Selective Synthesis Of Several Stilbene C-glucoside Monomers

Stilbene glycosides belong to natural polyphenolic compounds and are products of the combination of stilbene and glucose.Natural stilbenes are mainly distributed in plants such as Vitis,Polygonaceae,Legu minosae,and Veratrum.The water solubility of stilbenes is poor and prone to oxidation.The introduction of donor sugar on stilbene monomers enhances its stability,water solubility,antioxidant activity,and biological activities.Due to their complex and diverse biological activities,stilbene glucosides have broad application prospects in a variety of fields such as medicine and cosmetics.In recent years,studies have found that stilbene glucosides have pharmacological activities such as brain tissue protection,anti-inflammatory,anti diabetes,anti-aging,anti-tumor,blood lipid lowering,regulating cardiovascular activity,and regulating immunity.Therefore,they have high medicinal value and have attracted extensive attention.Among them,stilbene C-glucosides has better selectivity,stability,biological activity,and pharmacological effects than stilbene O-glucosides.However,stilbene C-glucoside monomers at present is maily obtained from the direct isolation in plants,and there are few reports on their chemical synthesis.Therefore,our research group intends to selectively synthesize several stilbene C-glucoside monomers by screening substrates and catalytic conditions,comparing the effects of different hydroxyl-protecting groups,optimizing the addition amount of reactants,and exploring the deprotection reaction conditions for the synthesis of target stilbene C-glucosides.The thesis conducts research analysis and discussion mainly through the following four chapters:In the first chapter,the natural distribution and structural types of stilbene monomers and their dimers,glucosides,and stilbene C-glucosides were briefly introducted.The pharmacological activities and synthetic methods of some C-glucosides natural products in recent years were reviewed.The research progress of stilbene glucoside monomers and their dimmers were also summarized.In the second chapter,the glycosyl receptors,donor sugar,and catalytic conditions for glycosylation reactions in the synthetic route of stilbene C-glucosides were screened.The regioselective synthesis of stilbene C-glucosides were accomplished by using the glycosylation reactions of stilbene monomers as the key step.The globally protected stilbene monomers was used as glycosyl receptors and acetyl sugar 2-6 protected by benzyl groups served as a sugar donor.The glycosylation reactions between them catalyzed by BF₃·Et₂O were performed in CH₂Cl₂ and the glucoside unit was installed at the desired position by selectively protecting the phenolic hydroxyl groups on stilbene in advance.The BF₃·Et₂O-catalyzed glycosylation reactions of methyl-protected resveratrol,rhapontigenin and oxyresveratrol with donor sugar 2-6 were carried out in CH₂Cl₂,respectively.Two types of resveratrol C-glucosides 2-25 and 2-26,and two types of rhapontigenin C--glucosides 2-33and 2-34 were synthesized.But no target products were obtained from the glycosylation reaction of methylated oxyresveratrol.BBr₃-promoted deprotection of compounds 2-25 and2-26 resulted in the products 2-27 and 2-28 with one methyl group remained.By using this synthetic strategy,six stilbene C-glucoside monomers were prepared in this chapter.In the third chapter,the introduction and removal methods of phenolic hydroxyl protection groups in recent year were reviewed.Due to the difficulty in the demethylation of stilbene glucosides,herein the methoxymethyl（MOM）,acetyl（Ac）,benzyl（Bn）,allyl（All）and tert-butyl dimethyl silyl（TBDMS）groups were chosen to protect the phenolic hydroxyl protection groups of stilbenes and reduce the difficulty of deprotection in the later stage.We found that the BF₃·Et₂O-catalyzed glycosylation reaction conditions were not applicable to resveratrol monomers protected by the MOM and Ac groups,which were partially removed in the glycosylation reactions,making the reaction products complex.The glycosylation reactions of resveratrol monomers globally protected by Bn,All and TBDMS groups smoothly generated the corresponding resveratrol C-glucoside monomers 3-21,3-24,3-25and 3-30.Resveratrol monomers protected partially by two TBDMS gave rise to a resveratrol O-glucoside 3-27 and a resveratrol C-glucoside 3-28.In this chapter,five stilbene C-glucoside and one stilbene O-glucoside were successfully synthesized.In the fourth chapter,the removal reactions for the allyl,TBDMS and Bn protecting groups of stilbenes are briefly introduced.The deprotection of stilbene C-glucosides 3-24,3-27,3-28,and 3-30 we synthesized in third chapter were carried out under different reaction conditions.It was found that these protecting groups were partially removed in the deprotection reations.The complex reaction products mixture formed were difficult to separate and purify to obtain the final singlet target product.Finally,compound 3-30 was subjected to Al Cl₃-CH₂Cl₂ catalytic system and the expected deprotected product 1-8 was synthesized with 40%yield.In summary,13 types of stilbene C-glucoside monomers were synthesized.These included a natural resveratrol C-glucoside,nine resveratrol C-glucosides,one resveratrol O-glucoside,and two rhapontigenin C-glucoside monomers.Additionally,several stilbene C-glucosides were efficiently prepared through exploration and optimization of reaction conditions.This synthetic strategy can be applied to the synthesis of more stilbene C-glucoside monomers and their oligomers with complex structures and diverse biological activities.