15 %), 92 (3%), 79 (6%), 77 2 15 (3%), 202 (2%), 149 (3 %), 135 (4%), 12 1 ( 10%); IH NMR(CDCh): 8 3.80 (s, 6 H, ArO-CH}), ( 100%),9 1 (8%),78 (10%), 65 (2%). 3.87 (s, 3H, CO ~ C H :l ), 6.62 (t, IH , p-Ar-H), 7. 12 (d, Synthesis of tralls-3,5,4'-tl"imethylstilbene 8 from 2H, o-Ar-H) . phosphonatc 7 and benzaldehyde 5. A mixture con­ taining 7 (4.70 g) in 30 mL DMF, NaOCH] (3.00 g) Synthesis of 3,5-dimethoxybenzaldehyde 5 from and catal ytic amount of tetrabutylammonium iodide 2. A mi xture of 2 (20.0 g) and 50% hydrazine hydrate was stirred at room temperature fo r I h1'. Then a solu ­ (70 mL) was reflu xed for 3 h1'. Water (200 mL) was ti on of 5 (3.00g) in 10 mL DMF was added under ni­ th en added. The white crystals 4 (y ield 93.3%, mp trogen. The reaction mi xture was all owed to stir for D 168-1 69 C) were obtained after cooling and filtering. 8 hr at 40De. The product thus obtained was poured The hydrazide 4 di ssolved in toluene (80 mL) and into 100 mL water and extracted with ether 25% ammoniulll soluti on (50 mL) with catal ytic (5 X 30 mL). The organic layer was washed with wa­ amount of PEG-400 were added. To this solution ter, dri ed over MgS04 followed by di stillation of the K3[Fe(CN)6] (30.0 g) in 70 mL water was carefully solvent. The residue was recrystallized from methanol D added within I hr with vigorous stirring at 10-15 e. to afford 8 as colourless crystalline needles, yield The reaction mixture was constantly stirred for an 60.7%, mp 54-56DC; lR (KSr, cm·I): 2990, 2832, additional 4 hI' when temperature was elevated to ca. 1592, 1511 , 1459, 1426, 1279, 1253, 1193, 11 55, D 20 e. The organic layer was separated from the aq ue­ 1070, 103 1, 954, 822; MS(I71/z): M+ 270 ( 100%), 255 ous layer by usin g toluene extract (3x 30 mL), (6%),239 (10%), 224 (8%), 2 12 (7 %), 196 (8%), 18 1 washed, dried (Na2S04), and concentrated to give th e (4%), 165 (4%), 152 (9%),141 (5%), 127 (3 %), 115 brownish solid. It was recrystalli zed from pet. ether (5 %); IH NMR(CDCI ): 8 3.80 (s, 9H, -OMe), 6.34 (t, D 3 (bp 60-90 C), and then purified by sili ca-gel column IH, 1=2 Hz, H-4), 6.64 (d, 2H, 1=2 Hz, H-2.6), 6.88, chromatography to give the desired compound 5 with 7 .04 (d, each I H, 1=16 Hz, CH=CH), 6.90 (2 H, d, 1=8 D I fairly hi gh yield (75.4%), mp 44-46 C ; IR(KSr, cm· ): Hz, H-3.5), 7.42 (d, 2H, 1=8 Hz, H-2,6). 2943,2842, 2715, 1699, 1600, 1470, 1207, 1050,823, Synthesis of trans-resveratrol 1 from tralls- 684 ; MS (I1I/Z): M+ 166 ( 100%), 135 (26%), 109 3,5,4'-trimethylstilbene 8. A solution of 8 ( LlO g) in (12%), 105 (8 %), 77 (10%) , 63 (10%), 51 (4%),41 CH2C1 2 (50 mL) was added into 30 mL BBr3 (ImollL 0 (2%); IH NMR (CDCI3): 8 3.85 (s, 6H, Ar-OCH}), CH2C1 2 soluti on) dropwise at 10 e. The red mixture 6.7 1 (s, IH, p-Ar-H), 7.02 (d, 2H, o-Ar-H), 9.91 was continuously stirred for 2 hr at room temperature. (s , I H, -CHO). . When the colour of solution started turning from red to colourless or pale, the product was poured into 100 Synthesis of diethyl( 4-methoxybenzyl)phos- mL ice-water with vigorous stirring. Then the solution phonate 7 from 4-methoxylbenzyl alcohol. A solu­ was extracted with ethyl acetate (2 X 25 mL) and tion of 4-meth oxybenzyl alcohol (2.75 g ) in CH2C1 2 dried over MgS04 . After re moval of the solvent, (30 mL) was cooled to ODC and PSr) (5.50 g) was white powder was obtained. Finally the product was added dropwise with stirring under nitrogen. The re­ recrystalli zed (acetone/hexane, 1: I) and further puri­ acti on was continuously stirred for an additional 3 hr fied with sili ca gel column chromatography to give 1, at room temperature. The product was poured into yield 90.0%, mp 253-255DC; IR (KSr, cm·I): 3290, 200 mL of ice-water and extracted with eth er (3 X 30 1589, 1511 , 963, 830, MS (m/z): M+ 228 ( 100%), 2 11 mL). The organic layer was washed with water and (10%), 199 (6%), 18 1 (19%), 165 (6%), 15 3 (9%), dri ed over MgS0 4 . On removal of the solv ent 4- 14 1 (5%), 128 (6%), 115 (10%), 107 (7%), 91 (5%), methoxybenzyl bromide 6 was obtain ed as an o il , 77 (9%), 69 (8%), 63 (7%), 55 (10%); yield 95 %; IR(KSr, cm·I): 1609, 15 13 , 1463, 1303, IH NMR(CDCI3): 6.10 (t, IH, 1=2 Hz, 4-H), 6.40 (d, 1253, 1175, 1033, 830, 596, 531; MS ( I1I/Z): M+ 20 I 2H, 1=2 Hz, 2,6-H), 6.73 (d, IH, 1=16 Hz, ex - H) , (5 %),200 (5 %), 121 ( 100%), 106 (4%), 91 (5 %),78 6.76 (d, 2H, 1=7.9 Hz, 3',5'-H), 6.96 (d, IH, 1=16 Hz, ( 12%), 51 (5 %). Then the equi valent tri ethyl (3 -H), 7.28 (d, 2 H, 1=7.9 Hz, 2',6'-H). phosphite and 6 were refluxed for 10 h1'. A pale brownish oil of 7 was obtained. This product was not References purified further and used directly for the next step. IR I I Carbo N, Caste lli P & Racci no F M, /Jiochelll & /J iophys Res (KEr, cm· ): 2982, 16 11 , 151 3, 1249, 1179, 103 1, COIlllln/II , 254, 1999.739. 2398 INOIAN J. CHEM., SEC B, NOVEMBER 2002

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