Synthesis Of Indolizine And Thiophene C-nucleoside Analogues

Nucleosides are an important class of compounds in which the C-C bond between the nucleobase and the sugar moiety,these compounds have good metabolic stability and have a variety of biological activities such as antibacterial,anti-tumor,anti-inflammatory.Therefore,the synthesis of C-nucleosides and their analogs has important theoretical significance and potential application value.Indolizine is an important class of heterocyclic compounds,which one with indolinazine structure are widely existed in the cells of animals and plants.In order to obtain a novel and potentially biologically active Indolizine C-nucleoside analogue,we report a new synthesis of 2,3-disubstituted indolizine C-nucleoside analogues via 1,3-dipolar cycloaddition between various pyridiums,various sugar alkynes and Cesium carbonate.We took D-fructose and pyridium bromide to explore a general reaction condition,then we explored the effects of solvent,temperature,base and other conditions and obtained the optimal reaction conditions.Next we investigated the scope of this reaction with various sugar alkynes and various pyridiums,we synthesized a series of compounds in high yields.Sugar alkynes were synthesized from cheap D-glucose,D-ribose,D-fructose,D-galactose,D-mannose by using classic synthetic methods.The synthetic approach of indolizine C-nucleoside analogues is a simple,mild and efficient method.18 novel C-nucleoside analogs were obtained under the optimal reaction conditions.And carried out various detection and characterization by ¹H NMR,¹³C NMR,DEPT-135,¹H-¹H COSY,HSQC,HMBC and HRMS.Thiophenes is an important class of heterocyclic compounds,a variety of molecules containing the thiophene structure display a wide range of biological activity and find application as pharmaceuticals.In order to obtain novel structural thiophene C-nucleoside analogues,we developed a new synthesis of2,5-disubstituted thiophene C-nucleoside analogues in one pot.First of all,we synthesized the intermediate by unsymmetric dimerization of various terminal sugar alkyne and various bromide under the catalysis of Cu I and Pd Cl₂（PPh₃）₂,then Na₂S·9H₂O and KOH was added to the mother liquid to reaction in one pot.We took D-fructose and 1-（bromoethynyl）-4-methylbenzene to explore the optimal reaction conditions.Then we explored the effects of solvent,temperature,oxidant,catalyst and other conditions and obtained the optimal reaction conditions.A mixture of sugar alkyne,1-（bromoethynyl）-4-methylbenzenee,Pd Cl₂（PPh₃）₂,Cu I,Et₃N and DMF was stirred under air atmosphere at rt until TLC indicated the disappearance of sugar alkyne.The mixture was filtered by diatomaceous earth.Na₂S·9H₂O and KOH was added to the mother liquid,and the solution was heated at60 ⁰C until TLC showed the completion of the reaction.The synthetic approach was concise,simple,and general.14 novel C-nucleoside analogs were obtained under the optimal reaction conditions and carried out various detection and characterization by¹H NMR,¹³C NMR,DEPT-135,¹H-¹H COSY,HSQC,HMBC,HRMS and IR.