Biomimetic Synthesis Of Cyano-substituted Resveratrol Dimers

The biomimetic synthesis and chemical synthesis of the natural resveratrol oligomers with diverse architectures have been successfully reported.Many biological activities exhibited by resveratrol oligomers have great research value and application potential in pharmacology.Their derivatives also possess similar or even higher biological activities,relatively lower toxic and side effects than resveratrol oligomers.α-Cyano-resveratrol,as an analogue of resveratrol,was found to inhibit the proliferation of cancer cells and very low toxicity,but the study on the synthesis of its dimers has not been reported to date.In this thesis,a structurally modified resveratrol derivative with a cyano-group atαcarbon were prepared as the coupling precursors to simulate the oxidative conditions of biosynthesis.Thereby we expect to efficiently synthesize several stable cyano-substitued resveratrol dimmers with novel structures.Additionally,other auxiliary groups such as COOH or COOMe was also introduced to replaceα-CN group in resveratrol monomer.These resveratrol derivatives were used as the coupling precursor to explore the effects of differentα-substituents on the regioselectivity and stereoselectivity in the oxidative coupling reactions as well as the structures of coupling products.The main research contents are summarized as follows:1.The structural modifications at vinyl,phenolic hydroxyl,benzene ring and other sites of resveratrol were briefly summarized.The biosynthesis process of common natural resveratrol oligomers in plants were introduced and the chemical synthesis of typical resveratrol dimers are reviewed.2.α-Cyano-resveratrol was prepared as the coupling monomer to conduct the oxidative coupling reaction catalyzed by HRP-H₂O₂ in acetone-H₂O solvent system and the M₈-M₅-coupled cyano-substituted resveratrol dimers with dihydrobenzofuran skeleton were firstly successfully synthesized.The acylation of coupling product was carried out to further confirm its dimeric structure.The single crystal of the dimeric acylated product was cultivated to examine the absolute architecture through the X-ray diffraction test,but failed and this work are still ongoing in our laboratory.3.Bromine atoms as positional protecting groups were introduced into resveratrol andα-cyano-brominated-resveratrol was thus prepared with moderate yield.The oxidative coupling reaction ofα-cyano-brominated-resveratrol in HRP-H₂O₂-acetone-H₂O system wasstudied and M₈-M₈-coupled indane-type coupling intermediates were successfully synthesized.A cyano-substituted resveratrol dimer was obtained after the debromination reaction of coupling products.4.Other auxiliary groups were introduced into the vinyl of resveratrol to investigate the effects of different substituents on the regioselectivity in the oxidative coupling reaction andthe structures of coupling products.Cis-α-carboxyl-resveratrol was firstly prepared by the Perkin condensation.And cis-trans-isomerization reactions of double bond were carried out under the diverse catalytic conditions including strong acids or bases,diphenyl sulfide and iodine,but the expected trans-α-carboxyl-resveratrol was not obtained.Secondly,the hydrolysis of trans-α-cyano-resveratrol was attempted under acidic（HCl,H₂SO₄）or basic（LiOH,NaOH）conditions to synthesize trans-α-carboxyl-resveratrol,but still faild.The resveratrol-derived dimer with dihydrobenzofuran skeleton was successfully synthesized by using trans-α-cyano-resveratrol as the coupling precursor in the enzyme-mediated aqueous acetone system.When the coupling reaction ofα-cyano-brominated-resveratrol was conducted under the same catalytic condition,the indane-type dimeric coupling intermediates were formed.The attempts to synthesize trans-α-carboxyl-resveratrol by the cis-trans-isomerization reactions ofα-carboxyl-resveratrol or the hydrolysis of trans-α-cyano-resveratrol were not successful,which are ongoing in our laboratory.The introduction of the diverse chiral auxiliary groups into the coupling precursor is still an effective route for the asymmetric biomimetic synthesis of stilbene dimers,which will be a great challenge for the asymmetric synthesis of natural resveratrol oligomers.