Synthesis Of Chiral Carbocyclic Nucleosides Via Asymmetric Allylic Amination Of Alicyclic MBH Adducts And Purine Base

Infectious diseases are caused by viruses,such as hepatitis B,hepatitis C and AIDS.This has become one of the most important diseases that threaten human health.At present,most drugs which have gone public or in clinical can only inhibit virus replication.However,because of arising viral resistances,many current chemotherapeutics have become less effective.Therefore,it’s necessary to develop novel antiviral drugs.Chiral carbocyclic nucleosides play an important role in antiviral chemotherapy.For example,Carbovir,Abacavir,Entecavir and so on.However,the crafts to produce these drugs have many disadvantages,such as multi-step process,high cost,difficultity in controlling stereoselectivity and so on.Therefore,it is desired to develop a more efficient and cheaper asymmetric catalytic strategy to synthesize a series of chiral carbocyclic nucleosides compounds.In view of this,the enantioselective synthesis of carbocyclic nucleosides through the palladium-catalyzed asymmetric allylic aminations of alicyclic MBH adducts with purines has been presented herein.According to literatures research,we synthesized chiral five-membered carbocyclic nucleosides via Asymmetric allylic amination using purines and rac-alicyclic MBH adducts as substrates.After a series of reaction conditions optimization,the optimal reaction conditions were as follow:2.5 mol%Pd₂（dba）₃,5.0mol%（S,S_p）-phosferrox,toluene（1.0 m L）,K₂CO₃（3.0 equiv）and 1-naphthol（10.0 mol%）,0℃,N₂,3days.A wide range of chiral five-membered carbocyclic nucleosides were obtained with high high up to99%yield and up to 99%ee.And the absolute configuration of the carbocyclic nucleoside was determined by single crystal diffraction.Subsequently the catalytic reaction was carried out on 5.0 mmol,1.08 g,giving the nucleoside analog with good yield and excellent enantioselectivity.Finally,the five-membered carbocyclic nucleoside products were further derivatized to synthesize a series of chiral carbocyclic nucleoside compounds bearing hydroxyl,fluorine atom,sulfur atom,chlorine atom and double bond on the carbocycle,and the results showed that the enantioselectivity of the products were well maintained.In this dissertation,a new chiral carbocyclic nucleosides via asymmetric allylic amination of alicyclic MBH adducts and purine base was developed,and a possible catalytic mechanism was proposed,which provided a new idea to efficiently synthesize chiral carbocyclic nucleosides.