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WO2001060774A1 - Synthese de resveratrol - Google Patents

Synthese de resveratrol Download PDF

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Publication number
WO2001060774A1
WO2001060774A1 PCT/US2001/005167 US0105167W WO0160774A1 WO 2001060774 A1 WO2001060774 A1 WO 2001060774A1 US 0105167 W US0105167 W US 0105167W WO 0160774 A1 WO0160774 A1 WO 0160774A1
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Prior art keywords
resveratrol
compound
group
protecting groups
benzyl
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Ceased
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PCT/US2001/005167
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English (en)
Inventor
Merritt Andrus
Erik Meredith
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Brigham Young University
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Brigham Young University
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Priority to AU2001241539A priority Critical patent/AU2001241539A1/en
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Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring

Definitions

  • the present invention relates to methods of chemical synthesis of naturally occurring organic compounds. More specifically, the invention relates to the chemical synthesis of (E)-3,5,4'-trihydroxystilbene, hereinafter resveratrol.
  • TECHNICAL BACKGROUND Plants have been a source for many of the drugs and other chemicals that humans use to fight disease and alleviate the symptoms of disease. Some plants such as herbs have been shown to contain compounds that relieve pain. Other plants have been shown to contain compounds that might be used to treat mental illness. Yet other plants contain compounds that treat are useful in treating high blood pressure. For example, epicatechins, found in green tea, have been shown to prevent certain types of cancer, lower blood pressure, and reduce inflamation. Genistein, from soy beans has also been shown to prevent cancer, lower blood pressure, and reduce osteoporosis. Gordon, M. H., Nat. Prod. Reports, 1996, 265-287.
  • Resveratrol has been noted for its disease preventative qualities in humans and has been attributed as the reason for the so-called "French Paradox.”
  • the French Paradox is that although the Mediterranean diet containing high levels of fat and alcohol, the expected increase in rates of cancer and heart disease is not observed. Renaud, S & DeLorgeril, M., Lancet 1992, 339:1523.
  • Resveratrol is a small organic molecule naturally occurring in grape skins, mulberries, peanuts, and other plants. Resveratrol inhibits the initiation, promotion, and the progression of cancer.
  • resveratrol has been shown to be a vasorelaxant, inhibiting the contractile response of the aorta to noradrenaline. Chen, C.K. & Pace-Nsciak, C.R. Gen. Pharac. 1996, 27: 363-366. Others have shown that resveratrol inhibits platelet aggregation and coagulation. Goldberg, et al., Clin. Chim. Acta 1995, 237: 155; Pace- Nsciak, C.R. Clin Chim Acta 1995, 235: 207; Nrrichi H., Chem. Pharm. Bull. 1982, 30: 1766.
  • N few methods of chemically synthesizing resveratrol have been introduced, although these methods require expensive starting materials which also raise the cost of producing resveratrol.
  • the methods of synthesizing resveratrol also produce large amounts of by-products. These by-products must be removed between the various steps of the synthesis to prevent interference and contamination of the end-product.
  • the purification of the reaction products is done by silica gel chromatography. However, such chromatography increases the overall time required for synthesis and can significantly add to the cost. Because of the product lost during the purification and to the by-products, the overall yield of resveratrol is reduced.
  • the present invention relates to a method of synthesizing (E)-3,5,4'- trihydroxystilbene, resveratrol.
  • a reliable Horner-Emmons coupling reaction is used to couple a benzylic phosphonate to a protected aldehyde.
  • This route of synthesizing resveratrol is relatively inexpensive and uses readily available starting materials and reagents.
  • the coupling step is illustrated by the following diagram:
  • R 1 , R 2 , and R 4 are protecting groups such as methyl, benzyl, alkyl, silyl, and the like.
  • R 1 , R 2 , and R 4 can be the same protecting group or may be different protecting groups.
  • R 5 is an alkyl group such as isopropyl, methyl, ethyl, butyl, and the like.
  • the method of synthesizing resveratrol can begin with a starting material such as resorcylic acid.
  • a starting material such as resorcylic acid.
  • protecting groups are added to the 3 and 5 hydroxy groups of the resorcylic acid.
  • the 3 and 5 protecting groups can be methyl, benzyl, alkyl, and the like. Both of the protecting groups can be identical, or each protecting group can be different.
  • the carboxylic group is reduced.
  • the reduced carboxylic group is halogenated with, for example, bromine to form a compound of the formula:
  • R 1 and R 2 are protecting groups and R 3 is a halogen. This compound is reacted with R 4 , an alkyl phosphite according to the following formula:
  • R 5 may be an alkyl group such as isopropyl, methyl, ethyl, butyl and the like.
  • the phosphonate of this reaction can be coupled to the substituted benzaldehyde as discussed above.
  • 3,5- dihydroxybenzoic acid is obtained as a starting material.
  • the 3 and 5 hydroxy groups are benzylated to form 3,5-dibenzyoxybenzoic acid.
  • the carboxylic group of the 3,5- dibenzyoxybenzoic acid is reduced to form 3,5-dibenzyloxybenzyl alcohol.
  • the hydroxy group of the reduced carboxylic acid is brominated to produce 3,5-dibenzyloxybenzyl bromide.
  • Isopropyl 3,5-dibenzyloxybenzyl phosphonate is created by reacting the 3,5- dibenzyloxybenzyl bromide with triisopropyl phosphite.
  • the phosphonate is coupled with 4-benzyloxybenzaldehyde to form (E)-3,5,4'-tribenzyloxystilbene via a Horner- Emmons coupling reaction. Finally, the 3, 4', and 5 benzyl groups are removed to form resveratrol.
  • the present invention also relates to another method of synthesizing resveratrol involving a palladium catalyst. Generally, the method involves obtaining a compound of the following formula:
  • R 1 and R 2 are protecting groups such as methyl, alkyl, and benzyl.
  • the compound is coupled with a protected 4-hydroxystyrene via a Heck coupling as follows:
  • R 3 can be a protecting group such as methyl, alkyl, and benzyl as well as an aceto group.
  • R 3 is an aceto group
  • the protected 4-acetoxy-3',5'-hydroxystilbene can be converted to a protected (E)-3,5- dihydroxy-4'-hydroxystilbene by removing the aceto group under basic conditions.
  • the 3 and 5 protecting groups are removed to yield resveratrol.
  • R 3 is a protecting group such as methyl, alkyl, or benzyl, all three protecting groups may be removed in the same step.
  • resveratrol is made according to the following method.
  • a quantity of 3,5-dimethoxybenzoyl chloride is coupled with 4-acetoxystyrene to form (E)-4-acetoxy-3',5'-dimethoxystilbene.
  • a Heck reaction using a palladium catalyst is used for the coupling step.
  • a base is added to the (E)-4-acetoxy-3',5'-dimethoxystilbene to remove the 4-aceto group and form (E)-3,5- dimethyoxy-4'-hydroxystilbene.
  • the methyl groups can be removed by the addition of BBr 3 to yield resveratrol.
  • the present invention relates to direct, efficient methods of synthesizing resveratrol from readily available inexpensive starting materials.
  • resveratrol is synthesized with a key Horner-Emmons coupling step.
  • a phosphonate is coupled to a protected para-hydroxybenzaldehyde in the presence according to the following reaction: wherein R 1 , R 2 , and R 4 , are protecting groups, and R5 is an alkyl group such as methyl, ehtyl, isopropyl, butyl, and the like.
  • the protecting groups can be benzyl groups, methyl groups, alkyl groups, or the like.
  • the yield of this reaction step is in the range of about 72%.
  • the protecting groups may be the same for R 1 , R 2 , and R 4 .
  • each of the protecting groups is a benzyl group.
  • 3,5- dibenzyloxybenzyl phosphonate is coupled to 4-benzyloxybenzaldehyde.
  • (E)-3,5,4'- tribenzyloxystilbene is formed from the coupling step in about an yield. After the coupling step, the protecting groups are removed, resulting in resveratrol with about 80% efficiency.
  • 3,5-dihdroxybenzoic acid is the starting material.
  • a protecting group is added to each of the 3 and 5 hydroxy groups.
  • benzyl bromide can be reacted with the 3,5-dihydroxybenzoic acid to give 3,5- dibenzyloxybenzoic acid.
  • the carboxylic group of the benzoic acid is reduced to produce the corresponding alcohol.
  • LAH is reacted with the 3,5- dibenzyloxybenzoic acid to give 3,5-dibenzyloxybenzyl alcohol.
  • the overall yield of 3,5- dibenzyloxybenzyl alcohol from 3,5-dihdroxybenzoic acid is about 89%.
  • the hydroxy group of the alcohol is halogenated to yield a protected benzyl halide.
  • 3,5-dibenzyloxybenzyl alcohol is halogenated to give 3,5- dibenzyloxybenzyl halide.
  • 3,5-dibenzyloxybenzyl alcohol is reacted with PBr 3 to give 3,5-dibenzyloxybenzyl bromide.
  • the bromination step is about 90% efficient.
  • the protected benzyl halide is then phonsphonated to give the produce the protected benzyl phosphonate described above.
  • 3,5- dibenzyloxybenzyl bromide is reacted with triisopropyl phosphite to produce isopropyl 3,5-dibenzyloxybenzyl phosphonate in about a 94% yield.
  • R 1 and R 2 are protecting groups such as methyl, alkyl, and benzyl.
  • the starting material is coupled with a protected 4-hydroxystyrene via a Heck to produce a protected (E)-4-acetoxy stilbene.
  • the aceto group is then removed under basic conditions to produce a protected 4'-hydroxystilbene.
  • the 3 and 5 protecting groups are removed to yield resveratrol.
  • a 3,5-substituted benzoic acid chloride was reacted with acetoxy styrene using catalytic amounts of palladium acetate and trialkylamine to give stilbene products.
  • acetoxy styrene using catalytic amounts of palladium acetate and trialkylamine to give stilbene products.
  • a quantity of 3,5-dimthoxybenzoyl chloride is obtained and coupled with 4-acetoxystyrene to form (E)-4-acetoxy-3',5'-dimethoxystilbene.
  • a Heck reaction using a palladium catalyst is used for the coupling step.
  • Example 1 - Resveratrol Synthesis Via the Phosphonate Route Resorcylic acid was reacted with benzyl bromide in acetone under basic conditions to give a protected benzyl ester. Treatment with KOH allowed for removal of the potassium benzoate from the benzyl alcohol by-product. The reaction mixture was acidified followed by LAH reduction to give benzyl alcohol in high overall yield. This procedure eliminates the need to chromatographically separate the benzyl alcohol. All intermediates in the sequence were isolated by recrystallization. Conversion to the bromide was achieved using phosphorus tribromide. The Arbuzov reaction was then conducted using isopropyl phosphite to give the corresponding phosphonate in high yield.
  • This method of producing resveratrol can be readily scaled up for production of large amounts of resveratrol.
  • Resorcylic acid the starting material, is readily available and inexpensive.
  • the overall yield of the method from resorcylic acid to resveratrol is about 50%. The high yield and low cost of the reaction makes it ideal for large scale production.
  • Example 3 3,5-Dibenzyloxybenzyl Alcohol
  • LiAlH 4 (0.196g, 5.18 mmol)
  • 5 mL of anhydrous Et j O 5 mL
  • the dropping funnel was charged with 3,5-Dibenzyloxybenzoic acid (1.73g, 5.18 mmol) and 60 mL of anhydrous Et 2 O.
  • the slurry of 3,5-Dibenzyloxybenzoic acid and Et 2 O was allowed to drip into the stirring LAH solution over 2 h.
  • the flask Since the acid is not completely soluble in the Et ⁇ O the flask was allowed to warm to ambient temperature and then the mixture was heated at reflux for 7 h with continuous extraction of the remaining acid. After 7 h all the acid had been pulled into the flask and the solution was maintained at reflux for an additional 5 h. The solution was again cooled to 0 °C and then 10 mL of 4:1 Et 2 O/MeOH solution was added drop wise to quench the excess LAH. The solution was warmed to ambient temperature and then diluted with 5 mL of H 2 O. The solution was then washed with 50 mL of 1 M HCl. Separation of the layers was then followed by further extraction of the aqueous layer with Et 2 O (4 x 50 mL).
  • Example 4 3,5-Dibenzyloxybenzyl Bromide To a stirred solution of 3,5-Dibenzyloxybenzyl alcohol (1.18g, 3.69 mmol) in 20 mL of anhydrous Et 2 O at ambient temperature under an atmosphere of nitrogen was added pyridine (0.009 mL, 0.112 mmol) and then PBr 3 (0.21 mL, 2.25 mmol) dropwise. The mixture was then warmed to reflux and maintained at that temperature for 3 h. The solution was then cooled to ambient temperature and poured over 25g of ice. After the ice had melted the layers were mixed and then separated. The aqueous layer was extracted further with Et 2 O (3 x 25 mL).
  • Example 7 (E)-3,5,4' ⁇ Trihydroxystilbene, Resveratrol A 50 mL round bottom flask was charged with 3,5,4'-tribenzyloxystilbene (1.50g, 3.06 mmol) and 10 mL of anliydrous CH 2 C1 2 . The resulting solution was then cooled to -60 °C under a nitrogen atmosphere. To the cooled solution was added BBr 3 (0.90 mL, 9.12 mmol) dropwise. The mixture was then allowed to warm gradually to ambient temperature and then allowed to stand at that temperature for 2 h. Then 10 mL of saturated NaHCO 3 solution was added to quench the reaction along with 15 mL of water.
  • An alternative method of producing resveratrol uses a newer, non-classical route involving palladium catalysis. 3,5-substituted benzoic acid chlorides were reacted with acetoxy styrene using catalytic amounts of palladium acetate and trialkylamine to give stilbene products. These conditions for the decarbonylative aromatic-olefin coupling reaction, a variation of the aryl halide-olefm Heck reaction with loss of carbon monoxide (CO), worked very well with unsubstituted acid chlorides giving yields of 80%. This method of producing resveratrol is summarized in the following reaction:
  • Example 9 (E)-4-Acetoxy-3',5'-dimethoxystilbene
  • 3,5-dimethoxybenzoyl chloride O.lOOg, 0.498 mmol
  • palladium (II) acetate 0.006g, 0.025 mmol
  • 1.0 mL of dry j-xylene The mixture was then stirred while 4- acetoxystyrene (0.095 mL, 0.622 mmol) was added via syringe.
  • the mixture was then warmed to 120-130 °C and allowed to stir for 18 h.
  • the present invention relates to novel methods of producing resveratrol, a naturally occurring compound that has shown potential in the treatment of cancer and other diseases.
  • resveratrol can be made starting with resorcylic acid though a number of steps.
  • the coupling of the modified resorcylic acid via a Horner-Emmons reaction yields a product that can be converted to resveratrol by removing protecting groups.
  • reaction products are coupled via a modified Heck reaction to form a protected 4'-hydroxystilbene that can also be converted to resveratrol by removing the protecting groups.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne de nouveaux procédés de production de resvératrol. L'acide resorcylique est mis à réagir avec du bromure de benzyle dans de l'acétone, dans des conditions basiques pour obtenir un ester de benzyle protégé. Le traitement avec du KOH permet d'éliminer le benzoate de potassium du sous-produit de l'alcool benzylique. L'acidification suivie par la réduction de LAH permet d'obtenir un alcool benzylique avec un rendement global élevé. L'alcool benzylique est transformé en bromure avec un tribomide phosphoreux. On réalise ensuite une réaction d'Arbuzov en utilisant du phosphite d'isopropyle pour obtenir le phosphonate correspondant, avec un rendement élevé. Le couplage de 4-benzyloxybenzaldéhyde selon une stoechiométrie 1:1 avec du méthylate de sodium a permit d'obtenir donné le E-stilbène comme isomère unique, avec un rendement élevé. Un autre procédé implique une catalyse de palladium. Les chlorures d'acide benzoïque 3,5-substitués réagissent avec styrène acétoxy dans des quantités catalytiques d'acétate de palladium et de trialkylamine pour donner des produits à base de stilbène.
PCT/US2001/005167 2000-02-16 2001-02-16 Synthese de resveratrol Ceased WO2001060774A1 (fr)

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003086414A1 (fr) * 2002-04-10 2003-10-23 Arizona Board Of Regents Modification structurelle du resveratrol: phosphate de resverastatine de sodium
WO2003094833A3 (fr) * 2002-05-10 2004-01-15 Orchid Chemicals & Pharm Ltd Nouveau procede stereoselectif pour produire du tris-o-substitue-(e)-1-(3,5-dihydroxyphenyl)-2-(4- hydroxyphenyl)ethene, un produit intermediaire dans la synthese de trans-resveratrol
EP1466884A1 (fr) * 2003-04-08 2004-10-13 Sochinaz SA Procédé de préparation du resvératrol et ses applications
US6844471B2 (en) * 2002-07-19 2005-01-18 Orchid Chemicals And Pharmaceuticals Limited Method for the conversion of a Z-isomer into E-isomer
WO2005023740A3 (fr) * 2003-09-05 2005-05-12 Dsm Ip Assets Bv Procede de preparation de derives de stilbene
WO2005069998A3 (fr) * 2004-01-20 2006-01-05 Univ Brigham Young Noveaux composes activant sirtuine et leurs methodes de preparation
WO2008012321A1 (fr) * 2006-07-28 2008-01-31 Clariant Specialty Fine Chemicals (France) Nouveau procédé de synthèse de dérivés (e)-stilbène permettant d'obtenir du resvératrol et du picéatannol
WO2008082169A1 (fr) * 2006-12-28 2008-07-10 Industrial Cooperation Foundation Chonbuk National University Dérivés de stylbène utilisés comme inhibiteurs de l'adp-ribosyl cyclase
WO2010046926A3 (fr) * 2008-10-17 2011-03-31 Aptuit Laurus Pvt Ltd Nouveaux analogues de stilbène
WO2012080120A1 (fr) 2010-12-15 2012-06-21 Dsm Ip Assets B.V. Procédé pour la préparation de resvératrol
US8399714B2 (en) 2007-10-03 2013-03-19 Clariant Speciality Fine Chemicals (France) Process for the synthesis of polyhydroxystilbene compounds
EP2774915A1 (fr) 2013-03-06 2014-09-10 Andrea Mattarei Nouveaux dérivés de resvératrol
WO2015073882A1 (fr) * 2013-11-14 2015-05-21 North Carolina Central University Technologie électrosensible
CN105037100A (zh) * 2015-06-23 2015-11-11 长沙理工大学 一种氧化芪三酚的合成方法
WO2024105686A1 (fr) * 2022-11-14 2024-05-23 Fertis India Pvt Ltd Procédé de synthèse de stilbène et de ses intermédiaires

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US4335055A (en) * 1980-05-13 1982-06-15 Ciba-Geigy Corporation Process for the preparation of alkenylbenzene derivatives or alkenylnaphthalene derivatives
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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7705188B2 (en) 2002-04-10 2010-04-27 Arizona Board of Regents, a body corporate of the State of Arizona, Acting for and on Behalf of the Arizona State University Structural modification of resveratrol: sodium resverastatin phosphate
WO2003086414A1 (fr) * 2002-04-10 2003-10-23 Arizona Board Of Regents Modification structurelle du resveratrol: phosphate de resverastatine de sodium
WO2003094833A3 (fr) * 2002-05-10 2004-01-15 Orchid Chemicals & Pharm Ltd Nouveau procede stereoselectif pour produire du tris-o-substitue-(e)-1-(3,5-dihydroxyphenyl)-2-(4- hydroxyphenyl)ethene, un produit intermediaire dans la synthese de trans-resveratrol
US6844471B2 (en) * 2002-07-19 2005-01-18 Orchid Chemicals And Pharmaceuticals Limited Method for the conversion of a Z-isomer into E-isomer
WO2004009539A3 (fr) * 2002-07-19 2005-05-26 Orchid Chemicals & Pharm Ltd Méthode de conversion d'un isomère z en un isomère e
EP1466884A1 (fr) * 2003-04-08 2004-10-13 Sochinaz SA Procédé de préparation du resvératrol et ses applications
WO2005023740A3 (fr) * 2003-09-05 2005-05-12 Dsm Ip Assets Bv Procede de preparation de derives de stilbene
US7820848B2 (en) 2003-09-05 2010-10-26 Dsm Ip Assets B.V. Process for the preparation of stilbene derivatives
JP2007504191A (ja) * 2003-09-05 2007-03-01 ディーエスエム アイピー アセッツ ビー．ブイ． スチルベン誘導体を製造する方法
US7714161B2 (en) 2004-01-20 2010-05-11 Brigham Young University Sirtuin activating compounds and methods for making the same
WO2005069998A3 (fr) * 2004-01-20 2006-01-05 Univ Brigham Young Noveaux composes activant sirtuine et leurs methodes de preparation
US8841477B2 (en) 2004-01-20 2014-09-23 Brigham Young University Sirtuin activating compounds and processes for making the same
US8101804B2 (en) 2006-07-28 2012-01-24 Clariant Specialty Fine Chemicals (France) Process for the synthesis of (E)-stilbene derivatives which makes it possible to obtain resveratrol and piceatannol
WO2008012321A1 (fr) * 2006-07-28 2008-01-31 Clariant Specialty Fine Chemicals (France) Nouveau procédé de synthèse de dérivés (e)-stilbène permettant d'obtenir du resvératrol et du picéatannol
EP2202215A3 (fr) * 2006-07-28 2010-09-08 Clariant Specialty Fine Chemicals (France) Nouveau procédé pour la synthèse des dérivés de (E)-stilbène qui permet d'obtenir du resvératrol et piceatannol
JP2009544663A (ja) * 2006-07-28 2009-12-17 クラリアント スペシャルティー ファイン ケミカルズ（フランス） レスベラトロールおよびピセアタンノールを得ることを可能にする（ｅ）−スチルベン誘導体を合成するための新規な方法
FR2904311A1 (fr) * 2006-07-28 2008-02-01 Clariant Specialty Fine Chem Nouveau procede de synthese de derives (e) stilbeniques perm permettant d'obtenir le resveratrol et le piceatannol
US8314082B2 (en) 2006-12-28 2012-11-20 Industrial Cooperation Foundation Chonbuk National University Stilbene derivatives for ADP-ribosyl cyclase inhibitors
WO2008082169A1 (fr) * 2006-12-28 2008-07-10 Industrial Cooperation Foundation Chonbuk National University Dérivés de stylbène utilisés comme inhibiteurs de l'adp-ribosyl cyclase
KR100879253B1 (ko) * 2006-12-28 2009-01-16 전북대학교산학협력단 에이디피-라이보실 사이클레이즈 억제제를 이용한 고혈압 및 당뇨병성 신증의 치료제
US8399714B2 (en) 2007-10-03 2013-03-19 Clariant Speciality Fine Chemicals (France) Process for the synthesis of polyhydroxystilbene compounds
WO2010046926A3 (fr) * 2008-10-17 2011-03-31 Aptuit Laurus Pvt Ltd Nouveaux analogues de stilbène
EP2468706A1 (fr) 2010-12-15 2012-06-27 DSM IP Assets B.V. Procédé de préparation de resvératrol
WO2012080120A1 (fr) 2010-12-15 2012-06-21 Dsm Ip Assets B.V. Procédé pour la préparation de resvératrol
EP2774915A1 (fr) 2013-03-06 2014-09-10 Andrea Mattarei Nouveaux dérivés de resvératrol
WO2015073882A1 (fr) * 2013-11-14 2015-05-21 North Carolina Central University Technologie électrosensible
US10344107B2 (en) 2013-11-14 2019-07-09 North Carolina Central University Electroresponsive technology
CN105037100A (zh) * 2015-06-23 2015-11-11 长沙理工大学 一种氧化芪三酚的合成方法
WO2024105686A1 (fr) * 2022-11-14 2024-05-23 Fertis India Pvt Ltd Procédé de synthèse de stilbène et de ses intermédiaires

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