Study On The Oxidative Dimerization Reactions Of Gnetol Or Oxyresveratrol And The Synthesis Of Their O-Glucoside Monomers

Stilbene and stilbene glucoside monomers as well as their oligomers are natural polyphenolic compounds present in a variety of plants and are one of the treasures of nature.Over the past 60 years,stilbene represented by resveratrol and its monomer derivatives have been deeply studied and found to have rich pharmacological activities such as anti-oxidation,anti-cancer,anti-aging and so on.The introduction of glucoside unit into the phenolic hydroxyl group of stilbene monomers can greatly enhance its water solubility and stability.In recent years,the oligomers of stilbene and its O-glucoside monomers have attracted wide interest from biologists and chemists due to their complex structures and diverse biological activities.Studies have shown that stilbene oligomers exhibit higher pharmacological activity than their monomers.Although stilbene O-glucoside monomers and oligostilbenes are widely distributed in nature,the low natural abundance,large polarity and complex structures always lead to a variety of problems such as high extraction cost,difficulty in separation and purification,and low yield,which considerably limit the further development of their applicatical potential in drugs and other fields.Therefore,it is urgent to carry out in-depth research on these compounds through artificial synthesis methods.However,the synthesis of stilbene oligomers and their O-glucosides still faces many challenges,such as long route,poor selectivity and low yield.In the past 20 years,our group has been investigating on the regioselective biomimetic synthesis of stilbene dimers and has achieved some results.On this basis,this paper intends to study the oxidative dimerization reactions of gentol and oxyresveratrol,and synthesize gentol O-glucoside and oxyresveratrol O-glucoside monomers,which lays a foundation for exploring the biomimetic synthesis of stilbene O-glucoside oligomers.This paper mainly analyzes and discusses from the following three chapters:In the first chapter,the structural modification of stilbene with isoprenyl and glycosyl groups was summarized.The synthesis methods of various natural isoprenyl stilbene analogues and glycosylated stilbene derivatives in recent years were summarized.The interaction and pharmacological activity between the stilbenes modified by isoprene and glucosyl groups and other functional groups were analyzed.In the second chapter,the synthesis of natural gentol monomer and its oxidative dimerization reactions were studied.Firstly,the intermediate phosphate was prepared through four steps using methyl 3,5-dihydroxybenzoate as the starting material.Polysubstituted benzaldehydes were prepared from 2,6-dihydroxybenzoic acid through four steps.Then the Wittig reaction of phosphorous ylide with substituted benzaldehyde and followed debenzylation reaction synthesized the target gentol.Next,we studied the oxidative dimerization reaction of gentol monomer under different catalyst conditions.We found that no new product was formed under the oxidative conditions including horseradish peroxidase（HRP）-H₂O₂,ferric chloride,potassium ferricyanide and silver oxide.When gentol was catalyzed by Ag₂O-K₂CO₃,3,3’,5,5’-tetrahydroxystilbene 2-21 was obtained as a single product.The mixture of arylnaphthalene 2-22 and symmetrical stilbene 2-21 with the same polarity was formed under the condition of formic acid at reflux.When the deprotection reation of benzylated oxyresveratrol was carried out with anhydrous Al Cl₃ and N,N-dimethylaniline in dichloromethane,a mixture of oxyresveratrol compound 2-21 with same polarity was produced,which was subjected to Ag₂O-K₂CO₃ or refuxed formic acid to give stilbene 2-21 as a final product.It was indicated the formation of compound 2-21 was directly related to the presence of 2-hydroxyl group in gentol and oxyresveratrol.The reaction mechanism was prelimarily speculated and need to further explored and verified.In the third chapter,gentol 2’-O-glucoside monomer was synthesized by chemical method for the first time.On the basis of this synthesis strategy and condition optimization,the 2’-O-glucoside monomer of oxyresveratrol was synthesized.First,The direct glycosylation reaction of gentol was attempted but failed.Then,the glycosylation of 3,5-dimethoxy-2,6-dihydroxy stilben also did not lead to the glycosylated product.Finally,the strategy of constructing stilbene double bond after the glycosylation of benzaldehyde was adopted.The reaction of 2,6-dihydroxybenzaldehyde with acetyl bromide-α-D-glucose gave rise to the expected 6-hydroxybenzaldehyde 2-O-glucoside.The Wittig reaction of glycosylated benzaldehyde with phosophorous Ylide and following debenzylation synthesized gentol 2’-O-glucoside monomer.Oxyresveratrol 2’-O-glucoside monomer was successfully prepared from 2,4-dihydroxybenzaldehyde by using a similar synthetic strategy.In summary,the oxidative dimerization of gentol under different catalytic conditions did not produce the expected dimers but surprisingly led to the symmetrical stilbene 2-21 or its mixture with aryl naphthalene 2-22.The stilbene monomer 2-21 was also obtained from the oxdiative dimerization of oxyresveratrol under similar reaction conditions.The formation mechanism of compound 2-21 need further exploration and verification.The basic strategy of selective glycosylation-Wittig reaction-debenzylation protection was applied in the synthesis of gentol 2’-O-glucoside and oxyresveratrol 2’-O-glucoside.By optimizing the glycosylation reaction and attempting different deprotection conditions,the target glycosylated stilbenes were successfully synthesized.This provides an effective methodology for the synthesis of glycosylated stilbene analogues and lays a foundation for the biomimetic study of their dimers.