Green Synthesis Of Nucleosides And Chiral Hydrobenzofuranpyrrolidine Compounds

Chemical research and application have played a great role in promoting the progress of human society and material civilization.On the other hand,it also brings damage to the ecological environment.With the improvement of environmental protection awareness,people pay more and more attention to how to reduce or eliminate the hazards to the environment in the process of chemical production and use.Green synthetic chemistry,containing reducing energy consumption,exploiting highly efficient catalytic system and designing high atom economic reactions,has received extensive attention from chemists.As important classes of heterocyclic compounds,nucleosides and hydrobenzofurans are prevalent in natural products and drug molecules,many of them exhibiting good biological activities.Searching for an efficient route in synthetic chemistry for the construction of this kind of compounds would be highly desirable.Based on the basic requirements of green synthesis,the modification of purine nucleosides,the synthesis of chiral pyrimidine acyclic nucleosides and the efficient synthesis of chiral hydrobenzofurans were successfully accomplished by visible light photocatalytic reaction,asymmetric allylation reaction or catalytic asymmetric dearomatization reaction（CADA reaction）.The main contents of this dissertation are as follows:1.Visible-Light-Mediated Mono-Selective Ortho C–H Arylation of 6-Arylpurine NucleosidesA combined palladium and Ru（bpy）₃Cl₂·6H₂O catalyzed monoselective arylation of6-arylpurine nucleosides has been developed by employing purine as a directing group via the photoredox reaction at room temperature in a short time.The reaction proceeded smoothly with various substituted aryldiazonium salts（bearing electronwithdrawing or electron-donating groups）.And,various of functionalized purines（nucleosides）which are potentially of great importance in medicinal chemistry could be obtained under visible light irradiation.We hypothesized the possible mechanism and provided the corresponding data support through the verification experiment.The green evaluation results show that the photoredox reaction possesses higher atom economy,the procedure is more efficient and the condition is more moderate.2.Regio-and Enantioselective Synthesis of Chiral Pyrimidine Acyclic Nucleosides via Rhodium-Catalyzed Asymmetric Allylation of PyrimidinesA direct route to branched N-allylpyrimidine analogues is herein reported via the highly regio-and enantioselective asymmetric allylation of pyrimidines with racemic allylic carbonates.With[Rh（COD）Cl]₂/（R）-DTBM-Segphos as the catalyst,a range of chiral N-allylation pyrimidine analogues could be obtained under neutral conditions in good yields（up to 95%yield）with high levels of regio-and enantioselectivities（up to>40:1 B/L and up to 99%ee）.A series of pyrimidine derivatives with different substituents at the C5 position and a variety of electron-neutral,electron-rich,or electron-deficient phenyl-substituted allylic carbonates and gave the corresponding chiral N-allylated thymine products in good results.Furthermore,chiral pyrimidine acyclic nucleoside bearing two adjacent chiral centers has been successfully synthesized by asymmetric dihydroxylation.The green evaluation results show that this reaction possesses higher Reaction Mass Efficiency.And,the Mass Intensityand and the E-factor were reduced.3.Enantioselective and Regiodivergent Allylation of Pyrimidines with Terminal Allenes:An Approach to Chiral Pyrimidine Acyclic NucleosidesAn atom-economic addition of pyrimidines to allenes has been developed for the diverse synthesis of branched or linear N-allylpyrimidine analogues.With[Rh（COD）Cl]₂/chiral MeOBIPHEP as the catalyst,the asymmetric allylation reaction proceeded well and afforded the branch selective adducts in good yields（up to 86%yield）,with high regio-and enantioselectivities（up to>20:1 B/L and up to 94%ee）.Meanwhile,when[Pd（η³-allyl）Cl]₂/DPPF was used as the catalyst,the linear-selective allylation of pyrimidines could be carried out in good yields.A series of pyrimidine derivatives with different substituents at the C5 position and a variety of allenes with different functional-groups could afford the desired products in good results.This method could be employed for the synthesis of chiral and acyclic nucleosides.Taken in concert,the new method provides a practical and facile approach for the synthesis of acyclic nucleoside phosphonate analogues.Compared with traditional method,the atom economy of this allylation reaction was high（up to 100%）.At the same time,the Reaction Mass Efficiency was higher.Meanwhile,the Mass Intensity and and the E-factor were lower.4.The Synthesis of Chiral 2,3-fused Benzofuranpyrrolidines via Cu-Catalyzed Asymmetric Dearomatization ReactionIntramolecular asymmetric dearomative[3+2]cycloaddition reactions of2-nitrobenzofurans with azomethine ylides were realized by a chiral Cu（I）/（S,S_p）-ⁱPr-phosferrox catalyst.A series of highly stereoselective chiral 2,3-fused hydrobenzofuranpyrrolidines bearing nitro on the quaternary carbon center were obtained in good to excellent yields（up to 85%）,diastereoselectivity（up to 11:1 dr）,and enantioselectivity（up to 99%ee）.The reaction has a broad substrate scope and tolerates a wide range of functional groups.Various azomethine ylide precursors and a wider variety of nitrobenzofurans could react smoothly and led to the corresponding adducts in good results.The gram-scale and transformations of products further evaluated the prospect of using the methodology in synthesis.Compared with traditional method,the advantages of this approach inclued simple raw materials,rich product structure and short synthetic steps.Meanwhile,the atom economy of this dearomatization reaction was high（up to 100%）,the Mass Intensity and and the E-factor were low.Both of these met the requirements of green synthesis.