Indian Journ al or Chcmistry Vol. 418, Novcmber 2002, pp . 239S-2398 Note A practical synthesis of lra ns-resveratro l HO Zhen Lu Shen . Guang Lan Zhuo & Xua n Zhen Ji ang* Department of Chcmistry. Z hejiang University, Yu QU :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 lin 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 li 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 bi 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 ni 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 si 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 an 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.